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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 165
- 试验地点
- 41
- 主要终点
- Mean Change in Perimetric Mean Deviation
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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,
排除标准
- •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)
- •Intraocular pressure currently > 28 mm Hg or > 30 mm Hg at any time in the past
- •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
- •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
- •Other disorders causing visual loss except for refractive error and amblyopia including cells in the vitreous or iritis
- •Optic disc drusen on exam or in previous history
- •Presence of diagnosed untreated obstructive sleep apnea
- •Inability to provide reliable and reproducible visual field examination (failure to maintain fixation using an eye monitoring device, more than 15% false positive errors)
- •Abnormal blood work-up indicating a medical or systemic condition associated with raised ICP
- •Study blood results showing severe anemia, leukopenia or thrombocytopenia, renal failure, or hepatic disease, based on the Site Investigator's judgment
- •Type I diabetes or the presence of diabetic retinopathy
- •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)
- •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)
- •Presence of a medical condition such as renal stones that would contraindicate use of the study drug (acetazolamide)
- •Pregnancy or unwillingness for subject of childbearing potential to use contraception during the first year of the study
- •Breastfeeding mothers are excluded from participation unless willing to discontinue breastfeeding by the baseline visit
- •Presence of a physical, mental, or social condition likely to affect follow-up (drug addiction, terminal illness, no telephone, homeless)
- •Anticipation of a move from the site area within six months and unwillingness to return for follow-up at an IIHTT study site
- •Allergy to pupil dilating drops or narrow angles precluding safe dilation
研究组 & 干预措施
Acetazolamide
Acetazolamide given in escalating doses
干预措施: Acetazolamide (Drug)
Acetazolamide
Acetazolamide given in escalating doses
干预措施: Formal weight loss counselling program (Behavioral)
Sugar pill
Given in escalating "dose" (number of pill)
干预措施: Placebo (Drug)
Sugar pill
Given in escalating "dose" (number of pill)
干预措施: Formal weight loss counselling program (Behavioral)
结局指标
主要结局
Mean Change in Perimetric Mean Deviation
时间窗: base line and 6 months
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.
次要结局
- Mean Change of Papilledema Grade on Fundus Photography(Baseline and 6 Months)
- Visual Acuity (No. of Correct Letters)(Baseline)
- Visual Function Questionnaire (VFQ-25)(baseline)