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Idiopathic Intracranial HypertensionPhase 3SIGHTNCT03501966

Surgical Idiopathic Intracranial Hypertension Treatment Trial

A Phase 3 study testing Acetazolamide, Optic Nerve Sheath Fenestration and Ventriculoperitoneal CSF Shunting in people with Idiopathic Intracranial Hypertension, run by Jaeb Center for Health Research at 36 sites in 3 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 63 years
Conditions the study is for
Idiopathic Intracranial Hypertension
What is being tested?
Acetazolamide, Optic Nerve Sheath Fenestration and Ventriculoperitoneal CSF Shunting
Could I receive a placebo?
No, everyone receives an active treatment
How many people
7 participants
Where
36 sitesin 3 countries
Study dates
6 Feb 2019to 28 Aug 2019
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 63 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • Subject Eligibility Criteria Inclusion Criteria
  • Diagnosis of IIH by modified Dandy criteria (Table 4)
  • Age 18 to <64 years at time of consent
  • 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)
  • Presence of bilateral papilledema
  • 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:
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  • 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.
  • At least one eye meeting all eligible eye inclusion criteria and no exclusion criteria.
  • Able to provide informed consent
  • 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.
  • 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
  • Visual acuity better than 20/200 (39 or more letters correct)

Who cannot join

  • Subject Exclusion Criteria Exclusion Criteria
  • 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.
  • 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.
  • Treatment with topiramate within two months and average cumulative dosage for the preceding month of more than 700 mg per week
  • Previous surgery for IIH, including ONSF, CSF shunting, subtemporal decompression, or venous sinus stenting; gastric surgery for obesity is allowed
Show all 29Show fewer
  • 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.
  • 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.
  • 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.)
  • Abnormal blood work-up indicating a medical or systemic condition associated with raised intracranial pressure
  • Diabetes mellitus with diabetic retinopathy
  • 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)
  • Laboratory test results showing severe anemia, leukopenia or thrombocytopenia, renal failure, or hepatic disease, based on the Site Investigator's judgment
  • 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.
  • Presence of a medical condition that would contraindicate use of acetazolamide or furosemide or significantly increase surgical risk
  • 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.
  • Presence of a physical, mental, or social condition likely to affect follow-up (drug addiction, terminal illness, no telephone, homeless)
  • Anticipation of a move from the site area within six months and unwillingness to return for follow-up at a SIGHT study site
  • Allergy to pupil dilating drops or narrow angles precluding safe dilation
  • Presence of a condition that contraindicates general anesthesia
  • 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
  • Intraocular pressure currently >28 mm Hg or >30 mm Hg at any time in the past
  • 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.
  • Other disorders causing visual loss except for refractive error and amblyopia, including cells in the vitreous or iritis
  • 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)

Trial locations and contacts

36 sites in 3 countries.

36 sites in 3 countries

United States33 sites

  • University of Colorado - Anschutz Medical Campus

    Aurora, Colorado, 80045

  • Johns Hopkins University School of Medicine

    Baltimore, Maryland, 21287

  • Brigham and Women's Hospital

    Boston, Massachusetts, 02115

  • University of Virginia

    Charlottesville, Virginia, 22904

  • Northwestern Medicine

    Chicago, Illinois, 60611

  • University of Illinois at Chicago

    Chicago, Illinois, 60612

  • Ohio Neuro-Ophthalmology, Orbital Disease and Oculoplastics

    Columbus, Ohio, 43214

  • State University of New York at Stony Brook

    East Setauket, New York, 11733

  • Neuro-Eye Clinical Trials-Houston

    Houston, Texas, 77005

  • University of Iowa

    Iowa City, Iowa, 52242

  • University of Kentucky

    Lexington, Kentucky, 40536

  • University of Southern California

    Los Angeles, California, 90033

  • NeuroEyeOrbit Institute

    Los Angeles, California, 90048

  • University of Wisconsin

    Madison, Wisconsin, 53705

  • University of Miami

    Miami, Florida, 33136

  • University of Minnesota

    Minneapolis, Minnesota, 55455

  • Vanderbilt University Medical Center

    Nashville, Tennessee, 37232

  • New York Eye & Ear Infirmary of Mount Sinai

    New York, New York, 10003

  • New York University School of Medicine

    New York, New York, 10016

  • Bethesda Neurology, LLC

    North Bethesda, Maryland, 20852

  • Dean McGee Eye Institute

    Oklahoma City, Oklahoma, 73104

  • University of Nebraska Medical Center

    Omaha, Nebraska, 68198

  • The Eye Care Group

    Orange, Connecticut, 06477

  • Stanford University

    Palo Alto, California, 94303

  • University of Pennsylvania

    Philadelphia, Pennsylvania, 19104

  • University of Kansas School of Medicine

    Prairie Village, Kansas, 64134

  • Virginia Commonwealth University

    Richmond, Virginia, 23298

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • University of Rochester

    Rochester, New York, 14642

  • University of Utah

    Salt Lake City, Utah, 84132

  • Swedish Medical Center

    Seattle, Washington, 98122

  • Washington University in St. Louis

    St Louis, Missouri, 36110

  • Saint Louis University

    St Louis, Missouri, 63104

Other trials in United States

Canada2 sites

  • University of Calgary

    Calgary, Alberta, T2V 1P9

  • Sunnybrook Health Science Center

    Toronto, Ontario, M4N 3M5

Other trials in Canada

Puerto Rico1 site

  • Rivera, Enrique J

    Bayamón, 00961

Other trials in Puerto Rico

About this study

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

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.

Read the 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.

Being tested
Acetazolamide, Optic Nerve Sheath Fenestration, Ventriculoperitoneal CSF Shunting
Keywords
headache, idiopathic intracranial hypertension (IIH), shunt, fenestration, acetazolamide, visual loss, diamox
Medical subject headings
Pseudotumor Cerebri, Headache, Vision Disorders

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AcetazolamideDrug

    Also called Diamox, water pill, diuretic

    Medical therapy including diet

  • Optic Nerve Sheath FenestrationProcedure or surgery

    Also called ONSF

    Medical therapy including diet + optic nerve sheath fenestration

  • Ventriculoperitoneal CSF ShuntingProcedure or surgery

    Also called VPS, CSF Shunt Surgery

    Medical therapy including diet + ventriculoperitoneal CSF Shunting

Study groups in NCT03501966
Study groupRoleWhat they receive
Acetazolamide including DietActive comparatorSubjects 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.
Receives: Drug: Acetazolamide
Optic Nerve Sheath FenestrationActive comparatorAcetazolamide 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.
Receives: Procedure: Optic Nerve Sheath Fenestration
Ventriculoperitoneal CSF ShuntingActive comparatorAcetazolamide 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.
Receives: Procedure: Ventriculoperitoneal CSF Shunting

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Perimetric Mean Deviation (PMD)

    Change from baseline to first of Month 6 (Week 26) or time of treatment failure in PMD (perimetric mean deviation) in eligible eye(s) with the size V stimulus

    Measured: 6 months

Secondary outcomes (9)

  1. Treatment Failure

    Time from randomization to treatment failure

    Measured: up to 3 years

  2. Cerebrospinal Fluid (CSF) Opening Pressure

    Change in CSF opening pressure measurement by lumbar puncture

    Measured: 6 months

  3. Papilledema Grade

    Change in papilledema grade

    Measured: 6 months

  4. OCT Retinal Nerve Fiber Layer Thickness

    Change in retinal nerve fiber layer thickness

    Measured: 6 months

  5. OCT Total Retinal Thickness

    Change in total retinal thickness

    Measured: 6 months

  6. Visual Acuity (VA) Using Early Treatment Diabetic Retinopathy Study (ETDRS) Chart

    Change in VA scores, determined by baseline VA of better than 20/200 (39 or more letters correct) and worsening indicated by less correct letters

    Measured: 6 months

  7. Quality of Life (QoL) 36 Item Short Form Health Survey (SF-36v2)

    Changes in QoL as measured by responses

    Measured: 6 months

  8. Quality of Life (QoL) Visual Function Questionnaire (VFQ-25)

    Changes in QoL as measured by responses

    Measured: 6 months

  9. Quality of Life (QoL) 10-item Neuro-ophthalmic Supplement to the VFQ-25

    Changes in QoL as measured by responses

    Measured: 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Apr 2018
  2. Study start6 Feb 2019
  3. Primary completion28 Aug 2019
  4. Study completion28 Aug 2019

Why it stopped: Low enrollment

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
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 blind
Who is masked
Outcomes assessor
Enrolment
7 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03501966
Sponsor's protocol ID
SIGHT
Other IDs
1U10EY025990-01A1
Acronym
SIGHT
Status last verified
Feb 2020
First submitted
10 Apr 2018
Last updated
16 Jun 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Acetazolamide, Optic Nerve Sheath Fenestration and Ventriculoperitoneal CSF Shunting in people with Idiopathic Intracranial Hypertension, run by Jaeb Center for Health Research at 36 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 16 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 36 sites in United States, Canada, Puerto Rico. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Jun 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Perimetric Mean Deviation (PMD) (time frame: 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03501966.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jun 2022.

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