Clinical trial NCT01003639: Idiopathic Intracranial Hypertension Treatment Trial
Official title: A Multicenter, Double-blind, Randomized, Placebo-controlled Study of Weight-Reduction and/or Low Sodium Diet Plus Acetazolamide vs Diet Plus Placebo in Subjects With Idiopathic Intracranial Hypertension With Mild Visual Loss
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Idiopathic Intracranial Hypertension
Keywords: papilledema
vision loss
headache
obesity
women
diplopia
tinnitus
Lead sponsor: St. Luke's-Roosevelt Hospital Center
Sponsor class: OTHER
Collaborators: name: National Eye Institute (NEI)
name: University of Rochester
name: University of Iowa
name: University of California, Davis
First posted: 2009-10-29
Enrollment: 165
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Idiopathic intracranial hypertension (IIH), also called pseudotumor cerebri, is a disorder of elevated intracranial pressure of unknown cause \[Corbett, et al., 1982; Wall, et al., 1991\]. Its incidence is 22.5 new cases each year per 100,000 overweight women of childbearing age, and is rising \[Garrett, et al., 2004\] in parallel with the obesity epidemic. It affects about 100,000 Americans. Most patients suffer debilitating headaches. Because of pressure on the optic nerve (papilledema), 86% have some degree of permanent visual loss and 10% develop severe visual loss \[Wall, et al., 1991\]. Interventions to prevent loss of sight, all with unproven efficacy, include diet, diuretics such as acetazolamide, repeated spinal taps, optic nerve sheath fenestration surgery, and cerebrospinal fluid (CSF) shunting procedures. The purported goal of these therapies is to lower intracranial pressure; however, it is unclear which treatments work and by what mechanism. None of these strategies has been verified by properly designed clinical trials. Thus, there is confusion, uncertainty, and weak scientific rationales to guide treatment decisions. This trial will study subjects who have mild visual loss from IIH to (1) establish convincing, evidence-based treatment strategies for IIH to restore and protect vision, (2) follow subjects up to 4 years to observe the long-term treatment outcomes and (3) determine the cause of IIH. To meet those aims, the trial will be divided into a 12-month intervention phase and a 3-year observational phase. Subjects are not required to complete the observational phase of the study, but will be asked to do so and consented for the observational phase of the study at the conclusion of the intervention phase (12 months).

Detailed description: Clinical Phase: Phase II Investigators: NORDIC Network sites Study Centers: 38 study centers Coordinating Center - University of Rochester Statistical Center - University of Rochester Study Period Planned enrollment duration: 2 years Planned duration of treatment: 6 months followed by open-label treatment Planned duration of follow-up: 4.5 years Study Objectives: The primary objective is determining the efficacy of diet plus acetazolamide vs diet alone in reducing or reversing visual loss in subjects with mild visual loss.

The secondary objective is to identify proteomic and genetic risk factors for IIH by screening a large cohort of IIH patients and controls.

Study Population This project will enroll 166 individuals with IIH who are 18-60 years of age. We anticipate that the population will be primarily composed of women in the childbearing years that are overweight. 154 control subjects will also be enrolled. Control subjects will be matched as closely as possibly by age, sex, race, ethnicity and weight to subjects enrolled at the site.

Study Design: Multi-center, double-blind randomized intervention study followed by a 4-year observation period. Subjects will be randomized to diet and acetazolamide or diet and placebo. The study will use 250 mg acetazolamide or matching placebo tablets taken with food at meals and at bedtime. The subject will begin with one tablet four times daily, at meals and at bedtime for the first week. Beginning on Day 7, subjects will increase the dosage by 1 tablet every 4 days until a final dosage of 4 tablets four times daily (4 grams) is reached or side effects prohibit increasing the dosage further. If the study drug is not tolerated at a dose of 250 mg, then 125 mg (1/2 tablet) will be tried. If this is not tolerated, no pharmacologic treatment will be given.

After the 6 month visit, all subjects will transition from study medication to acetazolamide (open label) by replacing one tablet of study drug with 250 mg of acetazolamide every four days. The acetazolamide dose will be titrated in a manner similar to the initial study drug schedule to the maximum tolerated dose of acetazolamide. To avoid treating subjects (who may have initially been assigned to placebo) unnecessarily, any subject with grade 0-1 papilledema will be tapered off study drug but not placed on acetazolamide unless they have persisting headaches or pulse-synchronous tinnitus. If so, they will be placed on acetazolamide regardless of the low papilledema grade. At the 9-month follow-up visit, we will make sure that the subjects' vision is stable after the transition off of study medication. After the 9 month visit, medication will be prescribed by the subject's treating physician. The intervention phase of the study will end at the subject's 12 month visit and subjects will be invited to participate in the observational phase of the study and consented to do so if willing.

Number of Subjects: 166 subjects with IIH and 154 control subjects Main Inclusion Criteria

1. Diagnosis of IIH by modified Dandy criteria
2. Diagnosis of IIH for 6 weeks or less
3. Age 18 to 60 years at time of diagnosis
4. Reproducible visual loss present on automated perimetry (in eye with greatest loss)\*
5. perimetric mean deviation (PMD) -2 decibel (dB) up to -5 dB in the worst eye
6. Presence of bilateral papilledema
7. Able to provide informed consent or parental permission with appropriate assent

Main Exclusion Criteria

1. Total treatment of IIH of more than one week in the past six weeks
2. Corticosteroids or surgery used for IIH treatment within the past two months
3. Abnormalities on neurologic examination aside from papilledema and its related visual loss or VI nerve paresis (unless pre-existing and unrelated to IIH)
4. Abnormal CT or MRI scan (intracranial mass, hydrocephalus, dural sinus thrombus or arteriovenous malformation) other than empty sella, dilated optic nerve sheath, flattened sclera, or secondary Chiari
5. CSF pressure less than 200 mm water (patients may have repeat CSF pressure measurements if the first is normal or no opening pressure obtained)
6. Abnormal CSF contents (increased cells, elevated protein, low glucose)
7. Intraocular pressure currently \> 28 mm Hg or \> 30 mm Hg at any time in the past
8. Refractive error \> +/- 6.00 sphere or \> +/- 3.00 cylinder in either eye
9. Other disorders causing visual loss except for refractive error and amblyopia including cells in the vitreous or iritis
10. Inability to provide reliable and reproducible visual field examination (failure to maintain fixation using an eye monitoring device, more than 15% false positive errors
11. Abnormal blood work-up indicating a medical or systemic condition associated with raised intracranial pressure (ICP)
12. Exposure to a drug, substance or disorder that has been associated with elevation of intracranial pressure within 2 months of diagnosis such as lithium, vitamin A, tetracycline, steroid withdrawal (see table in Manual of Procedures (MOP) for conditions and drugs)
13. Other condition requiring diuretics, steroids or other pressure lowering agents including topiramate
14. Presence of a medical condition such as renal stones that would contraindicate use of the study drugs (acetazolamide)
15. Pregnancy or unwillingness for subject with childbearing potential to use contraception during the first year of the study
16. Presence of a physical, mental, or social condition likely to affect follow-up (drug addiction, terminal illness, no telephone, homeless)
17. Anticipation of a move from the site area within six months and unwillingness to return for follow-up.

Route and Dosage Form: 250 mg acetazolamide tablets or matching placebo taken with food 4 times daily. Subjects will titrate to a maximum dose of 4 tablets 4 times daily (4 grams) as tolerated. If a subject is not able to tolerate a dose of 250 mg, 125 mg (1/2 tablet) may be tried. If this is not tolerated, no pharmacologic treatment will be given.

Duration of Treatment: 6 months of randomized treatment followed by open label acetazolamide treatment. After the 9-month visit medication will be prescribed by the subject's treating physician. The intervention phase of the study will end at Month 12 and the subject invited to continue in the observational phase.

Primary Outcome Measure(s): The primary outcome measure is the change from baseline to Month 6 in PMD (perimetric mean deviation) in the eye with the most severe initial visual loss.

Secondary Outcome Measure: CSF pressure measurement by lumbar puncture Number of abnormal perimetry test locations Visual field examination ratings (improved, remained the same, or worsened) Papilledema grade QOL assessments Dietary Outcomes (BMI, Waist circumference, urinary sodium) Safety Outcomes: Adverse events will be tabulated by treatment group, severity, and perceived relationship to the study intervention Sample Size Considerations

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of IIH by modified Dandy criteria Signs and symptoms of increased intracranial pressure Absence of localizing findings on neurologic examination Absence of deformity, displacement, or obstruction of the ventricular system and otherwise normal neurodiagnostic studies, except for evidence of increased cerebrospinal fluid pressure (\>200 mm water). Abnormal neuroimaging except for empty sella turcica, optic nerve sheath enlargement, and smooth-walled non flow-related venous sinus stenosis or collapse106 should lead to another diagnosis Awake and alert No other cause of increased intracranial pressure present
2. Diagnosis of IIH for 6 weeks or less
3. Age 18 to 60 years at time of diagnosis
4. Reproducible visual loss present on automated perimetry (in eye with greatest loss)
5. Average PMD -2 dB up to -5 dB in the worst eye
6. Presence of bilateral papilledema
7. Able to provide informed consent
8. Women of child-bearing potential must use an acceptable form of birth control during the intervention phase of the study. Acceptable forms include oral contraceptives, transdermal contraceptives,

Exclusion Criteria:

1. Total treatment of IIH of more than two weeks (except for acetazolamide which is limited to 1 week). For every day on treatment there must be a one-day washout period.
2. Previous surgery for IIH including optic nerve sheath fenestration, CSF shunting procedures, subtemporal decompression and venous stenting
3. Previous gastric bypass surgery
4. Abnormalities on neurologic examination aside from papilledema and its related visual loss or VI nerve paresis
5. Abnormal CT or MRI scan (intracranial mass, hydrocephalus, dural sinus thrombus or arteriovenous malformation) other than empty sella, unfolded optic nerve sheaths, flattened sclera, or smooth- walled venous stenosis
6. CSF pressure less than 200 mm water (patients may have repeat CSF pressure measurements if the first is normal or no opening pressure obtained)
7. Abnormal CSF contents: increased cells: \> 5 cells, elevated protein:

\> 45 mg%, low glucose: \< 30 mg% (If the lumbar puncture produces a cell count compatible with a traumatic needle insertion, the patient does not need to be excluded if the CSF WBC after correction is 5 wbc/mm3 or less- see Operations Manual for calculation) 8. Intraocular pressure currently \> 28 mm Hg or \> 30 mm Hg at any time in the past 9. Refractive error \> +/- 6.00 sphere or \> +/- 3.00 cylinder in either eye with the following exceptions: Subjects with myopia of \>-6.00 D sphere but less than or equal to - 8.00 D sphere are eligible if 1)there are no abnormalities on ophthalmoscopy or fundus photos related to myopia that are associated with visual loss (such as staphyloma, retinal thinning in the posterior pole or more than mild optic disc tilt), and 2) the subject wears a contact lens for all perimetry examinations with the appropriate correction. If either the Site Investigator or the PRC director (or his designate) decides there are optic fundus abnormalities of myopia that are associated with visual loss, then 9. Subjects with hyperopia of \> +6.00 D but less than or equal to

* 8.00 D sphere are eligible if 1) there is an unambiguous characteristic halo of peripapillary edema as opposed to features of a small crowded disc or other hyperopic change related to visual loss determined by the site investigator or the PRC director (or his designate) and 2) the subject wears a contact le 10. Other disorders causing visual loss except for refractive error and amblyopia including cells in the vitreous or iritis 11. Optic disc drusen on exam or in previous history 12. Presence of diagnosed untreated obstructive sleep apnea 13. Inability to provide reliable and reproducible visual field examination (failure to maintain fixation using an eye monitoring device, more than 15% false positive errors) 14. Abnormal blood work-up indicating a medical or systemic condition associated with raised ICP 15. Study blood results showing severe anemia, leukopenia or thrombocytopenia, renal failure, or hepatic disease, based on the Site Investigator's judgment 16. Type I diabetes or the presence of diabetic retinopathy 17. Exposure to a drug, substance or disorder that has been associated with elevation of intracranial pressure within 2 months of diagnosis such as lithium, vitamin A, various cyclines (see table in Operations Manual for conditions and drugs) 18. Other condition requiring diuretics, oral, I.V. or injectable steroids or other pressure lowering agents including topiramate (nasal, inhaled, or topical steroids are allowed since the systemic effects are small) 19. Presence of a medical condition such as renal stones that would contraindicate use of the study drug (acetazolamide) 20. Pregnancy or unwillingness for subject of childbearing potential to use contraception during the first year of the study 21. Breastfeeding mothers are excluded from participation unless willing to discontinue breastfeeding by the baseline visit 22. Presence of a physical, mental, or social condition likely to affect follow-up (drug addiction, terminal illness, no telephone, homeless) 23. Anticipation of a move from the site area within six months and unwillingness to return for follow-up at an IIHTT study site 24. Allergy to pupil dilating drops or narrow angles precluding safe dilation

Primary outcomes:
measure: Mean Change in Perimetric Mean Deviation
timeFrame: base line and 6 months
Secondary outcomes:
measure: Mean Change of Papilledema Grade on Fundus Photography
timeFrame: Baseline and 6 Months
measure: Visual Function Questionnaire (VFQ-25)
timeFrame: baseline
measure: Visual Acuity (No. of Correct Letters)
timeFrame: Baseline
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: Doheny Eye Center, University of Southern California
state: California
city: Waterbury
country: United States
facility: The Eye Care Group, PC
state: Connecticut
city: Miami
country: United States
facility: Bascom Palmer Eye Institute, University of Miami
state: Florida
city: Tallahassee
country: United States
facility: Neuro-Ophthamology & Balance Disorders Clinic
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Peoria
country: United States
facility: University of Illinois
state: Illinois
city: Iowa City
country: United States
facility: Department of Ophthamology and Visual Sciences, University of Iowa
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baton Rouge
country: United States
facility: Louisiana State University Health Sciences Center - Earl K. Long Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: Greater Baltimore Medical Center Department Of Ophthamology
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Universtiy - Wilmer Ophthamological Institute
state: Maryland
city: Bethesda
country: United States
facility: Bethesda Neurology, LLC
state: Maryland
city: Boston
country: United States
facility: Massachusetts Eye and Ear Infirmary - Neuro-Ophthamology Service
state: Massachusetts
city: East Lansing
country: United States
facility: Michigan State University Department of Neurology
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hosptial Research Institute
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University Eye Institute
state: Missouri
city: Saint Louis
country: United States
facility: University of St. Louis
state: Missouri
city: Newark
country: United States
facility: New Jersey Medical School/University Physicians Associates of New Jersey
state: New Jersey
city: New York
country: United States
facility: New York Eye and Ear Infirmary
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: The Mount Sinai Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester - Flaum Eye Institute
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University, Neurology Medical Service Group
state: New York
city: Durham
country: United States
facility: Duke Eye Center
state: North Carolina
city: Raleigh
country: United States
facility: Raleigh Neurology Associates, PA
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forrest University Eye Center
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: Dean A. McGee Eye Institute
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University - Casey Eye Institute
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania, Department of Ophthamology
state: Pennsylvania
city: Houston
country: United States
facility: The Methodist Hospital: Methodist Eye Associates
state: Texas
city: Houston
country: United States
facility: Universtiy of Houston - University Eye Institute
state: Texas
city: San Antonio
country: United States
facility: University of Texas Science Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, John A. Moran Eye Center
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia - Department of Ophthalmology
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
city: Calgary
country: Canada
facility: University of Calgary: Rockyview General Hospital
state: Alberta
city: Kingston
country: Canada
facility: Queen's University - Hotel Dieu Hospital
state: Ontario
Study officials:
affiliation: University of Iowa
name: Michael Wall, MD
role: STUDY_DIRECTOR
References:
citation: NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee; Wall M, McDermott MP, Kieburtz KD, Corbett JJ, Feldon SE, Friedman DI, Katz DM, Keltner JL, Schron EB, Kupersmith MJ. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA. 2014 Apr 23-30;311(16):1641-51. doi: 10.1001/jama.2014.3312.
citation: Wang JK, Kardon RH, Ledolter J, Sibony PA, Kupersmith MJ, Garvin MK; OCT Sub-Study Committee and the NORDIC Idiopathic Intracranial Hypertension Study Group. Peripapillary Retinal Pigment Epithelium Layer Shape Changes From Acetazolamide Treatment in the Idiopathic Intracranial Hypertension Treatment Trial. Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2554-2565. doi: 10.1167/iovs.16-21089.
citation: Wall M, Thurtell MJ; NORDIC Idiopathic Intracranial Hypertension Study Group. Optic disc haemorrhages at baseline as a risk factor for poor outcome in the Idiopathic Intracranial Hypertension Treatment Trial. Br J Ophthalmol. 2017 Sep;101(9):1256-1260. doi: 10.1136/bjophthalmol-2016-309852. Epub 2017 Jan 27.
citation: Bruce BB, Digre KB, McDermott MP, Schron EB, Wall M; NORDIC Idiopathic Intracranial Hypertension Study Group. Quality of life at 6 months in the Idiopathic Intracranial Hypertension Treatment Trial. Neurology. 2016 Nov 1;87(18):1871-1877. doi: 10.1212/WNL.0000000000003280. Epub 2016 Sep 30.
citation: Wall M, Johnson CA, Cello KE, Zamba KD, McDermott MP, Keltner JL; NORDIC Idiopathic Intracranial Hypertension Study Group. Visual Field Outcomes for the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). Invest Ophthalmol Vis Sci. 2016 Mar;57(3):805-12. doi: 10.1167/iovs.15-18626.
citation: Sibony PA, Kupersmith MJ; OCT Substudy Group of the NORDIC Idiopathic Intracranial Hypertension Treatment Trial. "Paton's Folds" Revisited: Peripapillary Wrinkles, Folds, and Creases in Papilledema. Ophthalmology. 2016 Jun;123(6):1397-9. doi: 10.1016/j.ophtha.2015.12.017. Epub 2016 Jan 14. No abstract available.
citation: Cello KE, Keltner JL, Johnson CA, Wall M; NORDIC Idiopathic Intracranial Hypertension Study Group. Factors Affecting Visual Field Outcomes in the Idiopathic Intracranial Hypertension Treatment Trial. J Neuroophthalmol. 2016 Mar;36(1):6-12. doi: 10.1097/WNO.0000000000000327.
citation: Sibony PA, Kupersmith MJ, Feldon SE, Wang JK, Garvin M; OCT Substudy Group for the NORDIC Idiopathic Intracranial Hypertension Treatment Trial. Retinal and Choroidal Folds in Papilledema. Invest Ophthalmol Vis Sci. 2015 Sep;56(10):5670-80. doi: 10.1167/iovs.15-17459.
citation: Fischer WS, Wall M, McDermott MP, Kupersmith MJ, Feldon SE; NORDIC Idiopathic Intracranial Hypertension Study Group. Photographic Reading Center of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT): Methods and Baseline Results. Invest Ophthalmol Vis Sci. 2015 May;56(5):3292-303. doi: 10.1167/iovs.15-16465.
citation: OCT Sub-Study Committee for NORDIC Idiopathic Intracranial Hypertension Study Group; Auinger P, Durbin M, Feldon S, Garvin M, Kardon R, Keltner J, Kupersmith MJ, Sibony P, Plumb K, Wang JK, Werner JS. Baseline OCT measurements in the idiopathic intracranial hypertension treatment trial, part II: correlations and relationship to clinical features. Invest Ophthalmol Vis Sci. 2014 Nov 4;55(12):8173-9. doi: 10.1167/iovs.14-14961.
citation: OCT Sub-Study Committee for NORDIC Idiopathic Intracranial Hypertension Study Group; Auinger P, Durbin M, Feldon S, Garvin M, Kardon R, Keltner J, Kupersmith M, Sibony P, Plumb K, Wang JK, Werner JS. Baseline OCT measurements in the idiopathic intracranial hypertension treatment trial, part I: quality control, comparisons, and variability. Invest Ophthalmol Vis Sci. 2014 Nov 4;55(12):8180-8. doi: 10.1167/iovs.14-14960.
citation: Keltner JL, Johnson CA, Cello KE, Wall M; NORDIC Idiopathic Intracranial Hypertension Study Group. Baseline visual field findings in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). Invest Ophthalmol Vis Sci. 2014 Apr 29;55(5):3200-7. doi: 10.1167/iovs.14-14243.
citation: Wall M, Kupersmith MJ, Kieburtz KD, Corbett JJ, Feldon SE, Friedman DI, Katz DM, Keltner JL, Schron EB, McDermott MP; NORDIC Idiopathic Intracranial Hypertension Study Group. The idiopathic intracranial hypertension treatment trial: clinical profile at baseline. JAMA Neurol. 2014 Jun;71(6):693-701. doi: 10.1001/jamaneurol.2014.133.