Idiopathic Intracranial Hypertension Treatment Trial (IIHTT)

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 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).

Clinical Phase: Phase II Investigators: NORDIC Network sites Study Centers: 44 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 154 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: 154 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. No treatment directed at IIH for at least 2 days prior to BEV
5. Reproducible visual loss present on automated perimetry (in eye with greatest loss)*
6. PMD -2 dB up to -5 dB in the worst eye
7. Presence of bilateral papilledema
8. 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 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

• Drug: Acetazolamide
  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.
  Other Names:

  • naproxen
  • acetaminophen
  • aspirin
  • ibuprofen
  • codein
  • butalbital
• Drug: Placebo
  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.
  Other Names:

  • naproxen
  • acetaminophen
  • aspirin
  • ibuprofen
  • codein
  • butalbital
• Behavioral: Formal weight loss counselling program
  Teleconference, web-based from central location, using site visits and subject self-assessment tools
  Other Names:

  • naproxen
  • acetaminophen
  • aspirin
  • ibuprofen
  • codein
  • butalbital

• Active Comparator: Acetazolamide
  Acetazolamide given in escalating doses
  Interventions:

  • Drug: Acetazolamide
  • Behavioral: Formal weight loss counselling program
• Placebo Comparator: Sugar pill
  Given in escalating "dose" (number of pill)
  Interventions:

  • Drug: Placebo
  • Behavioral: Formal weight loss counselling program

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 one week in the past six weeks
2. Corticosteroids used for IIH treatment within the past six weeks
3. Previous surgery for IIH including optic nerve sheath fenestration, CSF shunting procedures, subtemporal decompression and venous stenting
4. Previous gastric bypass surgery
5. Abnormalities on neurologic examination aside from papilledema and its related visual loss or VI nerve paresis
6. Abnormal CT or MRI scan (intracranial mass, hydrocephalus, dural sinus thrombus or arteriovenous malformation) other than empty sella, unfolded optic nerve sheath, flattened sclera, smooth- walled venous stenosis or secondary Chiari I Malformation
7. CSF pressure less than 200 mm water (patients may have repeat CSF pressure measurements if the first is normal or no opening pressure obtained)
8. 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)
9. Intraocular pressure currently > 28 mm Hg or > 30 mm Hg at any time in the past
10. Refractive error > +/- 6.00 sphere or > +/- 3.00 cylinder in either eye
11. Other disorders causing visual loss except for refractive error and amblyopia including cells in the vitreous or iritis
12. Optic disc drusen on exam or in previous history
13. Presence of diagnosed untreated obstructive sleep apnea
14. Inability to provide reliable and reproducible visual field examination (failure to maintain fixation using an eye monitoring device, more than 15% false positive errors)
15. Abnormal blood work-up indicating a medical or systemic condition associated with raised ICP
16. Study blood results showing severe anemia, leukopenia or thrombocytopenia, renal failure, or hepatic disease, based on the site investigator's judgment
17. Type I diabetes or the presence of diabetic retinopathy
18. 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, steroid withdrawal (see table in Operations Manual for conditions and drugs)
19. 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)
20. Use of topiramate, corticosteroids or diuretics for the treatment of IIH within 2 days of the BEV and during the study
21. Presence of a medical condition such as renal stones that would contraindicate use of the study drugs (acetazolamide)
22. Pregnancy or unwillingness for subject with childbearing potential to use contraception during the first year of the study
23. Nursing mothers are excluded from participation unless willing to discontinue breastfeeding by the baseline visit
24. Presence of a physical, mental, or social condition likely to affect follow-up (drug addiction, terminal illness, no telephone, homeless)
25. Anticipation of a move from the site area within six months and unwillingness to return for follow-up at an IIHTT study site
26. Allergy or to pupil dilating drops or narrow angles precluding safe dilation

• National Eye Institute (NEI)
• University of Rochester
• University of Iowa
• University of California, Davis