{ "title": "Folic acid — sole added active ingredient on common enalapril therapy × Reduction of first symptomatic stroke in Chinese adults with hypertension", "criteria_version": "NGM-v3107-FOLIC-ADDON-CSPPT-FIRST-STROKE-1.0", "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 original HTML bytes/SHA retained for 1585 and the principles from that time. No new full methodological text was read, no official tool was applied, and no certification was obtained in this review." }, { "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 and link studies and reports, and do not omit a study solely because its outcomes are not reported.", "review_level": "Reuses the original HTML bytes/SHA retained for 1585 and the principles from that time. No new full methodological text was read, no official tool was applied, and no certification was obtained in this review." }, { "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": "Hold the outcome and effect of interest fixed, then assess randomization, deviations, missing data, measurement and selective reporting.", "review_level": "Reuses the original HTML bytes/SHA retained for 1585 and the principles from that time. No new full methodological text was read, no official tool was applied, and no certification was obtained in this review." }, { "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 applicability. Sample size alone does not determine precision.", "review_level": "Reuses the original HTML bytes/SHA retained for 1585 and the principles from that time. No new full methodological text was read, no official tool was applied, and no certification was obtained in this review." }, { "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 efficacy questions. Case reports do not establish incidence.", "review_level": "Reuses the original HTML bytes/SHA retained for 1585 and the principles from that time. No new full methodological text was read, no official tool was applied, and no certification was obtained in this review." } ], "status_dictionary": { "Met": "The retained identity, values and interpretive boundaries of this criterion have been verified. This does not signify sufficiency of clinical efficacy/safety or certification.", "Partly verified": "Some dimensions of the data have been linked, but specific original sources, scope and comparisons remain unresolved.", "Unverified": "Required values, criteria or materials are lacking within the retained scope currently read. This does not mean an effect or event count of 0 or incomplete review of the table.", "Conflicting information": "A discrepancy for the same item is explicitly stated in the original retained manuscript. No arbitrary correction or substitution of denominators.", "Not applicable": "Not applicable as a requirement for the current narrow question. Not a substitute for external materials being unread or study families being unverified.", "Not applicable (spaced label)": "Display alias for Not applicable.", "Not read": "The relevant external original source has not been read in this review. Distinguished from reading the retained manuscript summary.", "Review incomplete": "Individual reviews for table creation remain to be completed. Distinguished from insufficient 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 comparison concerning first stroke is being asked about?", "needed": "The authoritative versions of the current claim, endpoint SOP and eligibility criteria, and a mapping to the original ID/URL.", "role": "Required", "role_reason": "Required to avoid merging other outcomes on the page into a single prevention claim.", "application_exception": "Recurrence, TIA, subarachnoid hemorrhage, silent stroke and death do not substitute for the primary endpoint.", "criterion": "Link the selected Chinese adults with hypertension, folic acid as the sole added ingredient, identical background therapy and time to the first symptomatic event to the original /ko/effect.", "basis": "Question clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to each question are internally designed; M03 §3.2.4; internally defined limits on extrapolation — an internal adaptation for the separate question. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Use an eligibility table for each question to classify recurrence, TIA, silent events and composite cardiovascular events separately, and compare only reports of first events." }, { "item_id": "N02", "question_type": "Added active ingredient", "question": "Was folic acid the only difference between randomized groups?", "needed": "Actual prescriptions by arm, the policy permitting background medication and a table of the common product composition.", "role": "Required", "role_reason": "Required to distinguish the contributions of common therapy and the selected intervention.", "application_exception": "Do not extrapolate to B-vitamin combinations that also differ in active ingredients other than folic acid, or to folic acid monotherapy without background treatment.", "criterion": "Distinguish the addition of folic acid 0.8 mg from enalapril common to both arms, and indicate whether other active ingredients changed.", "basis": "M03 §3.2.2–3.2.3; reverse-direction flagging and adaptations of checks are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — an internal adaptation for the added active ingredient. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Use a table of intervention components by arm to compare the sole added active ingredient and common therapy, and keep results from other combination products separate." }, { "item_id": "N03", "question_type": "Manufacturing identity", "question": "Have the salt, release type, batch and raw material been verified?", "needed": "Manufacturing specifications for the trial product, batch certificates, raw material and salt/release type, and the complete excipient list.", "role": "Required", "role_reason": "Needed to prevent automatic extrapolation of evidence from different formulations.", "application_exception": "Do not substitute folinic acid or 5-MTHF. Do not conflate an unreported salt designation with an unverified active ingredient when the ingredient has been verified.", "criterion": "Separate the verified folic acid and common enalapril maleate from the unverified raw material, separate folic acid salt, release type, batch/purity and excipients.", "basis": "M03 §3.2.2–3.2.3; reverse-direction flagging and adaptations of checks are internally designed — an internal adaptation for manufacturing identity. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Link historical trial product documents to the actual formulations in each arm, and separately review whether the trial products are identical to current products with different doses." }, { "item_id": "N04", "question_type": "Dose and formulation", "question": "What are the daily dose and capsule blinding method?", "needed": "Actual trial medication administration instructions, tablet/capsule appearance specifications and individual medication records.", "role": "Required", "role_reason": "Required to interpret the identity of actual exposure and blinding of measurement.", "application_exception": "Do not replace 0.8 mg with the dose in the warning document for the 5 mg product. Do not confuse capsule blinding with the active preparation itself being a capsule.", "criterion": "Link the nominal oral dose given 1 time per 1 day to blinding of tablets in matching capsules, without recasting it as actual individual intake.", "basis": "M03 §3.2.2–3.2.3; reverse-direction flagging and adaptations of checks are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application — an internal adaptation for dose and formulation. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Compare protocol administration instructions with dispensing records to distinguish nominal dose, administration frequency and blinding method from actual medication use." }, { "item_id": "N05", "question_type": "Planned and observed duration", "question": "Are the planned 5 years and median follow-up the same?", "needed": "Planned follow-up duration, actual follow-up distribution and individual randomization/censoring/end dates.", "role": "Required", "role_reason": "Required to interpret time-to-event estimates and the observation period underlying absolute event values.", "application_exception": "Do not arbitrarily establish a new minimum required duration. Do not automatically classify a difference between planned duration and the median as Conflicting information.", "criterion": "Retain the planned 5 years, median follow-up of 4.5 years/IQR and 3 weeks of run-in as separate time scales.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to each question are internally designed; M03 §3.2.1–3.2.4; details of dose, duration and effect modification are internally designed — an internal adaptation for planned and observed duration. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Compare the plan with the actual follow-up flow over time, without asserting that this was a study of participants completing a fixed 4.5 years or exposure for 5 years." }, { "item_id": "N06", "question_type": "Participant selection", "question": "Who were the participants who passed run-in?", "needed": "Inclusion and exclusion criteria, recruitment areas, selection flow before and after run-in, and reasons for exclusion.", "role": "Required", "role_reason": "Required to reveal differences in efficacy applicability and safety arising from selection.", "application_exception": "Do not recast run-in selection as proof of no effect or a definitive magnitude of bias. Children and patients with prior stroke or MI are outside the included population.", "criterion": "Verify Chinese adults aged 45–75 with hypertension, no history of stroke/MI, and run-in selection for tolerability/adherence.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; design considerations in M19 §19.2.2–19.2.4; detailed recording of confounding is internally designed — an internal adaptation for participant selection. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Reconstruct the flow from recruitment to randomization to document differences between the population selected for tolerability/adherence and the general population with hypertension." }, { "item_id": "N07", "question_type": "Prior TIA", "question": "Was prior TIA separately excluded?", "needed": "The original eligibility wording on TIA history, diagnosis and timing, and the baseline history table.", "role": "Required", "role_reason": "Needed to avoid mixing selection based on medical history with outcome definitions.", "application_exception": "Do not infer that patients with prior TIA must have been excluded merely because TIA was excluded from the primary endpoint.", "criterion": "Distinguish exclusion of prior stroke from the unverified separate TIA history criterion.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; question clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed — an internal adaptation for prior TIA. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Compare event definitions and medical-history criteria in the original protocol to separate TIA eligibility criteria from its exclusion as an outcome." }, { "item_id": "N08", "question_type": "Nutrition and setting", "question": "Were a setting without mandatory fortification and a diagnosis of deficiency distinguished?", "needed": "Baseline nutritional distributions, diagnostic criteria, individual dietary/fortification/concurrent supplement records and regional policies.", "role": "Required", "role_reason": "Needed to distinguish the applicability limits of the nutritional setting from interpretation of dose/population.", "application_exception": "Do not use a single median to assert deficiency in everyone or establish the same effect in other countries with fortification.", "criterion": "Separate the trial-era fortification setting and baseline folate distribution from correction of diagnosed deficiency or individual dietary intake.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.1–3.2.4; details of dose, duration and effect modification are internally designed — an internal adaptation for nutrition and setting. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Record baseline nutritional status and setting by stratum, and predefine and compare diagnosed deficiency status and differences in applicability across fortification settings." }, { "item_id": "N09", "question_type": "Common background therapy", "question": "Do aggregate blood pressure and medication use imply that they were identical for each individual?", "needed": "Background medication policies by arm, medication changes and doses at each visit, and records of additional B-vitamin/supplement use.", "role": "Required", "role_reason": "Required to distinguish the additional effect of the selected intervention from concurrent treatment.", "application_exception": "Do not require identical changes in every individual as a condition of validity. Do not use similar mean blood pressure as evidence that confounding has been completely removed.", "criterion": "Indicate separately the common policy, aggregates by arm and unverified individual medication changes.", "basis": "M03 §3.2.2–3.2.3; reverse-direction flagging and adaptations of checks are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; design considerations in M19 §19.2.2–19.2.4; detailed recording of confounding is internally designed — an internal adaptation for common background therapy. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "While retaining aggregate blood pressure and concomitant medication rates, compare medication and total exposure at each visit to distinguish attribution to assignment effects from attribution to adherence effects." }, { "item_id": "N10", "question_type": "Allocation and blinding", "question": "What level of detail is available on the actual design and allocation procedures?", "needed": "Original documentation of random sequence generation, stratification/concealment, implementation of allocation and blinding procedures.", "role": "Required", "role_reason": "Required to verify the actual design for the causal efficacy question.", "application_exception": "Do not impose a crossover/cluster design on the question addressed by the verified parallel comparison. Do not recast an unverified detail as a confirmed allocation error.", "criterion": "Distinguish the report of a multicenter parallel randomized double-blind trial from the level of detail retained on specific allocation/concealment and assessment procedures.", "basis": "M08 §8.1–8.2.3; internal application; M08 Table 8.2.a, M03 §3.2.4; internal application — an internal adaptation for allocation and blinding. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Compare the original protocol/SAP with allocation implementation records, and document allocation, concealment and blinding relevant to the actual outcome item by item." }, { "item_id": "N11", "question_type": "Clinical endpoint", "question": "What are the first symptomatic event and the excluded events?", "needed": "Endpoint SOP, event classification, case adjudication documents and definitions of other endpoints.", "role": "Required", "role_reason": "Required to define the measurement boundaries of the selected outcome and prevent clinical extrapolation.", "application_exception": "Do not extend benefit to all-cause mortality, every stroke subtype or silent lesions merely because this is a hard endpoint.", "criterion": "Indicate time to the first fatal/nonfatal symptomatic event and exclusion of subarachnoid hemorrhage and silent events within the scope of the original SOP.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to each question are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application; M03 §3.2.4; internally defined limits on extrapolation — an internal adaptation for the clinical endpoint. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Use an event definition table to compare included/excluded types and whether an event was the first, and prevent automatic substitution of biomarkers or composite events." }, { "item_id": "N12", "question_type": "Event adjudication", "question": "How were symptomatic events assessed?", "needed": "Assessor blinding, committee operations, imaging/medical records and information on disagreements in event adjudication.", "role": "Required", "role_reason": "Needed to distinguish differences in clinical event detection from the actual effect.", "application_exception": "Do not recast the description of an independent committee as independent clinical certification in this review.", "criterion": "Link the independent event adjudication committee, clinical records/imaging and SOP at the level verified.", "basis": "M08 Table 8.2.a, M03 §3.2.4; internal application; M03 §3.2.4, M15 §15.3.1–15.3.3; adaptations of outcomes to each question are internally designed — an internal adaptation for event adjudication. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Compare event adjudication procedures and diagnostic/verification pathways by arm, and record detection differences and the scope of unverified information." }, { "item_id": "N13", "question_type": "Randomized denominators", "question": "Do primary outcome event counts correspond to randomized denominators?", "needed": "CONSORT allocation flow, the primary outcome table, numbers analyzed/experiencing events by arm and censoring records.", "role": "Required", "role_reason": "Required to avoid confusing events, people and analysis populations.", "application_exception": "Do not arbitrarily change the verified total number randomized because of conflicting genotype totals.", "criterion": "Link the total of 20,702 participants, folic acid/control counts of 10,348/10,354 and first events of 282/355 to the same primary analysis.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations by study design are internally designed; M08 §8.2.2, M15 §15.3.1; internal application — an internal adaptation for randomized denominators. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Link randomized, analysis, event and safety sets separately, and compare the unit and denominator for each outcome." }, { "item_id": "N14", "question_type": "Assignment effect and censoring", "question": "What do ITT and censoring at the last observation estimate?", "needed": "Primary analysis SAP, individual event/censoring data, handling of deaths and loss to follow-up, and sensitivity analyses.", "role": "Required", "role_reason": "Required to distinguish the effect of assignment from time-to-event interpretation.", "application_exception": "Do not assume that the term ITT resolves all missing-data issues. Do not newly calculate person-years or fixed-time risks.", "criterion": "Indicate together the primary analysis according to randomized assignment, time to the first event and censoring of those lost to follow-up at the last confirmed observation.", "basis": "M08 §8.2.2, M15 §15.3.1; internal application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations by study design are internally designed — an internal adaptation for assignment effect and censoring. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Compare the effect of interest and handling of censoring in the original SAP, and distinguish assignment effects, adherence effects and competing-risk analyses." }, { "item_id": "N15", "question_type": "PP and loss to follow-up", "question": "Were PP exclusions and medication discontinuations combined as missing data?", "needed": "Medication use by arm, major violations, reasons for discontinuation, missed follow-up visits and PP/ITT flow.", "role": "Required", "role_reason": "Needed to avoid mixing adherence effects with loss of reported outcome data.", "application_exception": "Do not substitute PP results for the primary ITT effect or newly calculate the number with missing data from the number of PP exclusions.", "criterion": "Distinguish the PP criteria of ≥70% medication adherence/no major violations from PP participant counts and loss to follow-up.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations by study design are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application — an internal adaptation for PP and loss to follow-up. Not official certification of the method.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Link medication adherence violations, medication discontinuation and loss to follow-up as different events in the participant flow, and compare them with their handling in the original analysis." }, { "item_id": "N16", "question_type": "Primary HR and interval", "question": "Which analyses produced HR 0.79 and the P value?", "needed": "Original Cox/log-rank results tables, SAP, adjusted analyses and model diagnostic documents.", "role": "Required", "role_reason": "Required to interpret the reported measure and level of precision.", "application_exception": "Do not convert the HR to an RR or extrapolate it to the same absolute effect over every time period.", "criterion": "Attribute the unadjusted Cox HR, 95% CI and log-rank P to the relevant first-event question.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M15 §15.3.1–15.3.3; internal application — internal adaptation for the primary HR and interval. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Cross-check the analysis name, adjustment, censoring and measure for the reported values, and display the HR separately from cumulative risk ratios/absolute differences." }, { "item_id": "N17", "question_type": "Absolute difference and NNT", "question": "Were the earlier simple absolute difference and the paper's NNT distinguished?", "needed": "Original event tables, the paper's NNT calculation method, censoring-adjusted risks and historical calculation records.", "role": "Required", "role_reason": "Required for relative/absolute interpretation of effect size and preservation of historical calculations.", "application_exception": "A simple difference in proportions is not a fixed-time risk difference recalculated with adjustment for censoring. Do not correct 142.154 to the paper's 141 or automatically classify the numerical difference as conflicting information.", "criterion": "Preserve the existing simple difference in event proportions and its reciprocal separately from the paper's 4.5-year NNT as values derived by different methods.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; 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 — internal adaptation for absolute difference and NNT. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Link the paper's reported values and retained historical descriptive calculations to their respective sources, and specify whether they were reproduced using individual-level data and what censoring assumptions were used." }, { "item_id": "N18", "question_type": "Clinical importance", "question": "Was a universal MCID or the planned effect adopted as a new criterion?", "needed": "Original evidence for clinical importance, assumptions about the planned effect, and documents interpreting the reported CI and absolute event difference.", "role": "Required", "role_reason": "Needed to distinguish statistical significance and intervals from clinical importance.", "application_exception": "Do not newly assign C1 or sufficiency solely because the CI excludes 1. Do not arbitrarily require a minimum n, duration or number of trials.", "criterion": "Distinguish the original interpretation of importance from an unverified universal MCID, and do not create new effect grades or numerical criteria.", "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; design-specific adaptations are internally designed — internal adaptation for clinical importance. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Collect endpoint-specific evidence of importance and link it to the original interpretation, separating design assumptions, statistical significance and importance for decision-making." }, { "item_id": "N19", "question_type": "Stroke subtypes", "question": "Were ischemic and hemorrhagic values counted as independent replications?", "needed": "Original subtype event tables, definitions, denominators, analysis plans and records of unclassified subtypes.", "role": "Required", "role_reason": "Needed to prevent selective use of favorable subtypes from obscuring the full set of gaps.", "application_exception": "Do not add subtypes as independent trials or new participants. Do not interpret nonsignificance for hemorrhagic stroke as an effect of 0 or equivalence.", "criterion": "Preserve subtypes, findings of no detected difference and unverified subtypes within the same first-event family, regardless of direction.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; the distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed — internal adaptation for stroke subtypes. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Link total first events with their subtypes, indicate participant/event overlap and the analytical hierarchy, and do not extend them to separate clinical questions." }, { "item_id": "N20", "question_type": "Fatal stroke and mortality outcomes", "question": "Were the 18 versus 10 events and nonsignificance for mortality preserved?", "needed": "Fatal stroke definitions, HR/CI, original event tables and all-cause mortality results tables.", "role": "Required", "role_reason": "Required to preserve unfavorable values and boundaries on interpretation of different clinical events.", "application_exception": "Do not extend the reduction in total first strokes to a reduction in fatal stroke or all-cause mortality. Do not convert nonsignificance into equivalence.", "criterion": "Separate the unfavorable fatal stroke event counts, unverified precision and nonsignificant mortality results from total first events.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M03 §3.2.4; internally defined limits on extension; M15 §15.3.1–15.3.3; internal application — internal adaptation for fatal stroke and mortality outcomes. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Link the primary endpoint, fatal stroke suboutcome and all-cause mortality by their hierarchy, and record unfavorable findings/nonsignificance as reported in the sources." }, { "item_id": "N21", "question_type": "Conflicting genotype denominators", "question": "Do the genotype participant counts in Figure 1 and Table 1 agree?", "needed": "The original Figure 1 image, original genotype tables in Table 1, errata and definitions for participant counts.", "role": "Required", "role_reason": "Required to preserve the original scope without concealing conflicting subgroup denominators.", "application_exception": "The conflicting values are absent from the current retained summaries, so do not use old numerical IDs to fill in arbitrary participant counts. The overall randomized denominator and genotype denominators are distinct.", "criterion": "Preserve the discrepancy in counts for the same genotype specified in the manuscript, and do not arbitrarily replace the total randomized denominator.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed — internal adaptation for conflicting genotype denominators. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Compare the original figure/table and counting definitions side by side, recording where discrepancies occur, differences between recruited/randomized sets and official corrections." }, { "item_id": "N22", "question_type": "Effect modification", "question": "Does interaction P=0.16 establish genotype-specific optimal doses?", "needed": "Prespecified subgroup plans, denominators by genotype/folate stratum, separate HR/CI estimates and interaction analysis tables.", "role": "Supplementary; required for claims extending to genotype or nutrition", "role_reason": "Needed to prevent extension of the primary effect to effect modification by population/dose.", "application_exception": "A nonsignificant interaction does not prove equivalent effects in all groups. Do not determine genotype-specific optimal doses from a trial of one dose.", "criterion": "Distinguish the verification levels for MTHFR/folate interactions, subgroup denominators, prespecified plans and separate effect estimates.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed; M15 §15.3.1–15.3.3; internal application — internal adaptation for effect modification. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Cross-check interactions together with stratum-specific estimates, and record prespecification, multiple testing and denominator conflicts separately from claims about optimal doses." }, { "item_id": "N23", "question_type": "Planning and public registration", "question": "Are the protocol date and public registration the same event?", "needed": "Initial/revised protocols, SAP, documents on the start of recruitment and the full original registry history.", "role": "Required", "role_reason": "Required to distinguish the scope of verification of selective reporting from documented events.", "application_exception": "Do not elevate the date statement in S08 to a finding based on reading the full original S04 registry record. Do not equate original sources not having been obtained with nonregistration.", "criterion": "Link the initial protocol, the start of recruitment and the public registration date stated in the subsequent paper as events attributed to their respective sources.", "basis": "M08 Table 8.2.a, M04 §4.6.3; internal application; M04 §4.5, §4.6.3; limits on the current transformation of materials follow the user's scope and internal design — internal adaptation for planning and public registration. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Place dates and document versions on a timeline, and compare endpoints, analyses and reasons for changes to distinguish prior planning from public registration." }, { "item_id": "N24", "question_type": "Early stopping for benefit", "question": "Has the scope of decision-making on early stopping been verified?", "needed": "Interim analysis plans, stopping boundaries, data monitoring committee records and final estimates/SAP.", "role": "Required", "role_reason": "Required to distinguish the scope of planned analyses from reports of actual termination.", "application_exception": "Do not conclude that the benefit is false because the trial stopped early, or apply a new deduction to the original grade/effect.", "criterion": "Separate the reported early stopping for benefit from unverified planned interim analyses, stopping criteria and actual decisions.", "basis": "M08 Table 8.2.a, M04 §4.6.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed — internal adaptation for early stopping for benefit. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Compare prespecified stopping rules with actual interim analyses and termination decisions, recording implications for estimation/reporting and unverified items." }, { "item_id": "N25", "question_type": "Data lock and change history", "question": "Have the full registry history and data lock been verified?", "needed": "Original registry change history, initial/final SAP, final data lock and change approval records.", "role": "Required", "role_reason": "Needed to retain the scope of unchecked prior planning and analytical choices.", "application_exception": "Do not convert missing materials into established endpoint changes or selective reporting.", "criterion": "Distinguish the retained existence of initial planning from the unverified full history/data lock.", "basis": "M08 Table 8.2.a, M04 §4.6.3; internal application; M04 §4.5, §4.6.3; limits on the current transformation of materials follow the user's scope and internal design — internal adaptation for data lock and change history. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Link registry, plan and data-lock versions, and record actual primary-endpoint/analysis changes and unchecked portions for each document." }, { "item_id": "N26", "question_type": "CSPPT family", "question": "Were the original trial, protocol and safety tables grouped into one family?", "needed": "DOI/PMID, registry and report links, and family tables by cohort/participants and outcome/time point.", "role": "Required", "role_reason": "Required to prevent double-counting reports, studies and replications of harm findings.", "application_exception": "Do not add safety tables, the original paper, registry records and subsequent reports from the same family as separate replications or unique events.", "criterion": "Distinguish the original CSPPT trial, related documents and subsequent analyses from separate candidates/reviews.", "basis": "The distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M04 §4.6.1–4.6.2; adaptation for harm data is internally designed — internal adaptation for the CSPPT family. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Create a crosswalk of report identifiers and trial/participant links so that repeat citations of one CSPPT are not counted as independent replications or independent harm events." }, { "item_id": "N27", "question_type": "Review evidence map", "question": "Were the review's 21 RCTs and dietary observations counted as direct replications?", "needed": "Trials included in reviews, interventions/populations/endpoints, source-specific effect tables and links to repeat citations of CSPPT.", "role": "Required", "role_reason": "Needed to preserve differences and overlap between studies at the level verified.", "application_exception": "Do not repurpose a review average or the number of trials in its title as direct replications or a new participant denominator.", "criterion": "Display the composition/mixed scope of reviews separately from eligible families for the direct single-add-on intervention.", "basis": "The distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed — internal adaptation for the review evidence map. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Cross-check included trials in individual eligibility tables, separating B-vitamin combinations, different populations and dietary observations, and flag CSPPT overlap." }, { "item_id": "N28", "question_type": "Registered candidate results", "question": "Have the final direct results of the two CSPPT2 candidates been verified?", "needed": "Complete registry records/change histories for NCT04974138 and NCT04974151, final first-stroke results and actual populations/interventions/denominators.", "role": "Required", "role_reason": "Needed to prevent unpublished/registered candidates from being automatically counted as replications.", "application_exception": "The identities of two candidates do not mean 2 new eligible completed trials. Do not upgrade the original access_level metadata_shell_only to reading of the full record.", "criterion": "Distinguish the CC/CT and TT registration identities from unverified final direct results/current progress status.", "basis": "M04 §4.5, §4.6.3; limits on the current transformation of materials follow the user's scope and internal design; the distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — internal adaptation for registered candidate results. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Track the two candidates by their registration identities, but link them to the original family only after cross-checking the final reports' eligible questions, overlap and actual results." }, { "item_id": "N29", "question_type": "Subsequent report identity", "question": "Does the discovered S12 title establish a new direct effect?", "needed": "The original S12 report, publication identity, cohort/time points, outcomes and materials linking it to CSPPT.", "role": "Required", "role_reason": "Needed to distinguish the existence of an additional report from verification of its actual contents.", "application_exception": "Do not elevate discovery of a title to reading of the full text, a new direct effect or an independent confirmatory trial.", "criterion": "Distinguish the subsequent lifestyle report's identity in search metadata from its unverified detailed results.", "basis": "M04 §4.5, §4.6.3; limits on the current transformation of materials follow the user's scope and internal design; the distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application; data collection/selection principles in M04 §4.5–4.6; separation of access and reading, and hyperlink conventions, are internally designed — internal adaptation for subsequent report identity. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Cross-check the subsequent report's question, data level and family so that it is not mistaken for independent replication of the original trial or a new primary effect." }, { "item_id": "N30", "question_type": "Current and historical reading", "question": "Were reading retained summaries and reading original sources distinguished?", "needed": "Each report's original citation, actual access records/original bytes, and locations and dates of reading.", "role": "Required", "role_reason": "Required to accurately connect the user's summary-reading links with the verification status of the materials.", "application_exception": "Do not retrospectively count historical full-text reading as a success in this review, or label an unattempted access as an access failure.", "criterion": "Record actual reading of the current retained summaries separately from each report's historical access_level and the current status that access to original sources was not attempted and those sources were not read.", "basis": "Data collection/selection principles in M04 §4.5–4.6; separation of access and reading, and hyperlink conventions, are internally designed — internal adaptation for current and historical reading. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Separate summaries from original papers/registry records in the materials registry, and update a material's current reading record only when that original source has been read." }, { "item_id": "N31", "question_type": "Search and verification scope", "question": "Were the 2026-09-15 cutoff and this review date distinguished?", "needed": "Historical search/selection logs, the cutoff date and records of the currently authorized search/correction scope.", "role": "Required", "role_reason": "Required to retain the scope to which statements of absence or insufficiency apply.", "application_exception": "Do not label the absence of a new search as 0 human studies, absence of all unpublished studies or complete verification of the latest evidence.", "criterion": "Distinguish the original evidence cutoff, original review date, this table's review date and the fact that separate search logs were not read.", "basis": "M04 §4.5, §4.6.3; limits on the current transformation of materials follow the user's scope and internal design; data collection/selection principles in M04 §4.5–4.6; separation of access and reading, and hyperlink conventions, are internally designed — internal adaptation for search and verification scope. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Link the scope and dates of search/selection logs to publication, registration and unverified items, distinguishing transformation of retained materials from a complete up-to-date search." }, { "item_id": "N32", "question_type": "Funding and competing interests", "question": "Was AUSA support double-counted under independence and bias?", "needed": "Original documents on study funding, product provision, author disclosures/consulting, institutions/roles and competing interests in related reports.", "role": "Supplementary; required for a claim of independence", "role_reason": "Needed to assess claims and attribution of independent funding and replication.", "application_exception": "Do not automatically exclude results because competing interests exist, or assign I1 as a new judgment in this review.", "criterion": "Preserve mixed public, private and manufacturer funding, product provision, author relationships and the attribution of the original I1.", "basis": "Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not warrant all of these detailed items; the distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application — internal adaptation for funding and competing interests. This is not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Link funding, product/analytical roles and author relationships for each report, separating verified and unverified aspects of independence." }, { "item_id": "N33", "question_type": "Safety population", "question": "What are the safety denominators and the scope of event collection?", "needed": "Safety tables; definitions of analysis populations; collection at each visit; exposure time; and the flow of discontinuation/follow-up.", "role": "Supplementary; required to interpret harm frequency", "role_reason": "Needed to distinguish denominators and the scope of collection for efficacy and harms.", "application_exception": "Do not classify everyone omitted from the safety population as event-free or as having missing outcomes. Do not remove the efficacy effect.", "criterion": "Distinguish the safety analysis population, people/events, duration and collection/reporting limitations from the population randomized for efficacy analysis.", "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions internally designed; M19 §19.2 on harm questions by design; details of temporal relationships designed here; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application — internally designed adaptation for the safety population. Not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Compare the safety population and event collection system against the original tables, and separately link affected people/event counts, exposure time and loss to follow-up." }, { "item_id": "N34", "question_type": "GI and cough comparisons", "question": "Does nonsignificance for people with gastrointestinal events and cough mean no risk?", "needed": "Original AE tables; event/person definitions; background medication/collection by arm; CIs and discontinuation data.", "role": "Supplementary; required for claims comparing safety", "role_reason": "Needed to distinguish the scope of statements about harms actually compared, signals and causation.", "application_exception": "The comparison is on common enalapril therapy; do not establish folic acid as the cause of all reported cough. Do not interpret nonsignificance as equivalent safety.", "criterion": "Preserve the reported numbers of people, P values and interpretive limits of the comparison on the same common treatment.", "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions internally designed; M19 §19.2.2–19.2.4, M03 §3.2.3; internal application; design considerations in M19 §19.2.2–19.2.4; detailed recording of confounding designed here; Chamgap’s own interpretive boundaries. References M19 principles, without applying an official causality tool — internally designed adaptation for GI and cough comparisons. Not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Attribute the comparison values in the original table to distinguish background enalapril from added folic acid, and describe nonsignificance, equivalence and individual causation separately." }, { "item_id": "N35", "question_type": "SAEs and missing reports", "question": "Have the unique number of people with SAEs and discontinuation been verified?", "needed": "Unique people with serious AEs; event counts; overlap; exposure/reasons for discontinuation; and data on unreported events.", "role": "Supplementary; required to interpret overall harms/discontinuation", "role_reason": "Needed to avoid converting missing reports into absence of events.", "application_exception": "Do not combine PP exclusions, drug discontinuation, loss to follow-up and SAEs into the same count or calculate unavailable frequencies.", "criterion": "Distinguish unverified totals of unique people with serious AEs and unverified discontinuation/missing reports from 0.", "basis": "M19 §19.1.2–19.2.4; detailed distinctions internally designed; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application — internally designed adaptation for SAEs and missing reports. Not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Link the original safety tables and participant flow, and separately compare serious events, affected people, discontinuation/medication violations and loss to follow-up." }, { "item_id": "N36", "question_type": "Separate product warnings", "question": "Was the 5 mg SmPC used as the incidence estimate for the 0.8 mg trial?", "needed": "Original SmPC version; product/dose specifications; warning text; and evidence of identity with the trial product.", "role": "Supplementary; required to interpret product/special-population safety", "role_reason": "Needed to maintain the safety boundaries of a document for a different product.", "application_exception": "Do not convert the partial search extract from S05 ODS into full-text verification of all S11 warnings. Do not use the 5 mg warnings as personal instructions for taking 0.8 mg.", "criterion": "Distinguish the separate 5 mg product warnings, the current trial formulation/dose and the actual incidence of harm.", "basis": "M19 §19.1.2–19.2.4; internal application; Chamgap’s own interpretive boundaries. References M19 principles, without applying an official causality tool; M03 §3.2.2–3.2.3; reverse-direction flagging and adaptations of checks are internally designed — internally designed adaptation for separate product warnings. Not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Compare the population/dose and medication context in the product document with the trial to separate official warnings from trial incidence/individual safety." }, { "item_id": "N37", "question_type": "Vulnerable populations and long-term scope", "question": "Does this also answer questions about pregnancy, severe disease and higher doses?", "needed": "Original inclusion/exclusion criteria; hepatic/renal measures; and data for pregnancy/lactation, children and high-dose/long-term follow-up.", "role": "Supplementary; required for extension to vulnerable populations/long-term use", "role_reason": "Needed to avoid extending results from a selected population to overall safety/prevention.", "application_exception": "Do not require studies of every rare event/vulnerable population for the current narrow first-stroke question. Do not use unverified status to deny an effect in that population.", "criterion": "Link the populations excluded from the trial or unverified to the scope of missing direct information on longer-term/higher-dose use.", "basis": "M03 §3.2.1; detailed population criteria designed here; M19 §19.1.2–19.2.4; internal application; M03 §3.2.1–3.2.4; details of dose, duration and effect modification designed here — internally designed adaptation for vulnerable populations and long-term scope. Not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Compare the selected population with excluded and vulnerable populations, and record the data needed for each separate question." }, { "item_id": "N38", "question_type": "Optimal dose and effects after discontinuation", "question": "Are studies of optimal dose and effects after discontinuation required for the original question?", "needed": "If an expanded question is requested: direct comparisons of active doses, follow-up after discontinuation and prespecified subgroup data.", "role": "Not applicable (current primary question); required for extension", "role_reason": "A supplementary boundary to avoid requiring unnecessary extension studies for the narrow original question.", "application_exception": "Even with the original dose/observed effect, do not claim an optimal dose or lifelong effects. Future extension claims require newly adapted criteria.", "criterion": "Distinguish the current question about the observation period for 0.8 mg add-on therapy from dose optimization and persistence after discontinuation.", "basis": "M03 §3.2.1–3.2.4; details of dose, duration and effect modification designed here; question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules designed here — internally designed adaptation for optimal dose and effects after discontinuation. Not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Define the expanded question separately, then examine actual results and the scope of estimates through direct dose comparisons or follow-up designs after discontinuation." }, { "item_id": "N39", "question_type": "Replication across studies", "question": "Are comparisons across studies required for the current single direct trial family?", "needed": "Families, conditions and results of other independent direct trials/safety events, and data for comparing included trials.", "role": "Not applicable (currently one direct trial family); required for replication claims", "role_reason": "A supplementary boundary to avoid arbitrarily requiring comparisons across multiple studies within one verified family.", "application_exception": "Unverified registered candidates/reviews are not NA. Distinguish nonapplicability of comparisons across studies within the current scope from separate gaps in replication data.", "criterion": "Distinguish results from the one verified direct CSPPT family from unconfirmed candidates/reviews, and do not automatically generate heterogeneity or replication counts.", "basis": "M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage applied here; M04 §4.6.1–4.6.2; adaptation of harm data designed here — internally designed adaptation for replication across studies. Not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "When additional independent direct trial families are verified, compare distributions by population/intervention/endpoint/analysis and remove repeated citations of the same events." }, { "item_id": "N40", "question_type": "Original verdict and updates", "question": "Does conversion into a table change the original grade or deployment events?", "needed": "Original verdict/score; revision history; original canonical URL; and publication/server records for each event.", "role": "Required", "role_reason": "Required to avoid confusing conversion of retained content with reassessment/publication events.", "application_exception": "Do not newly calculate the number of criteria met, probabilities or grades for this table, or present the original self-review as independent clinical certification.", "criterion": "Preserve the original C, 56, 7 axes and publication/server metadata as historical values, separate from the current table creation/nondeployment.", "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules designed here; M04 §4.5, §4.6.3; the limits of the current data conversion follow the user's scope and the design developed here — internally designed adaptation for the original verdict and updates. Not official methodological certification.", "condition_origin": "A development criterion individually designed with prior knowledge of the retained content. Not clinical blinding or preregistration.", "proposed_research": "Preserve the entire pre-change version, and separately record criteria revisions, evidence updates, display changes and deployment events, linking them to the same ID/URL." } ], "language": "en", "translation_date": "2026-11-03" }