{ "title": "Single-ingredient riboflavin (vitamin B2) × Reduction of hs-CRP in adults with elevated hs-CRP", "criteria_version": "NGM-v3089-ORAL-RIBOFLAVIN-ELEVATED-HSCRP-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 document the question, eligibility conditions, and reasons for changes, and distinguish intervention variants.", "review_level": "Reuse of the methodological principles/versions preserved for 1585 and 5 actual HTML copies; no new reading of the full methodological text or execution of an official tool" }, { "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; do not omit studies solely because results are unreported.", "review_level": "Reuse of the methodological principles/versions preserved for 1585 and 5 actual HTML copies; no new reading of the full methodological text or execution of an official tool" }, { "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, attrition, missing data, measurement, and selective reporting.", "review_level": "Reuse of the methodological principles/versions preserved for 1585 and 5 actual HTML copies; no new reading of the full methodological text or execution of an official tool" }, { "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 values, intervals, importance, and applicability. Sample size alone does not determine precision.", "review_level": "Reuse of the methodological principles/versions preserved for 1585 and 5 actual HTML copies; no new reading of the full methodological text or execution of an official tool" }, { "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": "Harm questions may require different designs, populations, and follow-up from efficacy questions. Case reports do not establish incidence.", "review_level": "Reuse of the methodological principles/versions preserved for 1585 and 5 actual HTML copies; no new reading of the full methodological text or execution of an official tool" } ], "status_dictionary": { "Partly verified": "Some information in the retained summaries is verified, but gaps remain regarding the eligible population, assay, preparation, and results", "Unverified": "The specified necessary materials could not be established within the currently preserved scope; this does not mean an effect of 0, 0 studies worldwide, or safety", "Review incomplete": "The original sources were not cross-checked or searched within the permitted scope", "Not reported": "A scope-limited status indicating that the item was not stated in the specific material/section that was read", "Inaccessible": "Used only for materials that could not be accessed despite an actual attempt. Not assigned to clinical materials in this work", "Insufficient evidence meeting the criteria": "Used only when related studies within the defined scope have been reviewed and the evidence is insufficient to answer the criterion. It is not applied across the board in this work", "Not applicable": "Separate clinical-event/optimal-dose/long-term extensions are not imposed as additional mandatory requirements for the selected hs-CRP change question", "Conflicting data": "Used when materials that are difficult to reconcile for the same question, time point, and analysis have been compared. Not assigned merely because numerical values in reviews differ", "Met": "The specified question/scope/attribution/preservation linkage has been verified; distinguished from certification of direct hs-CRP efficacy or full-text reading" }, "schema_version": "chamgap-public-criteria-1.0", "condition_origin": "Chamgap’s own application conditions", "requirements": [ { "item_id": "N01", "question_type": "Separate claim", "question": "Which high-sensitivity CRP comparison is being defined?", "needed": "Definition of the question: a conventional oral B2 single-ingredient preparation, adults with elevated hs-CRP, change in high-sensitivity CRP, and placebo/no additional treatment on top of the same usual care", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid mixing general discussion of CRP with a single comparison question.", "application_exception": "Conventional CRP, redox associations, clinical anti-inflammatory efficacy, and IBD fatigue are separate questions.", "criterion": "Link the original effect wording and the actual scope of inclusion and exclusion to the same source location.", "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed; M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Compare the population, ingredients, endpoints, and comparison boundaries in the obtained manuscript and candidate studies." }, { "item_id": "N02", "question_type": "Molecule and actual route", "question": "Has actual oral administration of B2 alone been verified in an eligible result?", "needed": "Verification of the actual molecule, salt/derivative, route of administration, and single-ingredient composition in the relevant comparison", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid mistaking B2 as specified in the question for an actual administration record from an eligible study.", "application_exception": "Do not turn B1, B-vitamin combinations, or associations with blood vitamers into evidence of B2 administration.", "criterion": "Verify the actual molecule and route for an eligible result using administration documentation.", "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", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Link formulation and administration documentation to the population/results tables to verify actual oral exposure to B2 alone." }, { "item_id": "N03", "question_type": "Formulation and product", "question": "Are the release profile, manufacture/purity, and batch of the relevant eligible preparation known?", "needed": "The exact chemical form, release profile, manufacture/origin, purity, batch, and excipients of the conventional oral single-ingredient preparation", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid automatically combining results for specialized colonic-release preparations with those for conventional B2.", "application_exception": "Plant-part classification is not applicable, but this does not remove the unverified status of manufacture and formulation.", "criterion": "Verify the specifications of the preparation actually used for an eligible result.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Obtain product/trial-preparation documentation and review differences in applicability between conventional and specialized-release formulations." }, { "item_id": "N04", "question_type": "Dose", "question": "Can the eligible dose be distinguished from the 10 and 100 mg in related trials?", "needed": "Nominal/actual dose, frequency, adherence, and total exposure in an eligible comparison, and administration records from related studies", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid using doses from other populations as demonstrated or recommended doses for participants with elevated hs-CRP.", "application_exception": "10 mg/day and 100 mg/day are records from related studies, not an optimal-dose comparison.", "criterion": "Verify actual exposure in the relevant eligible arms separately from nominal doses in related studies.", "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; M03 §3.2.1–3.2.4; details concerning dose, persistence, and effect modification are internally designed", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Compare administration and actual doses in eligible arms using medication/preparation records and records of concomitant intake." }, { "item_id": "N05", "question_type": "Duration", "question": "Can the eligible duration be distinguished from the 28 days and 3 weeks in related studies?", "needed": "Administration, assessment, and follow-up periods in an eligible study, and the actual time points in candidate studies", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid fixing the short duration of another study as the appropriate duration for the selected question.", "application_exception": "Do not newly set a common minimum number of weeks or participants.", "criterion": "Verify the administration/assessment periods for each outcome in an eligible comparison.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application; M03 §3.2.1–3.2.4; details concerning dose, persistence, and effect modification are internally designed", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Link administration/follow-up and assessment time points using the schedule, assessment plan, and results tables." }, { "item_id": "N06", "question_type": "Population selection", "question": "Have the selection criteria and underlying diseases for participants with elevated hs-CRP been verified?", "needed": "The actual threshold for elevated hs-CRP, repeat testing, diagnoses, age, inclusion/exclusion criteria, and baseline distributions", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid equating general older-adult, Crohn disease, or healthy populations with a population selected for elevated levels.", "application_exception": "Do not combine results from different underlying diseases into a single population for application.", "criterion": "Verify the criteria for the actual comparison population selected for elevated levels using a high-sensitivity assay.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.1–3.2.4; details concerning dose, persistence, and effect modification are internally designed", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Obtain eligibility criteria, baseline tables, and assay records to compare population concordance and reasons for exclusion for each candidate." }, { "item_id": "N07", "question_type": "High-sensitivity assay", "question": "Have both the high-sensitivity assay and selection for elevated levels been verified?", "needed": "The hs-CRP assay name, sensitivity, specimen, and units, together with selection for elevated levels in the same population", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid arbitrarily substituting high-sensitivity CRP for conventional CRP.", "application_exception": "Do not infer units or high-sensitivity status from figures or product names.", "criterion": "Link the actual assay and population selection to the same study/result.", "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", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Compare the original assay methods with baseline assay tables to verify whether a result meets the high-sensitivity criteria." }, { "item_id": "N08", "question_type": "Actual comparator", "question": "Have placebo/no additional treatment and shared care been verified for an eligible result?", "needed": "The composition and schedule of concurrent comparator arms, shared care, and changes by arm", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid confusing the comparison specified by the question with the actual comparator.", "application_exception": "Do not turn an uncontrolled before-and-after study into a concurrently assigned placebo comparison.", "criterion": "Verify the actual comparator content and differences in care for the selected population/assay.", "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; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Link comparator/shared-care documentation to the results and review the meaning of the between-group difference." }, { "item_id": "N09", "question_type": "Reports and study families", "question": "Have the distinct studies and outcome relationships underlying the four reports been established?", "needed": "Bibliography → trial/study family → endpoint/time point/analysis linkage, and whether there is duplication", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid turning the number of stored source identifiers/bibliographic records into the number of independent direct replications.", "application_exception": "Do not create counts of unique participants or independent studies when they remain undetermined.", "criterion": "Compare actual identifiers to distinguish verified study-family relationships from those that remain undetermined.", "basis": "M04 §4.6.1–4.6.2 on distinguishing studies from reports; cohort/outcome linkage is an internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Link registry, paper, and study identifiers to review repeated citations of the same result and separate reports." }, { "item_id": "N10", "question_type": "Reading and material types", "question": "Has reading the summaries in this work been distinguished from historical access levels?", "needed": "Actual acquisition/reading for each material; historical abstract/figure-legend/institutional-abstract/registry-shell access; locations and dates", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid promoting a link or the originally recorded access level into a claim that the full text was read in this work.", "application_exception": "Do not re-record a historical failure to access registry results as a failed access attempt in this work.", "criterion": "Link the records while distinguishing reading the currently preserved summaries from the fact that access to each external original material has not been attempted and the material has not been read in this work.", "basis": "Material-collection/selection principles in M04 §4.5–4.6; the distinction between access and reading and the hyperlink rules are internally designed; M04 §4.5, §4.6.3; limits on the current conversion of materials follow the user's scope and are internally designed", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "If follow-up work is authorized, obtain the original file contents (bytes), source locations, and access dates for each material, and record actual reading histories separately." }, { "item_id": "N11", "question_type": "Cutoff date and search scope", "question": "Have the cutoff date and search limitations for the current materials been linked?", "needed": "The existing search cutoff and verification date, the current summary-review date, the input scope, and the record that no search was performed", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid exaggerating the preservation conversion as an up-to-date, exhaustive literature search.", "application_exception": "Do not identify the merely named tasks/R01-007/ or historical search records as files actually read in this work.", "criterion": "Separate the original dates and the documents' search scope from the scope of work actually performed now.", "basis": "M04 §4.5, §4.6.3; limits on the current conversion of materials follow the user's scope and are internally designed", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "In a separately authorized update, compare the actual search logs and registration/correction status with the original cutoff date." }, { "item_id": "N12", "question_type": "Eligible design", "question": "Has the actual comparative design for the same question been verified?", "needed": "The actual parallel, crossover, cluster/randomized design for an eligible population/assay", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid substituting the design label of a related trial for an eligible causal comparison.", "application_exception": "Do not assign a not-applicable status to crossover/cluster designs because the design is unverified.", "criterion": "Directly link the design in the methods to the relevant eligible result.", "basis": "M08 §8.1–8.2.3; internal application", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Review the design and population/assay concordance across the protocol, Methods section, and results tables." }, { "item_id": "N13", "question_type": "Allocation and baseline", "question": "Have sequence generation, allocation concealment, and baseline balance been verified for an eligible comparison?", "needed": "Allocation procedures, sequence generation, concealment, baseline distributions, and linkage to results", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid certifying the adequacy of allocation solely from the label placebo.", "application_exception": "Do not fill gaps in information from the original Methods by inventing a conclusion that bias has been established.", "criterion": "Verify whether allocation/baseline documentation for an eligible comparison supports each result.", "basis": "M08 §8.1–8.2.3; internal application", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Obtain the Methods section, allocation records, and baseline table to review gaps in confounding/allocation information for each outcome." }, { "item_id": "N14", "question_type": "Concomitant treatment and concurrent vitamins", "question": "Have concurrent treatments and all vitamins in the eligible arms been verified?", "needed": "Usual treatment, concurrent vitamins/supplements, medication changes, and rescue treatment by arm", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid mistaking differences in shared care for the contribution of B2 alone.", "application_exception": "Do not fill unverified concurrent-vitamin information with an exposure value of 0.", "criterion": "Link concomitant treatment/changes by arm in the eligible comparison to the effect of interest.", "basis": "M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Compare medication, supplementation, and rescue-treatment records with the analysis plan to review the contribution of concomitant treatment and the treatment policies actually compared." }, { "item_id": "N15", "question_type": "Total exposure and adherence", "question": "Have baseline B2, total dietary intake, actual intake, and adherence been verified?", "needed": "Deficiency status/measurement, dietary B2, other supplementary exposure, and actual medication intake/adherence by arm", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid turning the nominal B2 amount into total exposure or an effect of correcting deficiency.", "application_exception": "Do not combine results from a confirmed-deficiency population outside the question as effects of additional supplementation.", "criterion": "Link the population's baseline status, total intake, and actual amount to administration records.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; 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", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Obtain baseline nutritional tests and intake/medication records to review gaps in analyses of total exposure and adherence." }, { "item_id": "N16", "question_type": "Endpoint boundaries", "question": "Have changes in high-sensitivity CRP been distinguished from clinical anti-inflammatory efficacy?", "needed": "The actual selected endpoint, units, and direction, and boundaries separating it from other inflammatory markers/clinical events", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid extending a laboratory surrogate to disease treatment or event prevention.", "application_exception": "The original B/S describes the endpoint of the fixed question; it is not certification of an observed eligible clinical trial.", "criterion": "State the distinction between the selected hs-CRP change and ordinary CRP/other markers/clinical outcomes.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M03 §3.2.4; internally defined limits on extensions", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Link the original outcome definition to clinical results tables to review what belongs to the same question and what belongs to a separate question." }, { "item_id": "N17", "question_type": "Measurement procedures", "question": "Have sample collection, timing, blinding, and precision for the eligible assay been verified?", "needed": "The actual hs-CRP assay, specimen/measurement procedures, assessment time points, conditions by arm, and blinding of those taking measurements", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to distinguish measurement differences from intervention differences.", "application_exception": "Do not automatically judge unverified blinding as failed or adequate.", "criterion": "Verify the actual measurement conditions and differences between arms for the selected result.", "basis": "M08 Table 8.2.a, M03 §3.2.4; internal application; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Compare the assay SOP, collection time points, and blinding documents with the original results." }, { "item_id": "N18", "question_type": "Denominators", "question": "Has the actual analysis denominator for each hs-CRP result been verified?", "needed": "Numbers by arm (n) at recruitment/allocation, administration, measurement, completion, and analysis, and the outcome time points", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid repurposing 42·70 as eligible analysis denominators.", "application_exception": "Do not turn a historical numerical record merely named in the preserved source into material with available values by opening it in this work.", "criterion": "Verify the analysis denominators by arm corresponding to the selected result.", "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; M15 §15.3.1–15.3.3; internal application", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Use results tables, flow diagrams, and analysis materials to link denominators at each stage to reasons for exclusion." }, { "item_id": "N19", "question_type": "Missing data and attrition", "question": "Have the reasons for missing data and attrition, and the methods used to handle them, been verified for an eligible result?", "needed": "Losses, exclusions, discontinuations, missing measurements, and analytical handling/sensitivity analyses by arm", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid turning unverified information into complete follow-up or an absence of events.", "application_exception": "Do not calculate the number of dropouts, their reasons, or their impact from the existing sample size.", "criterion": "Verify information on observation losses and their analytical handling for the relevant result.", "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", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Link flow diagrams, plans for handling missing data, and analysis records to review limitations on interpretation of the results." }, { "item_id": "N20", "question_type": "Effect of interest and analysis", "question": "Have the eligible between-group effect and analysis population/adjustment been verified?", "needed": "Effects of assignment/adherence, between-group change/final values, ITT/PP, and adjusted/cross analyses", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid using uncontrolled before-and-after change and a between-group causal effect as the same value.", "application_exception": "Do not fill in ITT, an adjustment model, or dispersion from names alone.", "criterion": "Link the effect definition and actual analysis for the same question to the result.", "basis": "M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Compare analysis plans, models, and results tables by arm to distinguish the effect of interest from the preserved results." }, { "item_id": "N21", "question_type": "Numerical values and units", "question": "Have the effect value and units for the same eligible result been verified?", "needed": "hs-CRP values by arm, changes, units, dispersion, time points, and original results tables", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid arbitrarily repurposing ordinary-CRP values or numbers from search overviews.", "application_exception": "Do not perform new effect calculations/unit conversions or reverse calculations from rounded values.", "criterion": "Attribute only verified original values to their corresponding population, assay, comparison, and time point.", "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", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Compare original numerical tables and assay units to record the exact comparison values and what remains unverified." }, { "item_id": "N22", "question_type": "Precision and intervals", "question": "Have the original CI, dispersion, and denominator for the relevant effect been verified?", "needed": "The reported CI, dispersion, denominator, and model for the same between-group hs-CRP estimate", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid declaring a precisely estimated null effect or treatment effect from significance and sample size alone.", "application_exception": "Do not reconstruct intervals from P values, assignment counts, or the SD for a different endpoint.", "criterion": "Verify the original reported interval and its basis corresponding to the same estimate.", "basis": "M15 §15.3.1–15.3.3; internal application", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Link the estimate, dispersion, interval, and denominator in the relevant results table/model to review the range of effects compatible with them." }, { "item_id": "N23", "question_type": "Important difference", "question": "Is there a justified criterion for the importance of a change in high-sensitivity CRP?", "needed": "The basis for an important difference in the same population/assay and duration, and the corresponding interval", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid automatically interpreting a significant difference as a clinically meaningful anti-inflammatory effect.", "application_exception": "Do not propose an arbitrary hs-CRP reduction, minimum n, or duration.", "criterion": "Verify the relationship between the original basis for importance and the interval for the same comparison.", "basis": "M15 §15.3.1–15.3.3; internal application; M03 §3.2.4; internally defined limits on extensions", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Obtain the basis for clinical/patient importance and interpretation of the surrogate to review the scope of applicability of the results." }, { "item_id": "N24", "question_type": "Plans and registration", "question": "Have the prospective plans for the eligible primary endpoint, analysis, and time points been cross-checked?", "needed": "Cross-checking official registration, protocol, SAP, and changes against actual results", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid treating a basic registry page as a plan with verified planned/actual endpoints.", "application_exception": "Material not obtained does not establish nonregistration or selective reporting.", "criterion": "Compare the same eligible result with the primary endpoint, analysis, and time points in the original plan.", "basis": "M08 Table 8.2.a, M04 §4.6.3; internal application; material-collection and selection principles in M04 §4.5–4.6; separation of access from reading and the rules governing hyperlinks are internally designed", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Link official registration versions, protocols/SAPs, and actual results to review changes and areas that have not been cross-checked." }, { "item_id": "N25", "question_type": "Ordinary CRP in older adults", "question": "Is the nonsignificant result in S12 a direct result for this question?", "needed": "The actual high-sensitivity assay, selection for elevated levels, original result values/intervals, and denominator in S12", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid hiding a related result showing no significant difference or transferring it to a precisely established null effect on hs-CRP.", "application_exception": "The ordinary-CRP record for 42 participants, a 10 mg dose, and 28 days is not direct evidence of efficacy for the current question.", "criterion": "Verify whether the original population/assay/results in S12 meet the fixed eligibility criteria.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M15 §15.3.1–15.3.3; internal application", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Use the original abstract/Methods/results tables to cross-check the assay/selection criteria and the actual scope of the nonsignificant result." }, { "item_id": "N26", "question_type": "Before-and-after comparison in Crohn disease", "question": "Is the CRP result in S13 efficacy established through a concurrent comparison?", "needed": "The actual population/assay, comparison, timing, and endpoint/subgroup results in RISE-UP", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid turning uncontrolled before-and-after changes and a fecal-calprotectin subgroup into an hs-CRP effect.", "application_exception": "Do not automatically adopt the record of 70 participants, 100 mg, and 3 weeks as an eligible randomized comparison or analysis denominator.", "criterion": "Verify the extent to which the actual design/population/assay answers the selected question.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; 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; separation of statuses is internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Link the original abstract/figure captions, Methods, and results tables to review distinctions between before-and-after comparisons, subgroups, and controls." }, { "item_id": "N27", "question_type": "Associations in healthy participants", "question": "Is the redox/CRP association in S21 a direct reduction effect?", "needed": "The actual population, administration/design, and definitions of the redox/CRP analyses in RIBOGUT", "role": "Required (selected hs-CRP comparison)", "role_reason": "Needed to avoid reversing a correlation in healthy participants into a treatment effect in a population with elevated levels.", "application_exception": "Do not generate a new hs-CRP reduction value from an association or mechanism.", "criterion": "Verify whether the direction, endpoint, and population of the actual analysis match the causal question posed by the comparison.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; 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; separation of statuses is internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Compare the institutional abstract with the original analysis/results to review the boundary between an association and a randomized comparison estimate." }, { "item_id": "N28", "question_type": "Registry results not obtained", "question": "Have the actual population, formulation, and results of NCT05803811 been verified?", "needed": "The body of the official registry record, results tables, release formulation, population/assay, denominator, and linked reports", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid presenting search-result snippets or a registry address as evidence that actual results were obtained.", "application_exception": "Do not turn a historical record of failed access into an absence of research or a failed access attempt in the current work.", "criterion": "Verify the registry's exact results and their eligibility for the fixed question using the actual documents.", "basis": "Data-collection and selection principles in M04 §4.5–4.6; the distinction between access and reading and the rules governing hyperlinks were designed for this assessment; M08 Table 8.2.a, M04 §4.6.3; application for this assessment; M04 §4.6.3, M15 §15.3.1–15.3.3; distinctions between statuses were designed for this assessment", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "If follow-up work is permitted, obtain the official version/results and links to papers, and review the formulation, selection criteria, effect, and denominator." }, { "item_id": "N29", "question_type": "Funding and independence", "question": "Have actual research funding, product provision, and author/institutional interests been verified?", "needed": "Actual research funding, product provision, author employment/declarations, and independent study-family relationships for each report", "role": "Supplementary; required for independence claims", "role_reason": "This is needed to avoid upgrading unverified funding to a finding of independence or absence of bias.", "application_exception": "Do not automatically exclude results merely because funding was provided.", "criterion": "Compare the original declarations/funding for each material with the scope in which research independence has been verified.", "basis": "Chamgap's own conditions for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items; M04 §4.6.1–4.6.2, M15 §15.3.1; application for this assessment", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Obtain the original funding/conflict-of-interest declarations (Funding/COI) and institutional/study-family information to distinguish funding from relationships between reports and replications." }, { "item_id": "N30", "question_type": "Attribution of the retained original judgment", "question": "Have the original ?/empty values and the no-human-study flag with its bounded scope (no_human_study) been preserved exactly?", "needed": "The original grade, score, unused assessment axes, eligible scope, and literal wording of the search judgment at that time", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid turning an uncalculated value into no effect, 0 studies worldwide, or a condition-fulfillment rate for the new table.", "application_exception": "Do not upgrade the historical judgment in the original verdict into a new scoring result in the current work.", "criterion": "Preserve ?, empty values in the retained summaries, Boolean values/empty strings, and the bounded scope at their original locations and in their original bytes.", "basis": "Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules were designed for this assessment; M04 §4.5, §4.6.3; limits on the current conversion of materials follow the user's scope and were designed for this assessment", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "If new eligible material becomes available within a separately permitted scope, review it while distinguishing the original judgment/conditions from the new event." }, { "item_id": "N31", "question_type": "Additional candidate lead", "question": "Has the candidate concerning B6–B2 metabolic interactions been verified as a result of B2 administration?", "needed": "The actual candidate's bibliographic record, original text, molecule/administration/population/endpoint, and result location", "role": "Required (selected hs-CRP comparison)", "role_reason": "This is needed to avoid counting a merely identified, unverified candidate as a new human efficacy study.", "application_exception": "Do not invent a source identifier (source_id), number, or paper for the empty list of linked sources.", "criterion": "Use the candidate's actual original text to verify whether it concerns an effect of B2 administration.", "basis": "The distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/result linkage is an application for this assessment; data-collection and selection principles in M04 §4.5–4.6; the distinction between access and reading and the rules governing hyperlinks were designed for this assessment; M04 §4.5, §4.6.3; limits on the current conversion of materials follow the user's scope and were designed for this assessment", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "If follow-up work is permitted, establish the identifier and compare the original text with the question to review whether to include it." }, { "item_id": "N32", "question_type": "Underlying conditions and subgroups", "question": "Have eligible differences by underlying condition or baseline B2 status been compared?", "needed": "Prespecified subgroups, interactions, separate results, and baseline nutritional status within the same comparison", "role": "Supplementary; required for extensions to conditions/subgroups", "role_reason": "This is needed to avoid using differences between older adults, people with Crohn disease, and healthy participants as verification of subgroups in response to B2.", "application_exception": "Do not impose all subgroup studies as mandatory requirements for the principal question.", "criterion": "Check whether direct evidence from separate subgroup results or interaction analyses supports the extended claim.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.1–3.2.4; details concerning dose, persistence, and effect modification are internally designed", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "If follow-up work is permitted, compare prespecified hypotheses and separate results concerning population/baseline differences." }, { "item_id": "N33", "question_type": "Extension to optimal dose and persistence", "question": "Does the selected question include the optimal dose and persistence after discontinuation?", "needed": "Separate extended questions and materials for direct dose comparisons and follow-up after discontinuation/over the long term", "role": "Supplementary; required for extensions to optimal dose/maintenance", "role_reason": "This is needed to avoid imposing all extension studies as additional mandatory requirements for the narrow hs-CRP comparison.", "application_exception": "Do not present the unverified original duration as though the optimal duration or long-term effects have already been verified.", "criterion": "Distinguish whether separate claims about optimal dose/maintenance fall within this table's question scope.", "basis": "M03 §3.2.1–3.2.4; details concerning dose, persistence, and effect modification were designed for this assessment", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "If an extension is requested, review direct dose comparisons and treatment-discontinuation/follow-up materials as a separate question." }, { "item_id": "N34", "question_type": "Extension to clinical events", "question": "Does the hs-CRP question include disease treatment or event prevention?", "needed": "Separate boundaries between clinical anti-inflammatory effects, disease activity, quality of life/events, and the selected change in hs-CRP", "role": "Supplementary; required for extensions to clinical events", "role_reason": "This is needed to avoid unconditionally imposing a clinical-event trial as a requirement for a change in a surrogate marker.", "application_exception": "Do not remove the current question or extend it to clinical effects merely because it concerns a surrogate marker.", "criterion": "State whether the fixed question concerns a change in a numerical value or a separate clinical effect.", "basis": "M03 §3.2.4; extension boundaries developed for this assessment", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "If the scope is extended, review direct clinical events and patient-important outcomes as an independent question/sheet." }, { "item_id": "N35", "question_type": "Safety", "question": "Have harms/discontinuations for the same population, product, and duration been verified?", "needed": "AE collection, participant/event denominators, discontinuations, duration, concomitant use/vulnerable groups for eligible exposures", "role": "Supplementary; required for safety claims", "role_reason": "This is needed to avoid turning tolerability in a short trial in another population into long-term safety.", "application_exception": "Do not change the original unknown safety status and short-term contextual materials into a new safety grade.", "criterion": "Verify the actual harm data and scope of collection for the same population/product/duration.", "basis": "M19 §19.1.2–19.2.4; application for this assessment; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for individual study designs were designed for this assessment", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "Link harm-collection, discontinuation, denominator, and follow-up information to outcomes/exposures to review applicability over the long term and to vulnerable groups." }, { "item_id": "N36", "question_type": "Assay interference and drug interactions", "question": "Has any separate verification of interference/interactions actually been performed, and within what scope?", "needed": "Data on hs-CRP assay interference and interactions involving the relevant exposure/drugs, and the scope of searches performed", "role": "Supplementary; required for interpreting interference/interactions", "role_reason": "This is needed to avoid interpreting the absence of a separate search as absence of an influence.", "application_exception": "Do not turn the question into one about assay bias itself or record an area not searched as failed access.", "criterion": "Check whether the actual materials and review scope support statements about interference/interactions.", "basis": "M08 Table 8.2.a, M03 §3.2.4; application for this assessment; M19 §19.1.2–19.2.4; application for this assessment; M04 §4.5, §4.6.3; limits on the current conversion of materials follow the user's scope and were designed for this assessment", "condition_origin": "Development criteria individually designed with knowledge of the currently preserved materials; not blinded, clinically preregistered, or officially certified", "proposed_research": "If an extension is permitted, separately review interference and interaction data for the actual assay and concomitant exposures." } ], "language": "en", "translation_date": "2026-11-01" }