IIHTT
The Idiopathic Intracranial Hypertension Treatment Trial
Clinical Question
Does acetazolamide improve visual function when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss?
Study Overview
Objective
To determine whether acetazolamide improves visual function when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss
Study Summary
- Acetazolamide plus diet showed modest improvement in visual field function compared to diet alone (treatment effect 0.71 dB, P=0.050)
- Significant improvements in papilledema grade, quality of life measures, and weight loss
- More frequent adverse events with acetazolamide including paresthesia, dysgeusia, and GI symptoms
Intervention
Acetazolamide (up to 4 g/d) or placebo, both with low-sodium weight-reduction diet
Patients per Arm
86 acetazolamide, 79 placebo
Bottom Line
Acetazolamide combined with a low-sodium weight-reduction diet resulted in modest but statistically significant improvement in visual field function compared to diet alone in patients with IIH and mild visual loss, though the clinical importance remains uncertain
Major Points
- First multicenter, double-blind, randomized controlled trial of acetazolamide for IIH
- Primary outcome showed 0.71 dB greater improvement in visual field (PMD) with acetazolamide vs placebo (P=0.050)
- Significant improvements in secondary outcomes: papilledema grade (P<0.001), vision-related quality of life (VFQ-25, P=0.003), and weight loss (4 kg greater, P<0.001)
- Treatment effect was greater in patients with more severe papilledema (grade 3-5) compared to milder papilledema
- Common adverse events included paresthesia (48%), dysgeusia (15%), fatigue (16%), and GI symptoms
- 19% withdrawal rate with similar reasons between groups; more acetazolamide patients discontinued drug (9 vs 1)
- Mediation analysis showed weight loss did not explain the visual benefit of acetazolamide
Design
Study Type: Interventional, randomized controlled trial
Randomization: 1
Blinding: Double-masked (participants, investigators, outcome assessors)
Enrollment Period: March 2010 to November 2012
Follow-up Duration: 6 months
Centers: 38
Countries: United States, Canada
Sample Size: 165
Analysis: Intention-to-treat using ANCOVA with multiple imputation for missing data, adjusted for center, baseline PMD, and papilledema grade; secondary analysis used MMRM; statistical analysis performed with SAS version 9.3
Inclusion Criteria
- Age 18-60 years
- Diagnosis of IIH meeting modified Dandy criteria
- Reproducible mild visual loss (PMD between -2 and -7 dB)
- Bilateral papilledema
- Elevated CSF opening pressure
- Untreated with regard to IIH
- No secondary cause of increased intracranial pressure
Exclusion Criteria
- Visual loss more severe than -7 dB PMD (lack of clinical equipoise for randomization)
- Visual loss less than -2 dB (insufficient room for improvement)
- Secondary causes of intracranial hypertension
- Prior treatment for IIH
- Other exclusions detailed in trial supplement
Arms
| Field | Acetazolamide + Diet | Control |
|---|---|---|
| Intervention | Acetazolamide 250 mg tablets; initial dose 4 tablets daily (1 g/d) in 2 divided doses, escalated by 1 tablet weekly to maximum 16 tablets (4 g/d); plus low-sodium weight-reduction diet from New York Obesity Nutrition Research Center | Matching placebo tablets; same escalation schedule as acetazolamide arm; plus identical low-sodium weight-reduction diet |
| Duration | 6 months | 6 months |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change in perimetric mean deviation (PMD) from baseline to month 6 in the eye with the most severe visual loss at baseline (study eye), measured by Humphrey Field Analyzer SITA Standard 24-2 | Primary | 0.71 dB improvement (from -3.53 to -2.82 dB) | 1.43 dB improvement (from -3.53 to -2.10 dB) | 0.050 | |
| Change in PMD in fellow eye | Secondary | 0.42 dB improvement (from -2.28 to -1.86) | 0.87 dB improvement (from -2.28 to -1.41) | Treatment effect 0.44 dB (95% CI 0.01 to 0.87) | 0.045 |
| Change in papilledema grade (study eye, fundus photography) | Secondary | -0.61 (from 2.76 to 2.15) | -1.31 (from 2.76 to 1.45) | Treatment effect -0.70 (95% CI -1.00 to -0.40) | <0.001 |
| Change in papilledema grade (fellow eye, fundus photography) | Secondary | -0.52 (from 2.50 to 1.98) | -1.14 (from 2.50 to 1.36) | Treatment effect -0.62 (95% CI -0.91 to -0.32) | <0.001 |
| Change in papilledema grade (study eye, site investigator rating) | Secondary | -0.85 (from 2.60 to 1.75) | -1.75 (from 2.60 to 0.85) | Treatment effect -0.91 (95% CI -1.27 to -0.54) | <0.001 |
| Change in papilledema grade (fellow eye, site investigator rating) | Secondary | -0.76 (from 2.32 to 1.56) | -1.64 (from 2.32 to 0.68) | Treatment effect -0.88 (95% CI -1.19 to -0.58) | <0.001 |
| VFQ-25 total score | Secondary | +1.98 (from 82.97 to 84.95) | +8.33 (from 82.97 to 91.30) | Treatment effect 6.35 (95% CI 2.22 to 10.47) | 0.003 |
| VFQ-25 10-item neuro-ophthalmic supplement | Secondary | +1.59 (from 75.45 to 77.04) | +9.82 (from 75.45 to 85.27) | Treatment effect 8.23 (95% CI 3.89 to 12.56) | <0.001 |
| SF-36 Physical Component Summary | Secondary | +2.82 (from 45.82 to 48.64) | +5.84 (from 45.82 to 51.66) | Treatment effect 3.02 (95% CI 0.34 to 5.70) | 0.03 |
| SF-36 Mental Component Summary | Secondary | +2.17 (from 44.61 to 46.78) | +5.62 (from 44.61 to 50.23) | Treatment effect 3.45 (95% CI 0.35 to 6.55) | 0.03 |
| HIT-6 total score | Secondary | -9.11 (from 59.70 to 50.59) | -9.56 (from 59.70 to 50.14) | Treatment effect -0.45 (95% CI -3.50 to 2.60) | 0.77 |
| Visual acuity in study eye (number of correct letters) | Secondary | +2.64 (from 56.26 to 58.90) | +2.65 (from 56.26 to 58.91) | Treatment effect 0.01 (95% CI -1.45 to 1.46) | 0.99 |
| Visual acuity in fellow eye (number of correct letters) | Secondary | +1.73 (from 57.28 to 59.01) | +2.10 (from 57.28 to 59.38) | Treatment effect 0.37 (95% CI -1.17 to 1.90) | 0.64 |
| Weight change | Secondary | -3.45 kg (from 107.72 to 104.27 kg) | -7.50 kg (from 107.72 to 100.22 kg) | Treatment effect -4.05 kg (95% CI -6.27 to -1.83) | <0.001 |
| CSF pressure change (n=85: 47 acetazolamide, 38 placebo) | Secondary | -52.4 mm H2O (from 357.2 to 304.8) | -112.3 mm H2O (from 357.2 to 244.9) | Treatment effect -59.9 mm H2O (95% CI -96.4 to -23.4) | 0.002 |
| Presence of headache at month 6 | Secondary | 68% | 69% | Adjusted OR 1.10 (95% CI 0.53 to 2.28) | 0.80 |
| Treatment failure | Secondary | 6 participants | 1 participant | 0.06 | |
| Paresthesia | Adverse | 5 (6.3%) | 41 (47.7%) | <0.001 | |
| Dysgeusia | Adverse | 0 (0%) | 13 (15.1%) | <0.001 | |
| Fatigue | Adverse | 1 (1.3%) | 14 (16.3%) | <0.001 | |
| Decreased CO2 | Adverse | 0 (0%) | 9 (10.5%) | 0.003 | |
| Nausea | Adverse | 10 (12.7%) | 26 (30.2%) | 0.008 | |
| Vomiting | Adverse | 3 (3.8%) | 12 (14.0%) | 0.03 | |
| Diarrhea | Adverse | 3 (3.8%) | 12 (14.0%) | 0.03 | |
| Tinnitus | Adverse | 3 (3.8%) | 11 (12.8%) | 0.05 | |
| Serious Adverse Events | Adverse | 3 participants (2 rapidly failing vision requiring optic nerve sheath fenestration, 1 pneumonia) | 6 participants (renal impairment, transaminitis, elevated lipase with pancreatitis, diverticulitis, allergic reaction, hypokalemia) | ||
| Drug Discontinuation | Adverse | 1 (1.3%) | 9 (10.5%) |
Subgroup Analysis
Treatment effect on primary outcome was substantially greater in participants with baseline papilledema grade 3-5 (2.27 dB) compared to those with grade 1-2 (-0.67 dB). Interactions examined with age, race, baseline PMD, papilledema grade, weight change in previous 6 months, and constant visual loss
Criticisms
- 19% withdrawal rate, though similar between groups
- More participants discontinued acetazolamide (9) than placebo (1), which may have attenuated the treatment effect
- Estimated treatment effect (0.71 dB) was only about half of the pre-specified minimal clinically important difference (1.3 dB)
- Minimal clinically important difference was based on small pilot study and did not incorporate patient input
- Clinical significance of 0.71 dB improvement in PMD remains uncertain
- Only 85 of 165 participants (52%) agreed to repeat lumbar puncture at month 6 for CSF pressure measurement (47/86 [55%] acetazolamide, 38/79 [48%] placebo)
- Results apply only to patients with mild visual loss (PMD -2 to -7 dB), not more severe cases
- Unable to separate effect of acetazolamide from effect of diet, as all received dietary intervention
- Relatively short 6-month follow-up period
- Mean final dose was 2.5 g/d in acetazolamide group vs 3.5 g/d in placebo group
- Predominantly female population (97.6%) limits generalizability
Funding
National Eye Institute (NEI) grants 1U10EY017281-01A1, DCBC 1U10EY017387-01A1, ARRA for NORDIC 3U10EY017281-01A1S1, and DCBC 1U10EY017387-01A1S1, and supplements for NORDIC 3U10EY017281-01A1S2
Based on: IIHTT (JAMA, 2014)
Authors: The NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee (Michael Wall, Michael P. McDermott, Karl D. Kieburtz, ..., Mark J. Kupersmith)
Citation: JAMA. 2014;311(16):1641-1651. doi:10.1001/jama.2014.3312
Reviewed by: Keiko Ihara, MD
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