Idiopathic Intracranial Hypertension Treatment Trial

NCT01003639 | Completed Phase 2 Results DMC

• 3 other identifiers: NORDIC011U10EY017281-01A11U10EY017387-01A1
• Study Type: interventional
• Target: 165
• Locations: 2 countries
• Sites: 41

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).

Conditions

Idiopathic Intracranial Hypertension

Keywords

papilledema; vision loss; headache; obesity; women; diplopia; tinnitus

Outcome Measures

Primary Outcomes (1)

• Mean Change in Perimetric Mean Deviation

  Treatment Effects on the Primary Outcome Variable, Mean change From Baseline to Month 6 in Perimetric Mean Deviation (PMD) in the Study Eye. Perimetric mean deviation is a measure of global visual field loss (mean deviation from age-corrected normal values), with a range of 2 to -32 dB; larger negative values indicate greater vision loss.

  base line and 6 months

Secondary Outcomes (3)

• Mean Change of Papilledema Grade on Fundus Photography

  Baseline and 6 Months

• Visual Function Questionnaire (VFQ-25)

  baseline

• Visual Acuity (No. of Correct Letters)

  Baseline

Study Arms (2)

Acetazolamide

ACTIVE COMPARATOR

Acetazolamide given in escalating doses

Drug: Acetazolamide; Behavioral: Formal weight loss counselling program

Sugar pill

PLACEBO COMPARATOR

Given in escalating "dose" (number of pill)

Drug: Placebo; Behavioral: Formal weight loss counselling program

Interventions

Acetazolamide DRUG

Subjects will begin with four 250 mg tablets daily. Tablets will be divided among two doses, taken with meals. Beginning on day 7, subjects will increase the dose by 1 pill every week until 16 tablets daily is reached (4 grams acetazolamide or placebo) or side effects prohibit increasing the dosage further. Thus, subjects who are able to tolerate the study medication will reach the maximum dose by day 84.

Also known as: naproxen, acetaminophen, aspirin, ibuprofen, codein, butalbital

Acetazolamide

Placebo DRUG

Subjects will begin with four tablets daily. Tablets will be divided among two doses, taken with meals. Beginning on day 7, subjects will increase the dose by 1 pill every week until 16 tablets daily is reached (4 grams acetazolamide or placebo) or side effects prohibit increasing the dosage further. Thus, subjects who are able to tolerate the study medication will reach the maximum dose by day 84.

Also known as: naproxen, acetaminophen, aspirin, ibuprofen, codein, butalbital

Sugar pill

Formal weight loss counselling program BEHAVIORAL

Teleconference, web-based from central location, using site visits and subject self-assessment tools

Also known as: naproxen, acetaminophen, aspirin, ibuprofen, codein, butalbital

Acetazolamide; Sugar pill

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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
• Diagnosis of IIH for 6 weeks or less
• Age 18 to 60 years at time of diagnosis
• Reproducible visual loss present on automated perimetry (in eye with greatest loss)
• Average PMD -2 dB up to -5 dB in the worst eye
• Presence of bilateral papilledema
• Able to provide informed consent
• 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,

You may not qualify if:

• 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.
• Previous surgery for IIH including optic nerve sheath fenestration, CSF shunting procedures, subtemporal decompression and venous stenting
• Previous gastric bypass surgery
• Abnormalities on neurologic examination aside from papilledema and its related visual loss or VI nerve paresis
• 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
• CSF pressure less than 200 mm water (patients may have repeat CSF pressure measurements if the first is normal or no opening pressure obtained)
• 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
• 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

Sponsors & Collaborators

• St. Luke's-Roosevelt Hospital Center: lead
• National Eye Institute (NEI): collaborator
• University of Rochester: collaborator
• University of Iowa: collaborator
• University of California, Davis: collaborator

Study Sites (41)

University of Alabama Birmingham

Birmingham, Alabama, 35294, United States

Location

Doheny Eye Center, University of Southern California

Los Angeles, California, 90033, United States

Location

The Eye Care Group, PC

Waterbury, Connecticut, 06708, United States

Location

Bascom Palmer Eye Institute, University of Miami

Miami, Florida, 33136, United States

Location

Neuro-Ophthamology & Balance Disorders Clinic

Tallahassee, Florida, 32308, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

University of Illinois

Peoria, Illinois, 61637, United States

Location

Department of Ophthamology and Visual Sciences, University of Iowa

Iowa City, Iowa, 55242, United States

Location

University of Kentucky

Lexington, Kentucky, 40536, United States

Location

Louisiana State University Health Sciences Center - Earl K. Long Medical Center

Baton Rouge, Louisiana, 70810, United States

Location

Greater Baltimore Medical Center Department Of Ophthamology

Baltimore, Maryland, 21204, United States

Location

Johns Hopkins Universtiy - Wilmer Ophthamological Institute

Baltimore, Maryland, 21287, United States

Location

Bethesda Neurology, LLC

Bethesda, Maryland, 20814, United States

Location

Massachusetts Eye and Ear Infirmary - Neuro-Ophthamology Service

Boston, Massachusetts, 02114, United States

Location

Michigan State University Department of Neurology

East Lansing, Michigan, 48823, United States

Location

William Beaumont Hosptial Research Institute

Royal Oak, Michigan, 48073, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Saint Louis University Eye Institute

St Louis, Missouri, 63104, United States

Location

University of St. Louis

St Louis, Missouri, 63110, United States

Location

New Jersey Medical School/University Physicians Associates of New Jersey

Newark, New Jersey, 07103, United States

Location

New York Eye and Ear Infirmary

New York, New York, 10003, United States

Location

Weill Cornell Medical College

New York, New York, 10021, United States

Location

The Mount Sinai Medical Center

New York, New York, 10029, United States

Location

University of Rochester - Flaum Eye Institute

Rochester, New York, 14642, United States

Location

Stony Brook University

Stony Brook, New York, 11794, United States

Location

SUNY Upstate Medical University, Neurology Medical Service Group

Syracuse, New York, 13202, United States

Location

Duke Eye Center

Durham, North Carolina, 27710, United States

Location

Raleigh Neurology Associates, PA

Raleigh, North Carolina, 27607, United States

Location

Wake Forrest University Eye Center

Winston-Salem, North Carolina, 27157, United States

Location

Ohio State University

Columbus, Ohio, 43212, United States

Location

Dean A. McGee Eye Institute

Oklahoma City, Oklahoma, 73104, United States

Location

Oregon Health & Science University - Casey Eye Institute

Portland, Oregon, 97239, United States

Location

University of Pennsylvania, Department of Ophthamology

Philadelphia, Pennsylvania, 19104, United States

Location

The Methodist Hospital: Methodist Eye Associates

Houston, Texas, 77030, United States

Location

Universtiy of Houston - University Eye Institute

Houston, Texas, 77204, United States

Location

University of Texas Science Center

San Antonio, Texas, 78229, United States

Location

University of Utah, John A. Moran Eye Center

Salt Lake City, Utah, 84132, United States

Location

University of Virginia - Department of Ophthalmology

Charlottesville, Virginia, 22903, United States

Location

Swedish Medical Center

Seattle, Washington, 98014, United States

Location

University of Calgary: Rockyview General Hospital

Calgary, Alberta, T2V 1P9, Canada

Location

Queen's University - Hotel Dieu Hospital

Kingston, Ontario, K7L 5G2, Canada

Location

Related Publications (13)

• 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.

  PMID: 24756514 RESULT

• 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.

  PMID: 28492874 DERIVED

• 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.

  PMID: 28130349 DERIVED

• 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.

  PMID: 27694262 DERIVED

• 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.

  PMID: 26934136 DERIVED

• 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.

  PMID: 26778344 DERIVED

• 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.

  PMID: 26618282 DERIVED

• 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.

  PMID: 26335066 DERIVED

• 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.

  PMID: 26024112 DERIVED

• 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.

  PMID: 25370513 DERIVED

• 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.

  PMID: 25370510 DERIVED

• 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.

  PMID: 24781936 DERIVED

• 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.

  PMID: 24756302 DERIVED

Related Links

• Organization Web-site

MeSH Terms

Conditions

Pseudotumor Cerebri; Papilledema; Vision Disorders; Headache; Obesity; Diplopia; Tinnitus

Interventions

Acetazolamide; Naproxen; Acetaminophen; Aspirin; Ibuprofen; Codeine; butalbital

Condition Hierarchy (Ancestors)

Intracranial Hypertension; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Optic Nerve Diseases; Cranial Nerve Diseases; Eye Diseases; Sensation Disorders; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Pain; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases

Intervention Hierarchy (Ancestors)

Thiadiazoles; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Naphthaleneacetic Acids; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Acetanilides; Anilides; Amides; Aniline Compounds; Amines; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Phenylpropionates; Acids, Carbocyclic; Carboxylic Acids; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes

Limitations and Caveats

A limitation is the 19% withdrawal rate which may be due, in part, to the intensity of the visit schedule. Another limitation is the difficulty in the interpretation of the estimated treatment effect on PMD.

Results Point of Contact

• Title: Dr. Michael Wall
• Organization: University of Iowa Hospitals and Clinics

michael-wall@uiowa.edu

319-353-3942

Study Officials

• Michael Wall, MD

  University of Iowa

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 28, 2009
• First Posted: October 29, 2009
• Study Start: January 1, 2010
• Primary Completion: June 1, 2013
• Study Completion: January 1, 2014
• Last Updated: December 12, 2018
• Results First Posted: December 12, 2018

Record last verified: 2018-11

Locations

CA (2); US (39)