Maralixibat in PFIC (MARCH-PFIC + cohort)
PICO
| Population | Adults randomised in trials registered on ClinicalTrials.gov for Cholestasis. |
| Intervention | Maralixibat (AACT-verified intervention name in each trial). |
| Comparator | Active comparator or placebo as registered on AACT. |
| Outcomes | Trial-declared primary outcome (AACT design_outcomes); event counts harvested from AACT outcome_measurements. |
| Design | Interventional RCTs (post-2010 start date), Phase 2/3 or Phase 3/4. |
Eligibility (6-gate audit)
- GATE-A — NCT exists in AACT 2026-04-12 snapshot.
- GATE-B — Drug pattern "maralixibat" present in AACT
interventionsfor the NCT. - GATE-C — Condition pattern "cholestasis" present in AACT
conditions. - GATE-D — Primary PMID's PubMed title or abstract mentions the drug or condition.
- GATE-E — AACT
baseline_countsreports ≥2 per-arm participant rows. - GATE-F — AACT
design_outcomesdeclares a primary outcome with measure text.
Audit verdict: VIABLE requires ≥3 trials passing all 6 gates (k≥3 — current standard for new audit-first builds). Older builds use k≥2.
Pre-specified primary outcomes (per trial)
- Mean Change in the Average Morning ItchRO(Obs) Severity Score in the Primary Cohort
Statistical methods
Inverse-variance random-effects pooling on the log-OR scale (Woolf estimator from AACT event counts), REML τ² with Hartung-Knapp-Sidik-Jonkman (HKSJ) variance correction and tk-1 critical value (Cochrane Handbook v6.5 conventions). Single-trial entries report Wald 95% CI on the log scale.
Search strategy
Source-of-truth: AACT 2026-04-12 snapshot from the Clinical Trials Transformation Initiative (CTTI). Auto-discovery query:
SELECT nct_id FROM interventions WHERE lower(name) LIKE '%maralixibat%' INTERSECT SELECT nct_id FROM conditions WHERE lower(name) LIKE '%cholestasis%'
PubMed bridge: NCBI E-utilities + idconv API to fetch primary publication PMID and abstract for each NCT.
https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi?db=pubmed&term=maralixibat+AND+cholestasis+AND+RCT
Cross-checking: every NCT that survives intersection is verified to have a primary outcome declared in AACT design_outcomes AND a publication whose abstract mentions the drug or condition (GATE-D).
PRISMA-style screening
| Records identified (AACT × PubMed) | 2 |
| Records excluded (gate failure) | 1 |
| Records included (all 6 gates pass) | 1 |
Exclusions by first failing gate
| Gate | n |
|---|---|
| B_drug_in_intvs | 1 |
Screening is fully deterministic: every record is auto-flagged by the gate that first fails. No subjective inclusion/exclusion decisions are made — the 6 gates are an objective machine-checkable contract.
A Study to Evaluate the Efficacy and Safety of Maralixibat in Subjects With Progressive Familial Intrahepatic Cholestasis (MARCH-PFIC)
Primary outcome (AACT): Mean Change in the Average Morning ItchRO(Obs) Severity Score in the Primary Cohort
| Events | No event | Total N | |
|---|---|---|---|
| Intervention | 8 | 39 | 47 |
| Control | 4 | 42 | 46 |
Published MD: -1.1 [-1.8, -0.3] (V2 RCT extractor on PubMed abstract)
"difference of -1.1 (95% CI -1.8 to -0.3"
Forest plot — per-trial OR + pooled estimate
Pooled estimate (REML-DL + HKSJ, Cochrane v6.5)
0. Published vs Pooled cross-check
1 of 1 trials had an extractable published effect estimate in their PubMed abstract (V2 RCT extractor; HR/OR/RR/MD). The pooled estimate is from AACT event counts (Woolf log-OR) and is therefore a different estimand from the trial-published HR — agreement at the rank/direction level is the integrity check.
| Trial | Type | Published effect (95% CI) | Source |
|---|---|---|---|
| MARCH-PFIC | MD | -1.1 [-1.8, -0.3] | PMID 38723644 |
Pooled (from AACT event counts): OR 2.154 [0.601, 7.723]
1. Heterogeneity
Requires k≥2 trials with event data.
2. Prediction interval
Requires k≥3 trials (Cochrane v6.5).
3. Egger's test
Requires k≥3.
4. Leave-one-out sensitivity
Requires k≥3.
5. PRISMA 2020 status
| Identification | AACT × PubMed intersection (deterministic) |
| Screening | 6-gate audit (machine-checkable) |
| Eligibility | k=1 trials passed all 6 gates |
| Included | k=1 with extractable event counts |
6. Risk of Bias (audit-first scope)
Audit-first builds do not apply RoB 2.0 domain coding — that requires full-text trial reading. The 6-gate audit gives an integrity floor (registration, drug, condition, outcomes, baseline counts, abstract concordance) but not a domain-level RoB verdict.
For RoB 2.0 coding, see the matching curated *_REVIEW.html for this topic if one exists in the flagship portfolio.
7. GRADE certainty (auto-derived)
Certainty: Very low
Auto-derivation considers k and I² only; full GRADE requires RoB, indirectness, publication bias judgment, and effect-magnitude scoring (not applied in audit-first builds). Triggers: k=1 (imprecision).
8. Reproducibility fingerprint
sha256[:16] = 7fd3236b81b35adf
Bit-stable hash of {sorted NCT list, pooled OR + 95% CI}. Reproduce by re-running scripts/add_topic_autodiscover.py + generate_topic_html.py against the same AACT snapshot.
Audit-first build
This review was generated by the 6-gate audit-first pipeline after the 16-round portfolio cleanup. Every included trial was verified against AACT 2026-04-12 + PubMed at extraction time (not after).
- Full per-trial gate log:
outputs/new_topics/MARALIXIBAT_PFIC_REVIEW.json - Methodology: FINAL_INTEGRITY_REPORT_V2.md
- Main index: RapidMeta portfolio
- AACT attribution: Clinical Trials Transformation Initiative (CTTI), snapshot 2026-04-12.
- PubMed attribution: NCBI E-utilities + idconv API.
Limits of this build
- Pool estimand is an OR derived from AACT event counts; the trial-published HR (where applicable) is not parsed from the PubMed abstract in the audit-first pipeline. The published-HR vs pooled-OR comparison is part of the full RapidMeta workbench for hand-curated reviews.
- Risk-of-bias (RoB-2) is not coded here — see the parent NMA review or the curated
*_REVIEW.htmlfor the same topic if one exists. - The 6 gates are necessary but not sufficient for a Cochrane-grade review — they are an integrity floor, not a ceiling.