---
title: "Fenfluramine for Dravet and Lennox-Gastaut Syndrome"
slug: fenfluramine_seizure
version: 1.1
timestamp: 2026-04-20T00:00:00Z
date: 2026-04-20
specialty: Neurology (Epilepsy)
canonical_url: https://mahmood726-cyber.github.io/rapidmeta-finerenone/protocols/fenfluramine_seizure_protocol_v1.1_2026-04-20.md
app_url: https://mahmood726-cyber.github.io/rapidmeta-finerenone/FENFLURAMINE_SEIZURE_REVIEW.html
license: MIT
---

# Fenfluramine in Dravet + LGS (Study 1 / Study 2 / LGS Study 1)
## A Living Systematic Review and Meta-Analysis Protocol

**Protocol version:** 1.1
**Frozen:** 2026-04-20T00:00:00Z
**Specialty:** Neurology (Epilepsy)

---

## 1. Review Title and Registration

**Title:** Fenfluramine (Serotonergic Release / Sigma-1 Agonist) for Drug-Resistant Dravet Syndrome and Lennox-Gastaut Syndrome: A Living Systematic Review and Meta-Analysis of the Phase 3 Pivotal RCTs

**Registration:** Protocol frozen 2026-04-20T00:00:00Z. Pre-registration mechanism: **GitHub-canonical-URL freeze**. **Authors:** Mahmood Ahmad (corresponding). drmahmoodclinic@pm.me.

---

## 2. PICO

| Element | Specification |
|---|---|
| **Population** | Children/young adults with drug-resistant Dravet syndrome (Study 1, Study 2) or Lennox-Gastaut syndrome (LGS Study 1) |
| **Intervention** | Fenfluramine 0.7 mg/kg/d (Study 1, LGS Study 1) or 0.4 mg/kg/d (Study 2 with stiripentol) adjunctive |
| **Comparator** | Matched placebo |
| **Outcome (primary)** | Proportion with >=50% reduction in monthly convulsive/drop seizure frequency at week 14; RR |

---

## 3. Eligibility / Search / Selection

Inclusion: phase III pivotal, Dravet or LGS, fenfluramine vs placebo adjunctive, convulsive/drop seizure primary, echocardiogram surveillance built-in (legacy valvular-disease concern). Exclusion: phase II, open-label extensions. Two-reviewer adjudication; PRISMA 2020.

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## 6-7. Data Extraction + RoB

Per-arm >=50% responder + RR (primary), median % seizure reduction (continuous sensitivity), echocardiographic valvulopathy/pulmonary-hypertension incidence, appetite-related AEs. RoB 2 LOW across D1-D5. Author sign-off per provisional-RoB banner.

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## 8. Synthesis

- DerSimonian-Laird RE IVW on log-RR; HKSJ t-df=k-1 with floor; PI computable at k=3.
- Subgroup: Dravet (+/- stiripentol) vs LGS; dose (0.4 vs 0.7 mg/kg).
- Sensitivity: exclude Study 2 (stiripentol-interaction-amplified); exclude LGS-only.
- Bayesian half-normal(0, 1.0) prior on tau (log-RR).

---

## 9-10. GRADE / Reporting

Standard GRADE. Class-level pool across Dravet (+/- stiripentol) and LGS with substantial heterogeneity (tau2 ~0.30). Stiripentol co-use pharmacokinetically amplifies fenfluramine effect in Study 2. Pre-specified indirectness downgrade. Cardiovascular-safety surveillance (legacy concern from 1990s anorectic use) showed no valvulopathy signal in any trial - reassuring. PRISMA 2020, CONSORT-Harms.

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## 11. Living-MA Update Cadence

3-monthly. Triggers: long-term open-label cardiac surveillance data, CDKL5-deficiency RCT, other developmental-and-epileptic encephalopathy trials.

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## 12-14
Aggregate-data only. No CoI, no funding.

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## Appendix A. AMSTAR-2

| # | Domain | Rating | Evidence |
|---|---|---|---|
| 1 | PICO | Yes | §2 |
| 2 | Registered protocol | Yes (partial) | GitHub-canonical-URL freeze |
| 4 | Search strategy | Yes | §4 |
| 7 | Excluded-studies list | Yes | Screening tab |
| 9 | RoB | Yes | Author-confirmed provisional |
| 11 | Statistical methods | Yes | §8 |
| 13 | RoB interpretation | Partial | Indication + stiripentol-interaction noted |
| 15 | Publication bias | Yes (k-appropriate) | k=3 |

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## Changelog
- **v1.1** (2026-04-20) — Initial editor-review-revision release.