{ "schema_version": "chamgap-public-criteria-1.0", "title": "Berberine hydrochloride tablets × Reduced weekly diarrhea frequency in diarrhea-predominant irritable bowel syndrome", "language": "en", "translation_date": "2026-10-27", "criteria_version": "1.1", "criteria_date": "2026-10-05", "condition_origin": "Chamgap's own application conditions", "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 conditions and reasons for changes; distinguish intervention variants.", "review_level": "Retained method-application records were reused. External originals were not reread and method content was not reassessed." }, { "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": "Link studies and reports separately; do not omit studies solely because results are unreported.", "review_level": "Retained method-application records were reused. External originals were not reread and method content was not reassessed." }, { "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 result and effect of interest when examining randomization, deviations, missingness, measurement and selective reporting.", "review_level": "Retained method-application records were reused. External originals were not reread and method content was not reassessed." }, { "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": "Retained method-application records were reused. External originals were not reread and method content was not reassessed." }, { "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": "Retained method-application records were reused. External originals were not reread and method content was not reassessed." } ], "status_dictionary": { "Met": "The row’s narrow record, attribution, boundary or actual fact was checked. This does not certify efficacy, precision or safety.", "Partly verified": "Some required information is available, but actual exposure, definitions, denominators or other necessary material remain missing.", "Unverified": "The criterion cannot be established within the retained scope. This does not mean 0 effect, 0 studies or failed access.", "Not applicable": "The condition has no applicable subject within the current retained set and narrow question. This does not replace a material gap or unread status.", "Review incomplete": "A status for external original-material comparison not yet performed, distinguished from review of locally retained content.", "Not applicable (alias)": "The condition has no applicable subject within the current retained set and narrow question. This does not replace a material gap or unread status.", "Conflicting data": "Participant reports for the same concept conflict, so no single value was selected. This is distinct from differences in results at different time points.", "Not read": "The material was not directly read in the current work. This is distinct from not reported, inaccessible or no research." }, "requirements": [ { "item_id": "N01", "question_type": "Evidence condition", "question": "Which IBS-D diarrhea-frequency question is addressed?", "needed": "The original claim, population, formulation, route, nominal dose, actual comparator, endpoint at 8 weeks and canonical URL.", "role": "Required", "role_reason": "Needed to distinguish an ingredient-wide effect from a particular comparison and time point.", "application_exception": "The original subclaim list is empty. Do not invent subclaims or expand every combination of dimensions into a separate sheet.", "criterion": "Fix a single question about weekly diarrhea frequency at 8 weeks comparing oral berberine hydrochloride 400 mg/day with vitamin C 400 mg/day in adults with Rome III IBS-D.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare the original claim with the evidence comparison to check that persistence after stopping, urgency, pain and quality of life are not mixed into the principal effect." }, { "item_id": "N02", "question_type": "Evidence condition", "question": "Do the actual ingredient and tablet formulation match this question?", "needed": "The formulation name, composition, dosage form and reasons for including or excluding other products.", "role": "Required", "role_reason": "The same berberine name does not establish the same exposure.", "application_exception": "Unverified plant source or excipients do not establish that this was a different formulation.", "criterion": "Distinguish the berberine hydrochloride tablets in the material from plant extracts, other derivatives, combinations and topical products.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare product composition with Methods to distinguish whether results for berberine hydrochloride tablets can be transferred to other extracts, derivatives or combinations." }, { "item_id": "N03", "question_type": "Evidence condition", "question": "To what extent are the experimental tablet’s labeled ingredient and dosage form, source, manufacturer and excipients established?", "needed": "The experimental tablet’s manufacturer, manufacturing source, complete composition and product-supply records.", "role": "Required", "role_reason": "Product identity beyond the ingredient name is needed to explain whether the experimental exposure is the same.", "application_exception": "Do not convert an unverified source into a specific plant species or the presence of product impurities.", "criterion": "Check separately the labeled berberine hydrochloride 200 mg tablet information and the extent of verification of the actual source, manufacturer and complete composition. The labeled ingredient alone does not establish source, manufacture or excipients.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare the original product description and supply records to separate the labeled hydrochloride amount from complete product composition and origin." }, { "item_id": "N04", "question_type": "Evidence condition", "question": "Are route, nominal dose and dosing frequency specified?", "needed": "Route, labeled tablet amount, dosing frequency and nominal daily dose.", "role": "Required", "role_reason": "Needed to avoid substituting results from another product or dose for the nominal regimen.", "application_exception": "Do not interpret nominal 400 mg/day as actual adherent intake or blood exposure.", "criterion": "Directly connect the nominal oral regimen of 200 mg 2 times daily, 400 mg/day.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare administration instructions with formulation labeling to check for results from different doses or routes being mixed in." }, { "item_id": "N05", "question_type": "Evidence condition", "question": "Can actual intake, adherence and rescue treatment be established?", "needed": "Arm-specific tablet returns, adherence, actual administration, discontinuation and rescue-treatment records.", "role": "Required", "role_reason": "Assigned administration instructions alone do not establish equal actual exposure.", "application_exception": "Unverified adherence does not establish nonadherence or an incorrect nominal dose.", "criterion": "Check how arm-specific intake, adherence, drug discontinuation and rescue treatment affected the comparison at 8 weeks.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare nominal dose with actual dosing records and examine the effect of interest and analysis accounting for discontinuation and rescue treatment." }, { "item_id": "N06", "question_type": "Evidence condition", "question": "Is the eligibility scope for adults with Rome III IBS-D established?", "needed": "Application of Rome III diagnostic criteria, age, severity, eligibility, recruitment setting and baseline characteristics.", "role": "Required", "role_reason": "The same diarrhea symptoms do not establish the same diagnosis or selection process.", "application_exception": "Unverified detailed selection does not establish no effect in other IBS types.", "criterion": "Check age, severity, eligibility and recruitment setting of the diagnosed population without extending to general diarrhea or all IBS.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare eligibility criteria and baseline tables to examine applicability to the current adult IBS-D question and differences from other diarrhea or IBS types." }, { "item_id": "N07", "question_type": "Evidence condition", "question": "What did the comparator arm actually receive?", "needed": "The comparator tablet’s ingredient, dose, administration instructions and the trial’s placebo wording.", "role": "Required", "role_reason": "Hiding the actual comparator ingredient changes the meaning of the comparative effect.", "application_exception": "Do not automatically judge the vitamin C comparator identical to an inert placebo or equivalent treatment to berberine.", "criterion": "Distinguish that the actual comparator called placebo in the paper was vitamin C tablets 400 mg/day.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Review comparator formulation descriptions to distinguish the actual vitamin C comparison from assumptions of an inert control, and check administration differences between arms." }, { "item_id": "N08", "question_type": "Evidence condition", "question": "Are concomitant medication, diet and lifestyle changes in both arms established?", "needed": "Records of concomitant medication, diet, lifestyle interventions, arm-specific changes, rescue treatment and analytical handling.", "role": "Required", "role_reason": "Needed to avoid attributing differences in other treatments or behavior to berberine.", "application_exception": "Do not require all changes to be identical or fill unverified information with an absence of cointerventions.", "criterion": "Check how arm-specific concomitant treatment, diet, lifestyle interventions and rescue treatment during 8 weeks were handled in the actual comparison and analysis.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare arm-specific cointervention and change timelines to examine whether factors beyond berberine versus vitamin C were mixed into the results." }, { "item_id": "N09", "question_type": "Evidence condition", "question": "Can 8 weeks of treatment be distinguished from 4 weeks of off-treatment follow-up?", "needed": "Administration, discontinuation and assessment schedules and results at each time point.", "role": "Required", "role_reason": "Needed to avoid transferring the end-of-treatment result into a sustained effect.", "application_exception": "Differences in results at different time points do not constitute a numerical conflict at the same time point.", "criterion": "Distinguish the end of 8 weeks of administration from assessment at week 12 after a further 4 weeks off treatment, without merging time points.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare the time-point table to identify which results belong to on-treatment versus off-treatment observations." }, { "item_id": "N10", "question_type": "Evidence condition", "question": "Are the diarrhea-diary event definition and collection procedures established?", "needed": "Diarrhea event definition, diary form, aggregation unit, assessment procedures and handling of missing diaries.", "role": "Required", "role_reason": "The definition and collection of patient-recorded diarrhea frequency must be distinguished from the actual effect.", "application_exception": "The description as a direct patient-experienced endpoint does not certify a validated diary or complete measurement.", "criterion": "Check the event definition for weekly diarrhea episodes, aggregation period, diary completion, missing-entry handling and scale direction.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare diary forms and measurement instructions to examine how diarrhea episodes differ from bowel movements, urgency and pain." }, { "item_id": "N11", "question_type": "Evidence condition", "question": "Is the prospective co-primary hierarchy for diarrhea and urgency established?", "needed": "Co-primary endpoints, testing hierarchy and multiplicity handling in registration, protocol and SAP.", "role": "Required", "role_reason": "Needed to avoid extending a favorable diarrhea result alone into success for all co-primary endpoints.", "application_exception": "Do not interpret the coprimary_split flag as definitive proof of a plan violation or selective reporting.", "criterion": "Check diarrhea/urgency status and handling of multiple testing and selective reporting in the prospective plan.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare plans and reports to examine whether selecting diarrhea alone matches the prospective hierarchy and whether separate urgency reporting is missing." }, { "item_id": "N12", "question_type": "Evidence condition", "question": "Are the arm-specific weekly diarrhea values at 8 weeks connected?", "needed": "Arm-specific reported values at 8 weeks, printed ± values, P and the original table’s endpoint and time point.", "role": "Required", "role_reason": "Needed to avoid transferring retained figures to another endpoint or an off-treatment result.", "application_exception": "The meaning of ±, actual analysis denominator, between-arm difference and CI are separate conditions from checking these arm values.", "criterion": "Connect the reported weekly diarrhea values, printed ± values and P for berberine and vitamin C at 8 weeks to that time point.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare arms, endpoint, time point and units in the table at 8 weeks and check agreement between summary and printed values. Do not newly calculate a difference or CI." }, { "item_id": "N13", "question_type": "Evidence condition", "question": "Was the off-treatment result at 12 weeks preserved separately?", "needed": "Arm results at 12 weeks, printed ± values, P, and discontinuation/follow-up schedules.", "role": "Required", "role_reason": "Needed to avoid retaining only the favorable result at 8 weeks and presenting sustained benefit.", "application_exception": "Retain the manuscript’s null/no-difference wording as historical description. Do not newly judge P=.805 as exact 0 effect or equivalence.", "criterion": "Retain arm values and P at 12 weeks after 4 weeks off treatment without converting nonsignificance into 0 effect or equivalence.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare off-treatment result timing and arm-specific follow-up to examine persistence of the signal at 8 weeks within the reported scope, without newly estimating equivalence or relapse rates." }, { "item_id": "N14", "question_type": "Evidence condition", "question": "Are arm values final values or changes, and are baseline data available?", "needed": "Baseline diarrhea, original table headings at each time point, statistical summary type and change definition.", "role": "Required", "role_reason": "The same number can address different questions as final frequency versus change from baseline.", "application_exception": "If baseline values are absent from the current summary, do not subtract time-point values to fill in a change.", "criterion": "Check statistical summary type, final value/change and baseline diarrhea data at each time point.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare baseline and result tables to verify analysis definitions without substituting final values, changes and within-arm changes for one another." }, { "item_id": "N15", "question_type": "Evidence condition", "question": "Are the analysis population, adjustment and effect of interest at 8 weeks established?", "needed": "Analysis plan, ITT/PP definitions, time-specific analysis populations, covariates and models.", "role": "Required", "role_reason": "Needed to avoid converting completers into the analysis population for the assignment effect.", "application_exception": "The manuscript’s assessment as completer data does not establish a formal PP analysis or arm-specific analysis n.", "criterion": "Check assignment/adherence effects, ITT/PP, analysis population, adjustment and the actual between-arm analysis definition.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare plans with result analyses to examine whether the effect concerns all assigned participants or completers, and how adjustment and missing-data handling connect." }, { "item_id": "N16", "question_type": "Evidence condition", "question": "Is it established whether ± values are SD or SE?", "needed": "Original table legend, SD/SE definitions, analysis n for each value and measurement units.", "role": "Required", "role_reason": "The ± string alone cannot support calculation of dispersion or precision.", "application_exception": "Do not convert ± into CI or infer SD/SE to create a new interval.", "criterion": "Use the original table legend to establish which dispersion/error statistic the printed ± values at 8 and 12 weeks represent.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare table legends with Methods to distinguish SD, SE and other error expressions, checking only the meaning of reported statistics." }, { "item_id": "N17", "question_type": "Evidence condition", "question": "Do recruitment and randomization counts agree?", "needed": "CONSORT flow, original recruitment/randomization statements, abstract/body denominators and any corrections.", "role": "Required", "role_reason": "Needed to avoid hiding conflicting counts or using an arbitrary larger count as the analysis denominator.", "application_exception": "Do not automatically merge 196, 164 and 132 as counts for the same stage or select one as the correct answer.", "criterion": "Check recruitment flow and original report locations that could resolve inconsistent reports of 196 recruited, 164 or 132 randomized, and 132 completing.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare recruitment flow and participant counts in the abstract, Methods and results by the same stages to establish whether 164 and 132 refer to different stages or an error." }, { "item_id": "N18", "question_type": "Evidence condition", "question": "Are 70/62 completers connected to time-specific analysis denominators?", "needed": "Arm-specific allocation, completion, measurement/analysis counts at 8 weeks and measurement/analysis counts at 12 weeks.", "role": "Required", "role_reason": "Needed to avoid inheriting completers as actual analysis denominators at both time points.", "application_exception": "Do not automatically fill analysis n at 8 or 12 weeks with the completion counts 70/62.", "criterion": "Distinguish 70 versus 62 completers from analysis n at 8 and 12 weeks and check actual denominators for each result.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Connect each results table with the flow to distinguish completer counts, time-specific observation/analysis counts and shared participants." }, { "item_id": "N19", "question_type": "Evidence condition", "question": "Who was lost, and how were missing diarrhea results handled?", "needed": "Arm-specific reasons for dropout/missingness, missing diaries, time-specific analytical handling and sensitivity analyses.", "role": "Required", "role_reason": "Needed to establish which selection and losses preceded completer results.", "application_exception": "Do not treat the entire difference between recruitment and completion counts as on-treatment dropout.", "criterion": "Check arm-specific dropout/missingness reasons and missing-data handling and sensitivity analyses for results at 8 and 12 weeks.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare recruitment flow with missing diaries and examine robustness under missing-data handling and assumptions. Do not calculate a new missingness rate." }, { "item_id": "N20", "question_type": "Evidence condition", "question": "Are random sequence, allocation concealment and baseline balance established?", "needed": "Design, random sequence, allocation concealment in Methods and baseline tables.", "role": "Required", "role_reason": "The randomized label alone does not establish that allocation concerns are resolved.", "application_exception": "Unverified sequence/concealment does not establish failed randomization; do not assign crossover/cluster NA without evidence.", "criterion": "Check actual randomization method, concealment, baseline balance and design structure.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare allocation methods and baseline tables to examine allocation risk and balance beyond the randomized-trial label in the title." }, { "item_id": "N21", "question_type": "Evidence condition", "question": "Is blinding for diary completion/assessment and comparator tablets established?", "needed": "Who was blinded, tablet appearance/sensory matching, assessment procedures and unblinding or awareness records.", "role": "Required", "role_reason": "The double-blind label alone does not establish that measurement differences in subjective diarrhea records disappeared.", "application_exception": "The fact that the comparator was vitamin C alone establishes neither blinding failure nor success.", "criterion": "Check participant, assessor and analyst blinding, matching of comparator tablets and any unblinding.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare collection of the subjective diary endpoint with blinding procedures for both tablets to examine potential measurement differences." }, { "item_id": "N22", "question_type": "Evidence condition", "question": "To what extent are time-specific P values and their testing/adjustment definitions established?", "needed": "Statistical Methods, testing target, model, covariates, one-/two-sided testing and multiplicity handling.", "role": "Required", "role_reason": "Needed to avoid using a P string as a substitute for precision or clinical importance.", "application_exception": "Do not newly calculate significance/nonsignificance or interpret it as an equivalence test.", "criterion": "Check separately the reported P=.032 at 8 weeks and P=.805 at 12 weeks, their time points and the extent of verification of testing target, one-/two-sided testing, repeated measurement/adjustment and multiplicity handling. A P string does not establish the test definition.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare Methods with result notes to examine whether P concerns a between-arm comparison and how it relates to repeated measurement, adjustment and multiple endpoints." }, { "item_id": "N23", "question_type": "Evidence condition", "question": "Are the between-arm effect at 8 weeks and 95% CI directly reported?", "needed": "The between-arm effect estimate at 8 weeks, 95% CI, dispersion type, analysis n and model.", "role": "Required", "role_reason": "Significance and arm values alone do not reveal the effect interval.", "application_exception": "Do not subtract printed arm values to create a new effect difference or NNT.", "criterion": "Check the original estimate, 95% CI, dispersion and denominator for the effect of interest at 8 weeks.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare original result tables, estimate definitions, dispersion and analysis n to examine reported interval scope. Do not reconstruct a new CI from arm values." }, { "item_id": "N24", "question_type": "Evidence condition", "question": "Is a threshold for an important difference in diarrhea frequency justified?", "needed": "A prospective minimum important difference in weekly diarrhea frequency, responder definition and patient-centered basis.", "role": "Required", "role_reason": "Needed to avoid establishing clinically sufficient benefit from P=.032 alone.", "application_exception": "Do not invent minimum participant counts, duration, effect size or proportion-of-conditions-met thresholds.", "criterion": "Check patient-important differences, responder thresholds and prospective support for this IBS-D endpoint.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare defined important differences and responder thresholds with original results to distinguish a statistical signal from patient-important improvement." }, { "item_id": "N25", "question_type": "Evidence condition", "question": "Are trial registration, protocol and analysis plan established?", "needed": "Trial registration identifier, original registration, protocol, SAP and versions/dates.", "role": "Required", "role_reason": "Needed to reveal which material is required to examine favorable-result selection.", "application_exception": "Do not convert an unestablished registration field into confirmed nonregistration or 0 registration identifiers.", "criterion": "Directly compare registration identity and the prospective protocol/SAP for this report.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Connect the paper’s identity with registration, protocol and SAP to compare prospective recruitment, joint endpoints, analyses and timing with reports." }, { "item_id": "N26", "question_type": "Evidence condition", "question": "Is prospective-plan agreement for assessments and analyses at 8 and 12 weeks established?", "needed": "Prospective visit schedules, endpoints at 8/12 weeks, analysis plans and reasons for changes.", "role": "Required", "role_reason": "Knowing the nominal duration differs from agreement with a prospective plan.", "application_exception": "Unverified timing plans do not establish post hoc analysis.", "criterion": "Check agreement between prospective plans and reports for end-of-treatment/off-treatment timing and the corresponding analyses.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare planned visit, endpoint and analysis schedules with reported results and check for timing changes or additional analyses." }, { "item_id": "N27", "question_type": "Evidence condition", "question": "Were evidence and bibliographic descriptions of the same paper counted without duplication?", "needed": "Report title, PMID, DOI, evidence/citation links, trial family and participant relationships.", "role": "Required", "role_reason": "Needed to avoid counting bibliography, abstract and paper links as multiple independent trials.", "application_exception": "Connecting one report does not establish a worldwide unique trial count of 1.", "criterion": "Connect the same report in the corresponding evidence and citation entries without counting external identifier entry points as additional trials.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Connect titles, identifiers and results to check whether evidence-table, citation and PMID/DOI entries concern one report, and separately compare family identity for later material." }, { "item_id": "N28", "question_type": "Evidence condition", "question": "Is independent replication of the same question established?", "needed": "Full reports and registration of independent trials, population/regimen/comparator/timing, results tables and family links.", "role": "Required (independent-replication claim)", "role_reason": "Needed to avoid extending one report’s result into independent confirmation.", "application_exception": "No new search and 1 linked report do not establish an absence of independent research.", "criterion": "Check the same formulation, population, comparator, diarrhea result at 8 weeks and family relationships in other unique trials.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare trial-specific eligibility and family links to examine independent result distributions, contrary results and condition differences." }, { "item_id": "N29", "question_type": "Evidence condition", "question": "What was actually read, and what date scope is being described?", "needed": "Original input, byte hash, evidence reference date, actual review date and material-specific historical/current access records.", "role": "Required", "role_reason": "Needed to avoid overstating local-summary reading as new full-text reading or a current exhaustive search.", "application_exception": "Do not fill material-specific access dates from the global original-verdict review date or describe unattempted access as failed access.", "criterion": "Distinguish complete reading of the retained summary from historical PDF-review descriptions and current unattempted/unread external material, with dates.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare the access ledger with original material locations to distinguish summary versus external full-text reading and historical descriptions versus new actions, checking the scope of unverified wording." }, { "item_id": "N30", "question_type": "Evidence condition", "question": "Are funding, product support and author interests established?", "needed": "Funding, product provision, author employment/patents, COI declarations, institutions and roles.", "role": "Supplementary; required for independence claims", "role_reason": "An academic-support name alone does not reveal product support or conflicts of interest.", "application_exception": "Do not use the existing I2 axis as new certification of complete independence.", "criterion": "Check reported funding, product provision, employment, patents and declared interests separately from trial family.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare funding, product provision and author/institutional roles separately to check against unsupported conclusions of independent funding or replication." }, { "item_id": "N31", "question_type": "Evidence condition", "question": "Are arm-specific adverse-event/discontinuation counts and collection scope established?", "needed": "AE definitions, arm-specific event/person counts, safety denominators, duration, collection, severity and discontinuation/missingness.", "role": "Supplementary; required for safety questions", "role_reason": "Needed to avoid converting the existence of efficacy reports into no harms or completed safety accounting.", "application_exception": "Do not delete efficacy results because harms are unreported or infer events/denominators.", "criterion": "Check adverse-event events/persons, exposure denominators, collection, severity, discontinuation and missingness in the same trial.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Connect safety tables, collection instructions and flow to distinguish event counts from person counts, exposure denominators, discontinuation reasons and missingness." }, { "item_id": "N32", "question_type": "Evidence condition", "question": "Can adverse reactions such as diarrhea be distinguished from IBS symptoms by timing and comparison?", "needed": "Baseline symptoms, onset/worsening timing, stopping/recovery, arm-specific harm comparisons and concurrent exposures.", "role": "Supplementary; required for harm attribution", "role_reason": "Needed to avoid merging IBS-D diarrhea and intervention-related gastrointestinal reactions into the same event.", "application_exception": "Reporting after exposure alone does not establish causality; do not infer that changes in diarrhea frequency after stopping represent AE recovery.", "criterion": "Check baseline IBS symptoms, onset/worsening after dosing, stopping/recovery, arm-specific comparisons and alternative exposures.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare symptom/administration timelines, arm-specific harms and alternative exposures to distinguish disease from intervention-related signals and examine limits on causal/risk interpretation." }, { "item_id": "N33", "question_type": "Evidence condition", "question": "Is safety material available for pregnancy, lactation, infants and young children, concomitant drugs and long-term use?", "needed": "Exposure, population, duration and result material for vulnerable groups, CYP-related concomitant use and long-term/rare harms.", "role": "Supplementary; required for the relevant safety claim", "role_reason": "Results in a limited adult population and duration cannot guarantee safety in vulnerable groups or long-term use.", "application_exception": "Do not require every rare-harm study as a condition for checking diarrhea efficacy at 8 weeks.", "criterion": "Check direct material on vulnerable groups, interactions and long-term/rare harms and the applicability limits of original warnings.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Review safety material and drug-interaction evidence separately by exposure/population without extending a short-term adult efficacy trial into overall safety." }, { "item_id": "N34", "question_type": "Evidence condition", "question": "Does this question require an optimal dose or effects in specific subgroups?", "needed": "For extensions: direct dose comparisons, prospective subgroups, interaction tests and population-specific results.", "role": "Supplementary; required for dose or subgroup extensions", "role_reason": "Needed to avoid converting a principal effect at one dose into an optimal dose or a specific subgroup effect.", "application_exception": "Do not add optimal-dose or all-subgroup research requirements to the current narrow question.", "criterion": "Distinguish the narrow question of 400 mg/day in adults with Rome III IBS-D from separate dose/subgroup-extension requirements.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "When proposing dose/subgroup extensions, design separate questions using direct comparisons and prospective interaction material without merging them into the current principal effect." }, { "item_id": "N35", "question_type": "Evidence condition", "question": "Does this cover cure, relapse, pain and quality of life beyond diarrhea frequency?", "needed": "For extensions: each separate endpoint’s definition, population, duration, comparison and direct results.", "role": "Supplementary; required for the relevant extension claim", "role_reason": "Patient-experienced diarrhea frequency and other clinical/mechanistic outcomes are not the same effect.", "application_exception": "Do not require other clinical-event trials as conditions for checking weekly diarrhea frequency itself.", "criterion": "Distinguish weekly diarrhea frequency from cure, relapse prevention, microbiome normalization, pain and quality of life.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Design separate questions, measurements and follow-up for each endpoint to examine that a diarrhea-frequency signal does not replace conclusions about cure, relapse, mechanism or quality of life." }, { "item_id": "N36", "question_type": "Evidence condition", "question": "Does this scope produce pooled results across studies or repeated harm signals?", "needed": "For extensions: unique families, outcome-specific tables, contrary records, original repeated-harm material and recitation relationships.", "role": "Supplementary; required for pooled or repeated-harm claims", "role_reason": "Needed to avoid counting multiple time points/links in one report as across-study replication or repeated harms.", "application_exception": "Do not convert nonapplicability of current pooling into a finding of no independent research. Independent replication remains separately unverified.", "criterion": "Do not create across-study pooling or repeated harms from one linked report; distinguish unverified family relationships from scope nonapplicability.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "If multiple materials are added, separately examine suitability for pooling and repeated signals after comparing unique families, condition differences, contrary results and recitation." }, { "item_id": "N37", "question_type": "Evidence condition", "question": "Were the scope of the internal English correction and remaining generic wording distinguished?", "needed": "The correction event, current original Korean/English correspondence, original field types, absent keys and empty values.", "role": "Required (preservation accuracy)", "role_reason": "Needed to avoid inheriting a wording correction as new clinical verification or added content.", "application_exception": "A correction record describing one field change does not establish that all current generic wording has become specific.", "criterion": "Retain the scope of the 2026-09-14 internal English wording correction and current generic English wording, empty fields and absent keys.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare the correction event with current bilingual fields to check that generic English verification wording is not read as new participant, funding or analysis facts." }, { "item_id": "N38", "question_type": "Evidence condition", "question": "Were the existing grade, score and axes distinguished from this sheet review?", "needed": "The original grade, score, safety, axes, grade decision and current review scope.", "role": "Required (preservation accuracy)", "role_reason": "The original verdict and verification states for producing an evidence-gap sheet are different information.", "application_exception": "Do not use original I2, EX, CX, coprimary_split or historical cross-check wording as evidence of new clinical validation.", "criterion": "Retain original C 50, Warning and axes/flags as preserved original information without converting them into a new sheet completion proportion, grade or clinical certification.", "basis": "Existing method principles distinguish population, formulation, actual comparator, weekly diarrhea frequency, time points, participant reports, dispersion, analysis, study families, funding and harms. Detailed conditions are Chamgap’s own application.", "condition_origin": "These conditions compare berberine hydrochloride with vitamin C in adults with IBS-D and were developed with knowledge of the retained content. They were frozen before application, with historical clarification of questions and criteria also retained. This does not establish clinical preregistration, blinded development, official-method certification or independent clinical validation.", "proposed_research": "Compare original fields with sheet states to check that historical verdicts, null wording and Codex cross-check descriptions are not upgraded into current reassessment or specialist certification." } ] }