Surgical Idiopathic Intracranial Hypertension Treatment Trial
Condition: Idiopathic Intracranial Hypertension
MeSH terms: Intracranial Hypertension; Pseudotumor Cerebri; Hypertension
Intervention: Acetazolamide; Optic Nerve Sheath Fenestration; Ventriculoperitoneal CSF Shunting
Intervention description: Medical therapy including diet; Medical therapy including diet + optic nerve sheath fenestration; Medical therapy including diet + ventriculoperitoneal CSF Shunting
Intervention MeSH terms: Acetazolamide; Diuretics
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects will be randomly assigned with equal allocation to one of the three treatment groups. Using a permuted block design, randomization will be stratified by PMD (average of 2 size V stimulus tests) in the eligible eye(s) (-6 dB to >-12 dB; -12 dB to >-20 dB; -20 dB to -27 dB). If a subject has two eligible eyes, the average PMD of the two eyes will be used for stratification.
Masking: Single (Outcomes Assessor)
Masking description: Partially-masked technicians for perimetry, fundus photos, OCT, and refraction/ visual acuity
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Maximum age: 63 Years
Healthy volunteers: No
Keywords: headache; idiopathic intracranial hypertension (IIH); shunt; fenestration; acetazolamide; visual loss; diamox

Summary:

      Randomized trial of adults (≥18 years old) with idiopathic intracranial hypertension and
      moderate to severe visual loss without substantial recent treatment who are randomly assigned
      to (1) medical therapy, (2) medical therapy plus ONSF, or (3) medical therapy plus VPS. The
      primary outcome is visual field mean deviation change at first of Month 6 (26 weeks) or time
      of treatment failure of the eligible eye(s), followed by a continuation study to assess time
      to treatment failure. The determination of eligible eye(s) is based on meeting the
      eligibility criteria at baseline.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject Eligibility Criteria Inclusion Criteria

               1. Diagnosis of IIH by modified Dandy criteria (Table 4)

               2. Age 18 to <64 years at time of consent

               3. Age 18 to <61 years at time of diagnosis (time of diagnosis is the time at which
                  the patient meets the modified Dandy criteria, usually after the lumbar puncture
                  results are reviewed)

               4. Presence of bilateral papilledema

               5. Lumbar puncture within 6 weeks of screening visit or completed as part of
                  screening: Opening CSF pressure >250 mmH2O or 200 to 250 mmH2O with at least one
                  of the following:

                    -  Pulse synchronous tinnitus

                    -  Cranial nerve VI palsy

                    -  Echography for disc drusen negative and no other disc anomalies mimicking
                       disc edema present

                    -  Magnetic Resonance Venography (MRV) with lateral sinus collapse/stenosis,
                       partially empty sella turcica on coronal or sagittal views of MRI, and optic
                       nerve sheaths with filled out CSF spaces next to the globe on T2 weighted
                       axial MRI scans If the patient was treated with intracranial pressure
                       lowering agents (e.g., acetazolamide) prior to obtaining a lumbar puncture,
                       the agent(s) must be discontinued for at least 24 hours prior to performing
                       the diagnostic lumbar puncture.

               6. At least one eye meeting all eligible eye inclusion criteria and no exclusion
                  criteria.

               7. Able to provide informed consent

               8. Investigator believes participant is a good candidate for the study, including
                  the probability of returning for follow-up.

          -  Eye-Level Eligibility Criteria Subjects must have at least one eye meeting all of the
             inclusion criteria and none of the exclusion criteria.

        If both eyes meet eligibility criteria at the baseline examination, both will be included
        in the primary outcome analysis.

        Inclusion

          1. Visual field loss meeting the following criteria based on two full threshold 24-2 size
             V tests reviewed by the VFRC:

               -  PMD from -6 decibel (dB) to -27 dB

               -  Reproducible visual loss present on automated perimetry including no more than
                  15% false positive response

          2. Visual acuity better than 20/200 (39 or more letters correct)

        Exclusion Criteria:

          -  Subject Exclusion Criteria Exclusion Criteria

               1. Treatment of IIH within the past 3 months with either (1) the maximally tolerated
                  dosage of acetazolamide for at least one week or (2) more than one month of
                  acetazolamide with a cumulative dosage of more than 45 grams 'Maximally-tolerated
                  dose' is defined as dosage was reached where dosage could not be increased
                  further either because of side effects or because a daily total dosage of 4 grams
                  per day was reached.

                  If individual discontinued acetazolamide in the past due to side effects,
                  individual is only eligible if investigator believes that the individual is
                  likely to tolerate acetazolamide, as it will be prescribed in the study.

               2. Treatment of IIH within the past 3 months with either (1) the maximally tolerated
                  dosage of methazolamide for at least one week or (2) more than one month of
                  methazolamide with a cumulative dosage of more than 4.5 grams
                  'Maximally-tolerated dose' is defined as dosage was reached where dosage could
                  not be increased further either because of side effects or because a daily total
                  dosage of 400 mg per day was reached.

               3. Treatment with topiramate within two months and average cumulative dosage for the
                  preceding month of more than 700 mg per week

               4. Previous surgery for IIH, including ONSF, CSF shunting, subtemporal
                  decompression, or venous sinus stenting; gastric surgery for obesity is allowed

               5. Abnormalities on neurologic examination except for papilledema and its related
                  visual loss or cranial nerve VI to VII paresis; if other abnormalities are
                  present, the patient will need to be discussed with the Study Director (SD) for
                  study entry.

               6. Abnormal CT or MRI scan (intracranial mass, hydrocephalus, dural sinus thrombus,
                  or arteriovenous malformation) other than findings known to occur with increased
                  intracranial pressure. Abnormalities on MRI that are not known to cause increased
                  intracranial pressure are acceptable.

               7. Abnormal CSF contents: increased cells: > 8 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 white blood cell count (WBC) after correction is 8 cells/mm3 or less -
                  see Manual of Procedures (MOP) for calculation. If > 8 cells or > 45mg% in CSF
                  protein are documented in the CSF or calculated after conversion from a traumatic
                  lumbar puncture, the patient can be discussed with the Study Director for
                  possible inclusion.)

               8. Abnormal blood work-up indicating a medical or systemic condition associated with
                  raised intracranial pressure

               9. Diabetes mellitus with diabetic retinopathy

              10. Ingestion of a drug or substance, or presence of a disorder, that has been
                  associated with increased intracranial pressure within 2 months of diagnosis,
                  such as lithium, vitamin A related products (e.g., Retin-A), or various cyclines
                  (see MOP for conditions and drugs)

              11. Laboratory test results showing severe anemia, leukopenia or thrombocytopenia,
                  renal failure, or hepatic disease, based on the Site Investigator's judgment

              12. Other condition requiring continued use of oral, I.V. or injectable steroids
                  (nasal, inhaled, or topical steroids are allowed since the systemic effects are
                  small). Patients with a condition that resulted in recent or current use of
                  steroids but may be safely tapered off will be handled on a case-by-case basis
                  after discussion with Study Director/co-Director. See Manual of Procedures (MOP)
                  for details.

              13. Presence of a medical condition that would contraindicate use of acetazolamide or
                  furosemide or significantly increase surgical risk

              14. Pregnancy or unwillingness for a subject of childbearing potential to use
                  contraception during the first 6 months of the study Women of childbearing
                  potential must use an acceptable form of birth control during the first 6 months
                  of the study. Acceptable forms include oral contraceptives, transdermal
                  contraceptives, diaphragm, intrauterine devices (IUDs), condoms with spermicide,
                  documented surgical sterilization of either the subject or their partner, or
                  abstinence.

              15. Presence of a physical, mental, or social condition likely to affect follow-up
                  (drug addiction, terminal illness, no telephone, homeless)

              16. Anticipation of a move from the site area within six months and unwillingness to
                  return for follow-up at a SIGHT study site

              17. Allergy to pupil dilating drops or narrow angles precluding safe dilation

              18. Presence of a condition that contraindicates general anesthesia

              19. Participation in an investigational trial within 30 days of enrollment that
                  involved treatment with any systemic drug therapy or therapy that affects the
                  eligible eye(s)

          -  Eye Level Exclusion Criteria Exclusion

               1. Intraocular pressure currently >28 mm Hg or >30 mm Hg at any time in the past

               2. Refractive error of more than -6.00 or more than +6.00 sphere or more than 3.00
                  cylinder with the following exceptions:

                    -  Eyes with more than 6.00 D of myopia but less than 8.00 D of myopia are
                       eligible if: 1) there are no abnormalities on ophthalmoscopy 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 individual will wear a contact lens for all perimetry examinations with
                       the appropriate correction.

                    -  Eyes with more than 6.00 D of hyperopia but less than 8.00 D of hyperopia
                       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 Photographic Reading Center (PRC) Director (or his designate), and 2)
                       the individual will wear a contact lens for all perimetry examinations with
                       the appropriate correction (which can be corrected for perimetry or with the
                       patient's own contact lens with over correction by lens at the perimeter).

                  Note: Refractive error exclusion and exceptions refer to sphere not spherical
                  equivalent, with cylinder expressed in plus format.

               3. Other disorders causing visual loss except for refractive error and amblyopia,
                  including cells in the vitreous or iritis

               4. Large optic disc drusen on exam or known in previous history (small drusen of the
                  disc can occur with longstanding papilledema and are allowed if not so numerous
                  that investigator determines they are contributing to vision loss)