Idiopathic Intracranial Hypertension Treatment Trial

Condition(s) targeted: Idiopathic Intracranial Hypertension

Intervention: Acetazolamide (Drug); Placebo (Drug); Formal weight loss counselling program (Behavioral)

Phase: Phase 2/Phase 3

Status: Completed

Sponsored by: St. Luke's-Roosevelt Hospital Center

Official(s) and/or principal investigator(s):
Michael Wall, MD, Study Director, Affiliation: University of Iowa

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).

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Perimetric mean deviation change

Secondary outcome: Papilledema grade on fundus photography

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

Minimum age: 18 Years. Maximum age: 60 Years. Gender(s): Both.

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

University of Alabama Birmingham, Birmingham, Alabama 35294, United States

University of Calgary: Rockyview General Hospital, Calgary, Alberta T2V 1P9, Canada

Doheny Eye Center, University of Southern California, Los Angeles, California 90033, United States

The Eye Care Group, PC, Waterbury, Connecticut 06708, United States

Bascom Palmer Eye Institute, University of Miami, Miami, Florida 33136, United States

Neuro-Ophthamology & Balance Disorders Clinic, Tallahassee, Florida 32308, United States

Emory University, Atlanta, Georgia 30322, United States

University of Illinois, Peoria, Illinois 61637, United States

Department of Ophthamology and Visual Sciences, University of Iowa, Iowa City, Iowa 55242, United States

University of Kentucky, Lexington, Kentucky 40536, United States

Louisiana State University Health Sciences Center - Earl K. Long Medical Center, Baton Rouge, Louisiana 70810, United States

Greater Baltimore Medical Center Department Of Ophthamology, Baltimore, Maryland 21204, United States

Johns Hopkins Universtiy - Wilmer Ophthamological Institute, Baltimore, Maryland 21287, United States

Bethesda Neurology, LLC, Bethesda, Maryland 20814, United States

Massachusetts Eye and Ear Infirmary - Neuro-Ophthamology Service, Boston, Massachusetts 02114, United States

Michigan State University Department of Neurology, East Lansing, Michigan 48823, United States

William Beaumont Hosptial Research Institute, Royal Oak, Michigan 48073, United States

University of Minnesota, Minneapolis, Minnesota 55455, United States

Saint Louis University Eye Institute, Saint Louis, Missouri 63104, United States

University of St. Louis, St. Louis, Missouri 63110, United States

New Jersey Medical School/University Physicians Associates of New Jersey, Newark, New Jersey 07103, United States

New York Eye and Ear Infirmary, New York City, New York 10003, United States

The Mount Sinai Medical Center, New York, New York 10029, United States

Weill Cornell Medical College, New York, New York 10021, United States

University of Rochester - Flaum Eye Institute, Rochester, New York 14642, United States

Stony Brook University, Stony Brook, New York 11794, United States

SUNY Upstate Medical University, Neurology Medical Service Group, Syracuse, New York 13202, United States

Duke Eye Center, Durham, North Carolina 27710, United States

Raleigh Neurology Associates, PA, Raleigh, North Carolina 27607, United States

Wake Forrest University Eye Center, Winston Salem, North Carolina 27157, United States

Ohio State University, Columbus, Ohio 43212, United States

Dean A. McGee Eye Institute, Oklahoma City, Oklahoma 73104, United States

Queen's University - Hotel Dieu Hospital, Kingston, Ontario K7L 5G2, Canada

Oregon Health & Science University - Casey Eye Institute, Portland, Oregon 97239, United States

University of Pennsylvania, Department of Ophthamology, Philadelphia, Pennsylvania 19104, United States

The Methodist Hospital: Methodist Eye Associates, Houston, Texas 77030, United States

Universtiy of Houston - University Eye Institute, Houston, Texas 77204, United States

University of Texas Science Center, San Antonio, Texas 78229, United States

University of Utah, John A. Moran Eye Center, Salt Lake City, Utah 84132, United States

University of Virginia - Department of Ophthalmology, Charlottesville, Virginia 22903, United States

Swedish Medical Center, Seattle, Washington 98014, United States

Organization Web-site

Starting date: January 2010
Last updated: March 3, 2015