{
  "title": "Oral extended-release nicotinic acid added to atorvastatin × Improvement in brachial FMD in adults with coronary artery disease",
  "criteria_version": "NGM-v3091-ER-NICOTINIC-ACID-CAD-ATORVASTATIN-CROSSOVER-FMD-1.2",
  "criteria_date": "2026-10-05",
  "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."
  },
  "schema_version": "chamgap-public-criteria-1.0",
  "condition_origin": "Chamgap’s own application conditions",
  "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    }
  ],
  "language": "en",
  "translation_date": "2026-11-01"
}