PDF: SAHRANG
(2025)Objective
To examine the tolerability, safety, and preliminary efficacy of galantamine (acetylcholinesterase inhibitor) in patients with aneurysmal subarachnoid hemorrhage during early and subacute disease stages
Study Summary
• Bradycardia was the most common adverse event (37%); no difference in discontinuation rates between groups (1 patient each, p=0.92)
• Mortality at 90 days did not differ: 1 death (3.3%) in galantamine group vs 4 deaths (13.3%) in placebo group (p=0.34)
Intervention
Galantamine 8 mg or 12 mg orally every 12 hours (started within 36 hours of aneurysm securing, continued for 90 days) vs matching placebo
Inclusion Criteria
Adult patients with spontaneous aSAH, Fisher grade 3, Hunt and Hess grade 1-5, presentation within 72 hours of symptoms, cerebral aneurysm amenable to clipping/coiling, medication started within 36 hours of securing aneurysm
Study Design
Arms: Phase 1: Galantamine 8 mg q12h (n=15) vs Placebo (n=15); Phase 2: Galantamine 12 mg q12h (n=15) vs Placebo (n=15)
Patients per Arm: 30 patients received galantamine (15 in each dose cohort), 30 patients received placebo
Outcome
• No significant differences in mRS, MoCA scores, or absolute EQ5D5L scores at any timepoint
• Galantamine group showed significantly greater improvement in QOL (EQ5D5L VAS) between days 30-60 (10.7-point increase vs 1.04-point decrease, p<0.05)
Bottom Line
Galantamine was as tolerable and safe as placebo in patients with aSAH when administered early and continued for 90 days. While no significant differences were found in functional or cognitive outcomes, patients receiving galantamine showed greater improvement in quality of life during the early recovery phase (days 30-60).
Major Points
- First randomized placebo-controlled trial examining galantamine in acute aneurysmal SAH
- Two-phase dose-escalation design: Phase 1 tested 8 mg q12h, Phase 2 tested 12 mg q12h
- Interim safety analysis performed after first 30 patients showed no safety concerns
- Bradycardia was the most common adverse event (37%), but occurred equally in both groups
- No significant differences in adverse events, serious adverse events, or mortality between groups
- No significant differences in mRS distribution at any timepoint (discharge, 30, 60, or 90 days)
- No significant differences in MoCA cognitive scores at 30, 60, or 90 days
- Galantamine group showed significantly greater improvement in EQ5D5L VAS (quality of life) between days 30-60 (p<0.05)
- Proinflammatory cytokine levels in serum and CSF did not show consistent differences between groups
- Study underpowered for efficacy endpoints; designed as pilot/feasibility trial
Study Design
- Study Type
- Phase IIA prospective multicenter double-masked randomized placebo-controlled dose-escalation pilot trial
- Randomization
- Yes
- Blinding
- Double-masked (study participants and personnel blinded; ICU personnel and daily assessors blinded; research pharmacy performed unblinded randomization)
- Sample Size
- 60
- Follow-up
- 90 days after ictus
- Centers
- 2
- Countries
- United States
Primary Outcome
Definition: Tolerability: number of patients who stopped study medication due to adverse events associated with study drug; Mortality due to study drug assessed at 90 days
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 1 patient discontinued due to nausea; 4 deaths at 90 days | 1 patient discontinued due to skin rash; 1 death at 90 days | - | Discontinuation p=0.92; Mortality p=0.34 |
Limitations & Criticisms
- Pilot study not powered for efficacy outcomes - designed for feasibility assessment only
- Small sample size (60 patients total) limits generalizability and statistical power
- Low statistical power (25%) for detecting differences in adverse events
- Restrictive inclusion criteria (Fisher grade 3 only) limits generalizability to all SAH severity levels
- Relatively short follow-up period (90 days); long-term effects unknown
- Unequal losses to follow-up between groups (4 patients total)
- MoCA has large minimal detectable change (5 points), limiting sensitivity
- No measurement of serum galantamine levels to assess pharmacokinetics in SAH patients
- Cytokine measurements at relatively long intervals (≥24 hours) may have missed dynamic changes
- High baseline incidence of bradycardia in both groups may reflect disease severity rather than drug effect
- Interim analysis after 30 patients may have influenced enrollment dynamics
- No assessment of treatment effects in patients with Hunt and Hess grade 5 (most severe)
- Quality of life improvement marginally above minimal clinically important difference
Citation
Neurocrit Care. https://doi.org/10.1007/s12028-025-02349-3