Tofersen in SOD1+ ALS
PICO
| Population | Adults randomised in trials registered on ClinicalTrials.gov for Amyotrophic. |
| Intervention | Tofersen (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 "tofersen" present in AACT
interventionsfor the NCT. - GATE-C — Condition pattern "amyotrophic" 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)
- Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)
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 '%tofersen%' INTERSECT SELECT nct_id FROM conditions WHERE lower(name) LIKE '%amyotrophic%'
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=tofersen+AND+amyotrophic+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 |
|---|---|
| E_two_arms | 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.
An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS
Primary outcome (AACT): Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)
| Events | No event | Total N | |
|---|---|---|---|
| Intervention | 13 | -8 | 5 |
| Control | 10 | -7 | 3 |
Forest plot — per-trial OR + pooled estimate
Insufficient event-count data for pooled estimate.
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=0 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: no major downgrade triggers from audit data.
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/TOFERSEN_SOD1_ALS_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.