Surgical Idiopathic Intracranial Hypertension Treatment Trial

NCT ID: NCT03501966

Last Updated: 2022-06-16

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-02-06
• Study Completion Date: 2019-08-28

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.

Conditions

Idiopathic Intracranial Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Acetazolamide including Diet

Subjects will use 250 mg tablets of acetazolamide, divided into two doses, taken with meals. Initial dose will be 1,000 mg twice per day and increased per titration schedule (Table 6 in protocol).

Dietary consultation will include advising subjects to adopt a low sodium weight reduced diet.

Group Type: ACTIVE_COMPARATOR

Acetazolamide

Intervention Type: DRUG

Medical therapy including diet

Optic Nerve Sheath Fenestration

Acetazolamide including Diet plus Optic Nerve Sheath Fenestration (ONSF) Subjects will use 250 mg tablets of acetazolamide, divided into two doses, taken with meals. Initial dose will be 1,000 mg twice per day and increased per titration schedule (Table 6 in protocol).

Dietary consultation will include advising subjects to adopt a low sodium weight reduced diet.

ONSF performed by qualified, certified orbital surgeon using either a medial or supero-medial lid crease approach. ONSF will be performed in one or both eyes, depending on criteria.

Group Type: ACTIVE_COMPARATOR

Optic Nerve Sheath Fenestration

Intervention Type: PROCEDURE

Medical therapy including diet + optic nerve sheath fenestration

Ventriculoperitoneal CSF Shunting

Acetazolamide including Diet plus Ventriculoperitoneal CSF Shunting (VPS) Subjects will use 250 mg tablets of acetazolamide, divided into two doses, taken with meals. Initial dose will be 1,000 mg twice per day and increased per titration schedule (Table 6 in protocol).

Dietary consultation will include advising subjects to adopt a low sodium weight reduced diet.

VPS performed by qualified, certified neurosurgeon using a frameless image-guided stereotactic system and positioning a shunt catheter in the lateral ventricle of the cerebral hemisphere not associated with speech. The catheter will be connected to an adjustable valve, and a distal shunt system will be placed in the peritoneal cavity.

Group Type: ACTIVE_COMPARATOR

Ventriculoperitoneal CSF Shunting

Intervention Type: PROCEDURE

Medical therapy including diet + ventriculoperitoneal CSF Shunting

Interventions

Acetazolamide

Medical therapy including diet

Intervention Type: DRUG

Optic Nerve Sheath Fenestration

Medical therapy including diet + optic nerve sheath fenestration

Intervention Type: PROCEDURE

Ventriculoperitoneal CSF Shunting

Medical therapy including diet + ventriculoperitoneal CSF Shunting

Intervention Type: PROCEDURE

Other Intervention Names

Diamox; water pill; diuretic; ONSF; VPS; CSF Shunt Surgery

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.

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.

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

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)

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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 63 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Eye Institute (NEI)

NIH

Sponsor Role: collaborator

University of Iowa

OTHER

Sponsor Role: collaborator

Icahn School of Medicine at Mount Sinai

OTHER

Sponsor Role: collaborator

Jaeb Center for Health Research

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael Wall, MD

Role: STUDY_DIRECTOR

University of Iowa

Locations

University of Southern California

Los Angeles, California, United States

NeuroEyeOrbit Institute

Los Angeles, California, United States

Stanford University

Palo Alto, California, United States

University of Colorado - Anschutz Medical Campus

Aurora, Colorado, United States

The Eye Care Group

Orange, Connecticut, United States

University of Miami

Miami, Florida, United States

Northwestern Medicine

Chicago, Illinois, United States

University of Illinois at Chicago

Chicago, Illinois, United States

University of Iowa

Iowa City, Iowa, United States

University of Kansas School of Medicine

Prairie Village, Kansas, United States

University of Kentucky

Lexington, Kentucky, United States

Johns Hopkins University School of Medicine

Baltimore, Maryland, United States

Bethesda Neurology, LLC

North Bethesda, Maryland, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

Mayo Clinic

Rochester, Minnesota, United States

Washington University in St. Louis

St Louis, Missouri, United States

Saint Louis University

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

State University of New York at Stony Brook

East Setauket, New York, United States

New York Eye & Ear Infirmary of Mount Sinai

New York, New York, United States

New York University School of Medicine

New York, New York, United States

University of Rochester

Rochester, New York, United States

Ohio Neuro-Ophthalmology, Orbital Disease and Oculoplastics

Columbus, Ohio, United States

Dean McGee Eye Institute

Oklahoma City, Oklahoma, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Neuro-Eye Clinical Trials-Houston

Houston, Texas, United States

University of Utah

Salt Lake City, Utah, United States

University of Virginia

Charlottesville, Virginia, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Swedish Medical Center

Seattle, Washington, United States

University of Wisconsin

Madison, Wisconsin, United States

University of Calgary

Calgary, Alberta, Canada

Sunnybrook Health Science Center

Toronto, Ontario, Canada

Rivera, Enrique J

Bayamón, , Puerto Rico

Countries

United States; Canada; Puerto Rico

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

1U10EY025990-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

SIGHT

Identifier Type: -

Identifier Source: org_study_id