Idiopathic Intracranial Hypertension Treatment Trial

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

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