DRAIN
(2026)Objective
To assess whether low-dose acetazolamide improves gait function compared with placebo in patients with idiopathic normal pressure hydrocephalus (iNPH) awaiting ventriculoperitoneal shunt surgery.
Study Summary
• Adverse events more frequent with acetazolamide: 20/25 (80%) vs 15/25 (60%) with placebo
• Treatment discontinuation due to adverse events: 9/25 (36%) acetazolamide vs 2/25 (8%) placebo
• No serious adverse events were considered related to study treatment
• Findings do not support routine use of acetazolamide as pharmacological treatment for iNPH
Intervention
Low-dose acetazolamide (titrated up to 250 mg twice daily, max 500 mg/day) given orally until shunt surgery admission or for a maximum of 9 months.
Inclusion Criteria
Adults aged 50-82 years with probable idiopathic normal pressure hydrocephalus per international criteria, characteristic imaging findings (ventriculomegaly with narrow callosal angle or DESH), and MMSE >20 or iNPH grading scale cognitive domain score >30.
Study Design
Arms: Acetazolamide up to 250 mg twice daily (n=25) vs matching placebo (n=25)
Patients per Arm: 25 per arm (50 total randomized; 41 in mITT: 20 acetazolamide, 21 placebo)
Outcome
• Adverse events: 80% acetazolamide vs 60% placebo
• Discontinuation due to AEs: 36% acetazolamide vs 8% placebo
• 4 serious AEs total (2 in each arm), none treatment-related
• Median time to end-of-treatment: 121 days (acetazolamide) vs 187 days (placebo)
Bottom Line
Low-dose acetazolamide (up to 500 mg/day) did not improve gait or any secondary clinical outcome in idiopathic normal pressure hydrocephalus and was poorly tolerated, with high rates of adverse events and treatment discontinuation. These findings do not support its use as pharmacological treatment for iNPH; ventriculoperitoneal shunt surgery remains the only established effective treatment.
Major Points
- First randomised, double-blind, placebo-controlled trial of any pharmacological treatment in iNPH
- Acetazolamide did NOT improve the primary outcome (composite gait score): adjusted between-group difference 0.09 units (95% CI -3.61 to 3.79, p=0.96)
- No benefit on any secondary clinical outcomes (iNPH grading scale, EQ-5D-5L, patient-reported outcomes)
- Adverse events numerically more frequent with acetazolamide (80% vs 60%; p=0.22, not statistically significant)
- Treatment discontinuation due to adverse events 4.5x higher with acetazolamide (36% vs 8%; p=0.037)
- Minor MRI changes (ventricular volume, periventricular white matter lesions, callosal angle) seen in MRI subgroup but without clinical benefit
- Findings argue against routine use of acetazolamide in iNPH; shunt surgery remains the only established effective treatment
Study Design
- Study Type
- Investigator-initiated, randomised, double-blind, placebo-controlled, phase 2 trial
- Randomization
- Yes
- Blinding
- Double-blind (participants, investigators, clinical staff, and outcome assessors all masked)
- Sample Size
- 50
- Follow-up
- Until admission for shunt surgery or maximum 9 months
- Centers
- 1
- Countries
- Sweden
Primary Outcome
Definition: Change in composite gait score (unweighted mean of time and steps from 10 m walk, Timed Up and Go, and 3 m backward walk; higher values = worse performance; negative change = improvement) from baseline to end-of-treatment visit
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Placebo arm change in composite gait score | Acetazolamide arm change in composite gait score | - (-3.61 to 3.79) | 0.96 |
Limitations & Criticisms
- Single-center trial at Uppsala University Hospital limits generalizability
- Small sample size (n=50 randomized, n=41 in mITT) — though adequately powered per prespecified calculation
- Variable treatment duration (median 121 vs 187 days) because timing depended on clinical surgical scheduling; shorter exposure in acetazolamide arm partly due to discontinuations
- Low-dose regimen (up to 500 mg/day) selected for tolerability — higher doses not tested and could theoretically have different efficacy
- Primary outcome reported as absolute change rather than prespecified percentage change (post-hoc harmonization with secondary outcomes)
- Composite gait score was a novel, study-specific measure rather than an established clinical endpoint
- Population limited to patients with probable iNPH awaiting shunt surgery — findings may not generalize to other iNPH subgroups
- Phase 2 trial — confirmatory phase 3 trial not feasible per authors given tolerability and risk of delaying shunt surgery
Citation
Lancet Neurol 2026; 25: 550-59