Clinical trial NCT03501966
Conditions: Idiopathic Intracranial Hypertension
Keywords: headache idiopathic intracranial hypertension (IIH) shunt fenestration acetazolamide visual loss diamox
Sponsor: Jaeb Center for Health Research
Start date: 2019-02-06; Completion date: 2019-08-28
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: 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. arm 3: 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.
Interventions: intervention 1: Acetazolamide intervention 2: Optic Nerve Sheath Fenestration intervention 3: Ventriculoperitoneal CSF Shunting
Intervention descriptions: intervention 1: Medical therapy including diet intervention 2: Medical therapy including diet + optic nerve sheath fenestration intervention 3: Medical therapy including diet + ventriculoperitoneal CSF Shunting

Protocol documents:
ICF_000.pdf: 
 
 
SIGHT Protocol V3.2 - ICF V2.4  
 
Page 1 of 17 
CONSENT TO TAKE PART IN A RESEARCH STUDY 
 
STUDY TITLE: Surgical Idiopathic Intracranial Hypertension Treatment (SIGHT) Trial  
 
STUDY DOCTOR’S INFORMATION 
Name: [fillable field] 
Contact Number: [fillable field] 
Site Name: [fillable field] 
Site Address: [fillable field] 
Emergency (24-hour) Number: [fillable field] 
Study Coordinator Name/Contact: [fillable field] 
 
SUMMARY 
This consent form will give you important information about this study. It will help you decide if 
would like to take part in the study. You do not have to be in this study. You can stop the study 
at any time. You should read and discuss all the information in this consent form with the study 
doctor. 
• The study is being done to find out how different treatments work to reduce or reverse 
visual loss in people who have a condition where the pressure inside the skull increases 
for no known reason. This is called idiopathic intracranial hypertension (IIH).  
• You will be asked to be in the study for up to three years. The study will involve tests to 
make sure you are eligible. If you are eligible, you cannot choose your treatment group. 
A computer program will assign you to a treatment group. There are three treatment 
groups. One group will take diuretics (“water pills”) that helps your body get rid of fluid. 
The main diuretic used in this study is called acetazolamide. It is not FDA approved for 
the treatment of IIH, but it is often used for this purpose by doctors. For this study, 
acetazolamide is considered an experimental drug, even though you can receive it even if 
you were not in this study. Another group will take diuretics and have a surgical 
procedure called optic nerve sheath fenestration (ONSF). It involves making a cut into 
the covering of the optic nerve (the nerve that transmits vision from the eye to the brain) 
to try to relieve pressure. The last group will take diuretics and have a surgical procedure 
called ventriculoperitoneal shunting (VPS). It involves placing a tube from the fluid area 
of the brain to the abdomen to try to lower pressure around the brain. No matter which of 
the three groups you are in, there will be vision and blood tests performed at study visits. 
You also will be asked to fill out surveys at several visits.  
• There are a number of side effects from the study medication (including low energy, taste 
problems, loss of appetite, weight loss, frequent urination, tingling lips and limbs). The 
surgeries involve anesthesia. All surgeries have risks. The specific risks for these 
surgeries are described later in this document. 
• The possible benefits are that your vision may not get worse or your vision may improve. 
However, this is not a guarantee. You will receive careful follow-up to check your vision. 
The research may help other people with IIH in the future.  
• If you do not participate, you may receive any of the treatments being used in the study. 
You could also receive different medications or a different type of surgery. 


 
 
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WHAT IS INFORMED CONSENT? 
You are being asked to take part in this research study because you have idiopathic intracranial 
hypertension (IIH). IIH means the pressure in the fluid surrounding the brain is higher than it 
should be. The cause of IIH is unknown. It occurs most often in females who are overweight. IIH 
often causes headaches and swelling of the optic nerves. The optic nerve connects the eye to the 
brain. When it swells due to the pressure around the brain, vision loss can happen. We want to 
find out which treatment works best to reduce or reverse visual loss in people with IIH who have 
moderate to severe vision loss.  
 
Your study doctor will be talking with you about this study and this form. You can take as much 
time as you need to think about whether or not you want to be in this study. You can also take a 
copy of this form with you to discuss with friends, family, or other doctors to help you decide. 
Please read this document carefully. Do not agree to be in this study unless all of your questions 
have been answered. 
 
You do not have to be in this study. If you decide not to be in this study, you will not be treated 
differently. Also, your regular care will not be impacted.  
 
WHO IS DOING THE STUDY? 
This study is being done by doctors who are part of the Neuro-Ophthalmology Research Disease 
Investigator Consortium (NORDIC). The Jaeb Center for Health Research is coordinating the 
study. The study is being paid for by the National Eye Institute of the National Institutes of 
Health. The funding will be used to organize the study and to pay your study doctor’s office for 
their work on the study. Your study doctor and clinic staff will carry out this study. The name of 
the study doctor and the doctor’s contact information is listed on the first page of this form. If 
one of the study doctors gets money or benefits from a company that makes the drug in this 
study, then they have to tell the Jaeb Center. The Jaeb Center has a policy to make sure that 
study doctors cannot work on this study if they get money or benefits that would influence how 
they do the study. 
 
WHY IS THIS STUDY BEING DONE? 
When vision loss from IIH is moderate to severe, several medications and surgical treatments 
can be used. Although each of these treatments can be effective, doctors are still not sure which 
treatments work best. The purpose of this study is to find out which treatment works best to 
reduce or reverse visual loss in people with IIH. We expect that about 180 people will take part 
in this study from about 40 different medical centers in the United States and Canada. If you 
agree to take part in this study, your involvement will last for up to three years.  
 
WHO CAN PARTICIPATE IN THIS STUDY? 
In general, to take part in this study, you must:  
• have IIH with moderate to severe visual loss in one or both eyes 
 
Also, you must not:  


 
 
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Page 3 of 17 
• be currently taking certain medications to treat IIH, including corticosteroids, topiramate, 
and diuretics (other than furosemide) 
• have had previous surgery for IIH  
• have any treatments for IIH outside of the study, such as weight loss surgery, during the 
first six months of the study  
• be pregnant  
o If you are a woman who has the potential to get pregnant, we will do a test to be 
sure you are not pregnant before you enter the study. This will not be necessary if 
your last period was two years or more ago or if you have had a hysterectomy or 
tubal ligation. If you have the potential to become pregnant, you will need to use a 
form of birth control during the first six months of the study. Acceptable 
approaches include use of oral contraceptives, transdermal contraceptives 
(patches), diaphragm, intrauterine devices, condoms with spermicide, 
documented surgical sterilization of either you or your partner, or abstinence.  
 
If you are nursing a child, please speak with your doctor to discuss breastfeeding during the 
study. 
 
Your study doctor and staff will review more health-related requirements with you.  
 
WHAT WILL HAPPEN IN THIS STUDY? 
If you agree to take part in this study, your involvement will last for up to three years. There will 
be about 9-11 study visits. Further study visits may be required, depending on how you are 
doing. 
 
Screening Visit  
The Screening Visit will collect information from you and do testing to determine if you are 
eligible to take part in the study. The Screening Visit will take about six hours. Screening tests 
may be completed over multiple days. 
 
The Screening Visit will include a review of your medical history, eye exams, at least two tests 
of your side vision, pictures of your eyes after inserting eye drops, physical exams, blood tests, 
pregnancy test for females, and questionnaires. You will have blood drawn as part of your usual 
care.  
• If you agree, we also will draw blood (~20 ml or about 4 teaspoons) to use for further 
research. The blood samples might be used by researchers to evaluate for genetic, 
hormonal, and metabolic factors associated with IIH.  
 
In addition, you may need to have other tests done to confirm the diagnosis of IIH. These tests 
would be needed even if you are not in this study. The tests include magnetic resonance imaging 
(MRI scan) and lumbar puncture (LP).  
• An MRI takes pictures of your brain. 
• An LP involves numbing of the skin over the low back and inserting a thin needle into 
the sac of fluid below the spinal cord. A tube is then attached onto the needle to measure 
the pressure. Some spinal fluid is removed for laboratory tests. The testing is done to 


 
 
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make sure that you do not have another cause for high pressure, such as an infection or 
inflammation. If you have not had a recent LP, or if the pressure was not measured, the 
study doctor will arrange to have it performed. In that case, the procedure will be 
explained to you and you will sign a separate, standard consent form for the procedure. 
Generally, about 15-20 ml (4 teaspoons) of spinal fluid will be removed to temporarily 
lower the pressure. About 6 ml are needed for routine laboratory studies.  
 
Study Treatments 
If you are eligible to be in the study, the next step will be to determine your treatment group. 
You cannot choose your treatment group. This will be done with a computer program by a 
process similar to pulling a name out of a hat. You will have an equal chance of getting one of 
three treatments.  
 
The three treatments are: 
(1) medicine (water pills) and diet instructions only  
(2) medicine (water pills), diet instructions, and optic nerve sheath fenestration surgery 
(making a small cut on the outside of the eye-related nerve) 
(3) medicine (water pills), diet instructions, and ventriculoperitoneal shunt surgery (putting 
in the tube from the fluid area of the brain to the abdomen) 
 
If you are going to receive a surgical treatment, there may be additional tests needed as part of 
your standard care. 
 
The study team will instruct you in a low-sodium, weight loss diet. They may recommend a 
consultation with a dietician or referral to a medical weight loss program. If you are overweight, 
the goal will be to lose at least 6% of your initial body weight in 6 months. 
 
For medicine, you will be asked to take acetazolamide (water pills) twice a day. It is often used 
for the treatment of IIH, but it is not approved by the Food and Drug Administration for this 
purpose. Therefore, acetazolamide is considered an experimental drug for treating IIH, even 
though you can receive it without being in this study. The dose will be increased over time. You 
could be taking up to 16 of these pills a day. If you have too many side effects, the study team 
will work with you to decrease the dose. If you cannot tolerate acetazolamide at any dose, it will 
be discontinued. Instead, you will be given a prescription for another kind of diuretic (water pill) 
called furosemide. Also, if your vision worsens or other symptoms are a problem while taking 
acetazolamide, you will be given a prescription for furosemide to add to your treatment. You will 
be asked to take furosemide twice a day too. The dose will also be increased as needed. You will 
be monitored while you are taking these medications to help make sure you are safe and well.  
 
Your doctor(s) may give you other medications to help treat your condition.  
 
Optic Nerve Sheath Fenestration (ONSF)  
The optic nerves carry information from the eye to the brain. They are surrounded by fluid. The 
fluid is surrounded by a tough covering called a “sheath”. During the surgery, the surgeon will 
cut a window in the covering. This lets some of the fluid leak out into the area behind the eye. 


 
 
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Page 5 of 17 
ONSF is thought to improve vision by lowering the pressure on the optic nerve. The surgery will 
be described to you in detail by your surgeon. You will have an opportunity to ask questions.  
 
You will be admitted to the hospital for the surgery. The surgery is performed under general 
anesthesia. A cut will be made either through the crease above the upper eyelid or near the bridge 
of the nose. The surgery takes about an hour per eye. Your surgery may be video-recorded for 
the study team to review. 
 
You will stay in the hospital overnight. You may be discharged the next day if there are no 
complications. 
 
If both your eyes are eligible for the study, ONSF will be performed on the eye with worse 
vision first. If only one eye is eligible, the surgery will be performed first on that eye. Sometimes 
ONSF on one eye helps the other eye. If this happens, surgery on the other optic nerve may not 
be needed. The need for surgery on the other optic nerve will be decided about 2 weeks after the 
first surgery. 
 
If your vision and optic nerve swelling improve after surgery, your study doctor may start to 
decrease the dosage of the medicines (acetazolamide, furosemide or both). 
 
Ventriculoperitoneal Shunting (VPS)  
The optic nerves are surrounded by the same fluid that circulate in spaces inside the brain called 
ventricles. VPS drains fluid through a tube from the ventricles into the abdomen where the fluid 
is absorbed. VPS is thought to improve vision by decreasing the fluid pressure in the brain and 
surrounding the optic nerves. The surgery will be described to you in detail by your 
neurosurgeon. You will have an opportunity to ask questions. 
 
You will be admitted to the hospital for the surgery. The procedure is performed under general 
anesthesia. A brain scan (MRI or CT scan) will be done to precisely map the location of the 
ventricle that will be shunted (usually on the right side of the head). Prior to surgery, some of 
your hair will be shaved near the surgical site. While you are asleep, the neurosurgeon will cut 
through the skin to see the skull bone. Then a hole will be drilled in the skull about the size of a 
nickel. A small plastic tube will be put into the hole and through the brain into the ventricle. 
Then, a long piece of tubing will be tunneled under the skin into the abdomen. Your surgery may 
be video-recorded for review by the study team. 
 
You will be monitored carefully in the hospital. You may be treated with pain medications, 
antibiotics or both. If there are no complications, you usually will go home the next day. 
 
Your study doctor may start to decrease the dosage of medicines (acetazolamide, furosemide or 
both) on the day of this surgery. 
 
Follow-up Visits and Testing 
You will be asked to return for follow-up visits at 1 week, 2 weeks, 1 month, 2 months, 4 


 
 
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Page 6 of 17 
months, 6 months, 1 year, 2 years, and 3 years after you get your treatment group assignment. 
Additional visits may be scheduled depending on how you are doing. 
 
You will also receive phone calls from the study staff (at 3 months, 5 months, and 9 months) and 
from the Jaeb Center staff (about every 3 months after the 1 year visit).  
 
When you are taking acetazolamide, you should bring the bottle(s) with your unused tablets to 
every visit. At the follow-up visits the following may be done: medical history updates, eye 
exams, physical exams, questionnaires, blood tests, tests of your side vision (visual field test), 
and photos of your eyes. When necessary, your doctor may decide to repeat tests of your side 
vision during the study. 
 
You will be asked to undergo another lumbar puncture (LP) at the 6-month visit. This is often 
done as part of standard care, but it will be optional. This is to find out if the treatment has 
affected your fluid pressure levels. The procedure and fluid collection will be the same as at your 
screening exam.  
 
The table below shows what will happen at each follow up visit:  
Visit 
Medical 
History 
Update 
Eye 
Exam
Vital 
Signs
 
Questionnaires
Visual 
Field Test 
(side vision) 
Eye 
Photos 
Blood 
Tests 
OCT1
(eye 
images) 
LP2
1 week 
X 
X 
X 
 
X 
 
 
X 
 
2 weeks 
X 
X 
X 
 
X 
X 
 
X 
 
1 month 
X 
X 
X 
 
X 
X 
 
X 
 
2 months
X 
X 
X 
 
X 
X 
 
X 
 
4 months
X 
X 
X 
 
X 
X 
X 
X 
 
6 months
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 year 
X 
X 
X 
X 
X 
X 
X 
X 
 
2 years 
X 
X 
X 
X 
X 
X 
X 
X 
 
3 years 
X 
X 
X 
X 
X 
X 
X 
X 
 
1 Ocular coherence tomography, 2 Lumbar puncture (recommended but not required) 
 
WHAT ARE THE RISKS OF THIS STUDY? 
General Risks  
Because of the amount of your vision loss, there is a chance that your condition will worsen. 
This could occur whether or not you participate in the study. Your vision will be monitored 
carefully throughout the study. 
 


 
 
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Risks of Examination  
The risks of the examinations and testing are the same as those associated with an eye, 
neurological, and general medical examination in your doctors’ offices. There is a possibility of 
irritating the front surface of the eye from either the eye drops or the eye pressure check. If this 
occurs, it usually gets better within several hours. Your reading vision will be blurred and you 
will be light-sensitive for several hours after receiving the dilating drops. Your eyes may be 
“dazzled” by the bright light used to take the photographs, but the light will not damage the eyes. 
 
Risks of Lumbar Puncture (LP) 
The risks of the LP include discomfort, bruising, minimal bleeding, brief back pain, and allergy 
to the local anesthetic or to the antiseptic used to clean your skin. Extremely rare complications 
include bleeding around the spinal nerves or a herniated disc. You must tell your study doctor if 
you are allergic to local anesthesia (lidocaine) or to iodine. About 20% of patients having an LP 
develop a headache after the procedure. The headache generally starts within the first 3 days 
after the procedure. The pain is worse when standing and is better when lying down. If you 
develop a headache after the LP, the study doctor will recommend treatment, which may include 
drinking fluids, caffeine, pain medicine, or a blood patch at the LP site (injecting your own blood 
into the lower back to stop the fluid from leaking out). No additional risk beyond that of usual 
care is expected. 
 
Risks of Blood Draw  
The risks of drawing your blood are bruising, lightheadedness, and a low risk of infection. 
 
Risk of Collecting Genetic Information  
The study may collect and use your blood to learn more about how diseases occur more in some 
families than in other families. It may also be used to learn about why some medicines work 
better or have more side effects in some people than in other people. It is possible that others 
could misuse this information. 
 
A federal law called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. Be aware that this federal law does not protect 
you against genetic discrimination by companies that sell life insurance, disability insurance, or 
long-term care insurance. GINA also does not protect you against discrimination if you have 
already been diagnosed with the genetic disease being tested. 
 
Risks of Questionnaires  
It is possible that some of the questions on the various rating scales might embarrass or upset 
you. The format is self-assessment, but you do not have to answer any questions that make you 
feel uncomfortable. 
 
Risks to Confidentiality  
This study will be capturing some information about you that includes identifiable, personal 
information, like your date of birth. The study has procedures in place to protect that 
information. There is a chance that a loss of that protection could occur. This would be a loss of 


 
 
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confidentiality. Please see the “How will my information be protected and kept confidential” 
section below for more information. 
 
Risks of Acetazolamide  
The table below lists the severity and relative frequency of possible side effects from 
acetazolamide. 
Frequency of Risk 
Risks that may be 
mild 
Risks that may be  
more serious 
Risks that may be 
life-threatening 
More likely: 
happens with more 
than a third of 
people taking this 
drug 
• 
Low Energy 
• 
Taste Problems 
• 
Loss of Appetite 
• 
Weight Loss 
• 
Tingling Lips and 
Limbs 
• 
Frequent Urination 
 
 
Less Likely: 
happens with a 
about a third or less 
of people taking 
this drug 
• 
Depression 
• 
Kidney Stones 
• 
Drowsiness 
• 
Diarrhea 
• 
Increased Blood 
Acidity 
• 
Low Blood 
Sodium 
 
Rare: 
happens in less than 
1% of people 
taking this drug 
• 
Ringing in the Ears 
• 
Nearsightedness 
• 
Sun-Sensitive Skin 
 
• 
Low Blood Count 
• 
Low Blood 
Potassium  
• 
Kidney Failure 
• 
Allergic Skin 
Condition 
• 
Muscle Weakness 
• 
Abnormal Liver 
Function  
• 
Severe Allergic 
Reaction 
 
Risks of Furosemide  
Furosemide causes frequent urination. It can lead to loss of potassium from the body. This 
requires monitoring of your blood. You will be prescribed potassium replacement, if needed. The 
most common side-effects of low potassium levels are fatigue and muscle cramps. Very low or 
very high potassium levels may cause your heart to beat abnormally and can cause a heart attack 
or death. Furosemide also may lower your blood pressure, causing lightheadedness or, in 
extreme cases, fainting. Some people are allergic to furosemide. The most common allergic 
reaction is rash. 
 
Risks of Optic Nerve Sheath Fenestration  
There may be temporary swelling or bruising of the eyelids and the area around the eye. The eye 
area may be painful for several days. If the eye socket is entered next to the bridge of the nose, 
the white part of the eyeball will be bloodshot for several weeks after surgery, the eye may feel 
irritated, and you may experience double vision. The double vision usually gets better on its own, 


 
 
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but sometimes eye muscle surgery is needed if it does not resolve. As the surgery is being 
performed near the optic nerve, there is a very small chance that your vision could worsen after 
the surgery. There is a smaller possibility of blindness in the operated eye (despite the surgery). 
There is a small risk of local eye infection. 
 
Risks of Ventriculoperitoneal Shunting  
You should expect to have pain around the incision site after the surgery. There is a small risk of 
infection, which may occur at any time after the shunt is inserted. An infection could lead to 
meningitis, which may be life threatening. This requires immediate treatment with intravenous 
antibiotics and removal of the shunt. The shunt tubing or valve can clog or break at any time, and 
your shunt will stop working. In this case, the pressure in your head may rise again, causing 
worse vision and headache. If this happens, you may need another operation to fix the shunt. If 
the catheter in the abdomen touches your internal organs, pain or discomfort can occur. This is 
rarely severe enough to remove or move the tube. 
 
Risks of General Anesthesia 
If you have Optic Nerve Sheath Fenestration (ONSF) or Ventriculoperitoneal Shunting (VPS) 
surgery, you will have general anesthesia. General anesthesia involves medications that are 
injected into the blood or breathed into the lungs. A tube or device is inserted into your airway to 
help you breathe. You will be unconscious. You won’t feel pain during the procedure. The 
anesthesiologist will discuss the risks in detail. You will sign a separate consent form for 
anesthesia. Minor complications are injury to the lips, gums, teeth, vocal cords, and throat 
discomfort. Rare but serious risks include blood clots, nerve damage with weakness or loss of 
sensation, cardiac arrest, stroke, paralysis, permanent organ damage, brain damage, and death.  
 
Risks for Women  
The risks of acetazolamide on an unborn baby or a nursing child are unknown. For this reason, 
women who become pregnant during the first six months of the study will be asked to stay in the 
study but will no longer receive acetazolamide. A pregnancy test is done as part of screening for 
this study. You will also be asked about how you plan to make sure that you do not become 
pregnant while in the study (like if you use birth control). You will also be asked about 
pregnancy at each visit. If you plan to nurse a child during the study, please talk with your doctor 
before you decide to do so. 
 
Unknown Risks  
It is always possible that anyone taking acetazolamide for the first time may have an allergic 
reaction. Also, there may be additional risks from the acetazolamide or the study procedures that 
are not known. If we find out that there are any new risks, you will be told about them. You will 
be able to decide if you want to continue in the study based on this new information. 
 
Please discuss the risks with your study doctor or any other health care provider.  
 
WHAT ARE THE BENEFITS OF TAKING PART IN THIS STUDY?  
The possible benefits are that study treatment may keep your vision from worsening or improve 


 
 
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your vision. However, this is not a guarantee. You will receive careful follow-up during the 
study to check your vision. The research may help other people with IIH in the future.  
 
ARE THERE OTHER OPTIONS THAN BEING IN THIS STUDY? 
If you do not take part in this study, you could still receive any of the treatments being used in 
the study. You also could receive treatment listed below: 
• treatment with different medications including other diuretics (water pills) or steroids 
• lumboperitoneal shunting (running a tube from the fluid filled space in the lower spine to 
your abdomen) 
 
CAN I STOP BEING IN THE STUDY? 
You can stop being in the study at any time. If you decide to stop being in this study, you will 
not be treated differently. Also, your regular care will not be impacted. Please talk to your study 
doctor or staff so they know why you are stopping the study and can help you do so safely. 
 
If we find out that there are any new risks, you will be told about them. You will be able to 
decide if you want to continue in the study based on this new information. 
 
The study may stop or the study doctor may decide to take you out of the study at any time. You 
do not have to give permission for the study to stop or for the study doctor to remove you from 
the study. You will be told if this happens.  
 
Some reasons why you may be removed from the study include: 
• The doctors feel that it is in your best interest 
• The doctors think that being in the study may cause you harm 
• You experience an injury related to the study 
• You need additional or different medication not allowed in the study 
• You do not follow the study plan 
 
If you are removed from the study or the study is stopped, you may continue to receive care like 
you normally would if you were not in this study. 
 
The entire study could be discontinued at any time by the Study Director, the National Eye 
Institute/National Institutes of Health, the Institutional Review Board, or the U.S. Food and Drug 
Administration (FDA) if the safety of research subjects is found to be at significant risk. If your 
participation in the study ends for any reason, you may be asked to return for a final study visit to 
complete a neurological and visual exam. 
 
ARE THERE COSTS RELATED TO TAKING PART IN THE STUDY? 
The costs of routine treatment, office visits, and tests that are part of your regular care will be 
billed to you or your insurance company like they normally would if you were not in a study. All 
of the following medications, tests, and procedures are your or your insurance company’s 
responsibility: 
• Acetazolamide after the first 6 months of the study 


 
 
SIGHT Protocol V3.2 - ICF V2.4  
 
Page 11 of 17 
• Other medications and supplements that you may be prescribed or used during the study. 
This includes furosemide, potassium, and headache medicines. 
• Surgical procedures including ONSF and VPS and related hospitalizations 
• Standard of care tests (any tests or exams for your condition you would have even if you 
were not participating in a research study): 
o neuro-ophthalmologic examinations 
o routine laboratory tests 
o visual field testing (not including repeat testing) 
o MRI or CT scan 
o initial lumbar puncture 
o optic disc photographs at the Screening Visit, 6-month Visit, yearly visits after 6 
months, and any unscheduled visit  
 
Testing that is specifically for this study will be paid for by the study. The study will pay for: 
• acetazolamide for the first 6 months of the study 
• repeat visual field testing, as required by the study 
• optic disc photographs at the 2 week, 1 month, 2 month, and 4 month Visits 
• all optical coherence tomography (OCT) 
• the lumbar puncture at the 6-month Visit 
• dietary consultation 
• vital signs at each study visit 
• the pregnancy test at the Screening Visit (for women of childbearing potential) 
• additional blood drawn at the Screening Visit for future IIH research 
 
IS THERE PAYMENT FOR TAKING PART IN THIS STUDY? 
If you take part in the study, you will receive $50 per completed study visit (i.e., Screening, 1 
week, 2 week, 1 month, 2 months, 4 months, 6 months, 1 year, 2 years, and 3 years) to cover the 
cost of your time and travel. You will not receive compensation for extra visits that are required 
as part of your normal care.  
 
You may have trouble paying for some exams and tests if you do not have insurance. Also, 
depending on your insurance plan, it is possible that your insurance will not pay for some of the 
exams and tests listed in this form. If you qualify for financial assistance, the study will pay for 
the costs of study visits and surgery, but the study is only able to reimburse up to a certain 
amount ($1,890 for study visits, $38,500 for VPS, and $23,000 for ONSF; the VPS and ONSF 
amounts include fees for hospitalization, surgeon, and anesthesia costs). Costs for other tests, 
procedures, or therapies that are part of your usual care will not be covered by the study. 
 
The use of your samples may result in commercial profit. You will not be compensated for the 
use of your samples. 
 


 
 
SIGHT Protocol V3.2 - ICF V2.4  
 
Page 12 of 17 
WHAT HAPPENS IF I HAVE AN ILLNESS OR INJURY FROM BEING IN THE 
STUDY? 
If you have an illness or injury that is related to your participation in the study, then you can get 
care like you normally would. If you have an emergency, please seek emergency care as soon as 
possible. Please tell the emergency doctor that you are in a research study. Please also tell your 
study doctor about the emergency as soon as you can.  
 
The study will not provide costs for care or other expenses relating to illnesses or injuries. The 
costs of care for illnesses or injuries will be billed to you or your insurance company like they 
normally would. Your study doctor, the study doctor’s office, the Jaeb Center, and the National 
Eye Institute/National Institutes of Health are not offering payment for lost wages, direct losses, 
or indirect losses. 
 
CONTACT INFORMATION FOR QUESTIONS OR PROBLEMS 
If you have questions about this study; a research illness or injury; or have concerns, suggestions 
or questions about the study, then contact your study doctor using the contact information on the 
first page of this form. 
 
Contact the Jaeb Center for Health Research Institutional Review Board (IRB) Office at 813-
975-8690 or irb@jaeb.org if you: 
• Have questions about your rights as a research participant 
• Wish to talk about your concerns or suggestions about the research 
• Want additional information about the research, or 
• Want to provide comments about the research. 
 
HOW WILL MY INFORMATION BE PROTECTED AND KEPT CONFIDENTIAL? 
As required by law, study-related records with identifying information will be kept confidential. 
Safety measures for the access, security, and privacy of your information have been put in place 
by law. Unless the law requires it, your name, address, social security number, telephone 
number, or any other direct identifying information will not be used to identify you.  
 
Certificate of Confidentiality 
This study has a Certificate of Confidentiality. This adds special protection for study information 
that identifies you and allows us, in some cases, to refuse to give out information that could 
identify you without your consent. This could be done when the information is requested by a 
federal, state, local court or public agency. If you need medical help, we may still share your 
identifiable information. As described in this form or in other cases, we may share identifiable 
information. For example, if the government inspects us, they may see your identifiable 
information. Your study doctor and research team will follow local laws and will tell the local or 
state authorities: 
• if certain diseases are present; 
• if they suspect neglect, abandonment, or abuse of you; and 
• if your study doctor or research team learn that you plan to harm yourself or someone else 
 


 
 
SIGHT Protocol V3.2 - ICF V2.4  
 
Page 13 of 17 
Purpose of Authorization 
We have rules to protect information about you. Federal and state laws also protect your 
information. By signing this form you are giving your permission, called your “authorization,” 
for the use and disclosure of information protected by the law.  
 
You must sign the Protected Health Information Authorization at the end of this form if you want 
to be in the study. When you sign the form, you give permission for the use and sharing of your 
Protected Health Information (PHI) for the study. PHI is health information that identifies you. 
Your authorization is beneficial and important for the study. Without your authorization, you 
will not be able to be in this study. 
 
Using and Sharing Your PHI 
Your study doctor will collect information about you. This information includes things learned 
from study procedures as well as your name, address, date of birth, and information from your 
medical records. These are examples of identifiable information. A code number and your 
initials will replace your name, address, telephone number, or social security number in the 
results given to the Jaeb Center for Health Research in Tampa, Florida. 
 
The study doctor’s office will not share study results that can identify you except as explained in 
this form or when required by law. The Jaeb Center and your study doctor’s office will guard the 
privacy of your study PHI. 
 
The following people may see or receive your information from this study: 
1. The people who work for this doctor’s office 
2. The people who work for the Jaeb Center for Health Research, which is coordinating the study 
3. The people who work for the Neuro-Ophthalmology Research Disease Investigators 
Consortium (NORDIC) 
4. The doctors and other researchers who are involved in the study 
5. Any review board that oversees human investigations rules for your doctor’s office 
6. Any federal agency that oversees clinical trials 
7. If you have an adverse (unfavorable) event, the people outside this doctor’s office who 
assist in your care. 
8. National Institutes of Health (NIH/NEI) or its representatives (funding agency) 
9. Data Safety Monitoring Committee (DSMC) (the committee that follows the study data 
for any safety and enrollment concerns) 
10. Any laboratory that is receiving samples for the study 
11. Reading centers that will be responsible for evaluating and grading visual field tests, 
OCT tests, and photographs. 
12. A central lab which will store de-identified blood samples for future IIH research 
 
Study results without the identifiable information may be shared in medical journals and at 
scientific meetings. Your records will be confidential. No one will share your identity in a 
medical journal or at a scientific meeting. 
Results from the study will be sent to you from your study doctor or clinic after the main paper is 
published in a journal.  


 
 
SIGHT Protocol V3.2 - ICF V2.4  
 
Page 14 of 17 
 
Who Can Receive and Use Your Study Information? 
It is possible that people outside of this doctor’s office and the Jaeb Center may need to see or 
receive your information from this study. Some examples include government agencies (such as 
the Food and Drug Administration), committees that monitor safety, other sites in the study, and 
companies that sponsor the study. In most cases the information will have a code number with it 
instead of your name, address, telephone number, or social security number.  
 
There are some situations where the information will not have a code number but may include 
your name, address, telephone number, or social security number (PHI). If so, people outside this 
doctor’s office who assist in your care may see your study PHI. They may not be covered by the 
law. Everyone who needs to see your information will be told it is confidential, but we cannot 
guarantee full confidentiality once it leaves the doctor’s office.  
 
Other Considerations 
The information and samples collected in the study may be used in future studies without 
additional permission from you. This may include research done by other researchers. The 
information that may be shared will not contain any information that could identify you. There 
may still be a chance that someone could identify you, but this is not likely.  
 
A copy of the information collected as part of the study will be made public in a dataset. This 
will be done after the study ends.  This dataset will not contain any PHI. The study results will 
also be made public. These results will not have any information that could identify you.  
 
A limited dataset that contains some PHI may be provided to certain researchers. This PHI will 
not include things like your name, address, identifying pictures, or medical record numbers. Any 
researcher would need to sign an agreement to protect your PHI before getting this dataset as 
required by law. 
 
Separately from your research data, the Jaeb Center for Health Research in Tampa, Florida will 
be provided with information on how to contact you for the phone calls described earlier. 
 
If your study center is not able to locate you when they try to schedule your follow-up visit, a 
third-party search service may be used to try to contact you. 
 
If your surgery is video-recorded, the video will not be shared outside of the study. Also, it is 
very unlikely you could be identified by the video. 
 
Clinical Trial Reporting  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. A copy of one of the 
study consent form templates will also have to be posted on a federal website. 
 


 
 
SIGHT Protocol V3.2 - ICF V2.4  
 
Page 15 of 17 
Can You Cancel Your Authorization? 
You may cancel your permission for the use and sharing of your study PHI at any time. You will 
need to contact your study doctors and give them a written notice of cancellation. When you 
cancel your permission or when you withdraw from the study directly, you are no longer part of 
the study. No new information about you will be gathered for the study except when there is a 
safety concern related to the study. If there is a safety concern, your entire medical record may 
need to be reviewed. 
 
The Jaeb Center will receive all the information that was collected for the study up to the time 
that you cancel or withdraw from the study. The Jaeb Center will receive any new information 
about any safety concerns that may be related to the study. 
 
When Will the Use and Sharing of Your PHI Stop?  
Some of your study PHI does not have a code number with it. Your permission for the use and 
sharing of your PHI lasts 50 years from the date that you sign this form or until the end of the 
study, whichever comes first. 
 
The rest of your study information does have a code number with it. When it is collected, it 
becomes part of a research report. Your permission for the use and sharing of this coded 
information will never end. This coded data does not have your name, address, telephone 
number, or social security number. 
 
Identifiable Private Information for Future Use 
Your information that is identifiable will be stored, maintained or used for future research as 
required by the NIH. The identifiable information that will be used is the images that we have 
taken of your optic nerves. This information will be publically available. Your images could be 
used for other research, to help design future studies, or for teaching materials. 
   
Your identifiable private information may be stored and used indefinitely.   
 
You will not be told about the specific future uses of your identifiable private information 
because they are unknown at this time. This means that you will not be told about the purpose of 
the future research. If there is a certain kind of research study that you would not normally want 
to do, you won’t know if a future study is like that. Also, the results from the future studies will 
not be shared with you. 
 
There are plans to protect your information by removing any dates, names, initials, or other 
information from the images that could make it easier to identify you. There is still a chance that 
a loss of that protection could occur. This would be a loss of confidentiality.  
 
It is not expected that you will have any benefit by allowing your identifiable private information 
to be stored, maintained, or used for these future research purposes. You do not have to allow the 
study to store, maintain, or use your identifiable private information for future purposes if you 
don’t want to. If you decide not to, you will not be treated differently, and you can still be in this 
study. Also, your regular care will not be impacted.  


 
 
SIGHT Protocol V3.2 - ICF V2.4  
 
Page 16 of 17 
 
Please contact the Jaeb Center for Health Research Institutional Review Board (IRB) Office at 
813-975-8690 or irb@jaeb.org if: 
• you have questions about your rights as a research participant 
• you wish to talk about you concerns or suggestions about the storage, maintenance or use 
of your identifiable private information 
• you want to know about future research studies, want additional information, or want to 
provide comments  
 
 


 
 
SIGHT Protocol V3.2 - ICF V2.4  
 
Page 17 of 17 
Participant’s Full Name (printed)   
 
 
 
 
__________________ 
 
Study Participation and Protected Health Information Authorization 
 
Additional Blood Collection for Future Research 
 
Permission for Identifiable Private Information for Future Use 
 
Investigator’s Certification 
 
By signing below, you agree to take part in this study, and authorize the use and disclosure of 
your protected health information. This information is collected as part of participation in this 
study. You cannot be in this study if you do not provide this permission. Your signature means 
that: 
• you have read this informed consent form 
• you have been given the chance to discuss the study and to ask questions to your satisfaction 
• you authorize the use and disclosure of your protected health information 
• you freely choose to participate, you can withdraw at any time, and you will receive a copy 
of this consent form 
 
 
 
 
 
______ 
Participant Signature 
 
Date 
□ Yes      □ No 
By checking “yes” you are agreeing to have an additional ~20 ml (about 4 
teaspoons) of blood drawn at the Screening Visit to be used for future IIH 
research. You can still be in this study if you do not provide this permission.
 
 
 
 
 
______ 
Participant Signature 
 
Date  
 
☐ I do give my permission to allow for the storage, maintenance, and use of my identifiable 
private information from the images that have been taken of my optic nerve as described above, 
or 
 
☐ I do not give my permission to allow for the storage, maintenance, and use of my identifiable 
private information from the images that have been taken of my optic nerve as described above 
 
 
 
 
 
______ 
Participant Signature 
 
Date 
I certify that to the best of my knowledge the participant understands the nature, demands, 
risks, and benefits involved in the participation of this study.  
 
________________________      _________________________    ___________________ 
Investigator’s Printed Name      Investigator’s Signature 
Date 

SAP_002.pdf: 
SIGHT SAP v1.0 30Jan2019 clean 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
A Multicenter, Partially-Masked, Randomized, Controlled Study of Medical Therapy vs. 
11 
Medical Therapy plus Optic Nerve Sheath Fenestration vs. Medical Therapy plus 
12 
Stereotactic Ventriculoperitoneal Cerebrospinal Fluid Shunting in Subjects with Idiopathic 
13 
Intracranial Hypertension and Moderate to Severe Visual Loss 
14 
 
15 
Surgical Idiopathic Intracranial Hypertension Treatment Trial (“SIGHT”) 
16 
 
17 
STATISTICAL ANALYSIS PLAN 
18 
 
19 
Version 1.0 
20 
Protocol Version 3.2 
21 
 
22 
January 30, 2019 
23 
 
 
24 


SIGHT SAP v1.0 30Jan2019 clean 
Revision History 
The following table outlines changes made to the Statistical Analysis Plan.  
Version 
Number 
Protocol 
Version 
Author 
Approver 
Effective 
Date 
Study Stage 
Revision Description 
1.0 
3.2 
Nicole 
Foster 
Mike 
McDermott 
03-04-
2019 
No analyses 
done 
Original Version  
 
25 
 
26 
 
27 
 
28 
Author: ____________________________________ 
29 
 
30 
 
31 
 
32 
Approver: __________________________________ 
33 
 
34 
 
35 
 
36 
Study Lead: ______________________________ 
37 
 
 
38 


SIGHT SAP v1.0 30Jan2019 clean 
List of Abbreviations 
39 
Abbreviation 
Definition 
CBC 
Complete Blood Count 
CSF 
Cerebrospinal Fluid 
D 
Diopter 
dB 
Decibel 
DSMC 
Data and Safety Monitoring Committee 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
GCL 
Ganglion Cell Layer 
GEE 
Generalized Estimating Equations 
HIT-6 
Headache Impact Test 
IIH 
Idiopathic Intracranial Hypertension 
ITT 
Intention to Treat 
MAR 
Missing at Random 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
mm Hg 
Millimeters of Mercury 
NEI 
National Eye Institute 
ONSF 
Optic Nerve Sheath Fenestration 
PCS 
Physical Component Summary 
PMD 
Perimetric Mean Deviation 
PRC 
Photography Reading Center 
RNFL 
Retinal Nerve Fiber Layer 
SF-36v2 
Short Form Health Survey 
VFQ-25 
Visual Function Questionnaire 
VFRC 
Visual Field Reading Center 
VPS 
Sterotactic Ventriculo-Peritoneal CSF Shunting 
 
 
40 


SIGHT SAP v1.0 30Jan2019 clean 
1.0 Study Overview 
41 
The study is a randomized trial of adults (18-<64 years old) with idiopathic intracranial 
42 
hypertension and moderate to severe visual loss without substantial recent treatment who are 
43 
randomly assigned to (1) medical therapy, (2) medical therapy plus Optic Nerve Sheath 
44 
Fenestration (ONSF), or (3) medical therapy plus Sterotactic Ventriculo-Peritoneal CSF 
45 
Shunting (VPS). 
46 
 
47 
The primary study objective is to determine whether the efficacy of VPS with medical therapy is 
48 
superior to medical therapy alone or ONSF with medical therapy in reducing or reversing visual 
49 
loss in subjects with idiopathic intracranial hypertension and moderate to severe visual loss.  A 
50 
secondary objective is to compare the treatment groups with respect to the time from 
51 
randomization to treatment failure over up to 3 years.  
52 
 
53 
The study protocol consists of: 
54 
• 
Randomized Trial 
55 
o Screening visit 
56 
o Baseline visit 
57 
o Randomization 
58 
o Safety Visits (timing dependent on treatment group) 
59 
o Visit 1 (4 weeks from randomization) 
60 
o Visit 2 (8 weeks from randomization) 
61 
o Phone call 1 (12 weeks from randomization) 
62 
o Visit 3 (16 weeks from randomization) 
63 
o Phone call 2 (20 weeks from randomization) 
64 
o Visit 4 (Primary Outcome; 26 weeks from randomization) 
65 
• 
Treatment Failure Identification Phase 
66 
o Phone call (39 weeks from randomization) 
67 
o Visit 5 (52 weeks from randomization) 
68 
o Visit 6 (104 weeks from randomization) 
69 
o Visit 7 (Final visit; 156 weeks from randomization). 
70 
Unscheduled visits may occur if early termination of treatment is necessary (testing will be the 
71 
same as the primary outcome visit). 
72 
 
73 
This document describes the analyses that will be performed. 
74 
 
75 
2.0 Sample Size 
76 
In this clinical trial, 180 subjects with newly diagnosed IIH and moderate to severe visual loss (-
77 
27 dB ≤ PMD ≤ -6 dB) will be randomly assigned to receive either medical therapy, ONSF + 
78 
medical therapy, or VPS + medical therapy (60 per group). This sample size should provide high 
79 
power (~90%) to detect a difference in mean change of visual field between groups when the 
80 


SIGHT SAP v1.0 30Jan2019 clean 
true differences between any 2 of 3 groups is 4.5 dB with a two-tailed Bonferroni-adjusted 
81 
significance level of 1.7%, allowing for an anticipated 10% drop-out.  The rationale for the 
82 
choice of a clinically significant treatment group difference of 4.5 dB is explained in the last 
83 
paragraph of section 2.0. 
84 
The primary outcome variable in this trial will be the change from baseline to the first of Month 
85 
6 or time of treatment failure in PMD in an eligible eye.  The sample size considerations initially 
86 
focus on data from the best eligible eye, since most subjects are expected to contribute only one 
87 
eye to the primary analysis, but addition of the other eligible eye is also considered below. In 
88 
2012, the IIH Study Group performed a retrospective chart review of consecutive newly 
89 
diagnosed patients that met the modified Dandy criteria for IIH at 30 of the 41 participating sites. 
90 
Data on PMD were available from 91 patients at two time points, before and after intervention, 
91 
with the median follow-up time being 6.0 months (interquartile range 4.1 to 7.0 months). Patients 
92 
received either medical treatment (n = 43), ONSF (n = 24), or VPS (n = 24). The mean (± 
93 
standard deviation) changes in PMD (in dB) in the best eligible eye over the follow-up period 
94 
were 5.5 ± 6.9 in the medical group, 2.0 ± 8.9 in the ONSF group, and 8.2 ± 8.0 in the VPS 
95 
group; overall these values were 5.3 ± 8.0. The distribution of these changes was slightly more 
96 
peaked than would be expected for a normal distribution, as illustrated in Figure 1a and 1b. 
97 
 
98 
Figure 1a and 1b. Distribution of Changes in PMD in the Best Eligible Eye 
99 
The figure on the left (a) shows the distribution of changes in PMD in the best eligible eye according to 
100 
baseline PMD and intervention.  Most of the patients demonstrated improvement in PMD. The figure on the 
101 
right (b) shows a histogram of the changes in PMD in the best eligible eye regardless of intervention. The 
102 
distribution appears to be characterized by a high concentration of changes between 0 and 10 PMD and is 
103 
more peaked than normal. 
104 
Given the cross-sectional nature of the preliminary data, sample size determination based on the 
105 
use of GEE for the primary analysis is very similar to that based on the use of an analysis of 
106 
covariance model. If an analysis of covariance model is fit to the preliminary data, with change 
107 
in PMD as the outcome variable and treatment group and baseline PMD as the independent 
108 
variables, the standard deviation of the residuals is 6.3 dB. The differences between treatment 
109 
groups in adjusted mean response are quite small in this analysis: -0.09 dB difference between 
110 


SIGHT SAP v1.0 30Jan2019 clean 
the ONSF and medical groups, and 1.13 dB difference between the VPS and medical groups. 
111 
Also, a GEE analysis produces identical adjusted group means and slightly different estimated 
112 
standard errors than those from the analysis of covariance model. 
113 
It may be noted that the standard deviation of the residuals in the above analysis of covariance 
114 
model is substantially less than the standard deviations in the individual treatment groups, 
115 
reflecting adjustment for the baseline value of PMD in the analysis of covariance model and the 
116 
fairly strong correlation between the baseline and final PMD values (r = 0.52). When considering 
117 
only subjects who were followed for at least 5.5 months (n = 56), the correlation between the 
118 
baseline and final PMD values was actually somewhat higher (r = 0.62) and the residual standard 
119 
deviation in the analysis of covariance model was smaller (6.0 dB). 
120 
Assuming a standard deviation of 6.5 dB, and a Bonferroni-adjusted two-tailed significance level 
121 
of 1.7%, in order to detect a group difference assuming a true difference of 4.5 dB with 88% 
122 
power, a sample size of 54 subjects per group is required. The sample size will be inflated to 60 
123 
subjects per group (180 total) to accommodate an anticipated 10% rate of subject 
124 
withdrawal/dropout.   
125 
The assumed standard deviation of 6.5 dB was selected based on the calculated standard 
126 
deviation of the residuals from the above analysis of covariance model (6.3 dB) under the 
127 
following assumptions: 1) the distribution of baseline PMD in the study cohort will be similar to 
128 
that observed in the pilot study, and 2) the higher standard deviation observed in the pilot study 
129 
surgical groups can be attributed to the increased probability of those with worse PMD at 
130 
baseline to receive surgery (participants with worse PMD at baseline had higher variability of 
131 
change in PMD)a. The power remains above 80% even if the assumed standard deviation is as 
132 
large as 7.1 dB. 
133 
The inclusion of the worst eligible eye is expected to increase power, but the increase is expected 
134 
to be small (approximately 3%) because the preliminary data from the chart review indicate that 
135 
only ~40% of subjects will contribute a second eligible eye to the analysis and the correlation 
136 
between the outcomes in the two eyes is quite high (0.82 in our sample). This assumes that the 
137 
group difference will be comparable in the best and worst eligible eyes, as we anticipate. 
138 
The chosen effect size of 4.5 dB is based on the following rationale.  Visual field defects are 
139 
similar in IIH and glaucoma and data on the relationship between vision-specific quality of life 
140 
(as measured by the NEI-VFQ-25) and PMD from the better seeing eye are available from 213 
141 
subjects with glaucoma in the Los Angeles Latino Eye Study. A regression analysis yielded the 
142 
finding that a change of 1 dB in PMD corresponded to an approximately one-unit score change 
143 
on the NEI-VFQ-25 composite score.  In another study, Suner et al. used data from two clinical 
144 
trials in neovascular age-related macular degeneration and anchor-based methods to estimate the 
145 
change in NEI-VFQ-25 composite score that corresponds to a change of ≥ 15 letters (~ 3 lines) in 
146 
visual acuity, a value generally accepted as clinically significant. They concluded that a change 
147 
of 4-6 points on the NEI-VFQ-25 composite score should be considered clinically significant.  
148 
Taken together, the results of these two investigations suggest that a change in PMD of 4.5 dB 
149 


SIGHT SAP v1.0 30Jan2019 clean 
corresponds to a change in NEI-VFQ-25 score that would be considered to be of minimal clinical 
150 
significance. 
151 
 
152 
aThe DSMC calculated an estimated standard deviation of change in PMD of 6.9 dB based on the assumption that 
153 
the standard deviations in the pilot data were larger for participants who received surgery, and that the increased 
154 
variability was due to the surgical intervention itself.  Since the surgical groups were under-represented in the pilot 
155 
data, the estimated variances in these groups were appropriately up-weighted in the calculation of the pooled 
156 
standard deviation, resulting in the estimate of 6.9 dB.  The assumptions underlying the original calculation (6.5 dB) 
157 
and the DSMC calculation (6.9 dB) are both plausible. The DSMC agreed to move forward with the 6.5 dB standard 
158 
deviation. 
159 
 
 
160 


SIGHT SAP v1.0 30Jan2019 clean 
3.0 Analysis 
161 
 
162 
3.1 Intention-to-Treat Principle 
163 
The primary statistical analyses for this trial will be performed according to the intention-to-treat 
164 
principle and will include all randomized subjects and eligible eyes.  An eye is defined as 
165 
eligible if the following hold at the baseline visit: 
166 
• Inclusion criteria 
167 
o Visual field loss meeting the following based on two full threshold 24-2 size V 
168 
tests reviewed by the Visual Field Reading Center (VFRC) 
169 
▪ PMD from -6 dB to -27 dB 
170 
▪ Reproducible visual loss present on automated perimetry including no 
171 
more than 15% false positives 
172 
o Visual acuity better than 20/200 (39 or more letters correct) 
173 
• Exclusion criteria 
174 
o Intraocular pressure currently >28 mm Hg or >30 mm Hg at any time in the past 
175 
o Refractive error of more than -6.00 or more than +6.00 sphere or more than 3.00 
176 
cylinder with the following exceptions: 
177 
▪ Eyes with more than 6.00D of myopia but less than 8.00D of myopia are 
178 
eligible if: 
179 
• There are no abnormalities on ophthalmoscopy or fundus photos 
180 
related to myopia that are associated with visual loss (such as 
181 
staphyloma, retinal thinning in the posterior pole, or more than 
182 
mild optic disc tilt), and 
183 
• The individual will wear a contact lens for all perimetry 
184 
examinations with the appropriate correction 
185 
▪ Eyes with more than 6.00D of hyperopia but less than 8.00D of hyperopia 
186 
are eligible if: 
187 
• There is an unambiguous characteristic halo of peripapillary edema 
188 
as opposed to features of a small crowded disc or other hyperopic 
189 
change related to visual loss determined by the Site Investigator or 
190 
the PRC Director (or his designate), and 
191 
• The individual will wear a contact lens for all perimetry 
192 
examinations with the appropriate correction (which can be 
193 
corrected for perimetry or the patient’s own contact lens with over 
194 
correction by lens at perimeter) 
195 
o Other disorders causing visual loss except for refractive error and amblyopia, 
196 
including cells in the vitreous or iritis 
197 
o Large optic disc drusen on exam or in previous history (small drusen of the disc 
198 
can occur with longstanding papilledema and are allowed if not so numerous that 
199 
investigator determines they are contributing to vision loss). 
200 


SIGHT SAP v1.0 30Jan2019 clean 
  
201 
Every effort will be made to retain subjects in this study, to promote adherence to the study 
202 
protocol, and to collect all data at every visit. If a subject cannot tolerate study medication or 
203 
refuses to receive the study intervention, we will continue to follow and evaluate that subject if 
204 
he/she is willing. If a subject drops out, attempts will be made to bring the subject back for a 
205 
final evaluation. Compliance with trial procedures, drop-outs/drop-ins, and reasons for subject 
206 
withdrawal will be carefully tracked throughout the study. 
207 
 
208 
3.2 Analysis of the Primary Outcome Variable 
209 
3.2.1 Definition of Primary Outcome 
210 
The primary outcome variable will be the change from baseline to first of Month 6 or time of 
211 
treatment failure in PMD in an eligible eye, with data from all eligible eyes included in the 
212 
primary analysis (refer to the table below for a description of eyes included in the primary 
213 
analysis).   
214 
 
215 
Eyes at baseline 
Eyes included in primary analysis  
No eligible eyes→ subject not eligible 
 
None (subject not eligible) 
One eligible eye and non-eligible eye too good 
One eye that was eligible at baseline, 
regardless of what happened to either eye 
during study 
One eligible eye and non-eligible eye too bad 
One eye that was eligible at baseline, 
regardless of what happened to either eye 
during study 
Two eligible eyes 
Both eyes that were eligible at baseline, 
regardless of what happened to either eye 
during study 
 
216 
 
217 
Treatment of subjects who have reached criteria for treatment failure will be at the discretion of 
218 
the Site Investigator, and this treatment may yield a different outcome than randomized 
219 
treatment. For this reason, the primary outcome variable for subjects who reach criteria for 
220 
treatment failure prior to Month 6 will be the PMD measured at the time of treatment failure for 
221 
purposes of the primary analysis. It is anticipated that no more than 15% of subjects will reach 
222 
criteria for treatment failure prior to Month 6.   
223 
 
224 


SIGHT SAP v1.0 30Jan2019 clean 
PMD (baseline or outcome) will be the average PMD from the two reliable visual field 
225 
examinations (i.e. meeting Visual Field Reading Center criteria) performed at the visit; if only 
226 
one reliable result is obtained on the visual field examination, the one reliable result will be 
227 
analyzed; if a reliable result is not obtained on the visual field examinations, the PMD will be 
228 
considered missing. 
229 
 
230 
Outcome PMD (excluding PMD at time of treatment failure) from visual field testing performed 
231 
out of the window of 168-242 days from randomization will be considered missing for the 
232 
primary analysis.  Note this means a subject can be up to two weeks early and up to a full 60 
233 
days late, this latter choice was made with clinician input that they would rather have a 
234 
measurement than impute. 
235 
 
236 
3.2.2 Primary Statistical Model 
237 
The primary statistical analysis will involve fitting an analysis of covariance model using 
238 
generalized estimating equations (GEE) with treatment group as the factor of interest and 
239 
baseline PMD as a covariate. These analyses will accommodate correlation among the within-
240 
subject responses between the two eyes; an exchangeable working correlation structure will be 
241 
used.  Standard errors for the model parameters will be estimated using the robust “sandwich” 
242 
estimators. The model also does not rely on the assumption of normality. 
243 
This model will be used to determine Bonferroni-adjusted confidence intervals for the three pair-
244 
wise differences among the adjusted treatment group mean responses (treatment effects); 
245 
likewise, tests will be performed to compare the adjusted treatment group means using a 
246 
Bonferroni-adjusted two-tailed significance level. An overall confidence coefficient of 98.3% 
247 
and corresponding significance level of 1.7% for each comparison will be maintained, but as 
248 
discussed in section 3.7.2 below, the confidence coefficient for interval estimation and 
249 
significance level for hypothesis testing will be adjusted for the interim analysis for efficacy.  
250 
 
251 
3.2.3 Adjustment for Baseline Characteristics 
252 
Baseline characteristics of subjects will be summarized overall and by treatment group. Formal 
253 
statistical comparisons between treatment groups will not be performed; instead, potential 
254 
confounding will be explored by examination of the magnitudes of treatment group differences 
255 
in the distributions of visual acuity, papilledema grade, and duration of IIH.  Other variables for 
256 
which there are baseline differences among treatment groups that could be associated with the 
257 
outcome also will be evaluated for a potential confounding effect.  Continuous variables will be 
258 
described using means, standard deviations, medians, quartiles, and ranges, and categorical 
259 
variables will be described using percentages. 
260 
If clinically important differences are found between the groups at baseline, the primary outcome 
261 
analyses will be repeated after statistically adjusting for these differences. These analyses will be 
262 
considered secondary, however. 
263 


SIGHT SAP v1.0 30Jan2019 clean 
 
264 
3.2.4 Investigation of Treatment by Covariate Interactions 
265 
We will investigate the interaction between treatment group and selected baseline covariates 
266 
(age, race/ethnicity, PMD (average of measures from two reliable visual field examinations), 
267 
papilledema grade, RNFL thickness, total retinal thickness, optic nerve head volume, visual 
268 
acuity, presence of transient visual obscurations, and the symptom of constant visual loss) 
269 
separately by adding the appropriate main effect and interaction terms to the primary statistical 
270 
model and testing for significance of the interaction.  
271 
Since the power to detect potentially meaningful interactions will be limited, the magnitudes of 
272 
mean responses to treatment in the relevant subgroups will be examined. The observation of 
273 
clinically important subgroup differences in mean treatment response will serve as hypothesis 
274 
generation for possible future studies designed to address specifically the issue of differential 
275 
therapeutic response. Although these analyses are purely exploratory, those involving 
276 
papilledema grade, PMD, visual acuity, and race/ethnicity will be given higher priority. 
277 
Interpretation of subgroup analyses should be viewed with caution, irrespective of whether the 
278 
overall analysis demonstrates a significant treatment group difference.  Extreme caution is 
279 
particularly needed in the absence of such an overall difference.  
280 
 
281 
3.2.5 Verification of Model Assumptions 
282 
The underlying assumptions of the statistical model to be used in the primary analysis will be 
283 
thoroughly checked (e.g., linearity) through assessment of scatterplots of change in PMD versus 
284 
baseline PMD within treatment group, and remedial measures (e.g., inclusion of baseline PMD 
285 
categorized according to randomization strata) may be taken if serious violations of these 
286 
assumptions are detected. 
287 
 
288 
3.2.6 Treatment of Missing Data 
289 
Multiple imputation will be used to deal with missing data. This will be applied using a 
290 
regression-based imputation model. For subjects with complete data up to a particular visit, a 
291 
linear regression model (identity link) will be fit that includes the outcome at that visit as the 
292 
dependent variable and outcomes at previous visits and treatment group as independent 
293 
variables. Separate models will be similarly constructed for each visit (Weeks 4, 8, 16, and 26). 
294 
Using these regression models, a missing value for a subject at a particular visit will be imputed 
295 
as a draw from the predictive distribution given the outcomes at previous visits (some possibly 
296 
imputed) and treatment group. This will be done sequentially starting with the Week 4 visit and 
297 
ending with the Week 26 (Month 6) visit. This process will be repeated 100 times, resulting in 
298 
100 complete analysis data sets. The analyses (Section 3.2.2) will be performed separately for 
299 
each of the 100 complete analysis data sets, and the results will be combined into one multiple 
300 
imputation inference (estimated treatment effect and associated confidence interval and p-value) 
301 
using Rubin’s rules.  This approach is appropriate for data sets that have a monotone missing 
302 


SIGHT SAP v1.0 30Jan2019 clean 
data pattern.  If the data set does not precisely have this pattern, the monotone data augmentation 
303 
method using Markov-Chain Monte-Carlo as proposed by Li (1988) and Liu (1993) will be used 
304 
to impute the small amount of missing data that is required to make the missing data pattern 
305 
monotone before applying the multiple imputation algorithm described above. This approach 
306 
should accommodate missing data in an appropriate way under the missing at random (MAR) 
307 
assumption.  
308 
 
309 
3.2.7 Sensitivity Analysis 
310 
The primary analysis will be completed using the ITT principle described in Section 3.1.  The 
311 
primary analysis will be repeated with the following considerations as a secondary analysis: 
312 
• 
According to treatment received (whether or not this was the randomly assigned 
313 
treatment) 
314 
• 
Excluding participants without outcome PMD (Month 6 or exam at early treatment 
315 
failure) 
316 
• 
Exclude participants who took less than 80% of tolerated dosage of medication 
317 
• 
Exclude participants with major protocol violations such as: receipt of additional 
318 
treatment outside of treatment assignment prior to first of 6-month visit or visit at which 
319 
treatment failure declared, or major eligibility deviation that could impact the ability to 
320 
assess the primary outcome. 
321 
The identification of subjects to be excluded from these analyses will be determined before the 
322 
masking is broken (i.e., before data analysis). 
323 
 
324 
 
325 
3.3 Analysis of Secondary Outcome Variables for Efficacy 
326 
3.3.1 Definition of Secondary Outcomes 
327 
The following are secondary outcomes for efficacy: 
328 
• 
Change from baseline PMD to Month 6 PMD 
329 
o PMD defined as described in Section 3.2.1 
330 
o Month 6 PMD value will be used even for participants with treatment failure prior 
331 
to Month 6 
332 
• 
Change from baseline to Month 6 CSF opening pressure measurement by lumbar 
333 
puncture 
334 
• 
Change from baseline to Month 6 in papilledema grade 
335 
o Papilledema grade determined by reading center and grade determined by study 
336 
center will be considered separate outcomes and will be analyzed separately 
337 
• 
Change from baseline to Month 6 (pre-lumbar puncture) in RNFL thickness 
338 
• 
Change from baseline to Month 6 (pre-lumbar puncture) in total retinal thickness 
339 
• 
Change from baseline to Month 6 (pre-lumbar puncture) in optic nerve head volume 
340 
• 
Change from baseline to Month 6 (pre-lumbar puncture) in ganglion cell layer thickness 
341 


SIGHT SAP v1.0 30Jan2019 clean 
• 
Change from baseline to Month 6 (pre-lumbar puncture) in optic nerve canal shape 
342 
• 
Change from baseline to Month 6 in ETDRS visual acuity score 
343 
• 
Change from baseline to Month 6 in SF-36v2 scores 
344 
o Change will be calculated separately for each of the eight health domains and the 
345 
physical component summary (PCS) and mental component summary (MCS) 
346 
scores 
347 
o Scores determined via SF-36v2 scoring software 
348 
• 
Change from baseline to Month 6 in VFQ-25 score 
349 
o Score determined as an average of sub-scale scores as described in the VFQ-25 
350 
manual (..\..\References\Participant Questionnaires\VFQ25_Manual.pdf) 
351 
▪ 
Scoring of missing items will follow the scoring instrument 
352 
• 
Change from baseline to Month 6 in VFQ-25 Neuro-Ophthalmic Supplement score 
353 
o Score determined as described in the 10-item Neuro-Ophthalmic instructions 
354 
(..\..\References\Participant Questionnaires\Prior to Executed 
355 
Agreement\10ItemNeuroOpthalVFQ25.pdf) 
356 
▪ 
Scoring of missing items will follow the scoring instrument 
357 
• 
Change from baseline to Month 6 in HIT-6  
358 
o Score determined as a sum of scores for each question (Never = 6, Rarely = 8, 
359 
Sometimes = 10, Very Often = 11, Always = 13; total score range 36 to 78 with 
360 
higher score indicating greater life impact) 
361 
o Surveys with >1 missing responses will be given an overall null score for the visit 
362 
• 
Change in headache severity from baseline to Month 6 as reported on the Headache 
363 
Assessment form 
364 
o Analyzed as a continuous value with the following categories assigned for 
365 
display: 
366 
▪ 
Mild = score 1-4 | Moderate = score 5-7 | Severe = score 8-10 
367 
• 
Month 6 VFRC determination of whether the visual field examination has improved, 
368 
remained the same, or worsened 
369 
o All available visual field examinations will be analyzed.  For the initial secondary 
370 
outcome, the Month 6 VFRC rating will be used; a supplemental secondary 
371 
outcome will use the VFRC rating at time of treatment failure for subjects 
372 
experiencing treatment failure prior to Month 6. 
373 
• 
Change in weight from baseline to Month 6 
374 
 
375 
Data from all eligible eyes will be included in the analysis.  With the exception of CSF opening 
376 
pressure and VFRC determination of visual field status, the outcomes also will be examined with 
377 
change from baseline to Months 12, 24, 36. 
378 
 
379 
3.3.2 Secondary Statistical Models 
380 


SIGHT SAP v1.0 30Jan2019 clean 
Treatment effect on secondary outcome variables for efficacy that are continuous will be 
381 
analyzed using the same methods described in Section 3.2.2 for the primary outcome variable, 
382 
except that a working correlation structure will not be needed for variables that are not eye-
383 
specific.  Variables to be analyzed in this manner are: 
384 
• Change in PMD at Month 6 
385 
• Change in CSF opening pressure (does not require working correlation structure) 
386 
• Change in papilledema grade (both reading center and study center outcomes) 
387 
• Change in RNFL thickness 
388 
• Change in total retinal thickness 
389 
• Change in optic nerve head volume 
390 
• Change in ganglion cell layer thickness 
391 
• Change in optic nerve canal shape 
392 
• Change in ETDRS visual acuity score 
393 
• Change in SF-36 scores (8 subscale domains, PCS and MCS; does not require working 
394 
correlation structure) 
395 
• Change in VFQ-25 score (does not require working correlation structure) 
396 
• Change in VFQ-25 Neuro-Ophthalmic Supplement score (does not require working 
397 
correlation structure) 
398 
• Change in HIT-6 (does not require working correlation structure) 
399 
• Change in headache severity as reported on Headache Assessment form (does not require 
400 
working correlation structure) 
401 
• Change in weight 
402 
 
403 
The treatment effect on the ordinal outcome of Month 6 visual field examination status by 
404 
the VFRC (improved, no change, worse) will be assessed via a logistic regression model 
405 
(proportional odds model).  A likelihood ratio test will be performed for significance of the 
406 
adjusted treatment group odds ratios representing pair-wise treatment group comparisons; 
407 
98.3% confidence intervals will be constructed for these odds ratios. 
408 
 
409 
All models will include treatment group as the factor of interest and the baseline value of the 
410 
outcome variable as a covariate (to replace baseline PMD adjustment in the primary for 
411 
continuous outcomes; Month 6 visual field examination status by VFRC will retain inclusion 
412 
of baseline PMD). 
413 
 
414 
3.3.3 Adjustment for Baseline Covariates 
415 
Assessment for and implementation of adjustment for baseline covariates will follow methods 
416 
described in Section 3.2.3. 
417 
 
418 
3.3.4 Investigation of Treatment by Covariate Interactions 
419 


SIGHT SAP v1.0 30Jan2019 clean 
Investigation of interaction between treatment group and selected baseline covariates will follow 
420 
methods described in Section 3.2.4. 
421 
 
422 
3.3.5 Verification of Model Assumptions 
423 
Methods described in Section 3.2.5 will be used to check underlying assumptions of the 
424 
statistical model for each outcome. 
425 
 
426 
3.3.6 Treatment of Missing Data 
427 
Methods described in Section 3.2.6 will be used to impute missing data at Month 6 for 
428 
continuous outcomes. 
429 
 
430 
Missing values of Month 6 visual field examination status will not be imputed.   
431 
 
432 
3.4 Compliance Outcomes 
433 
Data concerning compliance with acetazolamide (pill counts, serum bicarbonate levels) and 
434 
surgical therapy will be summarized by treatment group and visit.  Subjects with two eligible 
435 
eyes will have this information summarized by eye as well as by treatment group and visit.   
436 
 
437 
3.5 Analysis of Safety and Tolerability Outcomes 
438 
3.5.1 Adverse Events 
439 
All reportable adverse events will be tabulated by treatment group in a listing of each reported 
440 
Medical Dictionary for Regulatory Activities (MedDRA) term and summarized over each 
441 
MedDRA System Organ Class.  Details will be provided in a listing of each event. 
442 
In addition, the following will be tabulated by treatment group. When applicable, events will be 
443 
tabulated by eye within person: 
444 
• Number of adverse events per subject 
445 
• Number of subjects with at least one event 
446 
• Number of subjects with at least one event per person-month (person-month based on 
447 
subject duration in the study) 
448 
• Number of serious adverse events per subject 
449 
• Number of subjects with at least one serious adverse event 
450 
• Number of hospitalizations and reasons for the hospitalization (overall and per subject, 
451 
separately) 
452 
• Number of adverse events thought by investigator to be related to study drug and 
453 
frequency of each type of such event 
454 
• Number of subjects who stopped the intervention in response to an adverse event 
455 


SIGHT SAP v1.0 30Jan2019 clean 
For binary variables (occurrence of at least one event, occurrence of at least one serious adverse 
456 
event, occurrence of at least one hospitalization, occurrence of at least one adverse event related 
457 
to treatment, occurrence of stopping the intervention in response to adverse event), Fisher exact 
458 
tests will be used to compare treatment groups.  For counts (number of adverse events per 
459 
subject, number of serious adverse events per subject, number of hospitalizations per subject), 
460 
groups will be compared using Poisson regression with inclusion of the logarithm of study 
461 
follow-up duration for the participant as an offset term; a negative binomial model will be 
462 
considered if overdispersion is present, and a zero-inflated negative binomial model will be used 
463 
if there appear to be excessive zero counts. 
464 
For each adverse event, the treatment groups will be compared in a pair-wise fashion regarding 
465 
the occurrence of at least one event using Fisher's exact tests; numbers of individual events will 
466 
also be described. The comparisons will be repeated excluding all mild symptoms. Similar 
467 
analyses will be performed after grouping adverse events by body system using Medical 
468 
Dictionary for Regulatory Activities (MedDRA) coding. All subjects will be included in these 
469 
analyses. 
470 
 
471 
3.5.2 Laboratory Test Results and Vital Signs 
472 
Continuous measures of safety such as laboratory test results (CBC with platelet count, 
473 
electrolytes, potassium, bicarbonate, and liver function tests) and vital signs and anthropometric 
474 
measures (blood pressure, weight, and waist circumference) will be analyzed descriptively 
475 
through summary statistics and tabulations. 
476 
Proportions of subjects with particular laboratory test abnormalities will be compared between 
477 
the treatment groups in a pair-wise fashion using Fisher’s exact tests. 
478 
 
479 
3.6 Analysis of Long-Term Follow-Up Data 
480 
The following outcome will be examined in analysis of long-term follow-up data: 
481 
• 
Time from randomization to treatment failure 
482 
 
483 
3.6.1 Analysis Model 
484 
Treatment group differences with respect to long-term outcomes will be assessed by fitting a Cox 
485 
proportional hazards regression model with treatment group as the factor of interest and baseline 
486 
PMD in the best eligible eye as a covariate.  Due to the discrete time data, Efron approximation 
487 
will be used to deal with tied event times.  The model will be used to determine Bonferroni-
488 
adjusted 98.3% confidence intervals for the adjusted hazard ratios for the three pair-wise 
489 
treatment group comparisons.  Likewise, likelihood ratio tests will be performed for the 
490 
significance of these hazard ratios using a Bonferroni-adjusted two-tailed significance level of 
491 
1.7%.  Kaplan-Meier curves will be used to describe the cumulative probability of treatment 
492 
failure over time in each treatment group. 
493 


SIGHT SAP v1.0 30Jan2019 clean 
 
494 
For subjects who do not experience the outcome, event times will be censored at the last subject 
495 
contact at which the subject was determined to not have experienced the outcome (e.g., at time of 
496 
premature withdrawal from the trial or at the final trial visit). 
497 
 
498 
 
499 
3.6.2 Adjustment for Baseline Covariates 
500 
Adjustment for additional baseline covariates (in addition to baseline PMD and papilledema 
501 
grade in best eligible eye) may be considered depending on the comparability of the treatment 
502 
groups at baseline (refer to Section 3.2.3). 
503 
 
504 
3.6.3 Investigation of Treatment by Covariate Interactions 
505 
Examination of interactions between treatment group and selected baseline covariates will be 
506 
performed using the Cox proportional hazards model following the guidelines established in 
507 
Section 3.2.4. 
508 
 
509 
3.6.4 Verification of Model Assumptions 
510 
The underlying assumptions of the Cox proportional hazards model will be checked and a 
511 
thorough analysis of the martingale residuals and other diagnostics will be performed.  Remedial 
512 
measures (covariate transformation) will be taken if serious violations of these assumptions are 
513 
detected. 
514 
 
515 
The proportional hazards assumption will be assessed graphically by plotting log(–log(Ŝ(t)) vs. 
516 
log(time) for each of the treatment groups, and by examining plots of smoothed Schoenfeld 
517 
residuals.  The assumption also will be examined by dividing the time scale into 6-month periods 
518 
and estimating the treatment group hazard ratios separately in each of these periods through the 
519 
use of time-dependent covariates. The period length of 6 months may be adjusted prior to 
520 
unmasking, based on the observed distribution of event times, if relatively few events occur 
521 
during 6-month periods. Treatment group comparisons will be described in this manner if the 
522 
proportional hazards assumption appears to be seriously violated. 
523 
 
524 
The assumption of independence between censoring time and the (unobserved) event time will 
525 
be assessed by performing a sensitivity analysis in which subjects with event times that are 
526 
censored prior to their scheduled end of follow-up will be treated as having experienced the 
527 
event a short time (one week) after censoring. 
528 
 
529 
3.7 Interim Analysis 
530 
3.7.1 Interim Analysis for Safety 
531 
Interim analyses of safety data will be performed periodically throughout the trial. While the 
532 
safety of subjects will be the primary concern of the DSMC, it is difficult to formulate precise 
533 


SIGHT SAP v1.0 30Jan2019 clean 
stopping guidelines that would cover all of the possible situations that might arise. Adverse 
534 
events, particularly serious adverse events and surgical complications, will have to be considered 
535 
carefully by the DSMC in terms of treatment group imbalances and severity. Events of particular 
536 
concern include the following: death, absence of light perception, hypokalemia (from Lasix use), 
537 
surgery-associated visual loss (from either VPS or ONSF), fenestration failure and orbital 
538 
infection (from ONSF), and shunt failure, infection, seizures, and subdural hematoma (from 
539 
VPS). If potential safety concerns are identified, the DSMC may require review of visual field 
540 
data in order to evaluate the risk-benefit of continuing the trial as planned or modifying (or 
541 
halting) the trial. 
542 
 
543 
3.7.2 Interim Analysis for Efficacy 
544 
We will perform a single interim analysis for efficacy based on the primary outcome efficacy 
545 
variable. This will be performed after ~50% of the subjects have completed (or were scheduled 
546 
to have completed, based on their randomization date) their Month 6 visit and will only include 
547 
data from these subjects. Given that recruitment of the 180 subjects will take place over 3 years, 
548 
assuming that recruitment is uniform over time, it is anticipated that slightly fewer than 70% of 
549 
the subjects will be enrolled at the time of the interim analysis.  
550 
The analysis will involve pair-wise comparisons among the treatment groups with respect to the 
551 
primary outcome efficacy variable; the significance level used for each comparison will be 
552 
determined by an O’Brien-Fleming α-spending function for a two-group comparison divided by 
553 
3 (Bonferroni correction). In this case, the boundaries will be Z = 3.394 for the interim analysis 
554 
and Z = 2.400 for the final analysis. Assuming that there are 30 subjects per group and that the 
555 
standard deviation is 6.5 dB at the interim analysis, the boundary will be crossed if a group 
556 
difference exceeds approximately 5.7 dB. This monitoring procedure will have a negligible 
557 
impact on the overall Type I error probability: the significance level at the final analysis 
558 
corresponding to Z = 2.400 is α = 0.0164. Point and interval estimates of treatment effects for the 
559 
primary analysis, as well as reported p-values, will be adjusted for the interim analysis. The bias-
560 
adjusted mean will be used for point estimation and confidence intervals and p-values based on 
561 
the MLE (sample mean) ordering of the sample space defined by the group sequential design 
562 
will be reported.  
563 
The efficacy boundary will be considered to be non-binding.  We believe that it may be prudent 
564 
to halt or modify the trial only if (1) two of the treatment groups are each shown to be superior to 
565 
the third (in which case the third group may be dropped) or (2) one of the treatment groups is 
566 
shown to be superior to each of the other two (in which case the trial may be halted). Of course, 
567 
the relative safety profiles of the treatments would have to factor into these considerations as 
568 
well.  
569 
 
570 
 
571 
3.8 Additional Tabulations 
572 


SIGHT SAP v1.0 30Jan2019 clean 
A flow chart will track all participants who were enrolled, indicating the reason for any who did 
573 
not complete the study and providing details on randomized subjects determined to be ineligible.  
574 
A summary of safety visits, phone calls, and information on completion of questionnaires will be 
575 
compiled. 
576 
 
577 
Tabulations will include:  
578 
• 
Demographic and clinical characteristics at enrollment by treatment group 
579 
• 
Eligible eye characteristics by treatment group 
580 
• 
Non-eligible eye characteristics by treatment group 
581 
• 
Overall number of treatment failures by treatment group 
582 
• 
Overall number of surgical malfunctions by treatment group (ONSF and VPS groups) 
583 
• 
Duration (days) from enrollment to randomization 
584 
• 
Duration (days) from randomization to surgery (ONSF and VPS groups) 
585 
 
586 
Specific Protocol Tabulations by Treatment Group 
587 
6-Month RCT 
588 
• 
Receipt of surgery other than that randomly assigned 
589 
• 
Adherence to medical management and diet by visit 
590 
• 
Daily dosage of acetazolamide and furosemide prescribed at each visit 
591 
• 
Medical therapy at each visit  
592 
• 
ONSF completion status (ONSF group) 
593 
• 
VPS completion status (VPS group) 
594 
• 
Surgical complications (separately for ONSF and VPS groups) 
595 
• 
Reoperations (ONSF) 
596 
• 
Shunt revisions (VPS) 
597 
• 
Headache by visit 
598 
• 
Weight by visit 
599 
• 
Visual field at follow-up (eligible eyes and non-eligible eyes, separately) 
600 
• 
Visual acuity at follow-up (eligible eyes and non-eligible eyes, separately) 
601 
• 
Papilledema grading at follow-up (eligible eyes and non-eligible eyes, separately) 
602 
• 
RNFL and macula GCL at follow-up (eligible eyes and non-eligible eyes, separately) 
603 
• 
Protocol deviations 
604 
 
605 
Treatment Failure Identification Phase (Post 6-Month RCT) 
606 
• 
Adherence to medical management and diet by visit 
607 
• 
Daily dosage of acetazolamide and furosemide prescribed at each visit 
608 
• 
Medical therapy at each visit 
609 
• 
Protocol deviations. 
610 

Prot_001.pdf: 
SIGHT PROTOCOL V4.0 11APR2019 
PAGE 1 OF 87 
 
A Multicenter, Partially-Masked, Randomized, Controlled Study of Medical Therapy vs. 
Medical Therapy plus Optic Nerve Sheath Fenestration vs. Medical Therapy plus 
Stereotactic Ventriculoperitoneal Cerebrospinal Fluid Shunting in Subjects with Idiopathic 
Intracranial Hypertension and Moderate to Severe Visual Loss 
 
Surgical Idiopathic Intracranial Hypertension Treatment Trial (“SIGHT”) 
IND Sponsor: Michael Wall, MD 
Version Number: 4.0 
11 April 2019 
 
 
CONFIDENTIAL 
This document is a confidential communication of the NORDIC Study Group.  The recipient 
agrees that no information contained herein will be published or disclosed without written 
approval.  This document may be disclosed to appropriate institutional review boards, 
independent ethics committees, or duly authorized representatives of the U.S. Food & Drug 
Administration, the Bureau of Pharmaceutical Assessment (Canada), or other regulatory 
authorities as appropriate; under the condition that confidentiality is requested. 
 


SIGHT: JAEB CENTER FOR HEALTH RESEARCH AND NORDIC 
SIGHT PROTOCOL V4.0 11APR2019 
PAGE 2 OF 87 
KEY ROLES 
 
Name, degree 
Michael Wall, MD 
Title 
Study Director 
Institution Name 
University of Iowa Hospitals and Clinics 
 
Name, degree 
Matthew Thurtell, MBBS, MSc 
Title 
Study co-Director 
Institution Name 
University of Iowa Hospitals and Clinics 
 
Name, degree 
Mark Kupersmith, MD 
Title 
Enrollment and Resource Centers Director 
Institution Name 
Mount Sinai 
 
Name, degree 
Stephanie DuBose, MPH 
Title 
Coordinator Center Director 
Institution Name 
Jaeb Center for Health Research (JCHR) 
 
Name, degree 
Robert Lindblad, MD 
Title 
Medical Monitor 
Institution Name 
EMMES Corporation 
 
 
 


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VERSION HISTORY 
The following table lists versions of the protocol: 
VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
1.0 
Michael Wall,  
Matthew Thurtell, 
Stephanie 
DuBose  
Stephanie 
DuBose 
04Jan2018 
Original version 
2.0 
Stephanie 
DuBose 
 
Stephanie 
DuBose 
 
20Feb2018 
 
Removed terms ‘maximal’ and ‘initial’ in reference to 
medical therapy and clarified that diet is part of medical 
therapy for all groups 
 
Replaced ‘study/non-study’ eye with ‘eligible/non-eligible’ 
eye throughout 
 
Modified lumbar puncture inclusion criteria to not require a 
repeat lumbar puncture if done within 6 weeks (instead of 
28 days) and to not require grade II to V papilledema 
 
Removed 200-mile inclusion criteria and instead added 
criteria of good candidate for study based on investigator 
judgement 
 
Added note that if neurologic exam abnormalities are 
found, the patient should be discussed with the Study 
Director to determine eligibility  
 
Clarification on exclusion criterion for abnormal CT or MRI 
 
Removed breastfeeding as exclusion criterion  
 
Clarification on how visual field examinations are 
determined to be reliable and when they will be repeated 
 
Removed assessment of furosemide compliance by pill 
counts since not feasible 
 
Removed CBC and Metabolic Panel from study visit 
procedures at 4 and 8 weeks  
 
Clarified that Adjudication Committee will be masked to 
treatment group and all cases will be reviewed first by the 
Study Director. 
 
Added details on treatment failure criteria and moved 
surgery specific criteria to appropriate section  
 
Clarification on discontinuation of study drug in relation to 
pregnancy, birth control, and breastfeeding 
 
Removed details related to certification of study surgeons, 
as this will be detailed in the MOP 
 
Clarified primary outcome throughout  
 
Added clarifications and revisions to statistical chapter 
 
Corrected typos 
2.1 
Stephanie 
DuBose 
Stephanie 
DuBose 
19Mar2018 
 
Revised SMRC criteria (text and figure) 
 
Updated study design figure to match primary outcome 
 
Corrected typos and clarified text throughout 
 
Removed extraneous text throughout 


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VERSION 
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
2.2 
Stephane 
DuBose 
Stephanie 
DuBose 
04Apr2018 
 
Revised titration and tapering schedule 
 
Clarified when to contact Study Director vs co-Director for 
questions 
 
Clarified management of non-eligible eye section to be 
consistent with rest of protocol 
 
Removed specification on timing of repeat perimetry 
3.0  
Stephanie 
DuBose  
Stephanie 
DuBose 
21May2018 
 
Exclusion criterion related to abnormal CSF contents 
changed to >8 cells, as 0-8 cells in CSF is considered 
within normal limits 
 
Clarified refractive error exclusion  
 
Updated AE reporting for known side effects of study drug 
and surgical AEs 
 
Updated details in Stored Specimens section and 
removed future testing that will not be done; removed 
duplicate text from data collection chapter 
 
Corrected typos 
 
Removed unnecessary abbreviations 
3.1 
Stephanie 
DuBose  
Stephanie 
DuBose 
09Jul2018 
 
Amended exclusion criterion related to abnormal CSF 
contents  
 
Corrected typos 
3.2 
Stephanie 
DuBose  
Stephanie 
DuBose 
23Jul2018 
 
Updated AE reporting for lab abnormalities 
 
Corrected typos 
4.0 
Nicole Foster, 
Stephanie 
DuBose 
Stephanie 
DuBose 
11Apr2019 
 
Revised exclusion criteria to allow greater monthly 
dosage of previous treatment with acetazolamide and 
methazolamide  
 
Revised exclusion criteria regarding conditions requiring 
steroid use and clarified that during study, steroids only 
permitted during ONSF surgery.  
 
Removed IOP requirement from follow up visits 
 
Clarified that size III VF test is optional at screening and 
not required at 26-week visit 
 
Updated amount of blood to be drawn for future research 
from 50 to 20 ml 
 
Revised OCT testing frequency at screening to only be 
required once instead of twice for all subjects 
 
Removed details on tapering schedule for participants in 
VPS group after shunt, to include in MOP instead 
 
Made clarifications to study procedures grid 
 
Clarified AE relatedness description to include all study 
procedures 
 
Revised a few analyses details in Statistical 
Considerations chapter to match Statistical Analysis Plan 
 
Corrected typos 


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TABLE OF CONTENTS 
KEY ROLES ..................................................................................................................................... 2 
VERSION HISTORY ......................................................................................................................... 3 
TABLE OF CONTENTS ..................................................................................................................... 5 
LIST OF ABBREVIATIONS .............................................................................................................. 10 
PROTOCOL SUMMARY .................................................................................................................. 11 
CHAPTER 1: INTRODUCTION ........................................................................................................ 16 
1.1 Background ........................................................................................................................................ 16 
1.2 Clinical Experience............................................................................................................................ 17 
1.2.1 Visual Loss in IIH ....................................................................................................................... 17 
1.2.2 Optic Nerve Sheath Fenestration for IIH ..................................................................................... 17 
1.2.3 CSF Shunting for IIH .................................................................................................................. 18 
1.2.4 Pilot Data for Management of Moderate to Severe Visual Loss in IIH ...................................... 19 
1.2.5 Use of OCT in Monitoring Papilledema in IIH ........................................................................... 20 
1.3 Rationale ............................................................................................................................................ 20 
1.3.1 Discussion of Study Design......................................................................................................... 20 
1.3.1.1 Visual Field Monitoring ......................................................................................... 20 
1.3.1.2 OCT Monitoring .................................................................................................... 21 
1.3.1.3 Discussion of Subject Characteristics .................................................................... 22 
1.3.2 Rationale for Medical and Surgical Treatment ............................................................................ 23 
1.3.2.1 Medical Therapy .................................................................................................... 23 
1.3.2.2 Optic Nerve Sheath Fenestration ........................................................................... 24 
1.3.2.3 CSF Shunting ......................................................................................................... 25 
1.4 Study Objectives ................................................................................................................................ 26 
1.4.1 Primary Objective ........................................................................................................................ 26 
1.4.2 Secondary Objectives .................................................................................................................. 26 
1.4.3 Other Outcomes ........................................................................................................................... 27 
1.5 Potential Risks and Benefits of the Study Interventions.................................................................... 27 
1.5.1 Known Potential Risks ................................................................................................................ 27 
1.5.1.1 Visual Loss ............................................................................................................ 27 
1.5.1.2 Acetazolamide ....................................................................................................... 27 
1.5.1.3 Furosemide ............................................................................................................. 28 
1.5.2 Known Potential Benefits ............................................................................................................ 28 


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1.5.3 Risk Assessment .......................................................................................................................... 28 
1.6 General Considerations...................................................................................................................... 29 
1.7 Schematic of Study Design ................................................................................................................ 29 
1.8 Schedule of Study Visits and Procedures .......................................................................................... 30 
1.8.1 Randomized Trial ........................................................................................................................ 30 
1.8.2 Treatment Failure Identification Phase ....................................................................................... 32 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING/BASELINE TESTING ................................. 33 
2.1 Subject Recruitment and Enrollment ................................................................................................. 33 
2.1.1 Informed Consent and Authorization Procedures ....................................................................... 33 
2.2 Subject Eligibility Criteria ................................................................................................................. 34 
2.2.1 Subject Inclusion Criteria ............................................................................................................ 34 
2.2.2 Subject Exclusion Criteria ........................................................................................................... 35 
2.3 Eye-Level Eligibility Criteria ............................................................................................................ 36 
2.3.1 Eye-Level Inclusion Criteria ....................................................................................................... 36 
2.3.2 Eye-Level Exclusion Criteria ...................................................................................................... 37 
2.4 Screening/Baseline Procedures .......................................................................................................... 37 
2.4.1 Data Collection and Testing ........................................................................................................ 38 
2.4.1.1 Visual Field Examinations ..................................................................................... 39 
CHAPTER 3: RANDOMIZATION VISIT ........................................................................................... 41 
3.1 Timing ............................................................................................................................................... 41 
3.2 Randomization ................................................................................................................................... 41 
3.3 Instructions to Subjects ...................................................................................................................... 41 
CHAPTER 4: STUDY TREATMENTS ............................................................................................... 42 
4.1 Medical Therapy including Diet ........................................................................................................ 42 
4.1.1 Acetazolamide ............................................................................................................................. 42 
4.1.1.1 Acquisition ............................................................................................................. 42 
4.1.1.2 Storage ................................................................................................................... 42 
4.1.1.3 Accountability of Acetazolamide Supplies ............................................................ 42 
4.1.1.4 Dosing and Administration .................................................................................... 42 
4.1.1.5 Stopping the Dosage Titration ............................................................................... 43 
4.1.2 Addition of Furosemide ............................................................................................................... 44 
4.1.3 Assessment of Subject Compliance with Medical Therapy ........................................................ 44 
4.1.4 Tapering of Medical Therapy ...................................................................................................... 45 
4.1.5 Discontinuation of Medical Therapy ........................................................................................... 45 
4.1.6 Dietary Consultation .................................................................................................................... 45 


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4.2 Optic Nerve Sheath Fenestration ....................................................................................................... 46 
4.3 CSF Shunting ..................................................................................................................................... 46 
4.4 Prohibited Medications, Treatments, and Procedures ....................................................................... 47 
4.5 Concomitant Medications .................................................................................................................. 47 
4.5.1 Allowed Concomitant Medications ............................................................................................. 47 
4.6 Management of the Non-Eligible Eye ............................................................................................... 48 
4.7 Treatment during the Treatment Failure Identification Phase ........................................................... 49 
CHAPTER 5: STUDY VISITS AND PROCEDURES ............................................................................ 50 
5.1 Randomized Trial .............................................................................................................................. 50 
5.1.1 Study Visits and Phone Contacts ................................................................................................. 50 
5.1.2 Safety Visits ................................................................................................................................ 50 
5.1.3 Study Visit Procedures ................................................................................................................ 50 
5.1.4 Phone Contact Procedures ........................................................................................................... 51 
5.1.5 Safety Visit Procedures ............................................................................................................... 51 
5.2 Treatment Failure Identification Phase .............................................................................................. 52 
5.2.1 Follow-up Visits .......................................................................................................................... 52 
5.2.2 Study Visit Procedures ................................................................................................................ 52 
5.2.3 Phone Contact Procedures ........................................................................................................... 52 
5.3 Unscheduled Visits ............................................................................................................................ 52 
5.4 Extra Assessments for Subjects Who Appear to be Worsening ........................................................ 53 
5.5 Early Termination .............................................................................................................................. 53 
5.6 Surgical Malfunction ......................................................................................................................... 53 
5.6.1 Criteria for SMRC Review .......................................................................................................... 53 
5.6.2 Surgical Malfunction Review by SMRC ..................................................................................... 53 
5.6.3 Temporary Treatment Failure ...................................................................................................... 54 
5.7 Treatment Failure .............................................................................................................................. 54 
5.7.1 Treatment Failure Criteria ........................................................................................................... 54 
5.7.2 Treatment Failure Review by Adjudication Committee .............................................................. 54 
5.7.3 Visit Schedule Once Treatment Failure is Reached .................................................................... 56 
CHAPTER 6: TESTING PROCEDURES, QUESTIONNAIRES, CLINICAL ASSESSMENTS, AND 
LABORATORY TESTING ................................................................................................................ 57 
6.1 Testing Procedures ............................................................................................................................ 57 
6.2 Intraocular Pressure ........................................................................................................................... 57 
6.3 Refraction and Visual Acuity ............................................................................................................ 57 
6.4 Papilledema Grading ......................................................................................................................... 57 
6.5 Perimetry ........................................................................................................................................... 57 


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6.6 OCT ................................................................................................................................................... 57 
6.7 Lumbar Puncture ............................................................................................................................... 58 
6.8 Quality of Life Assessment ............................................................................................................... 58 
6.9 Headache Disability Rating ............................................................................................................... 58 
6.10 Neurologic and Physical Examination............................................................................................. 58 
6.11 Clinical Laboratory Tests ................................................................................................................ 58 
CHAPTER 7: ADVERSE EVENT REPORTING ................................................................................. 59 
7.1 Adverse Events .................................................................................................................................. 59 
7.1.1 Definitions ................................................................................................................................... 59 
7.1.2 Reporting Adverse Events ........................................................................................................... 59 
7.1.3 Relationship of Adverse Event to Study ..................................................................................... 60 
7.1.4 Intensity of Adverse Events......................................................................................................... 60 
7.1.5 Coding of Adverse Events ........................................................................................................... 60 
7.1.6 Outcome of Adverse Event ......................................................................................................... 61 
7.2 Pregnancy Reporting ......................................................................................................................... 61 
7.3 Timing of Event Reporting ................................................................................................................ 61 
7.4 Stopping Criteria ............................................................................................................................... 62 
7.4.1 Subject Discontinuation of Study Drug ....................................................................................... 62 
7.5 Medical Monitor ................................................................................................................................ 62 
7.6 Independent Safety Oversight ........................................................................................................... 62 
7.7 Criteria for Suspending or Terminating Overall Study ..................................................................... 62 
CHAPTER 8: MISCELLANEOUS CONSIDERATIONS ....................................................................... 63 
8.1 Subject Compensation ....................................................................................................................... 63 
8.2 Subject Withdrawal ........................................................................................................................... 63 
8.3 Confidentiality ................................................................................................................................... 63 
CHAPTER 9: STATISTICAL CONSIDERATION ............................................................................... 64 
9.1 Statistical and Analytical Plans ......................................................................................................... 64 
9.2 Intention-to-Treat Principle ............................................................................................................... 64 
9.3 Analysis of the Primary Outcome Variable ....................................................................................... 64 
9.3.1 Primary Statistical Model ............................................................................................................ 64 
9.3.2 Adjustment for Baseline Characteristics ..................................................................................... 65 
9.3.3 Investigation of Treatment by Covariate Interactions ................................................................. 65 
9.3.4 Verification of Model Assumptions ............................................................................................ 65 
9.3.5 Treatment of Missing Data .......................................................................................................... 65 
9.4 Analysis of the Secondary Outcome Variables for Efficacy ............................................................. 66 


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9.5 Compliance Outcomes ....................................................................................................................... 67 
9.6 Analysis of Safety and Tolerability Outcomes .................................................................................. 67 
9.6.1 Adverse Events ............................................................................................................................ 67 
9.6.2 Tolerability Outcomes ................................................................................................................. 68 
9.6.3 Laboratory Test Results and Vital Signs ..................................................................................... 68 
9.7 Analysis of Long-Term Follow-Up Data .......................................................................................... 68 
9.8 Interim Analyses ................................................................................................................................ 69 
9.8.1 Interim Analyses for Safety ......................................................................................................... 69 
9.8.2 Interim Analyses for Efficacy ..................................................................................................... 70 
9.9 Baseline Characteristics ..................................................................................................................... 70 
9.10 Sample Size Determination ............................................................................................................. 70 
CHAPTER 10: DATA COLLECTION AND MONITORING ................................................................ 73 
10.1 Case Report Forms .......................................................................................................................... 73 
10.2 Study Records Retention ................................................................................................................. 73 
10.3 Quality Assurance and Monitoring .................................................................................................. 73 
10.4 Protocol Deviations ......................................................................................................................... 74 
10.5 Committees and Reading Centers .................................................................................................... 74 
10.5.1 Resource Center (RC)................................................................................................................ 74 
10.5.2 Visual Field Reading Center (VFRC) ....................................................................................... 74 
10.5.3 Photographic Reading Center (PRC) ......................................................................................... 75 
10.5.4 Optical Coherence Tomography Reading Center (OCTRC) ..................................................... 75 
10.5.5 Surgical Quality Assurance Committee (SQAC) ...................................................................... 75 
10.5.6 Surgical Malfunction Review Committee (SMRC) .................................................................. 75 
10.5.7 Adjudication Committee (AC) .................................................................................................. 76 
CHAPTER 11: ETHICS/PROTECTION OF HUMAN SUBJECTS ........................................................ 77 
11.1 Ethical Standard ............................................................................................................................... 77 
11.2 Institutional Review Boards ............................................................................................................ 77 
11.3 Informed Consent Process ............................................................................................................... 77 
11.3.1 Consent Procedures and Documentation ................................................................................... 77 
11.3.2 Subject and Data Confidentiality ............................................................................................... 77 
11.3.3 Future Use of Stored Specimens ............................................................................................... 78 
CHAPTER 12: REFERENCES .......................................................................................................... 80 
 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
CC 
Coordinating Center 
CFR 
Code of Federal Regulations 
CRF 
Case Report Forms 
CSF 
Cerebrospinal Fluid 
DSMC 
Data Safety Monitoring Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IIH 
Idiopathic Intracranial Hypertension 
IIHTT 
Idiopathic Intracranial Hypertension Treatment Trial 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
JCHR 
Jaeb Center for Health Research 
MOP 
Manual of Procedures 
MRI 
Magnetic Resonance Imaging 
NEI 
National Eye Institute 
NORDIC 
Neuro-Ophthalmology Research Disease Investigator Consortium 
OCT 
Optical Coherence Tomography 
OCTRC 
OCT Reading Center 
ONSF 
Optic Nerve Sheath Fenestration 
PMD 
Perimetric Mean Deviation 
PRC 
Photography Reading Center 
QoL 
Quality Of Life 
RC 
Resource Center 
RCT 
Randomized Clinical Trial 
SAE 
Serious Adverse Experience 
SIGHT 
Surgical Idiopathic Intracranial Hypertension Treatment Trial 
SMRC 
Surgical Malfunction Review Committee 
SQAC 
Surgical Quality Assurance Committee 
TF 
Treatment Failure 
VFRC 
Visual Field Reading Center 
VPS 
Stereotactic Ventriculo-Peritoneal CSF Shunting 
 


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PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Title 
A Multicenter, Partially-Masked, Randomized, Controlled Study of 
Medical Therapy vs. Medical Therapy plus Optic Nerve Sheath 
Fenestration vs. Medical Therapy plus Stereotactic Ventriculoperitoneal 
Cerebrospinal Fluid Shunting in Subjects with Idiopathic Intracranial 
Hypertension and Moderate to Severe Visual Loss (“SIGHT”) 
Précis 
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. 
Study Objectives 
Primary objective: to determine whether the efficacy of stereotactic 
ventriculo-peritoneal CSF shunting (VPS) with medical therapy is 
superior to medical therapy alone or optic nerve sheath fenestration 
(ONSF) with medical therapy in reducing or reversing visual loss in 
subjects with idiopathic intracranial hypertension and moderate to severe 
visual loss. 
Secondary objective: To assess time to treatment failure over up to 3 
years. 
Study Design 
Multi-center randomized single-masked phase 3 clinical trial 
 RCT is followed by a treatment failure identification phase (up to 
3 years of follow-up total) 
Number of Sites 
~40 sites 
Endpoint 
Primary Efficacy Outcome: 
 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. 
Key Secondary Efficacy Outcomes: 
 Time from randomization to treatment failure 
 CSF pressure measurement by lumbar puncture 
 Papilledema grade 
 OCT measures 
 QOL assessments 
 Visual field examination ratings (improved, remained the same, or 
worsened) 
Key Safety Outcomes: Vision loss, all reported adverse events 
Other Key Outcomes: Change in weight 


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PARTICIPANT AREA 
DESCRIPTION 
Population 
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 
 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.  
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 


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PARTICIPANT AREA 
DESCRIPTION 
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 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 WBC after 
correction is 8 cells/mm3 or less - see 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 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. Acceptable forms include oral contraceptives, IUDs 
transdermal contraceptives, diaphragm, 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 


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PARTICIPANT AREA 
DESCRIPTION 
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 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 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 
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 of 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 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) 
Sample Size 
180 subjects entering randomized trial 
 90% power to detect a difference in mean change of visual field 
between groups assuming a true population difference between any 
2 of 3 groups = 4.5dB with a two-tailed Bonferroni-adjusted 
significance level of 1.7%, assuming no more than 10% of subjects 
withdrawing. 


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PARTICIPANT AREA 
DESCRIPTION 
Treatment Groups 
Random assignment (1:1:1) to (1) medical therapy, (2) medical therapy 
plus ONSF, or (3) medical therapy plus VPS. 
Subject Duration 
~7 months- 3 years 
Protocol Overview/Synopsis 
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 OCT.  Questionnaires will be completed. Blood will be drawn for 
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 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 after 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. 
 


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Chapter 1: Introduction 
1 
1.1 Background 
2 
Idiopathic intracranial hypertension (IIH), previously called pseudotumor cerebri, is a disorder of 
3 
elevated intracranial pressure of unknown cause. Its incidence is rising with the obesity 
4 
epidemic, with about 22.5 new cases each year per 100,000 overweight women of childbearing 
5 
age. It affects at least 100,000 Americans. Because of pressure on the optic nerve (papilledema), 
6 
86% have visual loss and 10% develop severe visual loss.1 
7 
We recently completed the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), a 
8 
multicenter, randomized, double-masked, placebo-controlled study of 165 subjects with IIH and 
9 
mild visual loss. We showed that the acetazolamide-plus-diet regimen was significantly superior 
10 
to placebo-plus-diet for improving perimetric mean deviation (PMD), papilledema grade, quality 
11 
of life measures (QoL) and intracranial pressure.2 
12 
In patients with IIH who have moderate to severe visual loss at presentation, no intervention, 
13 
neither medical nor the various surgical treatments, has been verified as efficacious by well-
14 
designed clinical trials. The Neuro-Ophthalmology Research Disease Investigator Consortium 
15 
(NORDIC) Network has identified management of moderate to severe visual loss in IIH as an 
16 
investigational priority. The NORDIC Executive Committee has provided the guidance for the 
17 
development of a second prospective IIH treatment trial, the Surgical IIHTT (SIGHT– 
18 
pronounced “Sight”). NORDIC will provide the infrastructure to accomplish the proposed study, 
19 
consisting of experienced study leadership, ~40 sites (most of whom had successfully executed 
20 
the IIHTT), Coordinating Center, Reading Centers, and an Enrollment Center. The goals of the 
21 
proposed study are: (1a) to establish evidence-based treatment strategies to restore and protect 
22 
vision in IIH patients with moderate to severe visual loss; (1b) to compare currently used 
23 
treatment strategies with respect to the cumulative probability of treatment failure over time to 
24 
determine long-term outcomes; (2a) to determine how interventions that purportedly lower 
25 
intracranial pressure affect deformation of the peripapillary retinal pigment epithelial – Bruch’s 
26 
membrane layer (ppRPE/BM layer) using optical coherence tomography (OCT) imaging; and 
27 
(2b) to determine the predictive value of OCT retinal ganglion cell layer (GCL) thickness at 
28 
baseline for visual outcome. 
29 
To address these aims, we will enroll 180 newly diagnosed* IIH patients with a perimetric mean 
30 
deviation (PMD) between -6 and -27 dB in at least one eye, as determined by full threshold 
31 
standard automated perimetry using the size V stimulus. We will compare the efficacy of 1) 
32 
medical therapy alone, 2) surgical intervention via optic nerve sheath fenestration (ONSF) with 
33 
medical therapy, and 3) surgical intervention via ventriculo-peritoneal cerebrospinal fluid (CSF) 
34 
shunting with medical therapy. Subjects will be followed for an initial 6-month intervention 
35 
phase, followed by transition to the treatment failure identification phase with clinical follow-up 
36 
at 12 months, 24 months, and 36 months. After one year, there will be quarterly telephone 
37 
contact to determine the subject’s clinical status. 
38 
                                               
* Nearly all subjects will be “newly diagnosed;” however, if a patient was previously diagnosed but not treated, they 
will undergo another evaluation for IIH and visual loss to assess eligibility. We expect this situation to be rare. 


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1.2 Clinical Experience 
39 
1.2.1 Visual Loss in IIH 
40 
IIH has four stages based on severity of visual loss. The first stage (20% of IIH patients) exhibits 
41 
papilledema and symptoms, but no visual field loss. The second stage (40% of cases), the target 
42 
for the IIHTT, is characterized by mild visual field defects and prompts effective intervention. 
43 
The third stage (30% of cases), a target for the SIGHT, is characterized by moderate visual loss. 
44 
Stage three patients have symptomatic vision loss and current thinking, without class I or II 
45 
evidence, suggests that aggressive intervention is required to prevent blindness. In the fourth 
46 
stage (10% of cases), also a target for the SIGHT, severe visual loss occurs, which can worsen 
47 
rapidly to blindness. 
48 
Medical treatments, including diet, acetazolamide, and furosemide, are the interventions usually 
49 
employed for the first two stages of IIH. Several retrospective studies of obese patients with IIH 
50 
suggest that weight loss may be associated with reduction in papilledema grade. The IIHTT 
51 
demonstrated that acetazolamide-plus-diet led to a statistically significant improvement in vision 
52 
and significant improvements in papilledema grade, CSF pressure, and quality of life measures at 
53 
6 months compared to placebo-plus-diet in patients with mild visual loss.  
54 
Surgical treatments, such as ONSF and CSF shunting, with or without medical therapy, are 
55 
commonly employed in the third and fourth stages of IIH. 
56 
1.2.2 Optic Nerve Sheath Fenestration for IIH 
57 
Hayreh,3 using a primate model, demonstrated efficacy of ONSF for relief of experimental 
58 
papilledema. Later, Smith et al.4 reported successful relief of papilledema in a human after 
59 
ONSF. ONSF consists of either creating a window or making a series of slits in the optic nerve 
60 
dural sheath just behind the globe in one eye. This treatment has been used for patients with 
61 
progressive visual loss, and over 50% of patients with IIH have post-operative headache relief.5 
62 
Several hypotheses exist as to the mechanism of action of ONSF. The demonstration of fistula 
63 
formation6,7 and some improvement of papilledema in the unoperated eye suggest that ONSF 
64 
efficacy may be due to local decompression of the subarachnoid space with filtration of CSF into 
65 
the orbit.8 CSF pressure may be modestly lowered post-operatively, but the duration and 
66 
magnitude of this effect is unknown. Another possible long-term mechanism of action of ONSF 
67 
may be secondary closure of the subarachnoid space via fibrosis at the surgical site, thereby 
68 
preventing transmission of pressure to the optic nerve head.9,7 The success of surgical 
69 
decompression of the optic nerve, however, may be limited by several factors that are not yet 
70 
fully understood. Trabeculations within the retrobulbar subarachnoid space may contribute to 
71 
resistance of bidirectional CSF flow between the optic nerve sheath and the intracranial 
72 
subarachnoid space; this compartmentalization of CSF, demonstrated in vivo by Killer et al.,10 
73 
may be responsible for the occasional failure of the fellow eye to improve after ONSF.11 On the 
74 
other hand, there may be free flow from the fenestration site to the full CSF space and a 
75 
generalized pressure lowering effect may occur. It is not known which if either of these 
76 
mechanisms prevails. 
77 
A meta-analysis of large case series suggests efficacy of ONSF in IIH. Post-operative visual 
78 
acuity or visual field results were equal to, or better than, pre-operative results in 87% of patients 
79 


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reported; however, 13% of patients had worse vision in the post-operative period. A report on 75 
80 
eyes from 54 patients undergoing ONSF suggested that patients undergoing ONSF may have 
81 
substantial long-term failure rates.12 This study defined perimetric mean deviation worsening as 
82 
> 2 dB deterioration in PMD post-operatively on a single visual field exam.  By this criterion, 
83 
68% of eyes improved or stabilized and 32% worsened. However, these results are suspect since 
84 
a 2 dB or greater mean deviation worsening is within observed individual retest variability in 
85 
patients with moderate to severe visual field damage and a confirming visual field should have 
86 
been required.13 Although ONSF appears to be helpful in the short term for visual loss, other 
87 
interventions, such as weight loss or acetazolamide, may have a delayed, but long-term benefit. 
88 
There are no quality of life (QoL) studies of ONSF in IIH. The uncertainties concerning the 
89 
short- and long-term efficacy and safety of ONSF in moderate to severe IIH can only be 
90 
addressed with a prospective, randomized, controlled trial. 
91 
1.2.3 CSF Shunting for IIH 
92 
Various CSF shunting procedures have been employed for the treatment of IIH, including 
93 
lumbo-peritoneal (LP), ventriculo-atrial (VA), ventriculo-jugular, and ventriculo-peritoneal (VP) 
94 
shunting.14-17 In general, the indication for a CSF shunting procedure has been failed medical 
95 
therapy or intractable headache. Most series document efficacy in preserving vision in most 
96 
cases, but there was a high rate of shunt failure and shunt revisions were often required.14-18 
97 
While shunting preserved vision in many patients, long-term headache relief was achieved in 
98 
only 50% over 36 months.19 Many of the shunts inserted were lumbo-peritoneal; these are now 
99 
out of favor due to a high complication rate, which includes frequent shunt occlusion, infection, 
100 
and intracranial hypotension. Stereotactically inserted ventriculo-peritoneal shunts (VPS) have a 
101 
lower failure and complication rate, and are easier to monitor and adjust.19-22 
102 
There is no consensus regarding strategies for therapeutic intervention for IIH patients with 
103 
moderate to severe visual loss. Furthermore, the mechanisms of action of the treatments and their 
104 
effectiveness remain uncertain.23 Various therapies have been used to treat IIH, but prior to the 
105 
IIHTT, their safety and efficacy had not been adequately evaluated in prospective, randomized, 
106 
controlled trials. Although there are large variations in practice, most physicians wait until there 
107 
is more advanced visual loss before recommending a surgical intervention. However, all studies 
108 
evaluating interventions for IIH with more advanced visual loss are anecdotal, retrospective, and 
109 
uncontrolled. Also, the various surgical procedures for IIH have not been compared with regards 
110 
to efficacy, safety, complication rate, and long-term outcome. Thus, as confirmed by a recent 
111 
Cochrane review, there is an inadequate evidence base to guide clinicians in management of 
112 
IIH patients with moderate to severe vision loss.24 
113 
Based on Curry’s results and extrapolating to 2014, estimating 2500 CSF shunt surgeries per 
114 
year at a cost of about $38,500 per patient, and 250 ONSF surgeries at $23,000 per patient, 
115 
surgical costs for IIH are estimated at $102 million per year.25 Friesner and colleagues come to a 
116 
similar conclusion regarding surgical costs. In addition, they estimated in 2007 dollars the total 
117 
costs due to IIH to be $444 million per year,26 so it is imperative that we obtain high quality data 
118 
regarding the efficacy and safety of surgical treatments for IIH. 
119 


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1.2.4 Pilot Data for Management of Moderate to Severe Visual Loss in IIH 
120 
In 2012, the IIH Study Group performed a retrospective chart review of consecutive newly 
121 
diagnosed patients that met the modified Dandy criteria for IIH27 from 30 of the 40 IIHTT sites. 
122 
All patients were seen between January 2009 and September 2012, and had baseline PMD worse 
123 
than -8.5 dB in at least one eye, as in the eligibility criteria for the SIGHT; this cutoff was chosen 
124 
based on equipoise of the IIH Study Group – there was discomfort in randomizing subjects to 
125 
surgery if they did not have at least -8.5 dB PMD in one eye with size III SITA Standard testing. 
126 
Patients had undergone medical treatment, ONSF, or CSF shunting. Due to a small number of 
127 
shunt patients, 3 additional sites were asked to abstract charts. Visual field outcomes (PMD) at 3-
128 
12 months after intervention were analyzed. Of 298 subjects meeting eligibility criteria stated 
129 
above, 91 had pre- and post-intervention Humphrey Field Analyzer data available for analysis. 
130 
(Table 1). 
131 
Table 1. Mean and standard deviation (SD) of the PMD (in dB) of the 
132 
best eligible eye from each treatment group. 
133 
 
Initial 
SD 
Final 
SD 
Change 
SD 
Medical 
-14.6 
6.2 
-10.2 
9.2 
4.4 
7.4 
ONSF 
-15.3 
7.1 
-12.4 
9.0 
2.9 
8.3 
Shunt 
-17.0 
6.2 
-8.8 
8.4 
8.1 
7.7 
Although limited by their retrospective nature, these data suggest that both medical and surgical 
134 
interventions may be effective for treating IIH patients with moderate to severe visual field loss, 
135 
and that surgical procedures, especially CSF shunting, may be more effective (Figure 1). 
136 
 
137 
Figure 1. Average PMD in the best eligible eye at initial presentation vs  
138 
final visit 3-12 months later. 
139 


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1.2.5 Use of OCT in Monitoring Papilledema in IIH 
140 
Papilledema is typically quantified from fundus photographs using the Frisén grading scale.1 
141 
OCT can be used to objectively measure the degree of swelling and monitor treatment effects. 
142 
Time-domain OCT provides cross sectional images of multiple retinal layers and the 
143 
peripapillary retinal nerve fiber layer (RNFL) with a resolution of approximately 10 microns.2-5 
144 
OCT has several advantages, based on optics, when compared to photographic imaging. OCT is 
145 
also reasonably reproducible on repeat measurements in normal eyes and in eyes with 
146 
glaucoma.6-11 Limitations include no current algorithm specific for optic disc edema, particularly 
147 
when it is severe. Fundus photography, the current gold standard and the technique that was used 
148 
in the IIHTT, requires skilled interpretation of features that can be difficult to quantify. 
149 
Most prior OCT studies have investigated disorders that cause RNFL thinning; few report the 
150 
effects of papilledema on RNFL or total retinal thickness. Time-domain OCT has been compared 
151 
to fundus photographs in children with IIH.12 Another study measured RNFL thickness, using 
152 
scanning laser polarimetry (SLP) and not OCT, in IIH.13 OCT has demonstrated subretinal 
153 
macular fluid in patients with papilledema,14 and we and others have shown RNFL thickening 
154 
using OCT in patients with acute optic neuritis.15-17 We have also found that OCT is superior to 
155 
SLP in demonstrating and quantifying papilledema.18 Other studies have compared RNFL 
156 
thickness in papilledema and pseudopapilledema, but have not compared results with fundus 
157 
photograph grades.19,20 When using time-domain OCT in patients with severe papilledema, there 
158 
can be inaccurate placement of the peripapillary ring to measure optic disc elevation and RNFL 
159 
thickness, as well as failure of the algorithm used to measure RNFL thickness. 
160 
Newer three-dimensional spectral-domain OCT (SD-OCT) methods, such as the cube scan for 
161 
data collection, give flexibility to find the exact measures of interest with increased resolution 
162 
and scanning speed to acquire data over a wider area, thereby reducing sampling errors for 
163 
higher density and faster scans (512 x 128 axial B-scans for a 6 mm2 area).21 Coupling these 
164 
advances with refined algorithms will improve the reproducibility and quantification of 
165 
papilledema and RNFL alterations, even when swelling obscures the disc borders. Higher scan 
166 
density should improve measurement of localized RNFL defects, which can be related to visual 
167 
field loss. 
168 
1.3 Rationale 
169 
1.3.1 Discussion of Study Design 
170 
1.3.1.1 Visual Field Monitoring 
171 
Patients who are newly diagnosed with IIH with moderate to severe visual field loss (with PMD 
172 
between -6 dB and -27 dB with full threshold size V testing) may be treated with medical or 
173 
surgical therapy. The current thinking, without class I or II evidence, suggests that aggressive 
174 
intervention is required to prevent further visual deterioration and blindness. However, it is 
175 
unclear if any of these treatments are effective for treating this subset of IIH patients. Patients 
176 
with milder visual loss may benefit from medical therapy alone, as shown by the IIHTT. 
177 


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Being an average, the PMD is a summary statistic that is less prone to perimetric variability than 
178 
using individual or groups of test locations. It is assumed that visual loss by visual field 
179 
examination best reflects neural damage due to increased intracranial pressure and in the IIHTT 
180 
correlated well with QoL measures.  
181 
Standard automated perimetry uses size III stimuli. There is now considerable evidence that 
182 
automated perimetry using size V stimuli has advantages in patients with moderate to severe 
183 
visual loss.29,30,32-36 These advantages include lower retest variability and about one additional 
184 
log unit (10 dB) of useful dynamic range. Use of the larger size V stimuli also makes for an 
185 
easier test for the patient due to an increase in visual field area in moderate to severely damaged 
186 
visual fields. In addition, the size V stimulus was recently successfully used in another NEI 
187 
sponsored clinical trial investigating retinitis pigmentosa.31 Use in this trial will demonstrate its 
188 
utility for optic neuropathies and we will relate size V results to the conventional size III results. 
189 
1.3.1.2 OCT Monitoring 
190 
OCT analysis routines have been developed and optimized for glaucoma. Recent data suggest 
191 
that OCT appears to be the best imaging modality to monitor papilledema and other optic 
192 
neuropathies. In the IIHTT OCT sub-study, 89 subjects’ (43 acetazolamide and 46 placebo) OCT 
193 
measurements of swelling, average retinal nerve fiber layer thickness (RNFL), total retina 
194 
thickness (TRT), and optic nerve head volume (ONHV) were similar in both treatment groups at 
195 
baseline. At 6 months, the swelling in study eyes was reduced in both groups, but the 
196 
acetazolamide group showed more reduction in RNFL (174 µm vs. 93 µm, p=0.001), TRT (218 
197 
µm vs. 121 µm, p=0.001), and ONHV (4.9 µm3 vs. 2.4 µm3, p=0.001) when compared with the 
198 
placebo group.37 
199 
Furthermore, OCT showed greater improvements in the optic neural canal shape (inward 
200 
deviation of the peripapillary RPE/Bruch’s membrane borders) in the acetazolamide group than 
201 
in the placebo group.38 Sibony et al.39 in another study showed reduction in the RNFL and less 
202 
inward deviation of the peripapillary RPE/Bruch’s membrane borders following interventions 
203 
that lower intracranial pressure, such as lumbar puncture, VPS and acetazolamide treatment (see 
204 
Figure 2). 
205 


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206 
Figure 2. Mean posterior displacement of the RPE-Bruch’s membrane complex from pre- to post, 
207 
following interventions (left to right: LP, VP shunt, ACZ) to lower intracranial pressure in IIH39. 
208 
We have also shown in a case series that the peripapillary RPE/Bruch’s membrane positioning 
209 
normalized within days of intracranial pressure-lowering procedures. These changes can also be 
210 
seen in eyes with optic atrophy and no apparent papilledema. The deformation of the 
211 
RPE/Bruch's membrane position appears to be an acute biomarker of changes in intracranial 
212 
pressure, whereas the optic nerve morphology (edema) is a chronic biomarker that takes at least 
213 
1-2 weeks to respond. In some cases, the RNFL or ONH volume may be decreasing, but the 
214 
RPE/Bruch's membrane does not change, suggesting that intracranial pressure may not be 
215 
changing, yet axoplasmic flow may be improving or RNFL loss may be occurring. OCT will be 
216 
done before lumbar puncture at screening/baseline and again at 6 months, to further characterize 
217 
RPE/Bruch’s membrane changes. The RPE/Bruch's membrane biomarker may represent a non-
218 
invasive objective method of monitoring intracranial pressure and, thus, may serve as a surrogate 
219 
for identifying changes in intracranial pressure. 
220 
In another study evaluating 31 IIH patients with visual acuity of 20/25 or worse at presentation, 
221 
macula ganglion cell layer thickness at presentation was mildly correlated (r=0.44, p=0.005), and 
222 
at 2-3 weeks after presentation was strongly correlated (r=0.76, p=0.0001), with visual field 
223 
outcome. Furthermore, a reduction of the ganglion cell layer thickness of > 10 µm within 2-3 
224 
weeks of presentation was also associated with a worse visual field outcome.40 
225 
We plan to further study changes in OCT parameters to determine their validity as biomarkers 
226 
for changes in intracranial pressure and optic nerve damage. Preliminary studies suggest that 
227 
OCT may facilitate early identification of optic nerve injury due to papilledema and have 
228 
prognostic significance. We anticipate that OCT will provide information that helps guide 
229 
treatment decisions. 
230 
1.3.1.3 Discussion of Subject Characteristics 
231 
This study will enroll 180 individuals with IIH who are 18-63 years of age. This age range 
232 
represents the population that is most likely to be affected by IIH. Children under 13 will not be 
233 
included because IIH appears to be a different disease in this age group (no correlation with 
234 


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obesity or gender; often arises from a secondary cause). Adolescents will not be eligible for the 
235 
SIGHT since attrition in weight loss programs within this group of subjects is substantial, as high 
236 
as 73% in some reports.41 Only high intensity behavioral modification targeted towards children, 
237 
combined with physical activity program and/or drug therapies have been shown to be effective 
238 
in small studies. The SIGHT lacks the expertise and means to safely conduct this therapy of 
239 
weight management in children. Further, the IIHTT provided data to measure the risk of high 
240 
dose acetazolamide in adults. No such safety data is known in adolescents and the principal 
241 
safety measures in the SIGHT will center on preservation of vision and surgical complications. 
242 
We will exclude pregnant women and prisoners. We anticipate that the cohort will be primarily 
243 
composed of women in their childbearing years that are overweight. Data available on the 
244 
prevalence of IIH in the US population is limited. The best information on the demographic 
245 
distribution of this condition comes from the IIHTT.  Ninety-eight percent of trial subjects were 
246 
women with a mean age of 29 ± 7.4 years. With regard to race, 65% of subjects were White, 
247 
25% were Black, and 10% reported another race. Thirteen percent of IIHTT subjects reported 
248 
being Hispanic or Latino. As was the case for IIHTT, there will be substantial diversity in the 
249 
types of enrollment centers used in SIGHT including private and university–based practices in 
250 
both urban and rural settings. Every effort will be made to enroll a diverse population in the 
251 
SIGHT. 
252 
1.3.2 Rationale for Medical and Surgical Treatment 
253 
1.3.2.1 Medical Therapy 
254 
Medical therapy will consist of acetazolamide, furosemide when needed, and dietary 
255 
intervention. The dosage of acetazolamide will be titrated from eight tablets daily (2,000 mg 
256 
daily) to a maximum of 16 tablets daily (4 gm daily), as tolerated, taken in divided doses (bid) 
257 
with meals. Four grams daily is the largest dosage used in clinical practice. In the IIHTT, the 
258 
mean dosage used was 2.5 gm/day; 40% of subjects could tolerate 4 gm/day. 
259 
If the subject has side effects that substantially interfere with activities of daily living, we will 
260 
use the highest dosage of study medication tolerated with a minimum of 1/2 tablet (125 mg 
261 
acetazolamide) per day. Those failing to clinically improve by two weeks after achieving the 
262 
maximally tolerated dosage of acetazolamide will be titrated up to 80-100 mg twice daily of 
263 
furosemide (minimum dosage 20 mg per day) with potassium supplementation of 20 meq for 
264 
each 40 mg of furosemide, as hypokalemia commonly occurs with this regimen.42-44 A diet rich 
265 
in potassium (fresh fruits and vegetables) will be encouraged for those taking furosemide and 
266 
further supplementation will be given as needed. 
267 


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All enrolled subjects will be advised to adopt a low sodium weight reduction diet with lifestyle 
268 
modification developed by the Site Investigator. The treatment plan will be individualized and 
269 
may include consultation with a dietician or referral to a formal weight loss program. Regression 
270 
of papilledema and symptoms often occurs with a weight loss of 6% of initial body weight that 
271 
may take months to achieve.2,45,46 The IIHTT demonstrated that both the acetazolamide group 
272 
and the placebo group achieved a reduction in weight.2 The goal of the intervention in the 
273 
SIGHT will also be 6% weight loss at six months. 
274 
1.3.2.2 Optic Nerve Sheath Fenestration 
275 
ONSF consists of either creating a window or making a series of slits in the optic nerve dural 
276 
sheath just behind the globe. This treatment has been used for patients with progressive visual 
277 
loss due to IIH. The demonstration of fistula formation6,7 and some improvement of papilledema 
278 
in the unoperated eye suggest that ONSF efficacy may be secondary to local decompression of 
279 
the subarachnoid space with filtration of CSF into the orbit.8 CSF pressure may be modestly 
280 
lowered post-operatively, but the duration of this effect is unknown. In a meta-analysis of large 
281 
case series of ONSF for IIH (Table 2), post-operative visual acuity or visual field results were 
282 
equal to, or better than, pre-operative vision in 87% of patients reported. However, 13% of 
283 
patients had worse vision in the post-operative period. Up to 50% of patients have post-operative 
284 
headache relief with ONSF.5 A report on 75 eyes of 54 patients undergoing ONSF suggested that 
285 
patients undergoing ONSF may have substantial long-term failure rates.12 
286 
Table 2. Case series of visual outcome after ONSF. 
287 
Study 
Vision Worse 
Vision Not Worse 
Total 
Hupp47 
6 
11 
17 
Sergott48 
0 
23 
23 
Brourman49 
0 
10 
10 
Goh50 
9 
31 
40 
Corbett5 
1 
21 
22 
Plotnik51 
4 
27 
31 
Acheson52 
3 
17 
20 
Kelman53 
3 
26 
29 
Banta54 
11 
75 
86 
Yazici7 
1 
16 
17 
Alsuhaibani55 
2 
59 
61 
Pineles56 
12 
38 
50 
Fonseca57 
3 
11 
14 
Total: 
13% 
87% 
420 


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1.3.2.3 CSF Shunting 
288 
Various shunting procedures have been employed for the treatment of IIH. In general, the 
289 
indication for a CSF shunting procedure has been failed medical therapy or intractable headache. 
290 
The case series document efficacy in preserving vision in most cases (Table 3), but reveal a high 
291 
rate of shunt failure and, thus, shunt revisions were often needed.14-18 Compared to other 
292 
shunting approaches (e.g., lumbo-peritoneal shunts), stereotactic ventriculo-peritoneal shunts 
293 
(VPS) have lower failure and complication rates, and are easier to monitor and adjust.19-22 While 
294 
the shunting procedures preserved vision in many patients, long-term headache relief was 
295 
achieved in only 50% after 36 months in one study.19 
296 
Table 3. Case series of visual outcome after CSF shunting for IIH (NS = not studied). 
297 
Investigators 
Year 
Shunt Type 
Failures 
Vision Worse 
Vision Not 
Worse 
Total 
Rosenberg58 
1987 
LP/VP/V+ 
20/37 
9 
28 
37 
Johnston14 
1988 
LP/CA/VP/VA 
7/41 
0 
36 
36 
Eggenberger16 
1988 
LP 
15/27 
0 
27 
27 
Shapiro59 
1988 
LP 
0/4 
1 
3 
4 
Burgett15 
1992 
LP 
19/30 
1 
29 
30 
Bynke20 
1997 
VP 
7/17 
0 
17 
17 
Tulipan60 
1998 
VP 
0/7 
NS 
NS 
7 
Maher61 
2001 
VP 
3/13 
0 
13 
13 
McGirt19 
2004 
LP/VP/VA 
23/42 
NS 
NS 
42 
Abu-Serieh62 
2007 
VP 
6/9 
0 
9 
9 
Nadkarni63 
2008 
LP 
10/40 
NS 
NS 
40 
Abubaker21 
2011 
LP/VP 
12/25 
0 
25 
25 
Kandasamy64 
2011 
VP 
5/17 
0 
17 
17 
Sinclair65 
2011 
VP/LP 
27/53 
5 
48 
53 
Tarnaris22 
2011 
LP/VP 
12/29 
9 
20 
29 
El-Saadany66 
2012 
LP 
8/22 
NS 
NS 
22 
Yadav67 
2012 
LP 
2/24 
8 
16 
24 
Huang68 
2014 
VP 
7/19 
1 
18 
19 
Rizzo69 
2014 
VP/LP 
4/15 
0 
15 
15 
Fonseca57 
2014 
VP 
9/19 
4 
15 
19 
Total: 
 
 
40% 
8% 
92% 
374 


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1.4 Study Objectives 
298 
1.4.1 Primary Objective 
299 
The primary objective is to compare the efficacy of 1) medical therapy, 2) optic nerve sheath 
300 
fenestration (ONSF) plus medical therapy, and 3) stereotactic ventriculo-peritoneal CSF shunting 
301 
(VPS) plus medical therapy in newly diagnosed IIH patients with full threshold size V 24-2 
302 
PMD between -6 and -27 dB in at least one eye at study entry. Change in the PMD with stimulus 
303 
size V from baseline to the first of Month 6 or time of treatment failure in the eye(s) qualifying 
304 
for study entry will be the primary outcome variable. 
305 
1.4.2 Secondary Objectives 
306 
Secondary objectives are to compare changes in the following from baseline to 6 months among 
307 
the three study groups: 
308 
 PMD with stimulus size V in the best eye qualifying for study entry 
309 
 Papilledema grade (Photographic Reading Center and site investigator ratings) 
310 
 OCT measures of: 
311 
 Retinal nerve fiber layer thickness 
312 
 Retinal ganglion cell layer thickness 
313 
 Peripapillary retinal pigment epithelial (RPE)/Bruch’s membrane deformation 
314 
 CSF pressure 
315 
 Visual acuity 
316 
 Quality of life (QoL) measures (NEI-VFQ-25 + 10-item neuro-ophthalmic supplement 
317 
and the SF-36) 
318 
 Headache disability (HIT-6 Inventory) 
319 
 Headache severity 
320 
Other efficacy outcome variables, determined at Month 6, include treatment failure, surgical 
321 
failure, presence of headache, presence of transient visual obscurations, and visual field 
322 
examination ratings (improved, no change, worse) by the Visual Field Reading Center. 
323 
With the exception of CSF pressure, these outcome variables will also be examined at Months 
324 
12, 24 and 36. 
325 
Of special interest and a very important outcome is the time from randomization to treatment 
326 
failure. Subjects will be followed for up to 3 years and the number of surgical failures and 
327 
treatment failures will be analyzed. While a therapy may have a beneficial outcome at 6 months, 
328 
it may not have a good outcome 1-3 years later; therefore, this is an important analysis. 
329 


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Measures of safety include the following: 
330 
 Adverse events 
331 
 Serious adverse events 
332 
 Procedure complications and  transient malfunctions of surgical procedures 
333 
 Blood pressure 
334 
 Laboratory test results (CBC with platelet count, electrolytes, potassium, bicarbonate, and 
335 
liver function tests) 
336 
1.4.3 Other Outcomes 
337 
 Anthropometric measures (weight, waist circumference) 
338 
1.5 Potential Risks and Benefits of the Study Interventions 
339 
1.5.1 Known Potential Risks 
340 
1.5.1.1 Visual Loss 
341 
The primary risk of IIH is visual loss associated with papilledema.  Subjects reaching treatment 
342 
failure criteria will remain in the study but will be managed by the site investigators. 
343 
1.5.1.2 Acetazolamide 
344 
Acetazolamide frequently causes paresthesias, altered taste sensation, asymptomatic metabolic 
345 
acidosis (low serum bicarbonate), and fatigue. There is a small risk of kidney stones, and, very 
346 
rarely, renal failure from acute tubular necrosis, liver enzyme changes, elevation of serum 
347 
amylase, blood dyscrasias, Stevens-Johnson syndrome, and aplastic anemia. Based on the IIHTT, 
348 
we anticipate that renal stones and allergic rashes will occur, though infrequently. Guidance on 
349 
management of liver enzyme changes and renal stones is provided in the MOP. While there was 
350 
minimal potassium loss in some IIHTT subjects treated with acetazolamide, there were no 
351 
instances of hypokalemia requiring potassium supplementation. 
352 
Subjects will have laboratory studies throughout the study period to monitor their electrolytes. 
353 
Aplastic anemia can occur in an individual by an idiosyncratic hypersensitivity reaction and 
354 
cannot be predicted by routine monitoring of the blood count. Some patients may be allergic to 
355 
acetazolamide, developing a rash (most common reaction), angioedema, stridor, or rarely, 
356 
anaphylaxis. A history of sulfa allergy will not be an exclusion criterion due to the lack of 
357 
evidence for cross reactivity with acetazolamide.72  The study medication will be discontinued 
358 
immediately if there is any evidence of an allergic reaction. At the conclusion of the subject’s 
359 
participation in the study, their treating physician will arrange a treatment plan independent of 
360 
the study. 
361 


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Hypokalemia: Epstein et al.73 showed no evidence of clinically significant hypokalemia in 92 
362 
patients on acetazolamide unless they were also taking other diuretics. We confirmed this in the 
363 
IIHTT.2 Since acetazolamide-induced hypokalemia is so uncommon, serum electrolytes will be 
364 
obtained at 1 month, 4 months, and 6 months (unless subjects develop symptoms of 
365 
hypokalemia: weakness, fatigue, and muscle cramps). If a subject also requires treatment with 
366 
furosemide, he/she will have close monitoring of serum electrolytes (including serum sodium 
367 
and potassium) prior to each change in dosage, to be performed at a local laboratory. The dosage 
368 
of furosemide will not be increased until it is documented that the potassium level is in the 
369 
normal range. Once the final furosemide dosage has been reached, electrolytes will be checked at 
370 
each visit. 
371 
Aplastic Anemia: Acetazolamide-induced aplastic anemia is dosage independent, usually 
372 
delayed in onset, and usually fatal. According to prior studies74,75, the incidence has been 
373 
estimated as 1 per 15,000 patient years with a mean age of 71 years (range 56-86 years). The 
374 
average onset is 3.5 months after initiation of treatment; it rarely occurs after six months of 
375 
treatment. Monitoring of CBCs is not the standard of care. We will obtain a CBC at baseline and 
376 
4 months, and 6 months. 
377 
1.5.1.3 Furosemide 
378 
Hypokalemia is the most common important side effect of furosemide. Supplemental potassium 
379 
chloride and, if required, an aldosterone antagonist are helpful in preventing hypokalemia and 
380 
metabolic alkalosis. Cases of tinnitus and reversible or irreversible hearing impairment and 
381 
deafness have been reported in people taking furosemide. Reports usually indicate that 
382 
furosemide ototoxicity is associated with rapid injection, severe renal impairment, the use of 
383 
higher than recommended doses, hypoproteinemia or concomitant therapy with aminoglycoside 
384 
antibiotics, ethacrynic acid, or other ototoxic drugs. Excessive diuresis from furosemide can 
385 
occur that may require measures to prevent dehydration and hypotension. Asymptomatic 
386 
hyperuricemia can occur and gout may rarely be precipitated. 
387 
In summary, common side effects of furosemide are orthostatic hypotension and hypokalemia. 
388 
Less frequent side effects are hyponatremia, hypocalcemia, hypochloremia, and 
389 
hypomagnesemia. Also infrequent are cramps, diarrhea, drowsiness, dry mouth, loss of appetite, 
390 
stomach cramps and photosensitivity. 
391 
1.5.2 Known Potential Benefits 
392 
Benefits from participation in the study include assignment to a treatment routinely used in 
393 
clinical practice, easy access to care for IIH, closer and more careful follow-up assessments 
394 
evaluating vision. Hopefully, in the future, other people might benefit from this study because of 
395 
the knowledge that may be gained about IIH. 
396 
1.5.3 Risk Assessment 
397 
The risk level is considered to be research involving greater than minimal risk. 
398 


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1.6 General Considerations 
399 
The study is being conducted in compliance with the policies described in the study policies 
400 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
401 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
402 
Data will be directly collected in electronic case report forms, which will be considered the 
403 
source data. 
404 
1.7 Schematic of Study Design 
405 
 
406 


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1.8 Schedule of Study Visits and Procedures 
407 
1.8.1 Randomized Trial 
408 
 
Safety 
Visit1 
Safety 
Visit1 
 
 
 
 
 
Primary 
Outcome 
Overview of Study Procedures 
SC/BL 
Visit 
(-3-0 days) 
S Visit  
1 wk  
±4 days 
S Visit 
2 wks 
±4 days 
Visit 1 
4 wks 
±7 days 
Visit 2 
8 wks 
±7 days 
Phone 
call 
12 wks 
±7 days 
Visit 3 
16 wks 
±7 days 
Phone 
call 
20 wks 
±7 days 
Visit 4 
26 wks 
±7 days 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
Med/IIH History/Update 
X 
 
 
X 
X 
 
X 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
Lumbar Puncture 
X 
 
 
 
 
 
 
 
X 
Questionnaires 
X 
 
 
 
 
 
 
 
X 
Vital Signs with weight 
X 
X 
X 
X 
X 
 
X 
 
X 
Ocular Exam 
X2 
X 
X 
X 
X 
 
X 
 
X 
Refraction/Acuity 
X 
X 
X 
X 
X 
 
X 
 
X 
Perimetry 
X3 
X 
X 
X 
X 
 
X 
 
X3 
Fundus Photographs 
X 
 
X 
X 
X 
 
X 
 
X 
OCT 
X4 
X 
X 
X 
X 
 
X 
 
X4 
CBC with platelet count 
X 
 
 
 
 
 
X 
 
X 
Metabolic panel w LFTs, amylase and electrolytes 
X 
 
 
 
 
 
X 
 
X 
Electrolyte testing5 
 
 
 
X 
X 
 
X 
 
X 
Blood sample for storage 
X 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Drug Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
 
 
 
 


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Safety 
Visit1 
Safety 
Visit1 
 
 
 
 
 
Primary 
Outcome 
Overview of Study Procedures 
SC/BL 
Visit 
(-3-0 days) 
S Visit  
1 wk  
±4 days 
S Visit 
2 wks 
±4 days 
Visit 1 
4 wks 
±7 days 
Visit 2 
8 wks 
±7 days 
Phone 
call 
12 wks 
±7 days 
Visit 3 
16 wks 
±7 days 
Phone 
call 
20 wks 
±7 days 
Visit 4 
26 wks 
±7 days 
Dispense/prescribe acetazolamide 
X 
 
 
X 
X 
 
X 
 
X 
Prescribe furosemide/potassium as needed 
 
 
 
X 
X 
 
X 
 
X 
Review Drug Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dietary Counseling 
X 
 
 
X 
X 
 
X 
 
X 
1Timing of 1 week and 2 week safety visits dependent on treatment group (timing for medical therapy group relative to randomization and timing for surgery groups relative to 
409 
surgical procedure). The 2 week visit could be skipped if there is marked improvement (see section 5.1.2). One or both safety visits will be repeated after each surgical procedure. 
410 
2 IOP must be measured at Screening to assess eligibility  
411 
3Two sets of FT size V at Screening; same requirement for week 26.  
412 
4 If LP performed, OCT should be performed prior to LP. Another set of OCT testing after LP is optional at Screening. 
413 
5 For subjects taking furosemide, will be done at local lab prior to each dose increase, once the final dose is reached, and then at each visit 
414 


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1.8.2 Treatment Failure Identification Phase 
415 
 
Final Study 
Visit 
 
Overview of Study Procedures 
Phone Call 
39 wks 
±7 days1 
Visit 5 
52 wks 
±7 days 
Visit 6 
104 wks 
±4 wks 
Visit 7 
156 wks 
±4 wks 
Unscheduled 
Visit2 
Written Informed Consent 
 
 
 
 
 
Eligibility Criteria 
 
 
 
 
 
Med/IIH History/Update 
 
X 
X 
X 
X3 
Physical Exam 
 
 
 
 
X3 
Lumbar Puncture 
 
 
 
 
 
Questionnaires 
 
X 
X 
X 
 
Vital Signs w weight 
 
X 
X 
X 
X3 
Ocular Exam  
 
X 
X 
X 
X3 
Refraction/Acuity 
 
X 
X 
X 
X3 
Perimetry 
 
X 
X 
X 
X3 
Fundus Photographs 
 
X 
X 
X 
X3 
OCT 
 
X 
X 
X 
X3 
CBC with platelet count 
 
 
 
 
X3 
Metabolic panel w LFTs, amylase 
and electrolytes 
 
 
 
 
 
Electrolyte testing4 
 
X 
X 
X 
X 
Blood sample for storage 
 
 
 
 
 
Pregnancy Test 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Drug Therapy 
X 
X 
X 
X 
X 
Randomization 
 
 
 
 
 
Dispense acetazolamide 
 
 
 
 
 
Prescribe furosemide/potassium as 
needed 
 
X 
X 
 
X 
Review Drug Compliance 
X 
X 
X 
X 
X 
Dietary Counseling 
 
X 
X 
 
X 
1 Telephone contacts will occur quarterly after the year 1 visit  
416 
2 If early termination visit, testing will be the same as the primary outcome visit. 
417 
3 If clinically indicated 
418 
4 Only for subjects taking furosemide  
419 


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Chapter 2: Study Enrollment and Screening/Baseline Testing 
420 
2.1 Subject Recruitment and Enrollment 
421 
Study subjects will be recruited from ~40 clinical centers in the United States and Canada.  
422 
Enrollment will proceed with the goal of 180 subjects entering the randomized trial.  A 
423 
maximum of 400 individuals may be enrolled in the study in order to achieve this goal.  Subjects 
424 
who have signed consent and started the screening process may be permitted to continue into the 
425 
trial, if eligible, even if the randomization goal has been reached. 
426 
All eligible subjects will be included without regard to gender, race, or ethnicity.  There is no 
427 
restriction on the number of subjects to be enrolled by each site toward the overall recruitment 
428 
goal. Non-identifying information about individuals who are deemed ineligible or decline to 
429 
participate in the study will be recorded. 
430 
Some subjects will have been diagnosed with IIH prior to being referred to the study, whereas 
431 
others may need to go through the diagnosis and screening process after consent is signed. 
432 
Neuroimaging studies, diagnostic lumbar puncture, and blood tests are considered routine care 
433 
regardless of the timing. The patient may have already had a lumbar puncture and blood testing, 
434 
which may not need to be repeated if performed within 4-6 weeks of enrollment. 
435 
2.1.1 Informed Consent and Authorization Procedures 
436 
Potential eligibility may be assessed as part of a routine-care examination.  Before completing 
437 
any procedures or collecting any data that are not part of usual care, written informed consent 
438 
will be obtained. 
439 
For potential study subjects, the study protocol will be discussed with the potential study subject 
440 
by study staff.  The potential study subject will be given the Informed Consent Form to read.  
441 
Potential study subjects will be encouraged to discuss the study with family members and their 
442 
personal physicians(s) before deciding whether to participate in the study. 
443 
A copy of the consent form will be provided to the subject and another copy will be added to the 
444 
subject’s study record. 
445 
As part of the informed consent process, each subject will be asked to sign an authorization for 
446 
release of personal information.  The investigator, or his or her designee, will review the study-
447 
specific information that will be collected and to whom that information will be disclosed.   
448 
After speaking with the subject, questions will be answered about the details regarding 
449 
authorization. 
450 
A subject is considered enrolled when the informed consent form has been signed. 
451 


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2.2 Subject Eligibility Criteria 
452 
2.2.1 Subject Inclusion Criteria 
453 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate 
454 
in the study. 
455 
1. Diagnosis of IIH by modified Dandy criteria (Table 4) 
456 
2. Age 18 to <64 years at time of consent 
457 
3. Age 18 to <61 years at time of diagnosis (time of diagnosis is the time at which the 
458 
patient meets the modified Dandy criteria, usually after the lumbar puncture results are 
459 
reviewed) 
460 
4. Presence of bilateral papilledema 
461 
5. Lumbar puncture within 6 weeks of screening visit or completed as part of screening:  
462 
Opening CSF pressure >250 mmH2O or 200 to 250 mmH2O, with at least one of the 
463 
following: 
464 
a) 
Pulse synchronous tinnitus 
465 
b) Cranial nerve VI palsy 
466 
c) 
Echography for drusen negative and no other disc anomalies mimicking disc 
467 
edema present 
468 
d) MRV with lateral sinus collapse/stenosis, partially empty sella turcica on coronal 
469 
or sagittal views of MRI, and optic nerve sheaths with filled out CSF spaces next 
470 
to the globe on T2 weighted axial MRI scans 
471 
If the patient was treated with intracranial pressure lowering agents (e.g., 
472 
acetazolamide) prior to obtaining a lumbar puncture, the agent(s) must 
473 
be discontinued for at least 24 hours prior to performing the diagnostic 
474 
lumbar puncture. 
475 
6. At least one eye meeting all eligible eye inclusion criteria and no exclusion criteria 
476 
7. Able to provide informed consent 
477 
8. Investigator believes the participant is a good candidate for the study, including the 
478 
probability of returning for follow-up.  
479 
Table 4. Modified Dandy Criteria for IIH27 
480 
1. Signs and symptoms of increased intracranial pressure 
2. Absence of localizing findings on neurologic examination 
3. Absence of deformity, displacement, or obstruction of the ventricular system and otherwise normal 
neurodiagnostic studies, except for evidence of increased CSF pressure (>200 mm water). Abnormal 
neuroimaging except for empty sella turcica, optic nerve sheath with filled out CSF spaces, and 
smooth-walled non flow-related venous sinus stenosis or collapse,70 should lead to another diagnosis 
4. Awake and alert 
5. No other cause of increased intracranial pressure present 


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2.2.2 Subject Exclusion Criteria 
481 
Individuals meeting any of the following exclusion criteria at baseline will be excluded from 
482 
study participation. 
483 
1. Treatment of IIH within the past 3 months with either (1) the maximally tolerated dosage 
484 
of acetazolamide for at least one week or (2) more than one month of acetazolamide with 
485 
a cumulative dosage of more than 45 grams 
486 
‘Maximally-tolerated dose’ is defined as dosage was reached where dosage could not be 
487 
increased further either because of side effects or because a daily total dosage of 4 grams 
488 
per day was reached. 
489 
If individual discontinued acetazolamide in the past due to side effects, individual is only 
490 
eligible if investigator believes that the individual is likely to tolerate acetazolamide, as it 
491 
will be prescribed in the study. 
492 
2. Treatment of IIH within the past 3 months with either (1) the maximally tolerated dosage 
493 
of methazolamide for at least one week or (2) more than one month of methazolamide 
494 
with a cumulative dosage of more than 4.5 grams 
495 
‘Maximally-tolerated dose’ is defined as dosage was reached where dosage could not be 
496 
increased further either because of side effects or because a daily total dosage of 400 mg 
497 
per day was reached. 
498 
3. Treatment with topiramate within two months and average cumulative dosage for the 
499 
preceding month of more than 700 mg per week 
500 
4. Previous surgery for IIH, including ONSF, CSF shunting, subtemporal decompression, or 
501 
venous sinus stenting; gastric surgery for obesity is allowed. 
502 
5. Abnormalities on neurologic examination except for papilledema and its related visual 
503 
loss or cranial nerve VI or VII paresis; if other abnormalities are present, the patient will 
504 
need to be discussed with the Study Director for study entry. 
505 
6. Abnormal CT or MRI scan (intracranial mass, hydrocephalus, dural sinus thrombus, or 
506 
arteriovenous malformation) other than findings known to occur with increased 
507 
intracranial pressure. Abnormalities on MRI that are not known to cause increased 
508 
intracranial pressure are acceptable. 
509 
7. Abnormal CSF contents: increased cells: > 8 cells; elevated protein: > 45 mg%; low 
510 
glucose: < 30 mg% (If the lumbar puncture produces a cell count compatible with a 
511 
traumatic needle insertion, the patient does not need to be excluded if the CSF WBC 
512 
after correction is 8 cells/mm3 or less - see MOP for calculation. If >8 cells or >45mg% 
513 
in CSF protein are documented in the CSF or calculated after conversion from a 
514 
traumatic lumbar puncture, the patient can be discussed with the Study Director for 
515 
possible inclusion.) 
516 
8. Abnormal blood work-up indicating a medical or systemic condition associated with 
517 
raised intracranial pressure 
518 
9. Diabetes mellitus with diabetic retinopathy 
519 


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10. Ingestion of a drug or substance, or presence of a disorder, that has been associated with 
520 
increased intracranial pressure within 2 months of diagnosis, such as lithium, vitamin A 
521 
related products (e.g., Retin-A), or various cyclines (see MOP for conditions and drugs) 
522 
11. Laboratory test results showing severe anemia, leukopenia or thrombocytopenia, renal 
523 
failure, or hepatic disease, based on the Site Investigator’s judgment 
524 
12. Other condition requiring continued use of oral, I.V. or injectable steroids (nasal, 
525 
inhaled, or topical steroids are allowed since the systemic effects are small). Patients 
526 
with a condition that resulted in recent or current use of steroids but may be safely 
527 
tapered off will be handled on a case-by-case basis after discussion with Study 
528 
Director/co-Director. See MOP for details. 
529 
13. Presence of a medical condition that would contraindicate use of acetazolamide or 
530 
furosemide or significantly increase surgical risk 
531 
14. Pregnancy or unwillingness for a subject of childbearing potential to use contraception 
532 
during the first 6 months of the study 
533 
Women of childbearing potential must use an acceptable form of birth control during the 
534 
first 6 months of the study. Acceptable forms include oral contraceptives, transdermal 
535 
contraceptives, diaphragm, intrauterine devices, condoms with spermicide, documented 
536 
surgical sterilization of either the subject or their partner, or abstinence. 
537 
15. Presence of a physical, mental, or social condition likely to affect follow-up (drug 
538 
addiction, terminal illness, no telephone, homeless) 
539 
16. Anticipation of a move from the site area within six months and unwillingness to return 
540 
for follow-up at a SIGHT study site 
541 
17. Allergy to pupil dilating drops or narrow angles precluding safe dilation 
542 
18. Presence of a condition that contraindicates general anesthesia 
543 
19. Participation in an investigational trial within 30 days of enrollment that involved 
544 
treatment with any systemic drug therapy or therapy that affects the eligible eye(s) 
545 
2.3 Eye-Level Eligibility Criteria 
546 
To be eligible, an individual must have at least one eye meeting the following inclusion criteria 
547 
and none of the exclusion criteria. 
548 
If both eyes meet eligibility criteria, then both will be included in the primary outcome analysis. 
549 
2.3.1 Eye-Level Inclusion Criteria 
550 
1. Visual field loss meeting the following criteria based on two full threshold 24-2 size V 
551 
tests reviewed by the VFRC: 
552 
 PMD from -6 dB to -27 dB 
553 
 Reproducible visual loss present on automated perimetry including no more than 15% 
554 
false positives 
555 
2. Visual acuity better than 20/200 (39 or more letters correct) 
556 


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2.3.2 Eye-Level Exclusion Criteria 
557 
1. Intraocular pressure currently >28 mm Hg or >30 mm Hg at any time in the past 
558 
2. Refractive error of more than -6.00 or more than +6.00 sphere or more than 3.00 cylinder 
559 
with the following exceptions: 
560 
 Eyes with more than 6.00 D of  myopia but less than 8.00 D of myopia are eligible if: 
561 
1. there are no abnormalities on ophthalmoscopy or fundus photos related to myopia 
562 
that are associated with visual loss (such as staphyloma, retinal thinning in the 
563 
posterior pole, or more than mild optic disc tilt), and 
564 
2. the individual will wear a contact lens for all perimetry examinations with the 
565 
appropriate correction. 
566 
 Eyes with more than 6.00 D of hyperopia but less than 8.00 D of hyperopia are 
567 
eligible if: 
568 
1. there is an unambiguous characteristic halo of peripapillary edema as opposed to 
569 
features of a small crowded disc or other hyperopic change related to visual loss 
570 
determined by the Site Investigator or the PRC Director (or his designate), and  
571 
2. the individual will wear a contact lens for all perimetry examinations with the 
572 
appropriate correction (which can be corrected for perimetry or the patient’s own 
573 
contact lens with over correction by lens at the perimeter). 
574 
Note: Refractive error exclusion and exceptions refer to sphere not spherical equivalent, with 
575 
cylinder expressed in plus format. 
576 
3. Other disorders causing visual loss except for refractive error and amblyopia, including 
577 
cells in the vitreous or iritis 
578 
4. Large optic disc drusen on exam or in previous history (small drusen of the disc can 
579 
occur with longstanding papilledema and are allowed if not so numerous that investigator 
580 
determines they are contributing to vision loss) 
581 
2.4 Screening/Baseline Procedures 
582 
After informed consent has been signed, a potential subject will be evaluated for study eligibility 
583 
through the elicitation of a medical history, performance of an ophthalmic exam including visual 
584 
acuity testing and visual field testing, physical examination by study personnel and local 
585 
laboratory testing if needed to screen for exclusionary medical conditions. 
586 
 Screening/baseline assessments must be completed within 3 days of signing the consent 
587 
form.  
588 
 The only exceptions are 1) if there are perimetry performance issues requiring repeat 
589 
examinations; 2) if there are unforeseen circumstances that delay the evaluation such as 
590 
transportation issues, weather related delays or work-related issues. If an exception 
591 
occurs, two additional days are allowed. During the screening/baseline visit, especially if 
592 
there are unforeseen delays, the Site Investigator has the option to begin acetazolamide 
593 
using the titration schedule in section 4.1.1.4. 
594 


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Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
595 
date per investigator discretion. 
596 
Individuals who meet study eligibility requirements and agree to participate must discontinue 
597 
any medications being used to treat IIH, except for acetazolamide. All diuretics other than 
598 
acetazolamide must be discontinued immediately. 
599 
2.4.1 Data Collection and Testing 
600 
The following procedures will be performed/data collected/eligibility criteria assessed: 
601 
 Inclusion and exclusion criteria assessed 
602 
 Demographics (date of birth, sex, race and ethnicity) 
603 
 Contact information  
604 
 Medical history 
605 
 Concomitant medications 
606 
 QoL questionnaires  
607 
 HIT-6 questionnaire  
608 
 Physical examination to include: 
609 
 
Weight, height, waist circumference, vital signs including measurement of blood 
610 
pressure and pulse 
611 
 
Neurologic exam 
612 
 Refraction  
613 
 Visual Acuity tested following refraction using ETDRS charts 
614 
 Humphrey Visual Field testing (see section 2.4.1.1 below)   
615 
 Intraocular Pressure (Goldmann tonometry) 
616 
 Ophthalmoscopy with optic disc edema grading (Frisén scale) 
617 
 Biomicroscopy 
618 
 Fundus photographs 
619 
 Optical Coherence Tomography (OCT)* (optic nerve head and macula)  
620 
 Blood testing (CBC, electrolytes, liver function tests, renal function tests, amylase) if not 
621 
done as part of routine care within 4 weeks (to be used in screening) 
622 
 Urine or serum pregnancy test for all women who have reached menarche and are 
623 
premenopausal and are not surgically sterile 
624 
 Blood draw for storage (at screening only, with subject approval, discarded if patient not 
625 
enrolled): 
626 


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 
With subject agreement, up to 20 ml of blood may be drawn and stored to use in 
627 
future research of IIH.  
628 
 Lumbar puncture (if not completed within 6 weeks of screening visit) 
629 
*If lumbar puncture done as part of screening, OCT testing should be done before the lumbar 
630 
puncture. Another set of OCT testing after the lumbar puncture is optional. 
631 
2.4.1.1 Visual Field Examinations 
632 
At the screening visit, a Humphrey visual field result with 24-2 SITA-standard program using 
633 
stimulus size III may be performed prior to two size V tests if a recent size III result is not 
634 
available. The size III test can be used as a guide as to whether the subject is likely to have at 
635 
least one eye meet eligibility criteria when size V testing is done.   
636 
 PMD using the size III stimulus should be approximately in range of -8.5 to -30 dB. 
637 
Two size V stimulus fields will be performed in each eye.  
638 
 The two size V stimulus visual field examinations will be transmitted to the Visual Field 
639 
Reading Center which will evaluate the visual field results: In order for an eye to qualify 
640 
for the trial, the average PMD with stimulus size V will have to be equal to or worse than 
641 
-6 dB and better than -27 dB. 
642 
 If the Visual Field Reading Center confirms that the subject is eligible for randomization, 
643 
it will document the average mean deviation of the two size V tests as well as which eyes 
644 
qualify as eligible eyes. 
645 
 If the Visual Field Reading Center finds performance issues on the perimetry results, the 
646 
examination will need to be repeated for the subject to be considered for the randomized 
647 
trial. 
648 
Depending on the subject’s condition (e.g., suspected visual deterioration, fatigue), perimetry 
649 
may be repeated later that day, or up to the 3-day deadline for randomization; the only exception 
650 
being if a perimetry result is unreliable and requires a repeat examination, the site will have an 
651 
additional two working days to complete the visual field examination. These additional sets of 
652 
perimetry examinations will be submitted to the Visual Field Reading Center for 
653 
confirmation/denial of eligibility. 
654 
There will be times that perimetry results are not reliable and a repeat examination will be 
655 
necessary. This may occur not only at the screening/baseline visit but also at any visit. Whenever 
656 
two examinations are required (baseline, 6 months, treatment failure protocol) the following 
657 
outcomes are possible: 
658 
1. Two examinations performed and: (1) performance criteria are met and (2) 
659 
pathophysiologic appropriate visual field patterns match. The average of the mean 
660 
deviations is used for the outcome. Acceptable performance criteria are: the false positive 
661 
rate is less than 15%, the false negative rate is judged not to be excessive for the amount 
662 
of visual loss, and gaze tracking data confirms acceptable fixation. All data from eyes in 
663 
the study must meet these criteria; only results from eyes that do not meet these criteria 
664 


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require a repeat examination. However, the criteria are eye specific so one eye may need 
665 
to be retested. 
666 
2. If the conditions listed in 1 are not met, for a particular eye (or eyes), then for that eye (or 
667 
eyes) the following should be done: 
668 
a. a 3rd examination will be performed; if 2 of the examinations meet VFRC criteria, 
669 
these 2 will be averaged for the outcome 
670 
b. if 2 of the 3 examinations do not meet VFRC performance standards, the VFRC 
671 
will discuss the subject’s performance with the Site Perimetrist (masked) to 
672 
determine the reason for poor results, assessing drowsiness, headache, effort and 
673 
lens alignment 
674 
c. if any of the above issues can be remedied, further visual field examinations will 
675 
be performed under the new conditions until 2 acceptable tests are completed; the 
676 
PMD average of these two twill be used for analysis 
677 
d. if no reliable results are obtainable, the data will be treated as a missing value 
678 


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Chapter 3: Randomization Visit 
679 
3.1 Timing 
680 
Randomization should occur within 3 days of the start of screening/baseline testing, once the 
681 
patient has met criteria for eligibility. 
682 
3.2 Randomization 
683 
Prior to randomization, the subject’s understanding of the study protocol and willingness to 
684 
participate and accept assignment to any of the three treatment groups should be confirmed. 
685 
Randomization will occur on the study website after eligibility is verified and the VFRC has 
686 
approved randomization of the subject. 
687 
Once a study subject is randomized, that subject will be counted regardless of whether the 
688 
assigned treatment is received.  Thus, the investigator must not proceed to randomize an 
689 
individual until he/she is convinced that the individual is eligible and will accept whichever 
690 
treatment group is assigned through randomization. 
691 
Subjects will be randomly assigned with equal allocation to one of the three treatment groups. 
692 
 medical therapy 
693 
 medical therapy plus ONSF 
694 
 medical therapy plus VPS 
695 
Using a permuted block design, randomization will be stratified by PMD (average of 2 size V 
696 
stimulus tests) in the eligible eye(s) (-6 dB to >-12 dB; -12 dB to >-20 dB; -20 dB to -27 dB).  If 
697 
a subject has two eligible eyes, the average PMD of the two eyes will be used for stratification. 
698 
3.3 Instructions to Subjects 
699 
Subjects in all groups will be dispensed acetazolamide (see section 4.1) and receive dietary 
700 
counseling (see section 4.1.6). Acetazolamide should be started on the day of randomization 
701 
unless the Site Investigator deems delays occurring during the screening/baseline examination 
702 
may be harmful to the patient. In this case, the acetazolamide titration according to section 
703 
4.1.1.4 may be started prior to randomization. 
704 
For subjects in the two surgery groups, surgery should be performed as soon as possible, ideally 
705 
within 3 days of randomization, but not more than 7 days. 
706 


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Chapter 4: Study Treatments 
707 
4.1 Medical Therapy including Diet 
708 
4.1.1 Acetazolamide 
709 
4.1.1.1 Acquisition 
710 
Taro Pharmaceutical Industries will supply commercially available 250 mg acetazolamide tablets 
711 
in bottles of 100. Supplies will be shipped to the study central pharmacy, which will package, 
712 
label, and distribute the drug kits to the sites. Sites will dispense acetazolamide at visits during 
713 
the 6-month randomized trial. At the 6-month visit, the subject will be given a prescription for 
714 
acetazolamide and it will be the subject’s responsibility to obtain the drug. 
715 
Table 5. Composition of Acetazolamide 
716 
Component and Quality Standard 
(and Grade, if Applicable) 
Function 
Strength 
mg/tablet 
% 
Acetazolamide, USP 
Active drug 
250.0 
48.56 
Lactose NF Monohydrate 200 mesh 
 
200.0 
38.85 
Corn Starch NF/EP 
 
48.0 
9.32 
Gelatin NF 
 
3.2 
0.62 
Glycerine USP 
 
1.6 
0.31 
Purified Water USP/EP (1) 
N/A 
(80.00) 
 
Talc USP 
 
9.0 
1.75 
Sodium Starch Glycolate NF/EP 
Binder 
1.5 
0.29 
Magnesium Stearate NF/EP 
Lubricant 
1.5 
0.29 
Total 
 
514.8 
100 
4.1.1.2 Storage 
717 
All study-supplied medication must be kept in a secure, safe area under recommended storage 
718 
conditions as stated on the labeling with access limited to persons directly involved in the study. 
719 
4.1.1.3 Accountability of Acetazolamide Supplies 
720 
The site must maintain accurate records (including dates) of receipt, dispensing, return, and 
721 
destruction of the study acetazolamide. Further details on the drug accountability process will be 
722 
described in the manual of procedures. 
723 
4.1.1.4 Dosing and Administration 
724 
All subjects in the three groups will be given acetazolamide with instructions for use.  
725 
 The study will use 250 mg tablets of acetazolamide. 
726 
 Tablets will be divided into two doses, taken with meals. 
727 


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The initial dose will be 1,000 mg twice day and then increased. 
728 
Beginning on Day 3, the dose will be increased by 250 mg every 2 days until a dosage of 4 
729 
grams daily (16 tablets) is reached (day 17) or adverse events (including side effects that 
730 
interfere with activities of daily living) prohibit increasing the dosage further. 
731 
During the titration period, subjects will be instructed to call the Site Coordinator to report any 
732 
intolerable adverse events. The subject may need to be seen for an unscheduled visit for clinical 
733 
assessment. 
734 
Table 6. Acetazolamide titration schedule (number of 250 mg tablets) 
735 
Start Day 
End Day 
Breakfast 
Dinner 
Total Daily 
1 
2 
4 
4 
8 (2000 mg) 
3 
4 
4 
5 
9 (2250mg) 
5 
6 
5 
5 
10 (2500 mg) 
7 
8 
5 
6 
11 (2750 mg) 
9 
10 
6 
6 
12 (3000 mg) 
11 
12 
6 
7 
13 (3250 mg) 
13 
14 
7 
7 
14 (3500 mg) 
15 
16 
7 
8 
15 (3750 mg) 
17 
-- 
8 
8 
16 (4000 mg) 
 
736 
If the subject is unable to tolerate the initial acetazolamide dosage, the dosage may be lowered to 
737 
3 tablets daily. The dosage may be subsequently decreased by one tablet every other day (or 
738 
sooner if the subject is substantially symptomatic) if the subject is unable to tolerate it. If the 
739 
subject is then able to tolerate the lower dosage, the daily dosage should be increased according 
740 
to the table above, or more slowly at the Site Investigator’s discretion. Additional attempts to 
741 
increase the acetazolamide dosage beyond 17 days may be initiated at the Site Investigator’s 
742 
discretion, but not above a total of 4 grams per day. The dosing level achieved by Day 90 will be 
743 
considered the subject’s final dosage. This dosage will be maintained through the remainder of 
744 
the treatment period unless the subject improves such that the dosage can be tapered or develops 
745 
intolerable side effects. 
746 
If the acetazolamide is not tolerated at a dosage of 250 mg, then 125 mg (1/2 tablet) will be tried. 
747 
If this is not tolerated, furosemide will be initiated as described in section 4.1.2. 
748 
4.1.1.5 Stopping the Dosage Titration 
749 
The Site Investigator can stop or decrease the dosage titration if the subject has reached maximal 
750 
benefit (in the SI’s opinion) or there is a safety concern. He/she can consult the Study co-
751 
Director as necessary. 
752 
See section 4.1.4 below for tapering details regarding VPS group. 
753 


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4.1.2 Addition of Furosemide 
754 
If a participant cannot tolerate any dose of acetazolamide or fails to improve clinically (for 
755 
example, worsening on the basis of: 1) subject report of progressive visual loss, 2) papilledema is 
756 
worsening, 3) OCT measures are worsening, 4) ETDRS acuity worsens more than 4 letters, or 5) 
757 
PMD worsens more than 2 dB) after 2 weeks on the maximally tolerated dosage of 
758 
acetazolamide, furosemide will be added, initiated at 20 mg bid. If the decision is unclear, the 
759 
case should be discussed with the Study co-Director.  
760 
The furosemide dose will be increased up to a maximum of 80 mg bid unless adverse events 
761 
prohibit further dosage increase, with electrolytes checked ~4 days after each dose increase.  
762 
After ~4 days of furosemide treatment, electrolytes will be checked (including serum sodium and 
763 
potassium).  If sodium and potassium are normal, the dose will be increased to 40 mg bid. Again 
764 
after ~4 days, electrolytes will be checked and if normal the dose will again be increased to 60 
765 
mg bid and then if after another ~4 days and normal sodium and potassium, the dose will be 
766 
increased to 80 mg bid and electrolytes checked after ~4 days. Subsequently, electrolytes will be 
767 
checked at every visit as long as furosemide is being taken. Standard of care electrolyte testing 
768 
will be done at a local laboratory. 
769 
 An unscheduled visit may be needed to initiate furosemide. 
770 
 Subjects requiring furosemide will be given a prescription for the medication (the study 
771 
will not provide the drug). 20 meq of potassium per day will be prescribed to take 
772 
concomitant with furosemide and increased by 20 meq per day for each 40 mg of 
773 
furosemide dosed. 
774 
 If the Site Investigator determines there has been improvement with a dose of 80 mg bid 
775 
(160 mg/day) and expects that a higher dosage may be beneficial, the dose may be 
776 
increased to 100 mg bid (200 mg/day) with close monitoring for hypokalemia and 
777 
hyponatremia. 
778 
Table 7. Furosemide titration schedule (20 or 40 mg tablets may be dispensed) 
779 
Start Day 
End Day 
Breakfast 
Dinner 
Total Daily 
(20 mg) 
1 
2 
1 
1 
2 (40 mg) 
4 
5 
2 
2 
4 (80 mg) 
8 
9 
3 
3 
6 (120 mg) 
12 
13 
4 
4 
8 (160 mg) 
*16 
17 
5 
5 
10 (200 mg) 
*This optional dosage escalation is continued to 200 mg per day only if the Site Investigator determines there 
780 
has been improvement up to this point and expects that a higher dosage may be beneficial, with close 
781 
monitoring for hypokalemia and hyponatremia. 
782 
4.1.3 Assessment of Subject Compliance with Medical Therapy 
783 
Subjects will be asked to bring the used study drug bottles to each visit.  At each study visit 
784 
during the first 6 months, the subject’s compliance with the acetazolamide dose will be assessed 
785 


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by pill counts and chloride levels. If the chloride level is not below normal limits, whether the 
786 
subject is taking the drug should be questioned unless he/she was prescribed a very low dosage.  
787 
4.1.4 Tapering of Medical Therapy 
788 
All subjects will have their pharmacotherapy tapered when the Site Investigator believes that the 
789 
dosage should be decreased if he/she believes the subject has achieved maximal benefit. For 
790 
example if the papilledema grade becomes < 1 in both eyes, and the PMD has improved 
791 
substantially and IIH symptoms are not interfering with activities of daily living, the taper could 
792 
begin.  
793 
The Site Investigator can also taper pharmacotherapy when subject safety dictates a change.  
794 
For subjects in the VPS group, the acetazolamide dosage should be tapered starting on the day of 
795 
the surgery. See the MOP for details.  
796 
Otherwise, it is suggested that dosages of each drug be tapered in increments of 25% of the 
797 
maximum daily dose of one or both study drugs biweekly until either the patient is off 
798 
medications or reaches a dosage where there is recurrence or worsening of IIH. 
799 
The Site Investigator may consult with the Study co-Director at any time regarding tapering if 
800 
needed. 
801 
4.1.5 Discontinuation of Medical Therapy 
802 
Subjects who permanently discontinue taking study medication should be encouraged to remain 
803 
in the study off medication and continue to be seen according to their original study visit 
804 
schedule, but will not have routine blood testing performed.   
805 
Discontinuation of therapy will be reported on either a visit or phone contact form. 
806 
4.1.6 Dietary Consultation 
807 
All subjects will be advised to adopt a low sodium weight reduction diet with lifestyle 
808 
modification by the Site Investigator. The treatment plan will be individualized and may include 
809 
consultation with a dietician or referral to a formal weight loss program. 
810 
 
 
811 


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4.2 Optic Nerve Sheath Fenestration 
812 
ONSF will be performed by a qualified orbital surgeon, with timing indicated below. See MOP 
813 
for orbital surgeon qualifications. Either a medial or supero-medial lid crease approach may be 
814 
utilized (see MOP more details). The surgery will make a window in the dural sheath of at least 4 
815 
mm in length under the operating microscope. The procedure will be considered successful if 
816 
CSF egress is noted at the time of fenestration. Post-operative visits will be performed according 
817 
to the surgeon’s usual routine. 
818 
 If both eyes meet study entry criteria, ONSF will be performed on the eye with the worst 
819 
PMD first, ideally within three days of randomization. If the other eye still meets eye-
820 
level eligibility criteria at two weeks after surgery on the first eye, ONSF will be 
821 
performed on the second eye. If the second eye improves at two weeks after surgery on 
822 
the first eye and no longer meets eligibility criteria, ONSF will not be performed on that 
823 
eye. 
824 
 If only one eye meets entry criteria as an eligible eye, ONSF will be performed on the 
825 
eligible eye ideally within three days of randomization. 
826 
 
If the second eye is not eligible for the study because visual field MD is too good, but 
827 
the eye worsens (i.e. PMD -6 dB or worse with size V perimetry at any time during 
828 
study follow-up), ONSF will be performed on the non-eligible eye. Also, if the non-
829 
eligible eye meets criteria for temporary treatment failure (see section 5.6.3 below), it 
830 
will be operated on even if the PMD is not worse than -6 dB. 
831 
 
If the second eye is not eligible for the study because visual loss is too severe, ONSF 
832 
will be considered at two weeks after surgery on the eligible eye. 
833 
 
834 
See section 4.6, Management of the Non-Eligible Eye, for exceptions. 
835 
 
836 
Administration of intravenous and topical corticosteroids is permitted intra-operatively, but 
837 
systemic corticosteroids are not to be administered post-operatively (see MOP for details). 
838 
Medical therapy will be continued until the Site Investigator believes that the dosage should be 
839 
stopped or decreased because the subject has improved; he/she may contact the Study co-
840 
Director to decide on how to proceed.  See section 4.1.4, Tapering of Medical Therapy. 
841 
4.3 CSF Shunting 
842 
CSF shunt surgery will occur ideally within 3 days of randomization by a certified neurosurgeon. 
843 
See MOP for surgeon qualifications. Using a frameless image-guided stereotactic system, a 
844 
ventricular shunt catheter will be positioned in the lateral ventricle of the cerebral hemisphere not 
845 
associated with speech. The ventricular catheter will be connected to an adjustable valve and the 
846 
distal shunt system will be placed in the peritoneal cavity. Post-operative computed tomography 
847 
of the brain will be obtained to confirm shunt tip placement. Post-operative visits will be 
848 
performed according to the surgeon’s usual routine. 
849 
Since the purpose of this procedure is to normalize CSF pressure, the Site Investigator will taper 
850 
medical therapy at the time of the surgery and then further if/when he/she is confident that the 
851 
VPS is working (see section 4.1.4, Tapering of Medical Therapy). 
852 


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4.4 Prohibited Medications, Treatments, and Procedures 
853 
Corticosteroids, topiramate, methazolamide, and additional diuretics (other than furosemide) 
854 
may not be used during the study period (except intra-operative corticosteroids with ONSF). 
855 
Should a subject begin an excluded treatment during the trial, this will be reported on a visit or 
856 
phone contact form.  The Study Director/co-Director will determine whether there is a potential 
857 
safety risk and whether study treatment needs to be discontinued.  
858 
Other treatments for IIH, including bariatric surgery and transverse sinus stenting, will not be 
859 
allowed during the first six months.  
860 
4.5 Concomitant Medications 
861 
4.5.1 Allowed Concomitant Medications 
862 
All concomitant medications must be used in accordance with approved labeling and as 
863 
prescribed unless they are commonly used off-label for the prescribed purpose. 
864 
Headaches may persist as a major management problem in IIH patients after study treatments 
865 
have been given.82,83 The headache can be treated with standard prophylactic vascular headache 
866 
remedies: non-steroidal anti-inflammatory drugs and tricyclic antidepressants may be effective. 
867 
Low dosage amitriptyline is suggested; the initial dosage will be 10 mg at bedtime, gradually 
868 
increasing to a maximum of 50 mg at bedtime, if needed. Weight gain is a well-known side 
869 
effect of amitriptyline; by using a low dosage and monitoring the subject’s weight, we anticipate 
870 
minimizing this untoward effect. Acute headache may be treated with non-steroidal anti-
871 
inflammatory drugs (naproxen 500 mg bid), but their use will be limited to no more than three 
872 
days per week to prevent analgesic rebound (medication overuse) headache. Table 8 below gives 
873 
the Site Investigator a group of medications from which to choose. These medications should not 
874 
be used more than 3 days per week. 
875 
Table 8. Medications available for the symptomatic treatment of headache. 
876 
Medication* 
Maximum Daily Dosage** 
Naproxen sodium 
1 gram 
Acetaminophen 
1500 mg 
Aspirin 
1950 mg 
Ibuprofen 
1600 mg 
Acetaminophen with codeine 30 mg  
4 tablets 
Butalbital/APAP or Butalbital/ASA 
4 tablets 
* Acetaminophen, aspirin, and non-steroidal anti-inflammatory drugs are preferred. 
877 
** Symptomatic treatment should be limited to 3 times weekly or less to prevent 
878 
analgesic rebound (medication overuse) headache. Subjects requiring symptomatic 
879 
headache treatment more than 3 times per week should be prescribed a preventive 
880 
medication. 
881 
There is no single agent that will be effective and tolerated by all subjects needing prophylactic 
882 
headache therapy. Table 9 below takes into consideration the undesirable side effects of many 
883 
available agents for headache prevention. Gabapentin has few drug interactions, but may 
884 


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increase the serum concentration of barbiturates and morphine. The selective serotonin reuptake 
885 
inhibitors may produce a small amount of weight gain within the first year of usage. Protriptyline 
886 
is the least sedating of the tricyclic antidepressants and is least likely to produce weight gain of 
887 
medications in this class, but also may not be as effective at headache relief. 
888 
 
 
Table 9. Preventive medications for headache. 
889 
1st-Tier Medications 
Medication 
Suggested Starting and Final Dosages 
Amitriptyline 
10 mg qhs, up to 50 mg qhs if needed* 
Vivactil™ (protriptyline) 
5 mg qhs, up to 10 mg bid if needed* 
Naproxen 
Up to 1 gram daily in divided doses 
Nortriptyline 
25 mg qhs 
* May be associated with weight gain; monitoring required 
2nd-Tier Medications 
Medication 
Suggested Starting and Final Dosages 
Gabapentin 
100 mg qhs, up to 400 mg TID if needed 
Fluoxetine 
20 mg daily 
Subjects already taking preventive medication for headache at study entry may continue using 
890 
their preventive medication unless they are taking topiramate. It is uncertain if the carbonic 
891 
anhydrase inhibition associated with topiramate is sufficient to have potential therapeutic value 
892 
in IIH; this could confound the results of the study. 
893 
4.6 Management of the Non-Eligible Eye 
894 
In general, non-eligible eyes are treated the same as eligible eyes. The non-eligible eye will have 
895 
the same evaluations as the eligible eye. The only difference between eligible and non-eligible 
896 
eyes is only the eyes that qualify at baseline (i.e., eligible eyes) will be included in the primary 
897 
outcome analysis. 
898 
If a non-eligible eye worsens, the protocol for worsening of an eligible eye will be used. In the 
899 
case of medical therapy, the dosage protocols for acetazolamide and if needed furosemide will be 
900 
used.  If there is worsening of a non-eligible eye in the optic nerve sheath fenestration group, the 
901 
procedure will be performed on the 2nd eye if PMD worsens to -6 dB or worse with size V 
902 
perimetry at any time during study follow-up or if the non-eligible eye meets criteria for 
903 
temporary treatment failure (see section 5.6.3 below).  If there is worsening of a non-eligible eye 
904 
in the CSF shunting arm, medical therapy will be given and an evaluation for shunt failure will 
905 
be done. Non-eligible eyes can be used to classify the subject as a treatment failure. 
906 
If only one eye meets study entry criteria and the other eye has worse vision by PMD than the 
907 
eligible eye (e.g. PMD worse than -27 dB, refractive error too great, previous damage to the eye 
908 
due to trauma, inflammation or infection) treatment of the eligible eye will take precedence; so in 
909 
the case of optic nerve sheath fenestration, the eligible eye will be done first. However, there 
910 
may be situations where the non-eligible eye requires the first operation. For example, if fixation 
911 
is threatened only in the non-eligible eye. If the Site Investigator has concerns about the non-
912 


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eligible eye and believes it should be operated first, a decision will be made with the Study co-
913 
Director as to which eye is operated first. 
914 
4.7 Treatment during the Treatment Failure Identification Phase 
915 
After the 26 Week primary outcome visit, subjects will transition to the Treatment Failure 
916 
Identification Phase.  Ongoing treatment will continue following the guidelines for the first six 
917 
months (26 weeks) as long as treatment failure criteria are not met at which time treatment will 
918 
be at the discretion of the Site Investigator.  Investigators are urged to employ treatments from 
919 
another arm of the study before other treatments under these circumstances. 
920 


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Chapter 5: Study Visits and Procedures 
921 
5.1 Randomized Trial  
922 
5.1.1 Study Visits and Phone Contacts 
923 
During the randomized trial, follow-up visits for all three groups will occur at weeks 4, 8 16, and 
924 
26 (± 7 days) timed from the day of randomization. 
925 
Post-operative visits may also be performed by the surgeon according to the surgeon’s usual 
926 
routine. 
927 
Additional office visits may occur as needed. 
928 
Phone contacts will occur at 12 and 20 weeks (±7 days). 
929 
5.1.2 Safety Visits 
930 
Safety visits will occur in addition to study visits, with the timing dependent on the treatment 
931 
group. The medical therapy only group generally will have visits 7 days and 14 days (± 4 days) 
932 
following randomization whereas the surgery groups generally will have visits 7 days and 14 
933 
days (± 4 days) following each surgical procedure. Visit schedules can be modified at 
934 
investigator discretion based on the participant’s course and the 14-day visit could be skipped if 
935 
there is substantial improvement in papilledema after 7 days. Additional visits can be scheduled 
936 
as indicated. Reoperations at any time also will have a similar safety visit schedule. 
937 
5.1.3 Study Visit Procedures 
938 
The following procedures will be performed for all subjects at each study visit, unless otherwise 
939 
specified: 
940 
 Medical/IIH history update 
941 
 Adverse Events 
942 
 Concomitant Medications 
943 
 Vital signs, including weight; (waist circumference at 26 Week only) 
944 
 Clinical Laboratories  
945 
 Refraction  
946 
 Visual Acuity 
947 
 Ocular Examination 
948 
 Metabolic Panel (16 and 26 Week only) 
949 
 CBC (16 and 26 Week only) 
950 
 Humphrey visual field testing with 24-2 full-threshold program using size V stimulus  
951 
 at 26 Week, two visual field examinations 
952 


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 At other study visits, one visual field examination will be done, but the VFRC may 
953 
request the visual field examination be repeated 
954 
 Fundus Photographs  
955 
 OCT* (optic nerve head and macula) 
956 
 Dispense/prescribe acetazolamide and, if needed, furosemide  
957 
 Drug Compliance/Accountability 
958 
 Dietary counseling 
959 
 QoL questionnaires (26 Week only) – at study site or online 
960 
 HIT-6 questionnaire (26 Week only) – at study site or online 
961 
 Lumbar puncture for CSF opening pressure measurement (26 Week; voluntary) 
962 
*The 26 Week OCT must be done before the lumbar puncture. 
963 
5.1.4 Phone Contact Procedures 
964 
The Site Coordinator will contact the subject by telephone to review adverse events. 
965 
 Medical/IIH History update 
966 
 Adverse Events 
967 
 Review of Concomitant Medications 
968 
 Review of Drug Compliance 
969 
Additional phone contacts, texts, and emails may be performed as needed. 
970 
5.1.5 Safety Visit Procedures 
971 
The following procedures will be performed for all subjects at each safety visit: 
972 
 Adverse Events 
973 
 Concomitant Medications 
974 
 Vital signs, including weight  
975 
 Refraction  
976 
 Visual Acuity 
977 
 Ocular Examination 
978 
 Humphrey Visual Field testing with 24-2 full-threshold program using size V stimulus  
979 
 OCT (optic nerve head and macula) 
980 
 Fundus Photographs (only at week 2) 
981 
 Drug Compliance/Accountability 
982 


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5.2 Treatment Failure Identification Phase 
983 
5.2.1 Follow-up Visits 
984 
Follow-up visits will occur at weeks 52 (12 months), 104 (2 years), and 156 (3 years) +4 weeks 
985 
as long as the study is ongoing. 
986 
5.2.2 Study Visit Procedures 
987 
Procedures at these visits will include the following: 
988 
 Medical/IIH history update (includes all new treatments and adjustments of dosages) 
989 
 Adverse Events 
990 
 Concomitant Medications 
991 
 Vital signs, including weight 
992 
 Refraction 
993 
 Visual Acuity 
994 
 Ocular Examination 
995 
 Humphrey Visual Field testing with 24-2 full-threshold program using size V stimulus 
996 
 Fundus Photographs 
997 
 OCT (optic nerve head and macula) 
998 
 Drug Compliance 
999 
 QoL questionnaires – at study site or online 
1000 
 HIT-6 questionnaire – at study site or online 
1001 
If subject wants to discontinue birth control after the 6-month RCT, this should be discussed with 
1002 
the Site Investigator.  
1003 
5.2.3 Phone Contact Procedures 
1004 
A phone, text or email contact will occur at 39 weeks by site staff.  Subsequent contacts (every 3 
1005 
months, starting at month 15 through month 33) will be by Coordinating Center staff for a 
1006 
structured interview to determine if IIH symptoms have worsened. If the caller has concerns 
1007 
about the subject, the site investigator will be notified and will be responsible for contacting the 
1008 
subject. 
1009 
5.3 Unscheduled Visits 
1010 
An unscheduled visit can be performed at any time at investigator discretion, including the 
1011 
circumstance where the subject reports that IIH symptoms have worsened or if any unexpected 
1012 
adverse events develop. Testing performed and management decisions will be dependent on the 
1013 
circumstances of the visit and the findings. 
1014 


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5.4 Extra Assessments for Subjects Who Appear to be Worsening 
1015 
If a subject appears to be worsening, the subject will receive a combination of frequent contact 
1016 
(phone, text, email) and unscheduled visits. The Site Investigator will determine at the end of 
1017 
each visit whether the subject appears to be worsening clinically [guidelines being: 1) subject 
1018 
report of progressive visual loss, 2) papilledema is worsening, 3) OCT measures are worsening, 
1019 
4) ETDRS acuity worsens more than 4 letters, or 5) PMD worsens more than 2 dB]. If the Site 
1020 
Investigator is unsure how to proceed, he/she will review the case with the Study co-Director. 
1021 
5.5 Early Termination 
1022 
For subjects who are withdrawing or being withdrawn from the study, a final visit should be 
1023 
scheduled as soon as possible. 
1024 
Procedures to be performed during the visit are the same as those listed in section 5.1.3. 
1025 
5.6 Surgical Malfunction 
1026 
VPS and ONSF malfunction will be evaluated at every visit if symptoms and findings suggest it. 
1027 
If the Site Investigator, based on all clinical findings, believes that there may be a surgical 
1028 
procedure malfunction/failure, he/she will request an SMRC review. Similarly, if the Photo 
1029 
Reading Center or Visual Field Reading Center identify lack of improvement or worsening, a 
1030 
SMRC review can be triggered.  
1031 
5.6.1 Criteria for SMRC Review 
1032 
Any of the below can trigger an SMRC review: 
1033 
1. Either visual criteria for treatment failure are met (see section 5.7.1) 
1034 
2. Papilledema: failure of papilledema to improve from baseline or worsening of 
1035 
papilledema following improvement  
1036 
3.  Site investigator believes there is substantial worsening of the subject’s condition even if 
1037 
none of the other criteria are met  
1038 
5.6.2 Surgical Malfunction Review by SMRC 
1039 
When triggered, the SMRC will review all available clinically-related information and reading 
1040 
center results to determine whether there is a non-disease associated cause (mechanical cause) 
1041 
for the lack of improvement or worsening. The site surgeon and investigator will participate in 
1042 
the review process as needed.  The SMRC may request that certain exams be repeated for further 
1043 
evaluation. The evaluation for VPS may include a radionuclide shunt study. The evaluation for 
1044 
ONSF may consider orbital MRI or echography. If the SMRC believes a surgical malfunction is 
1045 
likely, the subject’s surgical procedure will be evaluated to check the viability of the procedure.  
1046 
If the SMRC decides there was a problem with the surgery or a surgical device malfunction, they 
1047 
will discuss the case with the site investigator, the surgeon, and the Study co-Director (or 
1048 
committee member) to determine whether re-operation is indicated. 
1049 


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The subject’s safety is priority so if a site investigator or the SMRC Chair is confident a surgical 
1050 
malfunction occurred and emergent re-operation is needed, re-operation may be performed prior 
1051 
to full SMRC review.  
1052 
5.6.3 Temporary Treatment Failure 
1053 
Temporary treatment failure is a situation that can occur in either of the surgical arms where the 
1054 
subject meets criteria for treatment failure (see section 5.7.1) and then has their surgical 
1055 
procedure revised or, in the case of ONSF, either revised or the other eye operated on. If the 
1056 
subject then recovers vision and no longer meets the criteria for treatment failure, they will 
1057 
continue the protocol treatment. If repeat surgery is not successful in improving vision out of the 
1058 
treatment failure criteria range, the case goes to the Adjudication Committee to determine if 
1059 
treatment failure has occurred. 
1060 
5.7 Treatment Failure 
1061 
Possible treatment failure will be evaluated at every visit if symptoms and findings suggest it. If 
1062 
the Site Investigator, based on all clinical findings, believes that there may be a treatment failure, 
1063 
the worsening will be confirmed with a repeat visual field examination (and ETDRS acuity 
1064 
testing if needed) on the same day or within four days of the original visual field. If the Visual 
1065 
Field Reading Center identifies lack of improvement or worsening, the site will be notified and 
1066 
repeat testing performed.  If the worsening is confirmed (both visual field examinations having 
1067 
PMD that exceeds the cutoff value in 5.7.1 below), the case goes to the Adjudication Committee 
1068 
to determine if treatment failure has occurred.  
1069 
5.7.1 Treatment Failure Criteria 
1070 
If either of the below criteria for worsening are met, the subject will be considered for treatment 
1071 
failure by the Adjudication Committee: 
1072 
1. Worsening of Full Threshold Size V 24-2 Perimetry.  
1073 
a. Average baseline MD is equal to or better than -4 dB and visual function worsens 
1074 
more than 2 dB MD from the baseline average. 
1075 
b. Average baseline MD is worse than -4 dB and equal to or better than -6 dB and 
1076 
visual function worsens more than 3 dB MD from baseline average. 
1077 
c. Average baseline MD is worse than -6 dB and visual function worsens more than 
1078 
4 dB MD from baseline average. 
1079 
2. Worsening of 2 or more lines of ETDRS visual acuity 
1080 
5.7.2 Treatment Failure Review by Adjudication Committee 
1081 
The Adjudication Committee will review possible treatment failures and determine if a treatment 
1082 
failure has occurred. The committee will be masked to treatment assignment and using all 
1083 
available clinically-related information, including fundus photo results, will decide whether the 
1084 
failure is most likely due to increased intracranial pressure or from another cause, such as 
1085 
perimetric artifact, poor subject effort, or the presence of another unrelated cause of visual loss. 
1086 


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If the Adjudication Committee determines that a possible treatment failure is most likely due to 
1087 
IIH, the subject will be classified as having experienced a treatment failure. All cases that are 
1088 
sent to the Adjudication Committee will be reviewed first by the Study Director. If it is obvious 
1089 
that the patient meets criteria for treatment failure, they will be so designated. The case will 
1090 
subsequently be reviewed by the Adjudication Committee. 
1091 
When a subject meets the criteria for treatment failure, it is preferred that subsequent therapy 
1092 
come from one of the other two treatment arms but this decision will be deferred to the judgment 
1093 
of the Site Investigator. These subjects will continue to be followed at their set times for the full 
1094 
follow-up period (up to 3 years). The date of a confirmed treatment failure will be the date of the 
1095 
first visual field that triggered the Adjudication Committee review. 
1096 
If treatment failure is not confirmed, the subject will continue to follow his/her treatment group’s 
1097 
protocol. 
1098 
 
 
1099 


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Figure 3. Algorithm for Review by Surgical Malfunction Review Committee 
1100 
 
1101 
 
1102 
5.7.3  Visit Schedule Once Treatment Failure is Reached 
1103 
When a subject reaches treatment failure prior to the 6 Month visit window, the subject should 
1104 
be brought back as soon as possible for an unscheduled visit and all 6 Month visit procedures 
1105 
should be performed. The subject should be directed to remain on medical therapy (if on medical 
1106 
therapy) until seen for this visit, unless instructed otherwise by the Site Investigator. The subject 
1107 
should then return for the scheduled 6 Month visit and then the 12 Month visit. After the 12 
1108 
Month visit, subjects will then continue in the Treatment Failure Identification Phase of the study 
1109 
with annual visits. 
1110 


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Chapter 6: Testing Procedures, Questionnaires, Clinical 
1111 
Assessments, and Laboratory Testing 
1112 
6.1 Testing Procedures 
1113 
The testing procedures are noted below and details are provided in the Site Procedures Manual. 
1114 
6.2 Intraocular Pressure  
1115 
Intraocular pressure will be measured using Goldmann tonometry. 
1116 
6.3 Refraction and Visual Acuity 
1117 
At each protocol visit, a standardized refraction will be performed in both eyes. This will be 
1118 
followed by testing of visual acuity using ETDRS charts. Both will be administered by a certified 
1119 
technician masked to treatment group as best as possible.  
1120 
Although it is not possible to fully mask the technician to whether or not a subject had ONSF, all 
1121 
subjects will wear hairnets during the testing after randomization through the Week 8 visit in 
1122 
order to provide masking to VPS. 
1123 
6.4 Papilledema Grading 
1124 
Site investigators will be trained to grade papilledema using the Frisén scale.77 
1125 
Fundus photography: Digital fundus photographs centered on the optic disc will be taken at each 
1126 
visit. The severity of papilledema will be graded by the Photography Reading Center (PRC) 
1127 
using the Frisén scale.77,78 
1128 
6.5 Perimetry 
1129 
Automated perimetry will be performed using the Humphrey Field Analyzer (HFA) 24-2 full-
1130 
threshold program using a size V stimulus in both eyes by a certified technician masked as best 
1131 
as possible to treatment group. The MOP provides a detailed description of this procedure. 
1132 
Although it is not possible to fully mask the visual field technician to whether or not a subject 
1133 
had ONSF, all subjects will wear hairnets during the visual field examination after randomization 
1134 
through the Week 8 visit in order to provide masking to VPS. The use of a standardized visual 
1135 
field protocol should limit the influence of the visual field technician on the results of the 
1136 
examination. 
1137 
6.6 OCT 
1138 
Spectral-domain OCT evaluations of the optic nerves, peripapillary RNFL, and macula will be 
1139 
obtained  using a Cirrus™ (Carl Zeiss-Meditec, Inc, Dublin, CA) or Spectralis® (Heidelberg 
1140 
Engineering, Inc, Carlsbad, CA) spectral-domain OCT. The subject must have the same brand of 
1141 
OCT machine used for data collection at each visit. 
1142 


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6.7 Lumbar Puncture 
1143 
Lumbar puncture is performed as part of usual care at baseline. Although repeat lumbar puncture 
1144 
is not considered standard of care, subjects will undergo a second voluntary lumbar puncture for 
1145 
CSF opening pressure measurement at the 6-month visit, following the procedure detailed in the 
1146 
MOP. 
1147 
6.8 Quality of Life Assessment 
1148 
The NEI VFQ-25 and the 10-item Neuro-ophthalmic Supplement to the VFQ-25 will be used, as 
1149 
well as the SF-36v2.79 Testing time is approximately 20 minutes. 
1150 
6.9 Headache Disability Rating 
1151 
Headache disability will be rated using the HIT-6 (Headache Impact Test),80 a 6-item scale that 
1152 
is commonly used to rate migraine disability and has been validated for IIH. Testing time is 1-2 
1153 
minutes. 
1154 
6.10 Neurologic and Physical Examination 
1155 
A standard neurological evaluation will be performed at screening. When indicated, a general 
1156 
medical examination will be performed. 
1157 
6.11 Clinical Laboratory Tests 
1158 
CBC with platelet count will be obtained at Baseline and at Weeks 16 and 26 for all subjects. 
1159 
A comprehensive metabolic profile, including liver function tests, electrolytes, and amylase, will 
1160 
be obtained at Baseline and at Weeks 16 and 26 for all subjects. 
1161 
For subjects taking furosemide, serum potassium and sodium levels will be checked prior to each 
1162 
dosage change, after reaching the maximum tolerated dosage, and then at each subsequent visit. 
1163 
This testing will be performed at a local laboratory. 
1164 
Routine clinical laboratory tests will be performed locally by the site or the subject’s local 
1165 
laboratory if travel to the site is not convenient.  The Site Investigator will review the laboratory 
1166 
values. The Site Investigator will prescribe appropriate supplementation for hypokalemia, 
1167 
hyponatremia and symptomatic bicarbonate deficiency, and may enlist the help of the subject’s 
1168 
primary physician to help manage abnormal laboratory results, if necessary. 
1169 


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Chapter 7: Adverse Event Reporting 
1170 
7.1 Adverse Events 
1171 
7.1.1 Definitions 
1172 
Adverse Event (AE): Any untoward medical occurrence in a study subject, irrespective of the 
1173 
relationship between the adverse event and the study drug or surgery (see 7.1.2 for what adverse 
1174 
events require reporting in this protocol). 
1175 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
1176 
 Results in death. 
1177 
 Is life-threatening; (a non-life-threatening event which, had it been more severe, might 
1178 
have become life-threatening, is not necessarily considered a serious adverse event). 
1179 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
1180 
 Results in persistent or significant disability/incapacity or substantial disruption of the 
1181 
ability to conduct normal life functions. 
1182 
 Is a congenital anomaly or birth defect. 
1183 
 Is considered a significant medical event by the investigator based on medical judgment 
1184 
(e.g., may jeopardize the subject or may require medical/surgical intervention to prevent 
1185 
one of the outcomes listed above). 
1186 
7.1.2 Reporting Adverse Events 
1187 
Symptoms and signs, including visual symptoms and headaches, that are considered to be due to 
1188 
IIH will be captured on a visit/phone case report form and are not considered to be adverse 
1189 
events unless SAE criteria are met. 
1190 
Certain adverse events that are known side effects of acetazolamide and furosemide will be 
1191 
captured on a visit/phone case report form (including paresthesia, dizziness, nausea, vomiting, 
1192 
diarrhea, loss of appetite, acid reflux, skin rash, dyspnea, hypercapnia, depression, anxiety, 
1193 
tinnitus, fatigue) for all subjects, regardless of whether taking study medication.  A separate 
1194 
Adverse Event Form is only completed for these specific events if SAE criteria are met or the 
1195 
event was severe enough that it resulted in discontinuation of study drug. 
1196 
Expected symptoms post-surgery will be captured on a visit/phone case report form.  A separate 
1197 
Adverse Event Form is only completed for these specific events if SAE criteria are met or if the 
1198 
onset date is outside the expected duration of occurrence post-surgery, regardless of intensity.   
1199 
Laboratory results of interest will be recorded on a laboratory data case report form.  A separate 
1200 
Adverse Event Form is only completed for laboratory abnormalities that are considered clinically 
1201 
significant by the investigator.   
1202 


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During the first 6 months, all other events (not described above) meeting the definition of 
1203 
adverse event will be reported on an Adverse Event Form.  After the first 6 months, only those 
1204 
events meeting SAE criteria will be reported on an Adverse Event Form. 
1205 
7.1.3 Relationship of Adverse Event to Study  
1206 
The study investigator will assess the relationship of any adverse event reported on an Adverse 
1207 
Event Form to be related or unrelated to a study intervention or procedure by determining if there 
1208 
is a reasonable possibility that the adverse event may have been caused by the intervention or 
1209 
procedure. 
1210 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1211 
following general guideline when determining whether an adverse event is related: 
1212 
Yes 
1213 
There is a plausible temporal relationship between the onset of the adverse event and the study 
1214 
intervention/procedure, and the adverse event cannot be readily explained by the subject’s 
1215 
clinical state, intercurrent illness, or concomitant therapies; and/or the adverse event follows a 
1216 
known pattern of response to the study intervention/procedure; and/or the adverse event abates or 
1217 
resolves upon discontinuation of the study intervention/procedure or dose reduction and, if 
1218 
applicable, reappears upon re-challenge. 
1219 
No 
1220 
Evidence exists that the adverse event has an etiology other than the study 
1221 
intervention/procedure (e.g., preexisting medical condition, underlying disease, intercurrent 
1222 
illness, or concomitant medication); and/or the adverse event has no plausible temporal 
1223 
relationship to study intervention/procedure. 
1224 
7.1.4 Intensity of Adverse Events 
1225 
The intensity of an adverse event will be rated on a three-point scale: (1) mild, (2) moderate, or 
1226 
(3) severe. It is emphasized that the term severe is a measure of intensity; thus, a severe adverse 
1227 
event is not necessarily serious.  For example, itching for several days may be rated as severe, 
1228 
but may not be clinically serious. 
1229 
 MILD: Usually transient, requires no special treatment, and does not interfere with the 
1230 
subject’s daily activities. 
1231 
 MODERATE: Usually causes a low level of inconvenience or concern to the subject and 
1232 
may interfere with daily activities, but is usually ameliorated by simple therapeutic 
1233 
measures. 
1234 
 SEVERE: Interrupts a subject’s usual daily activities and generally requires systemic 
1235 
drug therapy or other treatment. 
1236 
7.1.5 Coding of Adverse Events 
1237 
Adverse events will be coded using the MedDRA dictionary.   
1238 


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7.1.6 Outcome of Adverse Event 
1239 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
1240 
 RECOVERED/RESOLVED: The subject recovered from the AE/SAE without sequelae.  
1241 
Record the AE/SAE stop date. 
1242 
 RECOVERED/RESOLVED WITH SEQUELAE: The event persisted and had stabilized 
1243 
without change in the event anticipated.  Record the AE/SAE stop date. 
1244 
 NOT RECOVERED/NOT RESOLVED: An ongoing AE/SAE is defined as the event 
1245 
was ongoing with an undetermined outcome. 
1246 
 
An ongoing outcome will require follow-up by the site in order to determine the final 
1247 
outcome of the AE/SAE. 
1248 
 
The outcome of an ongoing event at the time of death that was not the cause of death, 
1249 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
1250 
date. 
1251 
 FATAL: A fatal outcome is defined as the SAE that resulted in death.  Only the event 
1252 
that was the cause of death should be reported as fatal. AEs/SAEs that were ongoing at 
1253 
the time of death; however, were not the cause of death, will be recorded as “resolved” at 
1254 
the time of death. 
1255 
 UNKNOWN: An unknown outcome is defined as an inability to access the subject or the 
1256 
subject’s records to determine the outcome (for example, a subject that was lost to 
1257 
follow-up). 
1258 
All clinically significant abnormalities of clinical laboratory measurements or adverse events 
1259 
occurring during the study and continuing at study termination should be followed by the 
1260 
subject’s physician and evaluated with additional tests (if necessary) until diagnosis of the 
1261 
underlying cause, or resolution.  Follow-up information should be recorded on source 
1262 
documents. 
1263 
If any reported adverse events are present when a subject completes the study, or if a subject is 
1264 
withdrawn from the study due to an adverse event, the subject will be contacted for re-evaluation 
1265 
within 2 weeks.  If the adverse event has not resolved, additional follow-up will be performed as 
1266 
appropriate.  Every effort should be made by the Investigator or delegate to contact the subject 
1267 
until the adverse event has resolved or stabilized. 
1268 
7.2 Pregnancy Reporting 
1269 
If pregnancy occurs during the 6-month RCT, study drug will be discontinued. The occurrence of 
1270 
pregnancy will be reported on an AE Form. 
1271 
7.3 Timing of Event Reporting 
1272 
Serious, unexpected treatment-related adverse events must be reported to the Coordinating 
1273 
Center within 24 hours via completion of the online serious adverse event form. 
1274 
Other reportable adverse events as defined in section 7.1.2 will be reported within 3 days of the 
1275 
investigator becoming aware of the event by completion of an electronic case report form. 
1276 


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The Coordinating Center will notify all participating investigators of any adverse event that is 
1277 
serious, related, and unexpected.  Notification will be made within 10 working days after the 
1278 
Coordinating Center becomes aware of the event.  
1279 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1280 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
1281 
Ethics Committee. 
1282 
The sponsor will report any serious, unexpected treatment-related adverse events to the FDA. 
1283 
 
1284 
7.4 Stopping Criteria 
1285 
7.4.1 Subject Discontinuation of Study Drug 
1286 
Rules for discontinuing study drug use are described below. 
1287 
 The investigator believes it is unsafe for the subject to continue to receive the drug.  This 
1288 
could be due to the development of a potential side effect of the drug, a new medical 
1289 
condition or worsening of an existing condition; or subject behavior contrary to the 
1290 
indications for use of the drug that imposes on the subject’s safety 
1291 
 The subject requests that the treatment be stopped 
1292 
 Subject pregnancy during 6-month RCT (discontinuation at investigator discretion during 
1293 
Treatment Failure Identification Phase)  
1294 
Even if the study drug is discontinued, the subject will be encouraged to remain in the study 
1295 
through the final study visit. 
1296 
7.5 Medical Monitor 
1297 
A Medical Monitor will review all reported adverse events reported on an Adverse Event Form, 
1298 
solicited events captured on a visit/phone case report form, and laboratory abnormalities.   
1299 
The Medical Monitor will assess each event for appropriate coding of intensity, criteria for SAE, 
1300 
relationship to study drug/procedure, and MedDRA classification.  The Medical Monitor’s 
1301 
coding will be considered final. 
1302 
7.6 Independent Safety Oversight 
1303 
A Data and Safety Monitoring Committee (DSMC), selected by the National Eye Institute, will 
1304 
provide study oversight.  The Committee will be sent serious, unexpected, treatment-related 
1305 
adverse events for expedited review and all adverse events in a cumulative report approximately 
1306 
every 6 months. 
1307 
7.7 Criteria for Suspending or Terminating Overall Study 
1308 
There are no pre-specified criteria for suspending or terminating the study.  Such decisions will 
1309 
be made by the DSMC based on their review of accumulated safety data. 
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Chapter 8: Miscellaneous Considerations 
1311 
8.1 Subject Compensation 
1312 
Subject compensation will be specified in the informed consent form. 
1313 
8.2 Subject Withdrawal 
1314 
Participation in the study is voluntary, and a subject may withdraw at any time.  For subjects 
1315 
who withdraw, their data will be used up until the time of withdrawal. If possible, a final visit 
1316 
will be completed for all subjects who are terminating the study early (see section 5.5). 
1317 
A subject may be withdrawn from the study at the discretion of the Site Investigator or the Study 
1318 
co-Director for the following reasons: 
1319 
 Adverse event, but only if follow-up presents a risk to the subject’s safety 
1320 
 Noncompliance with study medications, but only if follow-up presents a risk to the 
1321 
subject’s safety 
1322 
 Development of a condition, but only if follow-up presents a risk to the subject’s safety 
1323 
Prior to withdrawing subject from the study, the Site Investigator must contact the Study co-
1324 
Director to discuss the case. 
1325 
8.3 Confidentiality 
1326 
For security and confidentiality purposes, subjects will be assigned an identifier that will be used 
1327 
instead of their name.  Protected health information gathered for this study will be shared with 
1328 
the coordinating center, the Jaeb Center for Health Research in Tampa, FL and the enrollment 
1329 
center, Mount Sinai in New York, NY.  De-identified subject information may also be provided 
1330 
to research sites involved in the study. 
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Chapter 9: Statistical Consideration 
1332 
9.1 Statistical and Analytical Plans 
1333 
The approach to sample size and statistical analyses are summarized below.  A detailed statistical 
1334 
analysis plan will be written and finalized prior to viewing any outcome data.  The analysis plan 
1335 
synopsis in this chapter contains the framework of the anticipated final analysis plan. 
1336 
9.2 Intention-to-Treat Principle 
1337 
The primary statistical analyses for this trial will be performed according to the intention-to-treat 
1338 
principle and will include all randomized subjects and eligible eyes. Every effort will be made to 
1339 
retain subjects in this study, to promote adherence to the study protocol, and to collect all data at 
1340 
every visit. If a subject cannot tolerate study medication or refuses to receive the study 
1341 
intervention, we will continue to follow and evaluate that subject if he/she is willing. If a subject 
1342 
drops out, attempts will be made to bring the subject back for a final evaluation. Compliance 
1343 
with trial procedures, drop-outs/drop-ins, and reasons for subject withdrawal will be carefully 
1344 
tracked throughout the study. 
1345 
9.3 Analysis of the Primary Outcome Variable 
1346 
9.3.1 Primary Statistical Model  
1347 
The primary outcome variable will be the change from baseline to the first of Month 6 or time of 
1348 
treatment failure in PMD in an eligible eye, with data from all eligible eyes included in the 
1349 
primary analysis. The primary statistical analysis will involve fitting an analysis of covariance 
1350 
model using generalized estimating equations (GEE) with treatment group as the factor of 
1351 
interest and baseline PMD as a covariate. These analyses will accommodate correlation among 
1352 
the within-subject responses between the two eyes; an exchangeable working correlation 
1353 
structure will be used.  Standard errors for the model parameters will be estimated using the 
1354 
robust “sandwich” estimators. The model also does not rely on the assumption of normality. 
1355 
This model will be used to determine Bonferroni-adjusted confidence intervals for the three pair-
1356 
wise differences among the adjusted treatment group mean responses (treatment effects); 
1357 
likewise, tests will be performed to compare the adjusted treatment group means using a 
1358 
Bonferroni-adjusted two-tailed significance level. An overall confidence coefficient of 98.3% 
1359 
and corresponding significance level of 1.7% for each comparison will be maintained, but as 
1360 
discussed in section 9.8.2 below, the confidence coefficient for interval estimation and 
1361 
significance level for hypothesis testing will be adjusted for the interim analysis for efficacy.  
1362 
Treatment of subjects who have reached criteria for treatment failure will be at the discretion of 
1363 
the Site Investigator, and this treatment may yield a different outcome than randomized treatment 
1364 
(investigators are urged to employ treatments from another arm of the study before other 
1365 
treatments under these circumstances). For this reason, the primary outcome variable for subjects 
1366 
who reach criteria for treatment failure prior to Month 6 will be the PMD measured at the time of 
1367 
treatment failure for purposes of the primary analysis. It is anticipated that no more than 15% of 
1368 
subjects will reach criteria for treatment failure prior to Month 6. As the most important of the 
1369 
secondary outcome variable analyses, A secondary outcome analysis will be performed that will 
1370 


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include the PMD for these subjects that was obtained at Month 6, regardless of treatment 
1371 
received after treatment failure.  
1372 
9.3.2 Adjustment for Baseline Characteristics 
1373 
If clinically important differences are found between the groups at baseline, particularly with 
1374 
regard to important variables such as age, gender, race/ethnicity, or visual acuity, the primary 
1375 
outcome analyses will be repeated after statistically adjusting for these differences. These 
1376 
analyses will be considered secondary, however. 
1377 
9.3.3 Investigation of Treatment by Covariate Interactions 
1378 
We will investigate the interaction between treatment group and selected baseline covariates 
1379 
(age, race/ethnicity, PMD, papilledema grade, RNFL thickness, total retinal thickness, optic 
1380 
nerve head volume, visual acuity, presence of transient visual obscurations, and the symptom of 
1381 
constant visual loss) separately by adding the appropriate main effect and interaction terms to the 
1382 
primary statistical model and testing for significance of the interaction. Since the power to detect 
1383 
potentially meaningful interactions will be limited, the magnitudes of mean responses to 
1384 
treatment in the relevant subgroups will be examined. The observation of clinically important 
1385 
subgroup differences in mean treatment response will serve as hypothesis generation for possible 
1386 
future studies designed to address specifically the issue of differential therapeutic response. 
1387 
Although these analyses are purely exploratory, those involving papilledema grade, PMD, visual 
1388 
acuity, and race/ethnicity will be given higher priority. 
1389 
9.3.4 Verification of Model Assumptions 
1390 
The underlying assumptions of the statistical model to be used in the primary analysis will be 
1391 
thoroughly checked (e.g., linearity), and remedial measures (e.g., transformations) may be taken 
1392 
if serious violations of these assumptions are detected. 
1393 
9.3.5 Treatment of Missing Data 
1394 
Multiple imputation will be used to deal with missing data. This will be applied using a 
1395 
regression-based imputation model. For subjects with complete data up to a particular visit, a 
1396 
multiple regression model will be fit that includes the outcome at that visit as the dependent 
1397 
variable and outcomes at previous visits and treatment group as independent variables. Separate 
1398 
models will be similarly constructed for each visit (Weeks 1, 4, 8, 16, and 26). Using these 
1399 
regression models, a missing value for a subject at a particular visit will be imputed as a draw 
1400 
from the predictive distribution given the outcomes at previous visits (some possibly imputed) 
1401 
and treatment group. This will be done sequentially starting with the Week 1 visit and ending 
1402 
with the Week 26 (Month 6) visit. This process will be repeated 100 times, resulting in 100 
1403 
complete analysis data sets. The analyses will be performed separately for each of the 100 
1404 
complete analysis data sets, and the results will be combined into one multiple imputation 
1405 
inference (estimated treatment effect and associated confidence interval and p-value) using 
1406 
Rubin’s rules.93,94 This approach is appropriate for data sets that have a monotone missing data 
1407 
pattern.  If the data set does not precisely have this pattern, the monotone data augmentation 
1408 
method using Markov-Chain Monte-Carlo 95,96 will be used to impute the small amount of 
1409 
missing data that is required to make the missing data pattern monotone before applying the 
1410 
multiple imputation algorithm described above. This approach should accommodate missing data 
1411 
in an appropriate way under the missing at random (MAR) assumption.88,89 
1412 


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Separate secondary analyses may also be performed that, for example, may group subjects 
1413 
according to treatment actually received (whether or not this was the randomly assigned 
1414 
treatment) and/or exclude subjects who had incomplete follow-up, took less than a certain 
1415 
threshold of their medication, or had another major protocol violation. The identification of 
1416 
subjects to be excluded from these analyses will be determined before the masking is broken 
1417 
(i.e., before data analysis). Of course, such analyses may lead to biased estimates of the actual 
1418 
treatment effects, but they may provide an indication of the sensitivity of the analyses to drop-
1419 
ins/drop-outs and noncompliance. Methods such as those based on propensity score 
1420 
stratification90 or inverse probability weighting91 can be employed in this setting in which non-
1421 
randomized groups are to be compared. 
1422 
9.4 Analysis of the Secondary Outcome Variables for Efficacy 
1423 
The most important secondary outcome variable for efficacy will be change from baseline to 
1424 
Month 6 in PMD in an eligible eye, with data from all eligible eyes included in this analysis.  
1425 
This is in contrast to the primary outcome variable for efficacy that is change in PMD from 
1426 
baseline to the first of Month 6 or time of treatment failure in an eligible eye, with data from all 
1427 
eligible eyes included in this analysis.   
1428 
The following additional secondary outcome variables will be evaluated at six months: change in 
1429 
CSF opening pressure measurement by lumbar puncture; change in papilledema grade (PRC and 
1430 
Site Investigator); changes in OCT measures (RNFL thickness, total retinal thickness, optic 
1431 
nerve head volume, ganglion cell layer thickness, optic nerve canal shape); changes in ETDRS 
1432 
visual acuity scores; changes in QoL assessments (SF-36, VFQ-25 and its 10-item supplement), 
1433 
changes in headache assessments (HIT-6 Inventory and headache severity); Visual Field Reading 
1434 
Center (VFRC) determination by three visual field experts of whether the visual field 
1435 
examination has improved, remained the same, or worsened; treatment failure; and surgical 
1436 
failure (transient or otherwise depending on attempts to repair malfunctions). 
1437 
With the exception of CSF opening pressure, these outcome variables will also be examined at 
1438 
Months 12, 24, and 36.  Of special interest is the outcome of time from randomization to 
1439 
treatment failure.  Time from randomization to failure due to surgical malfunction (even if 
1440 
temporary) is also of interest in the long-term follow-up phase. 
1441 
Treatment effects on secondary outcome variables for efficacy that are continuous will be 
1442 
analyzed using the same methods described above for the primary outcome variable, except that 
1443 
a working correlation structure will not be needed for variables that are not eye-specific. 
1444 
Variables to be analyzed in this manner include CSF opening pressure, OCT measures, quality of 
1445 
life as measured by the NEI-VFQ-25 + 10-item neuro-ophthalmic supplement and the SF-36, 
1446 
headache disability (HIT-6 Inventory), and headache severity.  
1447 
The model will be used to determine Bonferroni-adjusted 98.3% confidence intervals for the 
1448 
three pair-wise differences among the adjusted treatment group mean responses (treatment 
1449 
effects) at Month 6; likewise, tests will be performed to compare the adjusted treatment group 
1450 
means at Month 6 using a Bonferroni-adjusted two-tailed significance level of 1.7%.  
1451 
For categorical outcome variables that are dichotomous (e.g., presence of headache, surgical 
1452 
failure) or ordinal (visual field examination ratings by the VFRC, graded as improved, no 
1453 


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change, or worse), logistic regression models (or proportional odds models for ordinal outcomes) 
1454 
will be used to assess treatment effects. These models will include treatment group as the factor 
1455 
of interest and the baseline value of the outcome variable (for presence of headache) or baseline 
1456 
PMD (for surgical failure) as covariates. Likelihood-ratio tests will be performed for significance 
1457 
of the adjusted treatment group odds ratios representing pair-wise treatment group comparisons, 
1458 
and 98.3% confidence intervals will be constructed for these odds ratios. Other aspects of the 
1459 
analysis of the primary outcome variable (e.g., further adjustment for baseline factors, 
1460 
examination of interactions, verification of model assumptions) will also be considered. 
1461 
For dichotomous outcomes that are measured repeatedly over time (e.g., presence of headache), 
1462 
if a subject is missing a response at a particular visit, missing data will be imputed using logistic 
1463 
regression-based multiple imputation.93 For subjects with complete data up to a particular visit, a 
1464 
logistic regression model will be fit that includes the outcome at that visit as the dependent 
1465 
variable and outcomes at previous visits and treatment group as independent variables. Separate 
1466 
models will be similarly constructed for each visit. Using these logistic regression models, a 
1467 
missing value for a subject at a particular visit will be imputed as a draw from the predictive 
1468 
distribution given the outcomes at previous visits (some possibly imputed) and treatment group 
1469 
of the subject. This will be done sequentially starting with the Week 1 visit and ending with the 
1470 
Month 6 visit. This process will be repeated 100 times, resulting in 100 complete analysis data 
1471 
sets. The analyses will be performed separately for each of the 100 complete analysis data sets, 
1472 
and the results will be combined into one multiple imputation inference (estimated odds ratios 
1473 
[treatment effects] and associated confidence intervals and p-values) using Rubin’s rules.93,94 
1474 
9.5 Compliance Outcomes 
1475 
Data concerning compliance with acetazolamide (pill counts, serum bicarbonate levels) and 
1476 
surgical therapy will be summarized by treatment group and visit.  Subjects with two eligible 
1477 
eyes will have this information summarized by eye as well as by treatment group and visit.  
1478 
Change in weight will be used as a summary of compliance with diet. 
1479 
9.6 Analysis of Safety and Tolerability Outcomes 
1480 
9.6.1 Adverse Events 
1481 
All reportable adverse events will be tabulated by treatment group in a listing of each reported 
1482 
Medical Dictionary for Regulatory Activities (MedDRA) term and summarized over each 
1483 
MedDRA System Organ Class.  Details will be provided in a listing of each event. 
1484 
In addition, the following will be tabulated by treatment group. When applicable, events will be 
1485 
tabulated by eye within person: 
1486 
 Number of adverse events 
1487 
 Number of subjects with at least one event 
1488 
 Number of serious adverse events 
1489 
 Number of subjects with at least one serious adverse event 
1490 
 Number of hospitalizations and reasons for the hospitalization 
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 Number of adverse events thought by investigator to be related to study drug 
1492 
 Number of subjects who stopped the intervention in response to an adverse event 
1493 
For binary variables, Fisher exact tests will be used to compare treatment groups.  For counts, 
1494 
groups will be compared using Poisson regression. 
1495 
For each adverse event, the treatment groups will be compared in a pair-wise fashion regarding 
1496 
the occurrence of at least one event using Fisher's exact tests; numbers of individual events will 
1497 
also be described. The comparisons will be repeated excluding all mild symptoms. Similar 
1498 
analyses will be performed after grouping adverse events by body system using Medical 
1499 
Dictionary for Regulatory Activities (MedDRA) coding. All subjects will be included in these 
1500 
analyses. 
1501 
9.6.2 Tolerability Outcomes  
1502 
Tolerability will be primarily measured by ability to complete 6 months of follow-up on the 
1503 
originally assigned treatment. A complete accounting of subject disposition will be summarized 
1504 
by treatment group, including a tabulation of subject withdrawals, dosage reductions/ 
1505 
discontinuations of study medication due to adverse events (with reasons for each), receipt of 
1506 
surgery other than that randomly assigned, and surgical failures. 
1507 
9.6.3 Laboratory Test Results and Vital Signs 
1508 
Continuous measures of safety such as laboratory test results (e.g., CBC with platelet count, 
1509 
electrolytes, potassium, bicarbonate, and liver function tests) and vital signs and anthropometric 
1510 
measures (e.g., blood pressure, weight, and waist circumference) will be analyzed descriptively. 
1511 
Proportions of subjects with particular laboratory test abnormalities will be compared between 
1512 
the treatment groups in a pair-wise fashion using Fisher’s exact tests. 
1513 
9.7 Analysis of Long-Term Follow-Up Data 
1514 
An important set of analyses will consider the outcome of time from randomization to treatment 
1515 
failure. The statistical analysis of this outcome variable will involve fitting a Cox proportional 
1516 
hazards regression model with treatment group as the factor of interest and baseline PMD in the 
1517 
best eligible eye as a covariate. This model will be used to determine Bonferroni-adjusted 98.3% 
1518 
confidence intervals for the adjusted hazard ratios for the three pair-wise treatment group 
1519 
comparisons; likewise, likelihood ratio tests will be performed for significance of these hazard 
1520 
ratios using a Bonferroni-adjusted two-tailed significance level of 1.7%. Kaplan-Meier curves 
1521 
will be used to describe the cumulative probability of treatment failure over time in each 
1522 
treatment group. For subjects who do not experience treatment failure, event times will be 
1523 
censored at the last subject contact at which the subject was determined to not have experienced 
1524 
treatment failure (e.g., at the time of premature withdrawal from the trial or at the final trial 
1525 
visit). 
1526 
As described above for the primary outcome variable for efficacy, secondary analyses of time to 
1527 
treatment failure that adjust for additional baseline covariates may be considered depending on 
1528 
the comparability of the treatment groups at baseline, and examination of interactions between 
1529 


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treatment group and selected baseline covariates will be performed using the Cox proportional 
1530 
hazards model. 
1531 
The underlying assumptions of the Cox proportional hazards models will be checked and a 
1532 
thorough analysis of the martingale residuals and other diagnostics will be performed102. 
1533 
Remedial measures (e.g., covariate transformation) will be taken if serious violations of these 
1534 
assumptions are detected. The proportional hazards assumption will be assessed graphically by 
1535 
plotting log(–log(Ŝ(t)) vs. log(time) for each of the treatment groups, and by plots of smoothed 
1536 
Schoenfeld residuals101. This assumption will also be examined by dividing the time scale into 6-
1537 
month periods and estimating the treatment group hazard ratios separately in each of these 
1538 
periods through the use of time-dependent covariates103. The period length of 6 months may be 
1539 
adjusted prior to unmasking, based on the observed distribution of event times, if relatively few 
1540 
events occur during 6-month periods. Treatment group comparisons will be described in this 
1541 
manner if the proportional hazards assumption appears to be seriously violated. 
1542 
An additional important assumption of the methods to be used to analyze time to treatment 
1543 
failure is the independence between the censoring time and the (unobserved) event time. 
1544 
Sensitivity analyses will be performed that treat subjects with event times that are censored prior 
1545 
to their scheduled end of follow-up as having experienced the event a short time (one week) after 
1546 
censoring. 
1547 
Analyses of the primary and secondary outcome variables for efficacy using data collected after 
1548 
the 6-month visit will be analyzed according to the initial treatment strategy using the same 
1549 
methods described above. This will include surgical procedure complications or transient 
1550 
malfunctions.  More complex analyses may be performed that take into account the introduction 
1551 
of other treatments (e.g., surgery in those assigned to medical therapy) depending on how often 
1552 
this occurs. It will necessarily be difficult to make inferences about the effectiveness of 
1553 
subsequent treatments; however, analyses using marginal structural models100,104 may prove 
1554 
useful for this purpose. Outcomes such as surgical failure and IIH recurrence (in those whose 
1555 
vision is initially restored) will be summarized descriptively over time. 
1556 
9.8 Interim Analyses 
1557 
9.8.1 Interim Analyses for Safety 
1558 
Interim analyses of safety data will be performed periodically throughout the trial. While the 
1559 
safety of subjects will be the primary concern of the DSMC, it is difficult to formulate precise 
1560 
stopping guidelines that would cover all of the possible situations that might arise. Adverse 
1561 
events, particularly serious adverse events and surgical complications, will have to be considered 
1562 
carefully by the DSMC in terms of treatment group imbalances and severity. Events of particular 
1563 
concern include the following: death, absence of light perception, hypokalemia (from Lasix use), 
1564 
surgery-associated visual loss (from either VPS or ONSF), fenestration failure and orbital 
1565 
infection (from ONSF), and shunt failure, infection, seizures, and subdural hematoma (from 
1566 
VPS). If potential safety concerns are identified, the DSMC may require review of visual field 
1567 
data in order to evaluate the risk-benefit of continuing the trial as planned or modifying (or 
1568 
halting) the trial. 
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9.8.2 Interim Analyses for Efficacy 
1570 
We propose to perform a single interim analysis for efficacy based on the primary outcome 
1571 
efficacy variable. This will be performed after 50% of the subjects have completed (or were 
1572 
scheduled to have completed, based on their randomization date) their Month 6 visit and will 
1573 
only include data from these 50% of subjects. Given that recruitment of the 180 subjects will 
1574 
take place over 3 years, assuming that recruitment is uniform over time, it is anticipated that 
1575 
slightly fewer than 70% of the subjects will be enrolled at the time of the interim analysis.  
1576 
The analysis will involve pair-wise comparisons among the treatment groups with respect to the 
1577 
primary outcome efficacy variable; the significance level used for each comparison will be that 
1578 
determined by an O’Brien-Fleming α-spending function for a two-group comparison divided by 
1579 
3 (Bonferroni correction).99 In this case, the boundaries will be Z = 3.394 for the interim analysis 
1580 
and Z = 2.400 for the final analysis. Assuming that there are 30 subjects per group and that the 
1581 
standard deviation is 6.5 dB at the interim analysis, the boundary will be crossed if a group 
1582 
difference exceeds approximately 5.7 dB. This monitoring procedure will have a negligible 
1583 
impact on the overall Type I error probability: the significance level at the final analysis 
1584 
corresponding to Z = 2.400 is α = 0.0164. Point and interval estimates of treatment effects, as 
1585 
well as reported p-values, will be adjusted for the interim analysis. The bias-adjusted mean will 
1586 
be used for point estimation and confidence intervals and p-values based on the MLE (sample 
1587 
mean) ordering of the sample space defined by the group sequential design 97,98 will be reported 
1588 
in this case.  
1589 
The efficacy boundary will be considered to be non-binding.  We believe that it may be prudent 
1590 
to halt or modify the trial only if (1) two of the treatment groups are each shown to be superior to 
1591 
the third (in which case the third group may be dropped) or (2) one of the treatment groups is 
1592 
shown to be superior to each of the other two (in which case the trial may be halted). Of course, 
1593 
the relative safety profiles of the treatments would have to factor into these considerations as 
1594 
well.  
1595 
9.9 Baseline Characteristics 
1596 
Baseline characteristics of subjects will be summarized overall and by treatment group; formal 
1597 
statistical comparisons between treatment groups will not be performed. Continuous variables 
1598 
will be described using means, standard deviations, medians, quartiles, and ranges, and 
1599 
categorical variables will be described using percentages. 
1600 
9.10 Sample Size Determination 
1601 
In this clinical trial, 180 subjects with newly diagnosed IIH and moderate to severe visual loss (-
1602 
27 dB ≤ PMD ≤ -6 dB) will be randomly assigned to receive either medical therapy, ONSF + 
1603 
medical therapy, or VPS + medical therapy (60 per group). This sample size should provide high 
1604 
power to detect group differences when the true differences are of clinical significance, allowing 
1605 
for an anticipated 10% drop-out.  The rationale for the choice of a clinically significant treatment 
1606 
group difference of 4.5 dB is explained in the last paragraph below. 
1607 
The primary outcome variable in this trial will be the change from baseline to the first of Month 
1608 
6 or time of treatment failure in PMD in an eligible eye.  An eye is defined as eligible if it 
1609 
satisfied the requirement of -27 dB ≤ PMD ≤ -6 dB at baseline. The sample size considerations 
1610 


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initially focus on data from the best eligible eye, since most subjects are expected to contribute 
1611 
only one eye to the primary analysis, but addition of the other eligible eye is also considered 
1612 
below. In 2012, the IIH Study Group performed a retrospective chart review of consecutive 
1613 
newly diagnosed patients that met the modified Dandy criteria for IIH27 at 30 of the 41 
1614 
participating sites. Data on PMD were available from 91 patients at two time points, before and 
1615 
after intervention, with the median follow-up time being 6.0 months (interquartile range 4.1 to 
1616 
7.0 months). Patients received either medical treatment (n = 43), ONSF (n = 24), or VPS (n = 
1617 
24). The mean (± standard deviation) changes in PMD (in dB) in the best eligible eye over the 
1618 
follow-up period were 5.5 ± 6.9 in the medical group, 2.0 ± 8.9 in the ONSF group, and 8.2 ± 8.0 
1619 
in the VPS group; overall these values were 5.3 ± 8.0. The distribution of these changes was 
1620 
slightly more peaked than would be expected for a normal distribution, as illustrated in Figure 4a 
1621 
and 4b. 
1622 
 
1623 
Figure 4a and 4b. Distribution of Changes in PMD in the Best Eligible Eye 
1624 
The figure on the left (a) shows the distribution of changes in PMD in the best eligible eye according to 
1625 
baseline PMD and intervention.  Most of the patients demonstrated improvement in PMD. The figure on the 
1626 
right (b) shows a histogram of the changes in PMD in the best eligible eye regardless of intervention. The 
1627 
distribution appears to be characterized by a high concentration of changes between 0 and 10 PMD and is 
1628 
more peaked than normal. 
1629 
Given the cross-sectional nature of the preliminary data, sample size determination based on the 
1630 
use of GEE for the primary analysis is very similar to that based on the use of an analysis of 
1631 
covariance model. If an analysis of covariance model is fit to the preliminary data, with change 
1632 
in PMD as the outcome variable and treatment group and baseline PMD as the independent 
1633 
variables, the standard deviation of the residuals is 6.3 dB. The differences between treatment 
1634 
groups in adjusted mean response are quite small in this analysis: -0.09 dB difference between 
1635 
the ONSF and medical groups, and 1.13 dB difference between the VPS and medical groups. 
1636 
Also, a GEE analysis produces identical adjusted group means and slightly different estimated 
1637 
standard errors than those from the analysis of covariance model. 
1638 
It may be noted that the standard deviation of the residuals in the above analysis of covariance 
1639 
model is substantially less than the standard deviations in the individual treatment groups, 
1640 
reflecting adjustment for the baseline value of PMD in the analysis of covariance model and the 
1641 
fairly strong correlation between the baseline and final PMD values (r = 0.52). When considering 
1642 


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only subjects who were followed for at least 5.5 months (n = 56), the correlation between the 
1643 
baseline and final PMD values was actually somewhat higher (r = 0.62) and the residual standard 
1644 
deviation in the analysis of covariance model was smaller (6.0 dB). 
1645 
Assuming a standard deviation of 6.5 dB, consistent with the preliminary data, and a Bonferroni-
1646 
adjusted two-tailed significance level of 1.7%, in order to detect a group difference assuming a 
1647 
true difference of 4.5 dB with 88% power, a sample size of 54 subjects per group is required. 
1648 
The sample size will be inflated to 60 subjects per group (180 total) to accommodate an 
1649 
anticipated 10% rate of subject withdrawal/dropout.  The power remains above 80% even if the 
1650 
assumed standard deviation is as large as 7.1 dB. 
1651 
The inclusion of the worst eligible eye is expected to increase power, but the increase is expected 
1652 
to be small (approximately 3%) because the preliminary data from the chart review indicate that 
1653 
only ~40% of subjects will contribute a second eligible eye to the analysis and the correlation 
1654 
between the outcomes in the two eyes is quite high (0.82 in our sample). This assumes that the 
1655 
group difference will be comparable in the best and worst eligible eyes, as we anticipate. 
1656 
The chosen effect size of 4.5 dB is based on the following rationale.  Visual field defects are 
1657 
similar in IIH and glaucoma1,85 and data on the relationship between vision-specific quality of 
1658 
life (as measured by the NEI-VFQ-25) and PMD from the better seeing eye are available from 
1659 
213 subjects with glaucoma in the Los Angeles Latino Eye Study86. A regression analysis 
1660 
yielded the finding that a change of 1 dB in PMD corresponded to an approximately one-unit 
1661 
score change on the NEI-VFQ-25 composite score.86,87 In another study, Suner et al. used data 
1662 
from two clinical trials in neovascular age-related macular degeneration and anchor-based 
1663 
methods to estimate the change in NEI-VFQ-25 composite score that corresponds to a change of 
1664 
≥ 15 letters (~ 3 lines) in visual acuity, a value generally accepted as clinically significant.87 
1665 
They concluded that a change of 4-6 points on the NEI-VFQ-25 composite score should be 
1666 
considered clinically significant.  Taken together, the results of these two investigations suggest 
1667 
that a change in PMD of 4.5 dB corresponds to a change in NEI-VFQ-25 score that would be 
1668 
considered to be of minimal clinical significance. 
1669 
 
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Chapter 10: Data Collection and Monitoring 
1671 
10.1 Case Report Forms 
1672 
The main study data are collected through electronic case report forms (CRFs).These electronic 
1673 
CRFs from the study website are considered the primary source documentation. 
1674 
When data are directly collected in electronic case report forms, this will be considered the 
1675 
source data.  Each participating site will maintain appropriate medical and research records for 
1676 
this trial, in compliance with ICH E6 and regulatory and institutional requirements for the 
1677 
protection of confidentiality of subjects. 
1678 
10.2 Study Records Retention 
1679 
Study documents should be retained for a minimum of 3 years in accordance with NIH and FDA 
1680 
requirements.  These documents should be retained for a longer period, however, if required by 
1681 
local regulations.  No records will be destroyed without the written consent of the sponsor, if 
1682 
applicable.  It is the responsibility of the sponsor to inform the investigator when these 
1683 
documents no longer need to be retained. 
1684 
10.3 Quality Assurance and Monitoring 
1685 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1686 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1687 
conducted and data are generated, documented and reported in compliance with the protocol, 
1688 
Good Clinical Practice (GCP) and the applicable regulatory requirements.  Adverse events will 
1689 
be prioritized for monitoring. 
1690 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1691 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
1692 
Investigations — A Risk-Based Approach to Monitoring” (August 2013).  Study conduct and 
1693 
monitoring will conform with 21 Code of Federal Regulations (CFR) 312. 
1694 
The data of most importance for monitoring at the site are subject eligibility and adverse events.  
1695 
Therefore, the RBM plan will focus on these areas.  As much as possible, remote monitoring will 
1696 
be performed in real-time with on-site monitoring performed to evaluate the verity and 
1697 
completeness of the key site data.  Elements of the RBM may include: 
1698 
 Qualification assessment, training, and certification for sites and site personnel 
1699 
 Oversight of Institutional Review Board (IRB) coverage and informed consent 
1700 
procedures 
1701 
 Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1702 
review of entered data and edits, statistical monitoring, study closeout 
1703 
 On-site monitoring (site visits): source data verification, site visit report 
1704 
 Agent/Device accountability 
1705 
 Communications with site staff 
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 Patient retention and visit completion 
1707 
 Quality control reports 
1708 
 Management of noncompliance 
1709 
 Documenting monitoring activities 
1710 
 Adverse event reporting and monitoring 
1711 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
1712 
order to maintain current and personal knowledge of the study through review of the records, 
1713 
comparison with source documents, observation and discussion of the conduct and progress of 
1714 
the study. 
1715 
10.4 Protocol Deviations 
1716 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1717 
requirements.  The noncompliance may be either on the part of the subject, the investigator, or 
1718 
the study site staff.  As a result of deviations, corrective actions are to be developed by the site 
1719 
and implemented promptly. 
1720 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements.  
1721 
Further details about the handling of protocol deviations will be included in the monitoring plan. 
1722 
10.5 Committees and Reading Centers 
1723 
10.5.1 Resource Center (RC) 
1724 
The Resource Center at Mount Sinai will oversee all three reading centers described below. The 
1725 
Resource Center will review quarterly quality control reports. Calls and on-site monitoring visits 
1726 
will be conducted as necessary to address substandard performance. The RC will also assist the 
1727 
reading centers in analyses of visual fields, fundus photos, and OCT images as needed. 
1728 
10.5.2 Visual Field Reading Center (VFRC) 
1729 
The Iowa VFRC will provide training and certification of all technicians (at least 2 per clinic 
1730 
site) so that valid perimetry results are transmitted, read, stored and archived. They will also 
1731 
provide ongoing analysis of the primary outcome variable, perimetric mean deviation (PMD) to 
1732 
the sites, Jaeb Center, RC, Adjudication Committee, Surgical Malfunction Review Committee 
1733 
and SSC.  
1734 
Sites will upload Humphrey Field Analyzer size V Full Threshold native data files using the 
1735 
secure VFRC upload facility. The VFRC will then generate a size V “Statpac”-like pdf printout 
1736 
with the necessary statistical indices and transfer the pdf back to the site for all valid submitted 
1737 
visual field examinations.  
1738 
Data will be stored on a secure server. Daily, weekly and monthly backups of the data will be 
1739 
made with offsite storage as well. 
1740 


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Each examination will have quality control checks for internal validity. Monthly and quarterly 
1741 
quality control reports will be generated for the RC and SSC. 
1742 
10.5.3 Photographic Reading Center (PRC) 
1743 
The Rochester PRC will provide training and certification of all technicians (at least 1 per clinic 
1744 
site) so that valid photographic images are transmitted, read, stored and archived. They will also 
1745 
provide ongoing grading of the photos to the sites, Jaeb Center, RC, Adjudication Committee, 
1746 
Surgical Malfunction Review Committee and SSC.  
1747 
Fundus photos will be transferred to the PRC from the site via a secure file transfer upload client. 
1748 
Each site will be given an internal address and password that allows the site to upload subject 
1749 
images. 
1750 
Data will be stored on a secure server. Daily, weekly and monthly backups of the data will be 
1751 
made with offsite storage as well. Quality Control reports will be prepared on a quarterly basis. 
1752 
10.5.4 Optical Coherence Tomography Reading Center (OCTRC) 
1753 
The OCTRC will provide training and certification of all technicians (at least 1 per clinic site) so 
1754 
that valid OCT images are transmitted, read, stored and archived. They will also provide ongoing 
1755 
assessment of thickness measurements and evaluation of the optic nerve head neural canal shape 
1756 
deformations to the sites, Jaeb Center, RC, Adjudication Committee, Surgical Malfunction 
1757 
Review Committee and SSC. 
1758 
Raw data will be transferred to the OCTRC from the site via UC Davis OCTRC’s secure File 
1759 
Transfer Protocol (FTP) site.  These raw data will be uploaded into the Cirrus Research Browser 
1760 
for assessment and quality control by the OCTRC. 
1761 
Data will be stored on a secure server. Daily, weekly and monthly backups of the data will be 
1762 
made with offsite storage as well. Quality control reports will be produced by the OCTRC on a 
1763 
quarterly basis. 
1764 
10.5.5 Surgical Quality Assurance Committee (SQAC) 
1765 
There will be a SQAC composed of two orbital surgeons and two neurosurgeons. They will 
1766 
certify study surgeons and provide quality control, as detailed in the MOP. 
1767 
10.5.6 Surgical Malfunction Review Committee (SMRC) 
1768 
The SMRC will review patients in the trial that are worsening and determine if possible surgical 
1769 
malfunction exists. The review is triggered if the criteria described in section 5.6.1 above are 
1770 
met. 
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10.5.7 Adjudication Committee (AC) 
1772 
A three member committee appointed by the Study Steering Committee (SSC), plus the Study 
1773 
Director, will review subjects that meet the criteria for possible treatment failure. All treatment 
1774 
failure cases will be reviewed first by the Study Director or committee chair for safety reasons.  
1775 
This committee will be charged with deciding whether the worsening of the subject is most 
1776 
likely due to increased intracranial pressure and is a failure of therapy, or the worsening of PMD 
1777 
is more likely due to another reason. A report of all decisions will be sent to the Data and Safety 
1778 
Monitoring Committee (DSMC). Records of visual fields, fundus photos, and OCTs will be 
1779 
provided to the coordinating center to organize with the clinical information for use by the Study 
1780 
Director and AC. 
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Chapter 11: Ethics/Protection of Human Subjects 
1782 
11.1 Ethical Standard 
1783 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1784 
the Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
1785 
CFR Part 56, and/or the ICH E6. 
1786 
11.2 Institutional Review Boards 
1787 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1788 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
1789 
form must be obtained before any subject is enrolled.  Any amendment to the protocol will 
1790 
require review and approval by the IRB before the changes are implemented to the study.  All 
1791 
changes to the consent form will be IRB approved; a determination will be made regarding 
1792 
whether previously consented subjects need to be re-consented. 
1793 
11.3 Informed Consent Process 
1794 
11.3.1 Consent Procedures and Documentation 
1795 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
1796 
the study and continues throughout the individual’s study participation.  Extensive discussion of 
1797 
risks and possible benefits of participation will be provided to the subjects and their families.  
1798 
Consent forms will be IRB-approved and the subject will be asked to read and review the 
1799 
document.  The investigator will explain the research study to the subject and answer any 
1800 
questions that may arise.  All subjects will receive a verbal explanation in terms suited to their 
1801 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
1802 
research subjects.  Subjects will have the opportunity to carefully review the written consent 
1803 
form and ask questions prior to signing. 
1804 
The subjects should have the opportunity to discuss the study with their surrogates or think about 
1805 
it prior to agreeing to participate.  The subject will sign the informed consent document prior to 
1806 
any procedures being done specifically for the study.  The subjects may withdraw consent at any 
1807 
time throughout the course of the trial.  A copy of the informed consent document will be given 
1808 
to the subjects for their records.  The rights and welfare of the subjects will be protected by 
1809 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
1810 
decline to participate in this study. 
1811 
11.3.2 Subject and Data Confidentiality 
1812 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, the 
1813 
coordinating center, reading centers, and their agents.  This confidentiality is extended to cover 
1814 
testing of biological samples and genetic tests in addition to the clinical information relating to 
1815 
subjects.  Therefore, the study protocol, documentation, data, and all other information generated 
1816 
will be held in strict confidence.  No information concerning the study or the data will be 
1817 
released to any unauthorized third party without prior written approval of NORDIC. 
1818 


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The study monitor, other authorized representatives of the coordinating center and NORDIC, and 
1819 
representatives of the IRB may inspect all documents and records required to be maintained by 
1820 
the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
1821 
pharmacy records for the subjects in this study.  The clinical study site will permit access to such 
1822 
records. 
1823 
The study subject’s contact information will be securely stored at each clinical site for internal 
1824 
use during the study.  At the end of the study, all records will continue to be kept in a secure 
1825 
location for as long a period as dictated by IRB, NIH, other regulatory bodies, and institutional 
1826 
regulations. 
1827 
Visual field data will be transmitted to the VFRC at the University of Iowa, OCT image data will 
1828 
be transmitted to the University of California at Davis Reading Center, and optic disc 
1829 
photographs will be transmitted to the Photographic Reading Center at the University of 
1830 
Rochester. These data will not include the subject’s contact or identifying information.  Rather, 
1831 
individual subjects and their research data will be identified by a unique study identification 
1832 
number.  All study subject research data, which is for purposes of statistical analysis and 
1833 
scientific reporting, will be transmitted to and stored at the Jaeb Center for Health Research. The 
1834 
study data entry and study management systems used by clinical sites and by the Jaeb Center 
1835 
research staff will be secured and password protected.  At the end of the study, all study 
1836 
databases will be de-identified and placed in the public domain by the Jaeb Center. 
1837 
The Certificate of Confidentiality provided by NIH further protects the privacy of study subjects. 
1838 
This certificate protects identifiable research information from forced disclosure.  It allows the 
1839 
investigator and others who have access to research records to refuse to disclose identifying 
1840 
information on research participation in any civil, criminal, administrative, legislative, or other 
1841 
proceeding, whether at the federal, state, or local level.  By protecting researchers and 
1842 
institutions from being compelled to disclose information that would identify research subjects, 
1843 
Certificates of Confidentiality help achieve the research objectives and promote participation in 
1844 
studies by helping assure confidentiality and privacy to subjects. 
1845 
11.3.3 Future Use of Stored Specimens 
1846 
Permission to collect and store blood samples for future use will be included in the informed 
1847 
consent. With the subject’s approval, blood specimens will be labeled by study ID and stored in a 
1848 
central lab for use by researchers, including those outside of the study. 
1849 
These samples could be used for research such as metabolomics studies on lipid and proteins, 
1850 
which include gender and obesity hormones, and microRNA for specific proteins or autoimmune 
1851 
factors.  
1852 
All studies will be performed after a written protocol for testing and analysis are approved by the 
1853 
study steering committee and local IRB(s). Specimens will be transferred to research labs at 
1854 
research institutions as needed to perform the approved investigations. 
1855 
The central lab will also be provided with a code-link for each subject that will allow linking the 
1856 
biological specimens with the clinical information collected during the trial, maintaining the 
1857 
masking of the identity of the subject. 
1858 


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During the conduct of the study, an individual subject can choose to withdraw consent to have 
1859 
biological specimens stored for future research.  However, withdrawal of consent with regard to 
1860 
biosample storage will not be possible after the study is completed. 
1861 


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Chapter 12: References 
1862 
1. 
Wall, M and George, D. Idiopathic intracranial hypertension. A prospective study of 50 
1863 
patients. Brain. 1991; 114:155-180. 
1864 
2. 
Wall, M, McDermott, MP, Kieburtz, KD, et al.  Effect of acetazolamide on visual function 
1865 
in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic 
1866 
intracranial hypertension treatment trial. JAMA. 2014;1641-1651. 
1867 
3. 
Hayreh, SS. Pathogenesis of oedema of the optic disc (papilloedema):  a preliminary report. 
1868 
Br J Ophthalmol. 1964; 48:522-542. 
1869 
4. 
Smith, JL, Hoyt, WF, and Newton, TH. Optic nerve sheath decompression for relief of 
1870 
chronic monocular choked disc. Am J Ophthalmol. 1969; 68:633-639. 
1871 
5. 
Corbett, JJ, Nerad, JA, Tse, DT, et al.  Results of optic nerve sheath fenestration for 
1872 
pseudotumor cerebri. The lateral orbitotomy approach. Arch Ophthalmol. 1988; 106:1391-
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1397. 
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6. 
Hamed, LM, Tse, DT, Glaser, JS, et al.  Neuroimaging of the optic nerve after fenestration 
1875 
for management of pseudotumor cerebri. Arch Ophthalmol. 1992; 110:636-639. 
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7. 
Yazici, Z, Yazici, B, and Tuncel, E. Findings of magnetic resonance imaging after optic 
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1879 
8. 
Keltner, JL, Albert, DA, Lubow, M, et al.  Optic nerve decompression. A clinical pathologic 
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1881 
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Smith, CH and Orcutt, JC. Surgical treatment of pseudotumor cerebri. Int Ophthalmol Clin. 
1882 
1986; 26:265-275. 
1883 
10. Killer, HE, Jaggi, GP, Flammer, J, et al.  Cerebrospinal fluid dynamics between the 
1884 
intracranial and the subarachnoid space of the optic nerve. Is it always bidirectional? Brain. 
1885 
2007; 130:514-520. 
1886 
11. Wilkes, BN and Siatkowski, RM. Progressive optic neuropathy in idiopathic intracranial 
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hypertension after optic nerve sheath fenestration. J Neuroophthalmol. 2009;281-283. 
1888 
12. Spoor, TC and McHenry, JG. Long-term effectiveness of optic nerve sheath decompression 
1889 
for pseudotumor cerebri. Arch Ophthalmol. 1993; 111:632-635. 
1890 
13. Wall, M, Johnson, CA, Kutzko, KS, et al.  Long- and short-term variability of automated 
1891 
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1892 
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1893 
14. Johnston, I, Besser, M, and Morgan, MK. Cerebrospinal fluid diversion in the treatment of 
1894 
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16. Eggenberger, ER, Miller, NR, and Vitale, S. Lumboperitoneal shunt for the treatment of 
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17. Rosenberg, M, Smith, C, and Beck, R. The efficacy of shunting procedures in pseudotumor 
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cerebri. Neurology. 1989; 39:209. 
1901 
18. Karabatsou, K, Quigley, G, Buxton, N, et al.  Lumboperitoneal shunts: are the complications 
1902 
acceptable? Acta Neurochirurgica 146(11):1193-7. 2004. 
1903 
19. McGirt, MJ, Woodworth, G, Thomas, G, et al.  Cerebrospinal fluid shunt placement for 
1904 
pseudotumor cerebri-associated intractable headache: predictors of treatment response and 
1905 
an analysis of long-term outcomes. Journal of Neurosurgery 101(4):627-32. 2004. 
1906 
20. Bynke, G, Zemack, G, Bynke, H, et al.  Ventriculoperitoneal shunting for idiopathic 
1907 
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1908 
21. Abubaker, K, Ali, Z, Raza, K, et al.  Idiopathic intracranial hypertension: lumboperitoneal 
1909 
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1910 
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22. Tarnaris, A, Toma, AK, Watkins, LD, et al.  Is there a difference in outcomes of patients 
1912 
with idiopathic intracranial hypertension with the choice of cerebrospinal fluid diversion 
1913 
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23. Lueck, C and McIllwaine, G. Interventions for Idiopathic Intracranial Hypertension. The 
1915 
Cochrane Library. 2009;1-10. 
1916 
24. Piper, RJ, Kalyvas, AV, Young, AM, et al.  Interventions for idiopathic intracranial 
1917 
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25. Curry, WT, Jr., Butler, WE, and Barker, FG. Rapidly rising incidence of cerebrospinal fluid 
1919 
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2002. Neurosurgery 57(1):97-108; discussion 97-108. 2005. 
1921 
26. Friesner, D, Rosenman, R, Lobb, BM, et al.  Idiopathic intracranial hypertension in the 
1922 
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1923 
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1924 
27. Smith, JL. Whence pseudotumor cerebri? J Clin Neuro-ophthalmol. 1985; 5:55-56. 
1925 
28. Wall, M, Kutzko, KS, and Chauhan, BC. Variability in patients with glaucomatous optic 
1926 
nerve damage is reduced using size V stimuli. Invest Ophthalmol Vis Sci. 1997; 38:426-
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29. Wall, M, Woodward, KR, Doyle, CK, et al.  Repeatability of automated perimetry: a 
1929 
comparison between standard automated perimetry with stimulus size III and V, matrix, and 
1930 
motion perimetry. Invest Ophthalmol Vis Sci. 2009; 50:974-979. 
1931 
30. Wall, M, Woodward, KR, Doyle, CK, et al.  The effective dynamic ranges of standard 
1932 
automated perimetry sizes III and V and motion and matrix perimetry. Arch Ophthalmol. 
1933 
2010; 128:570-576. 
1934 
31. Berson, EL, Rosner, B, Sandberg, MA, et al.  Clinical trial of lutein in patients with retinitis 
1935 
pigmentosa receiving vitamin A. Arch Ophthalmol. 2010; 128:403-411. 
1936 
32. Gardiner, SK, Swanson, WH, Goren, D, et al.  Assessment of the Reliability of Standard 
1937 
Automated Perimetry in Regions of Glaucomatous Damage. Ophthalmology. 2014;10. 
1938 
33. Swanson, WH, Felius, J, and Birch, DG. Effect of stimulus size on static visual fields in 
1939 
patients with retinitis pigmentosa. Ophthalmology. 2000; 107:1950-1954. 
1940 
34. Swanson, WH. Stimulus size for perimetry in patients with glaucoma. Invest Ophthalmol 
1941 
Vis Sci. 2013; 54:3984-12335. 
1942 
35. Swanson, WH, Dul, MW, Horner, DG, et al.  Assessing spatial and temporal properties of 
1943 
perimetric stimuli for resistance to clinical variations in retinal illumination. Invest 
1944 
Ophthalmol Vis Sci. 2014; %20;55:353-359. 
1945 
36. Wall, M, Doyle, CK, Zamba, KD, et al.  The repeatability of mean defect with size III and 
1946 
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