{ "schema_version": "chamgap-public-evidence-check-1.0", "public_id": "v3091-main", "verdict_number": "3091", "title": "Oral extended-release nicotinic acid added to atorvastatin × Improvement in brachial FMD in adults with coronary artery disease", "view_version": "1.0", "view_created_date": "2026-11-01", "criteria_version": "NGM-v3091-ER-NICOTINIC-ACID-CAD-ATORVASTATIN-CROSSOVER-FMD-1.2", "criteria_date": "2026-10-05", "review_date": "2026-10-05", "legacy_evidence_date": "2026-09-15", "review_scope": { "materials_read": "Retained Korean and English manuscripts and case-specific criteria and application records", "clinical_papers_directly_read": false, "new_clinical_search": false, "limitation": "No external clinical abstracts, full texts, registrations or analysis plans were newly read. Historical access records are distinguished from the retained summaries read in this review. The original judgment, numerical values and unverified information are preserved; no new searches, calculations or reassessment were performed.", "date_meaning": "This is the date on which the retained materials were checked, not the date of a search for the latest clinical literature." }, "claim_context": { "population": "Adults with coronary artery disease receiving common background treatment with atorvastatin 80 mg/day", "intervention": "Extended-release (ER); exact salt, brand and manufacturer unverified", "dose": "1500 mg/day", "comparator": "Placebo period on the same atorvastatin treatment; placebo ingredients unverified", "endpoint": "Page-priority endpoint: between-treatment comparison of brachial FMD at the end of each period; registered primary-endpoint status unverified", "duration": "Each treatment period lasts 3 months; titration and washout unverified", "excluded_extensions": [ "nicotinamide", "nicotinamide riboside", "nicotinamide mononucleotide", "IR or SR formulations", "no-flush formulations of unverified molecular identity", "niacin/laropiprant combinations", "niacin without statins", "healthy adults", "all metabolic or HIV populations", "MRI and ultrasound FMD assumed interchangeable", "cardiovascular event prevention" ] }, "requirements": [ { "item_id": "N01", "question_type": "Separate question", "question": "Which FMD comparison is being tabulated?", "needed": "The identity of the current claim and adjudicated question, descriptive attributes (facets), canonical URL, and actual list of keys in the retained summary.", "role": "Required", "role_reason": "Needed to avoid combining the ingredient as a whole, lipid endpoints and clinical-event endpoints into a single effect.", "application_exception": "Do not fill the absent subclaims key with a null value or an empty array. This is a development question narrowed after the results were known, not a preregistration.", "criterion": "Link the single question covering adults with CAD, common atorvastatin 80 mg/day, oral ER nicotinic acid 1500 mg/day, each 3-month period, and period-end brachial FMD in the placebo crossover comparison.", "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed — a specific adaptation for the separate question. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Cross-check included reports by population, intervention, comparator, endpoint and time point, keeping other questions separate in the scope-boundary table.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The original /ko/effect is improvement in brachial FMD in adults with coronary artery disease. The identity of the adjudicated question fixes the comparison as ER nicotinic acid versus placebo on common atorvastatin treatment, with each period lasting 3 months. The subclaims key is absent, and there is a single table for the original main question.", "condition_status": "Met", "status_reason": "The target of the judgment and the identity of the narrowly defined actual comparison were verified. This item does not declare that the evidence for FMD efficacy is sufficient.", "missingness": "Unverified information about the product, measurement and denominator remains in later items.", "uncertainty": "Retrospective definition of the scope and freezing of the criteria are separate events.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The identity of the current claim and adjudicated question, descriptive attributes (facets), canonical URL, and actual list of keys in the retained summary." }, { "item_id": "N02", "question_type": "Molecule and release formulation", "question": "Have the molecule, release formulation, salt and brand of the actual nicotinic acid product been verified?", "needed": "Trial product label, batch certification, basis for specifying the salt/active amount, manufacturing/quality information, and release-formulation information.", "role": "Required", "role_reason": "Needed to avoid treating similarities in release formulation or vitamin names as product equivalence.", "application_exception": "Do not automatically combine this with nicotinamide, NR, NMN, IR/SR, no-flush preparations or laropiprant combinations. Do not infer that NIASPAN was the main trial's brand.", "criterion": "Specify clinical nicotinic acid and ER, and distinguish the unverified exact salt, purity, origin, brand, manufacturer and excipients.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — a specific adaptation for molecule and release formulation. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Cross-check the trial batch against product documents, and code information on other release formulations, molecules and combination products separately.", "current_reports": [ "S01", "S12" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The main trial evaluated oral ER nicotinic acid as add-on therapy. The exact salt, manufacturing origin, brand/manufacturer and excipients are unverified. The original classification, kind M, denotes drug add-on therapy; do not reclassify it as a supplement solely because of the NUT module.", "condition_status": "Partly verified", "status_reason": "The molecule, ER formulation and route have been linked, but the detailed identity of the actual batch and formulation is unavailable.", "missingness": "Information on the salt, purity, batch, brand, origin and excipients remains to be verified.", "uncertainty": "Safety information in the label of another ER product cannot serve as verification of the actual product used in the main trial.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Trial product label, batch certification, basis for specifying the salt/active amount, manufacturing/quality information, and release-formulation information." }, { "item_id": "N03", "question_type": "Add-on therapy and comparator", "question": "Can background treatment in both periods be distinguished from the placebo comparison?", "needed": "Records of common treatment, concomitant medication, rescue treatment, placebo composition, changes and adherence by arm/period.", "role": "Required", "role_reason": "It is necessary to assess whether differences in other medications are mixed with the effect of add-on therapy.", "application_exception": "Do not copy the low-dose nicotinic acid placebo composition from AIM-HIGH into this trial. This is not a question about nicotinic acid monotherapy.", "criterion": "Compare the ER nicotinic acid add-on period with the placebo period on common atorvastatin 80 mg/day, retaining the unverified status of other concomitant treatments/placebo ingredients.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — a specific adaptation for add-on therapy and comparator. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Cross-check treatment changes by period against the effect of interest, and do not attribute the effect of the common statin treatment to added nicotinic acid.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The common atorvastatin dose is 80 mg/day, and the comparison is with the placebo crossover period on the same background treatment. The main trial's placebo ingredients, other common treatments and changes by period are unverified.", "condition_status": "Partly verified", "status_reason": "The background to the add-on comparison was verified, but not all concomitant-treatment/placebo conditions could be cross-checked.", "missingness": "Data on placebo composition, other treatments by period and handling of adherence are unavailable.", "uncertainty": "A stated background treatment does not mean that all concurrent treatments were balanced.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Records of common treatment, concomitant medication, rescue treatment, placebo composition, changes and adherence by arm/period." }, { "item_id": "N04", "question_type": "Dose and adherence", "question": "Can the nominal dose of 1500 mg/day be distinguished from actual exposure?", "needed": "Titration schedule, actual intake/adherence by period, washout/discontinuation, and the basis for specifying the active amount.", "role": "Required", "role_reason": "Needed to avoid turning a stated target dose into identical exposure for every participant.", "application_exception": "Do not substitute 1000/2000 mg or concomitant aspirin from another study for exposure in the main trial.", "criterion": "Cross-check the reported target dose of 1500 mg/day against actual doses taken, titration, discontinuation, adherence and the basis for specifying the active amount.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — a specific adaptation for dose and adherence. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Extract nominal dose and actual exposure separately by period, and do not convert or fill in unverified doses taken.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The original target dose is 1500 mg/day. Titration has no recorded value and is unverified; actual adherence, doses taken and discontinuation data by period were also not verified within the retained scope reviewed here.", "condition_status": "Partly verified", "status_reason": "The nominal dose is clear, but data needed to verify actual exposure remain outstanding.", "missingness": "Data on titration, adherence, individual exposure and the basis for the stated dose are unavailable.", "uncertainty": "Do not determine dose response or an effect of treatment adherence from the nominal target dose alone.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Titration schedule, actual intake/adherence by period, washout/discontinuation, and the basis for specifying the active amount." }, { "item_id": "N05", "question_type": "Duration and carryover", "question": "Have the 3 months per period and the crossover sequence, washout and handling of carryover been verified?", "needed": "Complete visit schedule, sequence allocation, washout, and analysis plans and results for period/sequence/carryover.", "role": "Required", "role_reason": "Because exposure in the preceding period and time effects may become mixed with the period-end FMD comparison.", "application_exception": "Do not remove washout/carryover considerations in a crossover design by marking them NA, or count unverified details as additional confirmed design defects.", "criterion": "Link each 3-month treatment period to baseline/period-end measurements, and verify sequence, washout, period effects and handling of carryover.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 §8.1–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application — a specific adaptation for duration and carryover. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Cross-check the crossover schedule and analysis equation, and do not add the individual 3-month periods together to create an arbitrary overall follow-up duration or a single treatment period.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "Each treatment period lasted 3 months, with measurements at baseline and at the end of each period. The detailed washout, period sequence and handling of period/carryover effects in the crossover model are unverified.", "condition_status": "Unverified", "status_reason": "The period length is known, but data needed to complete the review of crossover-specific time/carryover effects are unavailable.", "missingness": "Washout, sequence and period/carryover models remain to be verified.", "uncertainty": "The same 3-month duration label does not imply the same estimand as 12 weeks in a parallel-group trial.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Complete visit schedule, sequence allocation, washout, and analysis plans and results for period/sequence/carryover." }, { "item_id": "N06", "question_type": "CAD eligibility", "question": "Are the CAD population, screening for endothelial dysfunction and baseline characteristics known?", "needed": "CAD diagnosis, age/sex, baseline FMD, inclusion/exclusion criteria, and distributions of disease/nutritional status.", "role": "Required", "role_reason": "Because similarly named cardiovascular-risk groups cannot be assumed to be the same selected population.", "application_exception": "Do not invent an FMD cut-off or state that all participants had endothelial dysfunction defined by a threshold.", "criterion": "Verify adult CAD and common high-dose statin treatment, along with the FMD screening cut-off, diagnosis/inclusion/exclusion criteria and baseline distributions.", "basis": "M03 §3.2.1; detailed population criteria are internally designed — a specific adaptation for CAD eligibility. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Create an inclusion table by diagnosis and baseline status, and treat application beyond the verified population as a separate question.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The participants are adults with coronary artery disease receiving common atorvastatin treatment. The eligibility threshold for endothelial dysfunction has no recorded value. Do not fill in the full baseline/eligibility profile beyond the scope of the abstract accessed in the original review.", "condition_status": "Partly verified", "status_reason": "The disease scope has been linked, but screening thresholds and detailed data on representativeness are unavailable.", "missingness": "Detailed diagnosis/eligibility criteria, baseline FMD and sex/deficiency strata remain to be verified.", "uncertainty": "Do not combine results from HIV, metabolic-syndrome, healthy or low-HDL populations as direct replication in this population.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "CAD diagnosis, age/sex, baseline FMD, inclusion/exclusion criteria, and distributions of disease/nutritional status." }, { "item_id": "N07", "question_type": "FMD measurement", "question": "Have the measurement, blinding and unit conditions for brachial FMD been verified?", "needed": "The main trial's FMD SOP, device/analysis method, cuff/imaging timing, baseline diameter and assessment-blinding records.", "role": "Required", "role_reason": "Needed to avoid confusing differences in measurement conditions with actual changes in endothelial function.", "application_exception": "Do not conclude that blinding/standardization was completed solely because the measure is described as objective.", "criterion": "Link period-end brachial FMD to the unit %, and verify the device, cuff site/pressure/duration, imaging/interpretation, baseline diameter and assessment blinding.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application — a specific adaptation for FMD measurement. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Cross-check units/directions in the main trial's SOP and results tables, and do not substitute MRI or the protocol of an adjacent trial.", "current_reports": [ "S01", "S09" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The brachial FMD endpoint and comparisons at the end of each period were verified. The device method, cuff protocol, post-deflation imaging time and details of image analysis are unverified.", "condition_status": "Partly verified", "status_reason": "The endpoint name/time point was verified, but data needed to assess measurement limitations and differences in detection by arm remain outstanding.", "missingness": "Data on the device, cuff, imaging/interpretation, blinding and reproducibility are unavailable.", "uncertainty": "Do not copy the MRI measurement in S09 into S01 as its verified device.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The main trial's FMD SOP, device/analysis method, cuff/imaging timing, baseline diameter and assessment-blinding records." }, { "item_id": "N08", "question_type": "Randomization and allocation concealment", "question": "Have the actual randomization, allocation concealment and baseline balance in the crossover trial been verified?", "needed": "The randomized sequence, allocation concealment, baseline table and recruitment flow in the main trial's full text.", "role": "Required", "role_reason": "Because the label 'randomized' alone cannot establish that all allocation issues were resolved.", "application_exception": "Do not turn unverified sections into confirmed defects or a nonrandomized design.", "criterion": "Link the randomized crossover design to the verified scope of sequence generation, allocation concealment and baseline balance by period.", "basis": "M08 §8.1–8.2.3; internal application — a specific adaptation for randomization and allocation concealment. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Cross-check the actual allocation section and baseline table, distinguishing an RCT label from sections that have been verified.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "S01 is reported as a randomized crossover trial. Details of sequence generation/concealment and sequence-specific baseline balance are unverified within the abstract information retained and reused here.", "condition_status": "Partly verified", "status_reason": "The design type was verified, but detailed cross-checking of the allocation process remains outstanding.", "missingness": "Information on sequence generation and allocation concealment, and sequence-specific baseline tables, is unavailable.", "uncertainty": "Do not create new bias counts or scores beyond the small-sample defect in the original B1.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The randomized sequence, allocation concealment, baseline table and recruitment flow in the main trial's full text." }, { "item_id": "N09", "question_type": "Blinding and placebo", "question": "Did the placebo and assessment blinding address differences caused by flushing?", "needed": "The main trial's blinding section, placebo composition, flushing management/assessment of treatment guesses, and blinded interpretation.", "role": "Required", "role_reason": "Needed to examine how sensory differences in exposure affected outcome assessment.", "application_exception": "The label's flushing risk is separate from the success/failure of blinding in an individual trial.", "criterion": "Verify the main trial's placebo ingredients, participant/assessor blinding, and information on handling flushing and sensory differences.", "basis": "M08 Table 8.2.a, M03 §3.2.4; internal application; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — a specific adaptation for blinding and placebo. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare the placebo/blinding sections, and do not use the existence of a flushing risk as confirmation that blinding failed in the main trial.", "current_reports": [ "S01", "S12" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The main trial's placebo ingredients and active masking information have no recorded value. The FDA label warns about flushing but does not provide S01's blinding assessment results.", "condition_status": "Unverified", "status_reason": "The direct source section needed to verify the measurement/sensory differences of interest has not been obtained.", "missingness": "Information on placebo composition, blinded interpretation, and flushing management/assessment of treatment guesses remains to be verified.", "uncertainty": "Do not turn a known potential risk into confirmed measurement bias in the actual trial.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The main trial's blinding section, placebo composition, flushing management/assessment of treatment guesses, and blinded interpretation." }, { "item_id": "N10", "question_type": "Crossover effect of interest", "question": "Can the paired data, analysis population and effect of interest in the reported test be identified?", "needed": "The main trial's statistical methods section, paired/crossover model, analysis population, covariates and test results table.", "role": "Required", "role_reason": "Needed to avoid treating within-group changes or a simple difference in means as a verified crossover-model effect.", "application_exception": "Do not reconstruct an independent-groups Cohen d or a paired CI from ± and P alone.", "criterion": "Cross-check the period-end between-treatment test against the paired-data model, ITT/PP, adjustment, period effects and analysis population.", "basis": "M08 §8.2.2, M15 §15.3.1; internal application; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed — a specific adaptation for the crossover effect of interest. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Cross-check the comparison of interest against the actual model, and do not fill in an independent-groups analysis or an assumed ITT analysis.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The original report gives a between-treatment P=0.48 for FMD at the end of each period. The paired-model coefficient, ITT/PP, adjustment/analysis population and paired-data correlation are unverified. The +0.5%p figure is the existing simple descriptive difference.", "condition_status": "Unverified", "status_reason": "The comparison direction has been linked, but the actual model used for the test and details of the estimand are unavailable.", "missingness": "The crossover-model equation, analysis population, paired correlation/variance and adjustment information remain to be verified.", "uncertainty": "Do not treat a difference in changes from baseline as the same as a period-end contrast.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The main trial's statistical methods section, paired/crossover model, analysis population, covariates and test results table." }, { "item_id": "N11", "question_type": "Denominators and missing data", "question": "Can the study total of 66 participants be distinguished from the denominators for the actual FMD analysis and missing data?", "needed": "The main trial's flow diagram, analysis n by period, reasons for missing data/discontinuation, and their handling in the analysis.", "role": "Required", "role_reason": "Needed to avoid converting the retained sample size into the actual analysis denominator.", "application_exception": "Do not describe unverified missing-data information as 0 dropouts or complete data for all 66 participants.", "criterion": "Link the denominators for recruitment, allocation, completion, measurement by period and paired analysis, along with the reasons for missing data/discontinuation and how they were handled.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application — a specific adaptation for denominators and missing data. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Cross-check denominators in the flow diagram and results tables, and do not substitute the study total of 66 participants for the paired-analysis n.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The original study total is 66 participants; the FMD analysis denominator fields, evidence_core.analysis_n and endpoint_analysis_n, have no recorded value (null). Actual completion counts by period, paired-analysis n and handling of missing data are also unverified.", "condition_status": "Unverified", "status_reason": "The existence of a sample was verified, but data needed to verify the analysis denominator/losses for the selected outcome are unavailable.", "missingness": "Analysis n, losses by period, reasons, handling and follow-up remain to be verified.", "uncertainty": "Do not calculate new precision estimates or harm frequencies from the 66 participants.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The main trial's flow diagram, analysis n by period, reasons for missing data/discontinuation, and their handling in the analysis." }, { "item_id": "N12", "question_type": "Original FMD values and test", "question": "Have the period-end FMD values been distinguished from the scope of the failure to demonstrate improvement?", "needed": "Results in the original research abstract, original results tables, crossover-model estimates and baseline-change data.", "role": "Required", "role_reason": "Needed to avoid turning nonsignificance into an effect of 0, equivalence or exclusion of a meaningful benefit.", "application_exception": "The formal between-group CI/difference in changes from baseline has no recorded value; do not perform new arithmetic or back-calculation.", "criterion": "Attribute 6.6 ± 4.8% versus 6.1 ± 4.9%, P=0.48, and the existing +0.5%p only to the corresponding period-end/descriptive contrast.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is internally designed; M08 §8.2.2, M15 §15.3.1; internal application — a specific adaptation for original FMD values and the test. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Cross-check values, units and comparison direction in the abstract/results tables, and preserve the old simple difference as a separate descriptive historical record.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "Period-end FMD was 6.6 ± 4.8% with nicotinic acid and 6.1 ± 4.9% with placebo, P=0.48. The +0.5%p figure is simple subtraction in the original calculation history, not a verified crossover-model effect or a between-treatment difference in changes from baseline. Failure to demonstrate improvement does not mean an effect of exactly 0 or equivalence.", "condition_status": "Met", "status_reason": "The retained original values/analysis boundaries and the interpretation of nonsignificance were linked. Adequacy of precision remains an unverified condition in a later item.", "missingness": "The model contrast, changes from baseline and CI are still unavailable.", "uncertainty": "Do not present a small favorable descriptive difference as a confirmed estimate of clinical benefit.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Results in the original research abstract, original results tables, crossover-model estimates and baseline-change data." }, { "item_id": "N13", "question_type": "± and paired variance", "question": "Have the type of ± statistic and the paired variance for FMD been verified?", "needed": "SD/SE definitions in the original table, paired-data variance/correlation, test model and analysis n.", "role": "Required", "role_reason": "Because arbitrarily assigning an unknown ± statistic to SD/SE would change the interpretation of effect and precision.", "application_exception": "Do not apply independent-groups formulas to values from the same participant in two periods.", "criterion": "Verify the dispersion types for 4.8/4.9, paired variance, between-period correlation and analysis n, and retain the unverified status of the original source information.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M15 §15.3.1–15.3.3; internal application — a specific adaptation for ± and paired variance. Not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Even after cross-checking dispersion definitions in the table notes and statistical methods section, do not newly calculate an unreported CI.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The original ± figures are 4.8 for nicotinic acid and 4.9 for placebo, but the dispersion type field (dispersion_type) has no recorded value. Paired variance/correlation and analysis n were also not verified.", "condition_status": "Unverified", "status_reason": "The displayed period-end values are known, but data needed to verify the actual definition of dispersion are unavailable.", "missingness": "The SD/SE type, paired variance/correlation and denominator are unavailable.", "uncertainty": "The presence of ± is different from having obtained a formal effect CI.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "SD/SE definitions in the original table, paired-data variance/correlation, test model and analysis n." }, { "item_id": "N14", "question_type": "CI and important difference", "question": "Is there a paired between-group CI and an applicable important FMD difference?", "needed": "Between-group CI from the crossover model, paired variance/denominator, and evidence for an important difference in the same population/measure.", "role": "Required", "role_reason": "A P value alone cannot exclude a meaningful benefit or establish sufficient precision.", "application_exception": "Do not arbitrarily adopt a universal FMD MCID or a minimum sample size/duration.", "criterion": "Compare the crossover-contrast CI with a justified threshold for an important difference in the same analysis, and explain the range of effects compatible with the findings.", "basis": "M15 §15.3.1–15.3.3; internal application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for specific designs were developed internally — an individual adaptation for CIs and important differences. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare the reported CI with a justified threshold for an important difference, and leave unverified thresholds and CIs unverified.", "current_reports": [ "S01", "S13" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The reported paired-contrast CI (reported_paired_contrast_CI) and the difference in changes from baseline (baseline_change_difference) are blank (null). An applicable between-group MCID is also unverified, and the original CX indicates the current limits of access/verification. It does not assert that reconstruction is permanently impossible.", "condition_status": "Unverified", "status_reason": "Without the interval and a threshold for an important difference, it is not possible to assess which magnitudes of effect are excluded.", "missingness": "The paired CI, paired variance, analysis n, and a justified important difference remain unverified.", "uncertainty": "The nonsignificant P=0.48 is not evidence for C1 or equivalence.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Between-group CI from the crossover model, paired variance/denominator, and evidence for an important difference in the same population/measure." }, { "item_id": "N15", "question_type": "Registration and plans", "question": "Do the planned status, analysis, and timing of FMD agree with what was reported?", "needed": "Version-specific registry text, protocol, SAP, and the history of changes to endpoints/analyses.", "role": "Required", "role_reason": "This is needed to avoid elevating the page's priority endpoint to the status of a registered primary endpoint.", "application_exception": "Do not turn the historical record of obtaining only the basic registry display into confirmation that the study was unregistered or selectively reported.", "criterion": "Compare the original NCT00150722 registration/protocol/SAP with the reported endpoints/crossover analysis and the reasons for changes.", "basis": "M08 Table 8.2.a, M04 §4.6.3; internal application — an individual adaptation for registration and plans. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare the original versions of the registration/plans with the original study report, and indicate only the status/discrepancies that have been verified.", "current_reports": [ "S01", "S13" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "S01 is linked to NCT00150722, but the historical access level for S13 was registry_shell_only: only the basic registry display was available. FMD is the page's priority endpoint; its registered primary/co-primary status and the registry text on analyses and sponsorship are unverified.", "condition_status": "Unverified", "status_reason": "The registration number is linked, but the structured registry text needed to compare the plans with the actual report could not be read.", "missingness": "The registration/SAP/protocol, version history, and reasons for departures from the plans remain unverified.", "uncertainty": "Do not represent the historical access to the basic registry display as a registry lookup or successful reading of the registry text in this review.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Version-specific registry text, protocol, SAP, and the history of changes to endpoints/analyses." }, { "item_id": "N16", "question_type": "Direct trial family", "question": "Have the original study report and registration been linked to the same direct trial family?", "needed": "Identifiers and registry links for each report, and a family table of populations/doses/durations/outcomes.", "role": "Required", "role_reason": "This is needed to avoid counting the existence of a paper and a registration as two independent replications.", "application_exception": "The original designation of 1 direct trial, R1, does not certify confirmatory preregistration or the number of independent study families across the entire literature.", "criterion": "Place the Philpott original study report/PMID/DOI/NCT in the same direct trial family, and distinguish the number of reports from the number of independent replications.", "basis": "The distinction between studies and reports in M04 §4.6.1–4.6.2; internal application to cohort/outcome linkage; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for the direct trial family. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare the identifiers and actual comparisons, and do not double-count related reports or registrations as new independent trials.", "current_reports": [ "S01", "S13" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "S01 Philpott/PMID23174368/DOI10.1016/j.atherosclerosis.2012.10.067 and S13 NCT00150722 belong to one direct trial family, PHILPOTT-NCT00150722. Do not count the current 15 bibliographic records as 15 independent trials.", "condition_status": "Met", "status_reason": "The identity of the direct trial and its registration link are confirmed in the original manuscript; no total of unique trials/participants was newly produced.", "missingness": "Registry details and the complete relationships among adjacent reports remain limited.", "uncertainty": "Do not extend the meaning of the original R1 to a factual claim of repeated confirmation or independent funding.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Identifiers and registry links for each report, and a family table of populations/doses/durations/outcomes." }, { "item_id": "N17", "question_type": "INEF post-hoc subgroup", "question": "Have the analysis denominators for each arm, prespecified plans, and interaction testing been verified for the INEF whole-cohort and post-hoc low-HDL results?", "needed": "INEF whole-cohort/subgroup results tables, n for each arm, prespecified subgroup plans/SAP, and interaction testing.", "role": "Supplementary; required for an extension to that stratum", "role_reason": "This is needed to preserve both the unfavorable whole-cohort result and the favorable post-hoc result.", "application_exception": "The original post-hoc difference of 2.22%p is existing descriptive arithmetic. Do not produce new totals or recalculate it.", "criterion": "Separate the whole-cohort and post-hoc subgroup results, and verify the analysis denominator for each arm, whether the subgroup plan was prespecified, interaction testing, and eligibility as a direct comparison.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M03 §3.2.1–3.2.4; details of dose, persistence, and effect modification were developed internally — an individual adaptation for the INEF post-hoc subgroup. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare the whole-cohort/post-hoc results with the plans, and do not elevate a positive subgroup result to a whole-cohort result or to the current fixed comparison.", "current_reports": [ "S02" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "INEF randomized 107 participants and lasted 12 weeks, and did not establish a whole-cohort FMD benefit. Changes in the post-hoc low-HDL subgroup were 3.25 versus 1.03%p, P=0.047, and n for each arm is unverified. The original descriptive difference of 2.22%p belongs to the post-hoc context and is not direct replication.", "condition_status": "Partly verified", "status_reason": "The directions of the whole-cohort/post-hoc results were verified, but stratum-specific denominators and planning/interaction information remain unverified.", "missingness": "Subgroup n, prespecification, interaction testing, and evidence of direct applicability to the same fixed comparison are unavailable.", "uncertainty": "Do not label subgroup significance and whole-cohort nonsignificance as an actual conflict within the same analysis.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "INEF whole-cohort/subgroup results tables, n for each arm, prespecified subgroup plans/SAP, and interaction testing." }, { "item_id": "N18", "question_type": "Metabolic-syndrome study family", "question": "Have the actual study linkage for Thoenes/Vaccari and the between-group FMD estimate and CI been verified?", "needed": "Study identities, populations/durations/registrations, between-group results/CIs, and links to the original participants for the two reports.", "role": "Supplementary", "role_reason": "This is needed to prevent a positive within-group result and potentially overlapping reports from being turned into direct replication.", "application_exception": "A possible family relationship does not establish a confirmed number of independent trials. 22% is neither 22%p nor a between-group difference.", "criterion": "Link S03/S04 as a possible single family, while verifying whether the actual participants and study identities match and checking the between-group FMD estimate and CI; separately preserve the 52 weeks, 50 participants, and within-group 22% improvement.", "basis": "The distinction between studies and reports in M04 §4.6.1–4.6.2; internal application to cohort/outcome linkage; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for the metabolic-syndrome study family. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare report identities and results tables, and do not add the 50 participants twice across reports that may describe the same study.", "current_reports": [ "S03", "S04" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The original record treats Thoenes/Vaccari as a possible single metabolic-syndrome family. The randomized study had 50 participants and lasted 52 weeks, with a within-nicotinic-acid-group 22% improvement/P<0.001. The between-group FMD difference and CI are unverified.", "condition_status": "Partly verified", "status_reason": "The within-group result and the boundary around possible overlap have been linked, but the family identity and between-group contrast have not been fully compared.", "missingness": "Report relationships, the between-group estimate/CI, and direct applicability to the same population/dose remain unverified.", "uncertainty": "Do not combine the improvement-rate unit and within-group analysis with the main trial's end-of-period % as if they were the same effect.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Study identities, populations/durations/registrations, between-group results/CIs, and links to the original participants for the two reports." }, { "item_id": "N19", "question_type": "Differences between HIV analyses", "question": "Have the analysis denominators, adjustment models, between-group CIs, and plans been verified for Chow's two analyses?", "needed": "Chow results tables, adjustment models, between-group CIs, baseline/completion/analysis denominators, and SAP.", "role": "Supplementary", "role_reason": "This is needed to avoid selecting a single value from favorable/unfavorable results obtained from different analyses.", "application_exception": "Because the population and analyses differ, do not count these results as independent replication of the current CAD add-on treatment.", "criterion": "Separate the unadjusted change comparison in the HIV context of 10/9 participants and 12 weeks from the end-of-period test adjusted for baseline FMD/HDL-C, then link the extent of verification for each analysis population, adjustment model, between-group CI, and prespecified plan.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for differences between HIV analyses. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare unadjusted/adjusted estimands, covariates, and plans, and do not turn the two P values into a conflict within the same analysis.", "current_reports": [ "S05" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The Chow HIV trial had 10 participants receiving nicotinic acid and 9 receiving placebo, lasted 12 weeks, and used a maximum dose of 1500 mg/day. The between-group P value for unadjusted change was P=0.67; the end-of-period comparison adjusted for baseline FMD/HDL-C gave P=0.048, and the adjusted-contrast CI is unverified.", "condition_status": "Partly verified", "status_reason": "The original differences between analyses were preserved, but information needed to verify the adjusted-contrast interval/plans remains outstanding.", "missingness": "The adjusted coefficient/CI, analysis population, and prespecified analysis plan are unavailable.", "uncertainty": "The different conclusions of the two tests do not imply a numerical error for the same question/analysis.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Chow results tables, adjustment models, between-group CIs, baseline/completion/analysis denominators, and SAP." }, { "item_id": "N20", "question_type": "A different comparator in HIV", "question": "Have Dubé's actual analysis denominators, handling of missing data, and between-group FMD effect and CI been verified?", "needed": "Dubé's flow diagram, analysis denominators for each arm, co-intervention/active comparator, and between-group results/CI.", "role": "Supplementary", "role_reason": "This is needed to avoid turning an active comparison, co-intervention, and medians into the main trial's contrast for adding the single agent.", "application_exception": "Do not copy the aspirin co-intervention or the fenofibrate effect into the placebo composition/background treatment of the main trial.", "criterion": "Link ER nicotinic acid+aspirin versus fenofibrate, HIV, and 24 weeks with 99 participants assigned/74 with complete scans (35/39), and distinguish the extent of verification of actual analysis denominators for each arm, handling of missing data, between-group estimates, and CIs.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations were developed internally; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for specific designs were developed internally; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for a different comparator in HIV. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Extract the within-group tests separately from the actual comparator/co-intervention, and assign 99/74/35/39 only to their respective stages in that study's participant flow.", "current_reports": [ "S06" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "Dubé is a 24-week trial in HIV comparing ER nicotinic acid+aspirin with fenofibrate. There were 99 randomized participants/74 with complete scans (35/39); within-group median changes were 0.6%p/P=0.28 versus 0.5%p/P=0.19, and the between-group contrast CI is unverified.", "condition_status": "Partly verified", "status_reason": "The exposure, participant flow, and within-group results have been linked, but the between-group contrast of interest and its CI are unavailable.", "missingness": "The between-group effect/CI, analysis/handling of missing data, and direct applicability to CAD remain unverified.", "uncertainty": "Do not turn simple subtraction of the two within-group values or substitution of the total count into a new between-group effect.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Dubé's flow diagram, analysis denominators for each arm, co-intervention/active comparator, and between-group results/CI." }, { "item_id": "N21", "question_type": "Mechanistic evidence", "question": "Have HDL, eNOS, and cellular responses been kept from being used as direct effects on brachial FMD?", "needed": "The actual experimental systems, populations, assays, and links to clinical FMD outcomes in mechanistic studies.", "role": "Supplementary", "role_reason": "This is needed to prevent related biological explanations from being elevated to replication of a direct clinical endpoint.", "application_exception": "Do not use mechanistic plausibility as evidence of effect magnitude or prevention of clinical events.", "criterion": "Distinguish the level of outcomes in the mechanistic evidence and isolated-HDL/endothelial assays in S07/S11 from brachial FMD in the main trial.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to the specific question were developed internally; M03 §3.2.4; internally defined extension boundaries — an individual adaptation for mechanistic evidence. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Map the evidence by outcome level/experimental system, and do not substitute changes in cells or isolated HDL for comparative clinical effects.", "current_reports": [ "S07", "S11" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "S07 concerns mechanisms involving HDL, vasorelaxation/eNOS, while S11 concerns a diabetes/healthy comparison and endothelial assays of isolated HDL. The current bibliographic records and source locations (citation/locator) do not provide direct clinical results for brachial FMD in the CAD crossover comparison.", "condition_status": "Met", "status_reason": "The outcome levels in the original material were distinguished. This does not newly certify the clinical validity of the mechanisms as a whole.", "missingness": "Within this scope, there is no material linking the mechanisms to the same direct comparison.", "uncertainty": "Do not fill in an FMD benefit for the main trial based solely on improvement language in a bibliographic title.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The actual experimental systems, populations, assays, and links to clinical FMD outcomes in mechanistic studies." }, { "item_id": "N22", "question_type": "No-flush boundary", "question": "Have the actual molecule and composition of the S08 no-flush product and its direct applicability to the same comparison been verified?", "needed": "The original text on the actual molecule/composition, release formulation, population, comparator/outcomes for the S08 product.", "role": "Supplementary", "role_reason": "This is needed to prevent results from different molecules/formulations and selected populations from being mixed in as direct replication.", "application_exception": "Do not infer the molecular identity of no-flush products.", "criterion": "Verify the actual molecule, composition, release formulation, population, comparator, and outcomes of S08 to assess eligibility for the original ER-drug/CAD add-on comparison; separately preserve the currently known differences involving no-flush and a population with isolated low HDL/no other CAD risk.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations were developed internally; M03 §3.2.1; detailed population criteria were developed internally; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for the No-flush boundary. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Use a product/population eligibility table to identify differences, and do not claim equivalence with ER nicotinic acid based solely on the no-flush name.", "current_reports": [ "S08" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The source-location description (locator) for S08 concerns no-flush niacin and participants with isolated low HDL/no other CAD risk. Do not automatically combine it with the main question's ER nicotinic acid/CAD/common high-dose statin comparison.", "condition_status": "Partly verified", "status_reason": "The differences in formulation and population have been linked, but the exact product identity and direct applicability to the same comparison are unverified.", "missingness": "The exact molecule/composition, comparator/estimand, and eligibility for the main comparison remain unverified.", "uncertainty": "The historical access record for the original title/abstract is not current inspection of the physical product.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The original text on the actual molecule/composition, release formulation, population, comparator/outcomes for the S08 product." }, { "item_id": "N23", "question_type": "MRI results unverified", "question": "Have the original FMD results of the MRI modified-release study been verified?", "needed": "The FMD tables, measurement methods, analysis/population, and formulation information in the original full text of S09.", "role": "Supplementary", "role_reason": "This is needed to avoid using the existence of a link as verification of original results or replication of the main measurement.", "application_exception": "Access has not been attempted in this review. Do not recast the historical record of inaccessible material as an access failure in this review.", "criterion": "Separate the S09 bibliographic record/metadata from the historical inability to access the full text, and do not fill in unverified FMD results.", "basis": "The data-collection/selection principles in M04 §4.5–4.6; the distinction between access and reading, and the hyperlink conventions, were developed internally; M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to the specific question were developed internally; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for unverified MRI results. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "If obtained, compare the actual original results/measurement methods; do not infer the direction or magnitude of an effect from search/index titles.", "current_reports": [ "S09" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "S09 is an MRI-based modified-release study. Its historical access level was publisher_metadata_indexed_fulltext_inaccessible: indexed publisher metadata with inaccessible full text, and no original FMD results were extracted. In this review, only the retained bibliographic record was read; the external full text was not opened.", "condition_status": "Unverified", "status_reason": "The bibliographic identity is available, but the actual original results and the material needed to assess direct applicability have not been obtained.", "missingness": "The original FMD results, measurement methods, analysis, and detailed formulation information are unavailable.", "uncertainty": "An unverified effect does not mean a negative result or 0 studies.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The FMD tables, measurement methods, analysis/population, and formulation information in the original full text of S09." }, { "item_id": "N24", "question_type": "Combination with laropiprant", "question": "Have the positive combination result and the termination/nonposting of results been kept from being used as effects of nicotinic acid alone?", "needed": "The compositions, trial/registration identities, results tables, reasons for termination, and posting histories of the two studies.", "role": "Supplementary", "role_reason": "This is needed to prevent the contributions of combined active ingredients and unreported results from being attributed to the main add-on treatment.", "application_exception": "Do not merge S10 and S14 as the same trial without comparing their identifiers.", "criterion": "Separate the positive combination report S10 from the separate terminated registration S14, its actual enrollment of 8 participants, and its unposted results.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations were developed internally; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual adaptation for the combination with laropiprant. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare reports, registrations, and products, and do not invent ingredient-specific contributions to combination results or unposted FMD values.", "current_reports": [ "S10", "S14" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "S10 is a positive FMD report on an ER nicotinic acid/laropiprant combination after myocardial infarction. The separate S14 NCT01052311 had an actual enrollment of 8 participants, no results posted, and was terminated following the decision to withdraw the study drug from the market. Do not count either as a direct effect of nicotinic acid alone.", "condition_status": "Met", "status_reason": "The actual distinctions among positive findings, termination, and nonposting were preserved. Ingredient-specific causal contributions are not verified.", "missingness": "The contribution of the combination's ingredients and a direct estimate for the current fixed comparison are unavailable.", "uncertainty": "Do not replace unposted results with negative FMD values.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The compositions, trial/registration identities, results tables, reasons for termination, and posting histories of the two studies." }, { "item_id": "N25", "question_type": "Other vascular endpoints", "question": "Have carotid IMT and lipids been kept from substituting for success on brachial FMD?", "needed": "Material directly linking the endpoints/timing/population of S16 to clinical FMD outcomes.", "role": "Supplementary", "role_reason": "Calling outcomes vascular or lipid-related does not make them the same outcome.", "application_exception": "Retain positive results on other endpoints, but do not use them as the direct success criterion.", "criterion": "Separate the priority IMT endpoint and lipid values in S16 from the FMD and cardiovascular-event questions.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to the specific question were developed internally; M03 §3.2.4; internally defined extension boundaries — an individual adaptation for other vascular endpoints. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Map the material by endpoint, and do not transfer improvements in IMT or LDL/HDL into effects on brachial FMD.", "current_reports": [ "S16", "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "S16 is a 2-year carotid IMT study in participants who had reached their LDL target and had high Lp(a); the original HTML was used for screening at the time. It is not a main FMD result. The manuscript likewise does not use lipid improvement as this page's criterion for FMD success.", "condition_status": "Met", "status_reason": "The boundaries between related outcomes and direct FMD evidence were distinguished. No new efficacy judgment is made for other endpoints.", "missingness": "The current manuscript contains no estimate for the same direct FMD comparison.", "uncertainty": "The biological relevance of IMT and lipids does not permit endpoint substitution.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Material directly linking the endpoints/timing/population of S16 to clinical FMD outcomes." }, { "item_id": "N26", "question_type": "Funding and independence", "question": "Have funding, drug supply, and COI for the main trial been verified?", "needed": "Original records for S01 funding/acknowledgements, product supply, author COI, and the registry sponsor.", "role": "Supplementary; required for claims of independence", "role_reason": "This is needed to prevent unverified conflicts of interest from becoming evidence of independent replication.", "application_exception": "Do not automatically attribute sponsorship described in the Chow acknowledgements or the FDA document to S01.", "criterion": "Link the main trial's funding, product supply, and authors' employment/patents/COI to the actual sections in the report.", "basis": "Chamgap's own criteria for independence and attribution. The official methodology sections used in this pilot do not warrant all of these detailed items — an individual adaptation for funding and independence. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare disclosures in the original study report/registration with related reports, and do not turn unverified information into confirmation of independent/mixed funding.", "current_reports": [ "S01", "S05", "S13" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "Funding, drug supply, and author conflicts of interest for S01 are unverified. The original I1 applies the rule for unverified information in precedent 29 and does not mean that mixed funding was actually verified. The check of the Chow acknowledgements belongs to the history of an adjacent study.", "condition_status": "Unverified", "status_reason": "The disclosure/funding sections needed to support the main trial's independence have not been obtained.", "missingness": "Funding, product supply, COI, and sponsor details remain unverified.", "uncertainty": "The presence or absence of a disclosure also does not automatically establish the magnitude of bias or invalidate a study.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Original records for S01 funding/acknowledgements, product supply, author COI, and the registry sponsor." }, { "item_id": "N27", "question_type": "Reading status and reference dates", "question": "Have the reading of summaries in this review, historical external access, and document dates been distinguished?", "needed": "The bytes/SHA of the current input; original bibliographic source locations and access levels (citation locator/access_level); the original evidence cutoff and verification date (evidence_cutoff/verified_date); and historical search/selection records.", "role": "Required", "role_reason": "This is needed to avoid overstating the reading of retained summaries as new full-text verification or a current comprehensive search.", "application_exception": "The 15 bibliographic records (citation) have no individual access-date keys (accessed). Do not fill individual access dates with the overall verification date (verified_date). The original ZIP/search files were not opened in this review.", "criterion": "Separately preserve the 2026-09-15 evidence/review date, the reading of the retained summaries on 2026-10-05, and each report's access level and absence of access dates.", "basis": "The data-collection/selection principles in M04 §4.5–4.6; the distinction between access and reading, and the hyperlink conventions, were developed internally; M04 §4.5, §4.6.3; the limits of the current data conversion follow the user-defined scope and internal design — an individual adaptation for reading status and reference dates. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare access/obtaining/reading events for each material together with their dates, and distinguish external URLs from the current reader displaying the summaries actually read.", "current_reports": [ "S01", "S02", "S03", "S04", "S05", "S06", "S07", "S08", "S09", "S10", "S11", "S12", "S13", "S14", "S16" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The complete retained KO/EN, structural, evidence, and bibliographic summaries were read. The original evidence cutoff/verification date (verified_date) is 2026-09-15. Individual access dates for each bibliographic record (citation) are absent and remain blank; historical access levels/locations and the overall review date are preserved separately. Access to all 15 external materials was not attempted, and none were obtained or read in this review.", "condition_status": "Met", "status_reason": "The scope of current actions and of the original history/dates was separated for each material. This does not imply completeness of the latest literature as a whole.", "missingness": "The original search/selection/full-text files were not compared in this review.", "uncertainty": "The historical first-publication date (first_published_at) and the blank deployment timestamp (deployed_at, null) do not record a current deployment event.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The bytes/SHA of the current input; original bibliographic source locations and access levels (citation locator/access_level); the original evidence cutoff and verification date (evidence_cutoff/verified_date); and historical search/selection records." }, { "item_id": "N28", "question_type": "Preservation of the original assessment", "question": "Have the meanings of the original D28, axes, and uncertainties been retained unchanged?", "needed": "The original grade, score, and axes (grade/score/axes), rationales for each axis, and metadata on the original calculation/document review in the assessment record (assessment).", "role": "Required", "role_reason": "This is needed to avoid confusing the table's verification statuses with the existing efficacy grade.", "application_exception": "Apart from the small sample size underlying the original B1, do not count unverified design items as new defects.", "criterion": "Preserve the original D28/B/S/R1/I1/E0/B1/CX and the indicator for absence of human studies, no_human_study=false, solely as historical assessments.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses was developed internally; M04 §4.5, §4.6.3; the limits of the current data conversion follow the user-defined scope and internal design — an individual adaptation for preservation of the original assessment. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Check that the original values and their display match, and do not generate new scores, criterion-fulfillment rates, or a judgment of effect 0.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The original grade D, score of 28, and B/S/R1/I1/E0/B1/CX are retained. E0 means failure to demonstrate improvement; I1 denotes how unverified funding was handled; CX means precision remains unverified within the scope of access. Because direct human data exist, the original indicator for absence of human studies remains no_human_study=false.", "condition_status": "Met", "status_reason": "Accurate preservation of the original assessment and its interpretation was checked. This is not a new efficacy judgment or clinical certification.", "missingness": "Precision, replication, funding, and detailed information on bias each remain unverified.", "uncertainty": "The document's self-review grade B does not replace efficacy grade D or an independent clinical review.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The original grade, score, and axes (grade/score/axes), rationales for each axis, and metadata on the original calculation/document review in the assessment record (assessment)." }, { "item_id": "N29", "question_type": "Harms in the main trial", "question": "Are harm-collection data, person/event counts, and discontinuation denominators available for the same main trial?", "needed": "S01 harm/discontinuation tables, collection plan, exposure by group/period, person/event counts, severity, and missing-data records.", "role": "Supplementary; essential for safety under the same exposure", "role_reason": "Needed to avoid treating the existence of an efficacy summary as evidence of safety or a complete event tally.", "application_exception": "The original FMD result is not deleted or regraded because harms are unverified.", "criterion": "Link the S01 definitions of adverse events, systematic collection, severity, person/event counts, discontinuations, and exposure/follow-up denominators.", "basis": "M19 §19.1.2–19.2.4; own application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; own application — individually adapted to harms in the main trial. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare the harm tables with the flow diagram; do not fill unreported data with 0 or rates from a label used as adjacent evidence.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The numbers of people with adverse events or discontinuations in the main FMD trial and its long-term safety could not be verified. The original Caution status is retained, without inventing person counts, event counts, severity, systematic collection, or denominators.", "condition_status": "Unverified", "status_reason": "No material is available for reviewing a harm tally in the same population under the same exposure.", "missingness": "Trial-specific adverse-event (AE) and discontinuation data, person/event counts, exposure denominators, and collection methods remain to be verified.", "uncertainty": "Nonreporting establishes neither absence of events nor selective reporting.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "S01 harm/discontinuation tables, collection plan, exposure by group/period, person/event counts, severity, and missing-data records." }, { "item_id": "N30", "question_type": "Boundaries of FDA risk information", "question": "Have warnings in the FDA label been distinguished from the main trial's product and events?", "needed": "The product/release formulation, contraindications/warnings, and evidence scope of the original FDA label, together with the identity of the S01 trial batch.", "role": "Supplementary", "role_reason": "Needed because the existence of official warnings differs from verification of safety in the particular trial under consideration.", "application_exception": "A historical label is not treated as verification of current approval status or individual safety.", "criterion": "Distinguish the contraindications, warnings, and interactions in the 2020 NIASPAN product document from the unverified brand in S01.", "basis": "M19 §19.1.2–19.2.4; own application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; design considerations in M19 §19.2.2–19.2.4; detailed recording of confounding is internally designed; M04 §4.6.1–4.6.2; adaptation for harm data is internally designed; Chamgap's own interpretive boundaries. The M19 principles are referenced; no official causality tool was applied — individually adapted to the boundaries of FDA risk information. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare the product/safety sections of the label with the main trial's product and co-treatment conditions; do not count the regulatory document as an additional independent trial or event.", "current_reports": [ "S12", "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "S12 is the 2020 NIASPAN FDA label. Retain its information on flushing, liver injury, increased blood glucose/uric acid, the risk of myopathy/rhabdomyolysis with statin co-treatment, and contraindications including active liver disease. The brand in S01 is unverified, and the label is not a harm tally from the main FMD trial itself.", "condition_status": "Met", "status_reason": "The official document's risk information was linked with the limits on attribution to a product/trial. This does not certify individual safety.", "missingness": "Correspondence with the main trial batch, events/causality in the same population, and current approval status remain unverified.", "uncertainty": "Although the common statin dose of 80 mg is known, individual contraindications or alternative causes cannot be determined automatically.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "The product/release formulation, contraindications/warnings, and evidence scope of the original FDA label, together with the identity of the S01 trial batch." }, { "item_id": "N31", "question_type": "Pooled discontinuations and denominators", "question": "Have group-specific exposure denominators, discontinuation definitions, and the composition of the trials pooled in the NIASPAN data been verified?", "needed": "Group-specific/exposure denominators, discontinuation definitions/reasons, the composition of the original trials, and collection data for the label's pooled analysis.", "role": "Supplementary", "role_reason": "Needed to avoid using pooled discontinuations from a different data source as an event rate for a particular FMD trial.", "application_exception": "Do not substitute the total of 402 for each group's n. The median of 16 weeks and the periods of 3 months each belong to different sources.", "criterion": "Link the pooled NIASPAN data—402 participants, a median of 16 weeks, and AE-related discontinuations of 16% versus 4%—to the product document, then distinguish what has been verified about group-specific exposure denominators, discontinuation collection/definitions, and the composition of the pooled trials.", "basis": "M19 §19.2.2–19.2.4, M03 §3.2.3; own application; M19 §19.1.2–19.2.4; own application; M19 §19.1.2–19.2.4, M04 §4.6.3; own application — individually adapted to pooled discontinuations and denominators. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare the label's pooling definitions/denominators; do not transfer its rates to S01, with a total of 66 participants and periods of 3 months each, or newly back-calculate person counts.", "current_reports": [ "S12" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The FDA label's evidence comprises 402 pooled participants and a median treatment duration of 16 weeks; AE-related discontinuations were 16% with nicotinic acid versus 4% with placebo. These are not period-specific event rates or discontinuation counts for S01, and no individual-group denominators are newly filled in.", "condition_status": "Partly verified", "status_reason": "The original pooled comparison and duration were verified, but details of the corresponding group-specific denominators and composition are absent from the retained summary.", "missingness": "Group-specific exposure denominators, the composition of the pooled trials, and discontinuation collection/definitions remain to be verified.", "uncertainty": "Do not newly calculate the numbers of people with events from rates and the overall n.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Group-specific/exposure denominators, discontinuation definitions/reasons, the composition of the original trials, and collection data for the label's pooled analysis." }, { "item_id": "N32", "question_type": "Long-term safety and vulnerable groups", "question": "Has long-term safety or safety in vulnerable groups beyond the current observations been directly verified?", "needed": "Data on long-term exposure, rare/serious events, and follow-up by underlying-disease/co-treatment strata for the same formulation/population.", "role": "Supplementary; essential for that extension", "role_reason": "Needed to avoid extending results from a short observation period and a restricted population to overall long-term safety.", "application_exception": "This narrow FMD question does not require every study of rare harms, and contraindications/risks are not interpreted as permission for self-medication.", "criterion": "Distinguish the FMD observations over periods of 3 months each from the median of 16 weeks in the prescribing document when considering long-term/rare harms, liver disease/metabolic risks, and interactions.", "basis": "Design-specific harm questions in M19 §19.2; details of temporal relationships are internally designed; M19 §19.1.2–19.2.4; own application; M03 §3.2.1–3.2.4; details of dose, persistence, and effect modification are internally designed — individually adapted to long-term safety and vulnerable groups. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Review exposure, timing, and vulnerable-group data separately for each question and, where needed, address rare events with an appropriate long-term observational or pharmacovigilance design.", "current_reports": [ "S01", "S12" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "Long-term safety in the main trial is unverified. The label's contraindications, metabolic/muscle risks, and pooled data with a median of 16 weeks are not used to verify safety in all vulnerable groups or during long-term exposure.", "condition_status": "Unverified", "status_reason": "The follow-up information by time period and population directly needed for the extended safety question is unavailable.", "missingness": "Data on long-term/rare events, disease/co-treatment strata, and time to onset/recovery remain to be verified.", "uncertainty": "Temporal ordering or a single label warning does not establish trial-specific rates of causally related events or individual safety.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Data on long-term exposure, rare/serious events, and follow-up by underlying-disease/co-treatment strata for the same formulation/population." }, { "item_id": "N33", "question_type": "Event-outcome extension not applicable", "question": "Are trials of myocardial infarction, stroke, or mortality a mandatory condition for this FMD question?", "needed": "If an extension to event outcomes is requested: direct event trials in the same population with the same intervention, event definitions, durations, and denominators.", "role": "Supplementary; the obligation to extend the question does not currently apply", "role_reason": "Needed to avoid automatically extending a surrogate difference to a clinical-event benefit.", "application_exception": "The selected question concerns FMD itself. Absence of an event trial does not justify deleting the FMD observation or treating Not applicable as evidence that material was acquired.", "criterion": "Separate the current question about FMD values from the distinct question of clinical-event prevention or mortality.", "basis": "M03 §3.2.4; own boundaries for extensions; M03 §3.2.4, M15 §15.3.1–15.3.3; adaptation of outcomes to each question is internally designed — individually adapted to the non-applicability of the event-outcome extension. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "If an event-outcome question is added, review its separate, independent boundaries and extract the FMD and event estimates separately.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The original endpoint is the surrogate brachial FMD. Prevention of myocardial infarction, stroke, or death is a separate question and is not imposed as a mandatory event-trial condition in this table. No event benefit is estimated.", "condition_status": "Not applicable (spaced label)", "status_reason": "The obligation to extend the narrow numerical question to event outcomes was treated as inapplicable. This does not mean that event evidence exists.", "missingness": "The current table does not review direct evidence of event prevention.", "uncertainty": "Improvement in FMD or lipids does not automatically answer the question of effects on clinical events.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "If an extension to event outcomes is requested: direct event trials in the same population with the same intervention, event definitions, durations, and denominators." }, { "item_id": "N34", "question_type": "Optimal-dose extension not applicable", "question": "Does the current question also address the optimal dose, persistence of effects, and effects in specific strata?", "needed": "If an extension is requested: direct dose comparisons, discontinuation/long-term follow-up, and prespecified plans/interactions by stratum.", "role": "Supplementary; the obligation to extend the question does not currently apply", "role_reason": "Needed to avoid determining the optimal dose, persistence of effects, or effects in all subgroups from a single main effect.", "application_exception": "The positive post hoc low-HDL finding in INEF is not used to establish an optimal dose or stratum-specific effects across CAD populations.", "criterion": "Distinguish the fixed comparison of 1500 mg over periods of 3 months each from extensions to dose response, persistence after discontinuation, and prespecified interactions by stratum.", "basis": "M03 §3.2.1–3.2.4; details of dose, persistence, and effect modification are internally designed — individually adapted to the non-applicability of the optimal-dose extension. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Set a separate question for each extension and link only data from direct dose, persistence, or stratum-specific designs to the corresponding estimate.", "current_reports": [ "S01", "S02" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The current table concerns the fixed add-on comparison of 1500 mg over periods of 3 months each. It does not require every study of the optimal dose, persistence after discontinuation, or effects by deficiency status, sex, or low-HDL stratum. This does not mean that direct evidence for these extensions has been acquired.", "condition_status": "Not applicable (spaced label)", "status_reason": "The obligation to extend the assessment to optimal dose, persistence, or strata outside its target was treated as inapplicable. Unverified actual exposure remains recorded in N04/N05.", "missingness": "Direct dose comparisons and persistence/stratum-specific effects remain unverified within the present scope.", "uncertainty": "The existence of a fixed target dose does not verify the optimal dose.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "If an extension is requested: direct dose comparisons, discontinuation/long-term follow-up, and prespecified plans/interactions by stratum." }, { "item_id": "N35", "question_type": "Plant-part condition not applicable", "question": "Is plant-part information needed for a drug question?", "needed": "Manufacturing-origin/quality data for the actual trial batch; separate identity information if a botanical ingredient is claimed.", "role": "Not applicable: plant-part condition for a non-botanical drug", "role_reason": "Needed to avoid imposing an unsupported plant-part axis on a question about a drug molecule.", "application_exception": "Manufacturing origin (source_origin) remains unverified and is distinguished from the not_applicable designation for plant-part information (plant_part).", "criterion": "Distinguish the unverified manufacturing origin of the nicotinic acid drug from the non-applicability of plant-part information.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — individually adapted to the non-applicability of the plant-part condition. This is not official methodological certification.", "condition_origin": "A specifically developed criterion designed with knowledge of the currently retained content. Not blinded, preregistered or officially certified.", "proposed_research": "Compare formulation-identity data; do not interpret the non-applicability of plant-part information as verification of a synthetic or fermentation origin.", "current_reports": [ "S01" ], "existence": "Links to the identity, exact location and values in the currently retained summary; separate from obtaining external documents.", "acquired_read": "Summary reading: the currently retained KO/EN summaries were actually read. External sources, registrations and older separate files were not read.", "observation": "The original plant-part information (plant_part) is marked not_applicable, while manufacturing origin (source_origin) has no value (null) and remains unverified. The plant-part condition does not apply to the nicotinic acid drug, and its manufacturing origin is not assigned arbitrarily.", "condition_status": "Not applicable (spaced label)", "status_reason": "The applicability exception for a non-botanical intervention was verified. This does not verify formulation quality or origin.", "missingness": "Manufacturing origin remains unverified under N02.", "uncertainty": "NA for plant-part information and unverified manufacturing origin are different statuses.", "review_date": "2026-10-05", "reading_status": "Original source unread · Retained summary read", "additional_material": "Manufacturing-origin/quality data for the actual trial batch; separate identity information if a botanical ingredient is claimed." } ], "reports": [ { "report_id": "S01", "title": "Philpott AC et al. Niacin improves lipid profile but not endothelial function in patients with coronary artery disease on high dose statin therapy. Atherosclerosis. 2013;226(2):453–458.", "url": "https://pubmed.ncbi.nlm.nih.gov/23174368/", "report_type": "Direct randomized crossover trial", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "PHILPOTT-NCT00150722", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "Total of 66 participants; analysis n unverified. Periods of 3 months each, with ER nicotinic acid 1500 mg/day and common atorvastatin 80 mg/day. Period-end values: 6.6 ± 4.8% versus 6.1 ± 4.9%, P=0.48. The type of ± and the paired CI are unverified; +0.5%p is the original descriptive arithmetic.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "PubMed article abstract and bibliographic page", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Decisive direct FMD result; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S01-M1", "url": "https://pubmed.ncbi.nlm.nih.gov/23174368/" } ], "links": [ { "label": "Official source", "url": "https://pubmed.ncbi.nlm.nih.gov/23174368/" } ] }, { "report_id": "S02", "title": "Warnholtz A et al. Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: results of the randomized, double-blind, placebo-controlled INEF study. Atherosclerosis. 2009;204(1):216–221.", "url": "https://pubmed.ncbi.nlm.nih.gov/18822413/", "report_type": "Adjacent randomized trial", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "INEF", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "107 participants/12 weeks. An FMD benefit in the overall cohort was not demonstrated; post hoc low-HDL changes were 3.25 versus 1.03%p/P=0.047. Group-specific n is unverified; the original 2.22%p arithmetic belongs to the post hoc context and is not direct replication.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "PubMed article abstract and bibliographic page", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Overall-cohort/post hoc context under different conditions; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S02-M1", "url": "https://pubmed.ncbi.nlm.nih.gov/18822413/" } ], "links": [ { "label": "Official source", "url": "https://pubmed.ncbi.nlm.nih.gov/18822413/" } ] }, { "report_id": "S03", "title": "Thoenes M et al. The effects of extended-release niacin on carotid intimal media thickness, endothelial function and inflammatory markers in patients with the metabolic syndrome. Int J Clin Pract. 2007;61(11):1942–1948.", "url": "https://pubmed.ncbi.nlm.nih.gov/17935553/", "report_type": "Report possibly from the same study family", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "METABOLIC-THOENES-VACCARI-POSSIBLE", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "S03/S04 are treated as possibly belonging to the same metabolic-syndrome study family. 50 participants/52 weeks; a 22% within-nicotinic-acid-group improvement/P<0.001. The between-group FMD contrast and CI are unverified; this finding is not used as a direct effect for the main comparison.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "PubMed article abstract and bibliographic page", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Within-group change in a different population over a different duration; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S03-M1", "url": "https://pubmed.ncbi.nlm.nih.gov/17935553/" } ], "links": [ { "label": "Official source", "url": "https://pubmed.ncbi.nlm.nih.gov/17935553/" } ] }, { "report_id": "S04", "title": "Vaccari CS et al. Efficacy of controlled-release niacin in treatment of metabolic syndrome: Correlation to surrogate markers of atherosclerosis, vascular reactivity, and inflammation. J Clin Lipidol. 2007;1:605–613.", "url": "https://pubmed.ncbi.nlm.nih.gov/21291702/", "report_type": "Report possibly from the same study family", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "METABOLIC-THOENES-VACCARI-POSSIBLE", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "This report may overlap with S03: its authors, population, dose, and 52-week design match. The family's within-group 22% is not re-extracted as a new independent between-group effect for this report, and the 50 participants are not counted again.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "PubMed article abstract and bibliographic page", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Possible overlap and comparison boundaries; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S04-M1", "url": "https://pubmed.ncbi.nlm.nih.gov/21291702/" } ], "links": [ { "label": "Official source", "url": "https://pubmed.ncbi.nlm.nih.gov/21291702/" } ] }, { "report_id": "S05", "title": "Chow DC et al. Short-term effects of extended-release niacin on endothelial function in HIV-infected patients on stable antiretroviral therapy. AIDS. 2010;24(7):1019–1023.", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC2925834/", "report_type": "Adjacent placebo-controlled HIV trial", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "CHOW-NCT00986986", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "Nicotinic acid: 10 participants/placebo: 9 participants; 12 weeks/maximum 1500 mg/day. Unadjusted change P=0.67; period-end comparison adjusted for baseline FMD/HDL-C P=0.048, with the adjusted CI unverified. This is contrasting context from a different population/analysis.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "Online full text of the article (author manuscript HTML)", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Different analyses before/after adjustment; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S05-M1", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC2925834/" } ], "links": [ { "label": "Official source", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC2925834/" } ] }, { "report_id": "S06", "title": "Dubé MP et al. Extended-Release Niacin Versus Fenofibrate in HIV-Infected Participants With Low High-Density Lipoprotein Cholesterol: Effects on Endothelial Function, Lipoproteins, and Inflammation.", "url": "https://pubmed.ncbi.nlm.nih.gov/25979307/", "report_type": "Adjacent trial with an active comparator/co-intervention", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "DUBE-NCT01426438", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "ER nicotinic acid+aspirin versus fenofibrate; 24 weeks. 99 randomized/74 complete scans (35/39). Within-group median changes: 0.6%p/P=0.28 versus 0.5%p/P=0.19; the between-group CI is unverified.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "PubMed article abstract and bibliographic page", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Different exposure/denominator and within-group analysis; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S06-M1", "url": "https://pubmed.ncbi.nlm.nih.gov/25979307/" } ], "links": [ { "label": "Official source", "url": "https://pubmed.ncbi.nlm.nih.gov/25979307/" } ] }, { "report_id": "S07", "title": "Kuvin JT et al. A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: enhanced vasorelaxation and increased endothelial nitric oxide synthase expression. Am Heart J. 2002;144(1):165–172.", "url": "https://pubmed.ncbi.nlm.nih.gov/12094204/", "report_type": "Mechanistic study report", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "KUVIN-HDL-ENOS", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "Mechanistic data on HDL, vasorelaxation, and eNOS. The currently retained bibliography/source locator is not promoted to numerical evidence of a direct FMD effect in a CAD crossover trial or of clinical-event prevention.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "PubMed article abstract and bibliographic page", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Not used as a direct FMD result; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S07-M1", "url": "https://pubmed.ncbi.nlm.nih.gov/12094204/" } ], "links": [ { "label": "Official source", "url": "https://pubmed.ncbi.nlm.nih.gov/12094204/" } ] }, { "report_id": "S08", "title": "Benjó AM et al. Accumulation of chylomicron remnants and impaired vascular reactivity occur in subjects with isolated low HDL cholesterol: effects of niacin treatment. Atherosclerosis. 2006;187:116–122.", "url": "https://pubmed.ncbi.nlm.nih.gov/16458316/", "report_type": "Adjacent evidence with a different formulation/population", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "BENJO-NO-FLUSH-LOW-HDL", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "The original source locator concerns a no-flush product and a population with isolated low HDL and no other CAD risk. Equivalence of the exact molecule/product to ER is not assumed, and the report is not combined with the main CAD add-on comparison.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "PubMed article abstract and bibliographic page", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Direct relevance of the molecule, formulation, and population is unverified; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S08-M1", "url": "https://pubmed.ncbi.nlm.nih.gov/16458316/" } ], "links": [ { "label": "Official source", "url": "https://pubmed.ncbi.nlm.nih.gov/16458316/" } ] }, { "report_id": "S09", "title": "Lee JMS et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function. A randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol. 2009;54:1787–1794.", "url": "https://www.jacc.org/doi/10.1016/j.jacc.2009.06.036", "report_type": "Report with unverified original results", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "LEE-MRI-MODIFIED-RELEASE", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "At the time, only the publisher metadata/indexed identity was verified; the full text was inaccessible, and the original FMD result could not be extracted. The MRI method or title is not copied as the S01 result.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "Publisher's article webpage (link target for the full text; not acquired at the time)", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Full text, measurements, and direct relevance are unverified; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S09-M1", "url": "https://www.jacc.org/doi/10.1016/j.jacc.2009.06.036" } ], "links": [ { "label": "Official source", "url": "https://www.jacc.org/doi/10.1016/j.jacc.2009.06.036" } ] }, { "report_id": "S10", "title": "Bregar U et al. Extended-release niacin/laropiprant improves endothelial function in patients after myocardial infarction.", "url": "https://pubmed.ncbi.nlm.nih.gov/23712600/", "report_type": "Adjacent combination-treatment article", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "BREGAR-NIACIN-LAROPIPRANT", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "A report of a positive FMD finding for an ER nicotinic acid/laropiprant combination after myocardial infarction. No new values absent from the retained bibliography/manuscript are invented, and the finding is not attributed to a main effect of nicotinic acid alone.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "PubMed article abstract and bibliographic page", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Boundaries of the positive combination-treatment finding; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S10-M1", "url": "https://pubmed.ncbi.nlm.nih.gov/23712600/" } ], "links": [ { "label": "Official source", "url": "https://pubmed.ncbi.nlm.nih.gov/23712600/" } ] }, { "report_id": "S11", "title": "Sorrentino SA et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy.", "url": "https://pubmed.ncbi.nlm.nih.gov/20026785/", "report_type": "Mechanistic/adjacent-population report", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "SORRENTINO-NCT00346970", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "A diabetes/healthy-population comparison and endothelial assays using isolated HDL are retained. These are not counted as direct results or independent replication of brachial FMD in the main CAD crossover trial.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "PubMed article abstract and bibliographic page", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Outcome distinct from direct FMD; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S11-M1", "url": "https://pubmed.ncbi.nlm.nih.gov/20026785/" } ], "links": [ { "label": "Official source", "url": "https://pubmed.ncbi.nlm.nih.gov/20026785/" } ] }, { "report_id": "S12", "title": "NIASPAN (niacin extended-release tablets), FDA prescribing information revised 09/2020.", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020381s054lbl.pdf", "report_type": "Regulatory product safety document", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "FDA-NIASPAN-POOLED-NOT-FMD-TRIAL", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "Flushing, liver injury, increased blood glucose/uric acid, muscle risks with statin co-treatment, and contraindications. Pooled data: 402 participants/median 16 weeks, with AE-related discontinuations of 16% versus 4%; these are not event rates from the main FMD trial. The main trial's product brand is unverified.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "Full PDF of the official FDA product prescribing information", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Safety context separate from efficacy; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S12-M1", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020381s054lbl.pdf" } ], "links": [ { "label": "Official source", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020381s054lbl.pdf" } ] }, { "report_id": "S13", "title": "ClinicalTrials.gov NCT00150722, linked by Philpott 2013.", "url": "https://clinicaltrials.gov/study/NCT00150722", "report_type": "Link to the direct trial's registration", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "PHILPOTT-NCT00150722", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "The NCT00150722 link was verified in S01, but only the registry shell was acquired at the time. The structured registration content on endpoint status, analysis, and sponsorship could not be read. External access was not attempted in this review either.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "ClinicalTrials.gov registration webpage (only the shell was acquired at the time)", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Registration content/SAP unverified; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S13-M1", "url": "https://clinicaltrials.gov/study/NCT00150722" } ], "links": [ { "label": "Official source", "url": "https://clinicaltrials.gov/study/NCT00150722" } ] }, { "report_id": "S14", "title": "ClinicalTrials.gov NCT01052311 — The Impact of Tredaptive on Flow-Mediated Dilation in Cardiac Patients.", "url": "https://clinicaltrials.gov/ct2/show/study/NCT01052311", "report_type": "Registration for a different combination treatment", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "NCT01052311", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "Actual enrollment: 8 participants; no results posted; terminated following the decision to withdraw the study drug from the market. No FMD values are filled in, and the record is not automatically merged into the same study family as S10.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "Official ClinicalTrials.gov registration web document", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Context of unposted results/termination; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S14-M1", "url": "https://clinicaltrials.gov/ct2/show/study/NCT01052311" } ], "links": [ { "label": "Official source", "url": "https://clinicaltrials.gov/ct2/show/study/NCT01052311" } ] }, { "report_id": "S16", "title": "Song S et al. Effect of Niacin on Carotid Atherosclerosis in Patients at Low-Density Lipoprotein-Cholesterol Goal but High Lipoprotein (a) Level: a 2-Year Follow-Up Study. J Lipid Atheroscler. 2019;8(1):58–66.", "url": "https://e-jla.org/DOIx.php?id=10.12997/jla.2019.8.1.58", "report_type": "Adjacent article with a different endpoint", "existence": "Original identifiers/URL and source locator in the retained bibliography", "acquired_read": "Summary reading: the currently retained summary was actually read. Access to external material was not attempted, and the material was neither acquired nor read in this review.", "study_family": "SONG-LPA-CAROTID-IMT", "independent_replication": "The direct Philpott original article and registration belong to the same study family. Adjacent evidence, mechanistic reports, other endpoints, combination interventions, and official safety documents are not newly counted as independent direct replications.", "observed_result": "A 2-year carotid IMT study in people who had reached their LDL target but had high Lp(a); the HTML was used for eligibility screening at the time. It does not substitute for the same FMD effect or for clinical-event outcomes.", "result_level": "Reuses the findings and limits in the retained summary attributed to this report; this is not a new verification of the external full text.", "materials": [ { "material_type": "Article webpage (link target for the full text)", "public_status": "No lookup in this review", "access_status": "Not attempted in this review", "acquired": false, "actually_read": "Unread", "as_of": "2026-10-05", "qualification": "Not used as direct FMD evidence; this link's original access level is distinct from reading the retained summary and leaving the external material unread in this review.", "material_id": "S16-M1", "url": "https://e-jla.org/DOIx.php?id=10.12997/jla.2019.8.1.58" } ], "links": [ { "label": "Official source", "url": "https://e-jla.org/DOIx.php?id=10.12997/jla.2019.8.1.58" } ] } ], "method_sources": [ { "id": "M03", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-03", "section": "§3.1, §3.2.1–3.2.3, MECIR C5/C7/C13", "official_principle": "Clearly record the question, eligibility criteria, and reasons for changes, and distinguish variations in the intervention.", "review_level": "Reuses the existing methods copy for 1585 and historical principles. This is not a new full-text methods review, application of an official tool, or certification." }, { "id": "M04", "version": "Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-04", "section": "§4.5, §4.6.1–4.6.3, MECIR C42", "official_principle": "Distinguish studies from reports and link them; do not omit a study solely because results were not reported.", "review_level": "Reuses the existing methods copy for 1585 and historical principles. This is not a new full-text methods review, application of an official tool, or certification." }, { "id": "M08", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-08", "section": "§8.1–8.2.3, Table 8.2.a", "official_principle": "Fix the outcome and effect of interest when reviewing randomization, deviations, missing data, measurement, and selective reporting.", "review_level": "Reuses the existing methods copy for 1585 and historical principles. This is not a new full-text methods review, application of an official tool, or certification." }, { "id": "M15", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-15", "section": "§15.2.4, §15.3.1–15.3.3", "official_principle": "Distinguish effect estimates, intervals, importance, and application. Sample size alone does not determine precision.", "review_level": "Reuses the existing methods copy for 1585 and historical principles. This is not a new full-text methods review, application of an official tool, or certification." }, { "id": "M19", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-19", "section": "§19.1.2, §19.2.1–19.2.4", "official_principle": "Questions about harms may require designs, populations, and follow-up different from those for efficacy. Case reports do not establish incidence.", "review_level": "Reuses the existing methods copy for 1585 and historical principles. This is not a new full-text methods review, application of an official tool, or certification." } ], "status_dictionary": { "Met": "The identity, original values, and attribution/interpretation boundaries for this condition were verified within the retained material. This is separate from sufficient evidence of efficacy or certification.", "Partly verified": "Some information has been linked, but actual material, comparisons, or details remain to be verified.", "Unverified": "The required analyses, values, or material remain unverified within the retained material that was read. This is distinct from 0 events, no effect, or incomplete preparation of the table.", "Conflicting data": "Preserves an actual discrepancy in the original data for the same item. This is distinct from differences between analyses.", "Not applicable": "A condition or an obligation to extend the inquiry outside the narrow assessment target does not apply. This is distinct from insufficient data.", "Not applicable (spaced label)": "Gray-display alias for Not applicable.", "Unread": "The external material was not read directly in this review. This is distinct from actually reading the retained summary.", "Review incomplete": "Individual review work for preparing the table remains unfinished. This is distinct from unverified data." }, "study_overlap": { "state": "Retains the original R1 single direct study family and the contexts of possible overlap/adjacent evidence; the total number of reports is not newly totaled as unique trials or participants.", "unique_trial_count": null, "unique_participant_count": null, "reason": "Retains the original R1 single direct study family and the contexts of possible overlap/adjacent evidence; the total number of reports is not newly totaled as unique trials or participants." }, "history": [ { "date": "2026-11-01", "kind": "Separation of the public view and materials", "view_version": "1.0", "change": "The public view and materials were prepared from the existing 35 items. No new clinical search, change in verification status, or scoring was performed." } ], "language": "en", "translation_date": "2026-11-01" }