The Idiopathic Intracranial Hypertension Treatment Trial: Design Considerations and Methods Deborah I. Friedman, MD, MPH, Michael P. McDermott, PhD, Karl Kieburtz, MD, MPH, Mark Kupersmith, MD, Ann Stoutenburg, CCRC, John L. Keltner, MD, Steven E. Feldon, MD, MBA, Eleanor Schron, PhD, RN, James J. Corbett, MD, Michael Wall, MD; for the NORDIC IIHTT Study Group Background: The objectives of this study were to present the rationale for the main aspects of the study design and describe the trial methodology for the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). Methods: Eligible candidates with mild visual field loss (automated perimetric mean deviation [PMD] 22 to 27 dB) were randomized to receive either acetazolamide or matching placebo tablets. Randomized participants were offered partic- ipation in a supervised dietary program. The primary outcome variable, PMD, was measured at 6 months. Additionally, cere- brospinal fluid from subjects and serum from study partici- pants and matched controls were collected for genetic analysis and vitamin A studies. An ancillary optical coherence substudy was added to investigate the changes of papillede- ma in the optic nerve head and retina that correlate with Frisén grading, visual field deficits, and low-contrast visual acuity. Results: The randomized trial entered 165 participants from March 17, 2010, through November 27, 2012, from the United States and Canada. The primary outcome (month 6) visits were successfully completed by June 15, 2013. Blood specimens were obtained from 165 controls without IIH to investigate vitamin A metabolism and genetic markers of potential risk factors for IIH. Conclusions: The IIHTT is the first randomized, double- masked placebo-controlled trial to study the effectiveness of medical treatment for patients with IIH. Journal of Neuro-Ophthalmology 2014;34:107–117 doi: 10.1097/WNO.0000000000000114 © 2014 by North American Neuro-Ophthalmology Society I diopathic intracranial hypertension (IIH), also called pseu- dotumor cerebri, is a disorder of elevated intracranial pres- sure of unknown cause (1). Its yearly incidence is 22.5 per 100,000 in overweight women of childbearing age and is rising in parallel with the obesity epidemic (2,3). It affects about 100,000 Americans. Most patients suffer debilitating headaches. Because of pressure on the optic nerve (papille- dema), 86% have some degree of permanent visual loss and 10% develop severe visual loss (4). Although a number of interventions have been used in clinical practice to prevent loss of sight, none has been proven effective. The most recent Cochrane review stated, “There is insufficient information to generate an evidence-based management strategy for idio- pathic intracranial hypertension. Of the various treatments available, there is inadequate information regarding which are truly beneficial and which are potentially harmful. Properly designed and executed trials are needed” (5). No randomized clinical trial in patients with visual loss from IIH had been performed before the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) for several reasons. IIH is officially classified as a “rare disease” by the National Institutes of Health (www.rarediseases.info. nih.gov), raising concern over the feasibility of recruiting a sufficiently large sample of participants. A wide variety Departments of Neurology & Neurotherapeutics and Ophthalmol- ogy (DIF), University of Texas Southwestern Medical Center, Dallas, Texas; Departments of Ophthalmology, Neurology, Neurosurgery and Visual Science (SEF), Center for Human Experimental Thera- peutics (KK, AS), Department of Biostatistics and Computational Biology and Department of Neurology (MM), University of Rochester School of Medicine and Dentistry, Rochester, New York; Neurology (MW), University of Iowa College of Medicine and Iowa City Veterans Affairs Health Care System, Iowa City, Iowa; National Eye Institute (ES), Bethesda, Maryland; Department of Ophthal- mology and Vision Science (JK), University of California Davis Medical Center, Sacramento, California; Departments of Neurology and Ophthalmology (MK), Mount Sinai School of Medicine, New York, New York. Supported by National Eye Institute (1U10EY017281-01A1, 1U10EY017387-01A1, 3U10EY017281-01A1S1, 3U10EY017281-01A1S2). The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Deborah I. Friedman, MD, MPH, Uni- versity of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, MC 9036, Dallas, TX 75390-9036; E-mail: Deborah.Friedman@ utsouthwestern.edu Friedman et al: J Neuro-Ophthalmol 2014; 34: 107-117 107 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.