Clinical trial NCT03501966: Surgical Idiopathic Intracranial Hypertension Treatment Trial
Official title: Randomized Trial of Medical Therapy (MT) vs. MT Plus Optic Nerve Sheath Fenestration vs. MT Plus Ventriculoperitoneal Cerebrospinal Fluid Shunting in Subjects With Idiopathic Intracranial Hypertension and Moderate to Severe Visual Loss
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Idiopathic Intracranial Hypertension
Keywords: headache
idiopathic intracranial hypertension (IIH)
shunt
fenestration
acetazolamide
visual loss
diamox
Lead sponsor: Jaeb Center for Health Research
Sponsor class: OTHER
Collaborators: name: National Eye Institute (NEI)
name: University of Iowa
name: Icahn School of Medicine at Mount Sinai
First posted: 2018-04-18
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Maximum age (years): 63
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

Brief 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.

Detailed description: After signing the informed consent form, potential subjects will be assessed for eligibility, including eliciting medical and neurologic history, measurement of best-corrected visual acuity, visual field testing, ophthalmoscopy with optic disc edema grading, physical examination, and Optical Coherence Tomography (OCT). Questionnaires will be completed. Blood will be drawn for complete blood count (CBC), electrolytes, liver function tests, renal function tests, amylase if not done as part of routine care within 4 weeks and a pregnancy test will be performed (women of childbearing potential).

Two visual field examinations using a size V stimulus will need to be performed at the Screening/Baseline Visit. The size V fields will be sent to the Visual Field Reading Center (VFRC) to confirm eligibility or determine that testing must be repeated for the subject.

Eligible individuals will be randomly assigned with equal allocation to one of 3 treatment groups: (1) medical therapy, (2) medical therapy plus ONSF, or (3) medical therapy plus VPS. Acetazolamide should be started on the day of randomization. Surgery should be performed as soon as possible, ideally within 3 days of randomization, but not more than 7 days.

Medical therapy will consist of a low sodium weight loss diet and acetazolamide with or without furosemide. Treatment will start with acetazolamide 2 grams per day, with the dose increased as tolerated up to 4 grams per day. If there is no clinical improvement after 2 weeks of maximal dosage of acetazolamide, furosemide will be started at a dose of 40 mg per day (along with potassium) and titrated up to 160-200 mg per day. Pharmacotherapy will be tapered when there is improvement in the papilledema grade, substantial improvement in the PMD and improvement in symptoms or when there is a safety concern.

The primary outcome is measured at the first of 6 months (26 weeks) or time of treatment failure. During the randomized trial, follow-up visits will occur after weeks 4, 8, 16, and 26 (± 7 days). Safety visits will occur after weeks 1 and 2 (± 4 days). Additional office visits may occur as needed. Phone contacts will occur at 12 and 20 weeks (±7 days).

After the 6-month primary outcome visit, subjects will transition to the Treatment Failure Identification Phase for up to 3 years. Ongoing treatment will continue following the guidelines for the first six months as long as treatment failure criteria are not met at which time treatment will be at the discretion of the Site Investigator. Investigators are urged to employ treatments from another arm of the study before other treatments under these circumstances.

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)

Primary outcomes:
measure: Perimetric Mean Deviation (PMD)
timeFrame: 6 months
Secondary outcomes:
measure: Treatment Failure
timeFrame: up to 3 years
measure: Cerebrospinal Fluid (CSF) Opening Pressure
timeFrame: 6 months
measure: Papilledema Grade
timeFrame: 6 months
measure: OCT Retinal Nerve Fiber Layer Thickness
timeFrame: 6 months
measure: OCT Total Retinal Thickness
timeFrame: 6 months
measure: Visual Acuity (VA) Using Early Treatment Diabetic Retinopathy Study (ETDRS) Chart
timeFrame: 6 months
measure: Quality of Life (QoL) 36 Item Short Form Health Survey (SF-36v2)
timeFrame: 6 months
measure: Quality of Life (QoL) Visual Function Questionnaire (VFQ-25)
timeFrame: 6 months
measure: Quality of Life (QoL) 10-item Neuro-ophthalmic Supplement to the VFQ-25
timeFrame: 6 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Los Angeles
country: United States
facility: NeuroEyeOrbit Institute
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: University of Colorado - Anschutz Medical Campus
state: Colorado
city: Orange
country: United States
facility: The Eye Care Group
state: Connecticut
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Chicago
country: United States
facility: Northwestern Medicine
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Prairie Village
country: United States
facility: University of Kansas School of Medicine
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: North Bethesda
country: United States
facility: Bethesda Neurology, LLC
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: East Setauket
country: United States
facility: State University of New York at Stony Brook
state: New York
city: New York
country: United States
facility: New York Eye & Ear Infirmary of Mount Sinai
state: New York
city: New York
country: United States
facility: New York University School of Medicine
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Columbus
country: United States
facility: Ohio Neuro-Ophthalmology, Orbital Disease and Oculoplastics
state: Ohio
city: Oklahoma City
country: United States
facility: Dean McGee Eye Institute
state: Oklahoma
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Neuro-Eye Clinical Trials-Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Toronto
country: Canada
facility: Sunnybrook Health Science Center
state: Ontario
city: Bayamón
country: Puerto Rico
facility: Rivera, Enrique J
Study officials:
affiliation: University of Iowa
name: Michael Wall, MD
role: STUDY_DIRECTOR
References: