INFORMED CONSENT FORM AND HIPAA · PDF fileINFORMED CONSENT FORM AND HIPAA AUTHORIZATION . ... RedHill Biopharma Ltd. ... Crohn’s Disease will be considered a marker of RHB-104’s

Approved: 28Oct2016

INFORMED CONSENT FORM AND HIPAA AUTHORIZATION Name of Research Study: A Phase III Randomized, Double Blind, Placebo-

controlled, Multicenter, Parallel Group Study to Assess the Efficacy and Safety of Fixed-dose Combination RHB-104 in Subjects with Moderately to Severely Active Crohn’s Disease

Study #: RHB-104-01 Sponsor of the Study: RedHill Biopharma Ltd. Principal Investigator’s Name: Harry E Sarles Jr MD Research Site Address(es): DHAT Research Institute 3600 Shire Blvd Ste 106 Richardson TX 75082 Daytime Telephone Number(s): 972-265-8201 24-hour Contact Number(s): 972-771-2222 You should keep a copy of this form. If you have any questions or problems during the study, call the phone number(s) above.

Rev. 28Oct2016 Page 1 of 25 Version 6.1.0 Subject Initials: _______

Approved 28Oct2016 Introduction Please read this document carefully. This is important information about the research study you are being asked to take part in. This form, called informed consent, explains the study. This consent form tells you about what you will be asked to do before, during and after the study treatment. It also describes your rights, and the sponsor’s (the company that makes the research drug) responsibilities toward you. It also tells you about the risks and benefits of the study. It is important that you read and understand all the information in this document before you decide if you want to take part in this study. You can change your mind about taking part in this study at any time. You may leave the study at any time, even if you have signed this form. You do not have to give a reason. You may take home an unsigned copy of this consent form to think about your participation in the study or discuss with family and friends before making a decision. You should take part in this study only if you want to. If you decide to take part in this study, you will be asked to sign this Informed Consent Form to confirm that you have read about the nature of the study and what is involved. You will be given a copy for future reference. This Informed Consent Form does not take away any of your legal rights, but it ensures that you have been informed about the study in which you will be participating. You are being invited to participate in this research study because you have symptoms due to Crohn’s disease. About 410 subjects will be studied across at up to 150 clinical sites in Canada, United States, Israel, Australia, Poland, New Zealand, Serbia, Bulgaria, Czech Republic, Romania, and Slovakia. This study involves research with an experimental drug called RHB-104. “Experimental” means that RHB-104 is currently being tested and has not been approved by any government regulatory agency, including the United States Food and Drug Administration (FDA). RHB-104 is composed of three active drugs: clarithromycin, rifabutin, and clofazimine. These drugs are individually-approved medications and have been on the market for many years in many different countries for the treatment of various infections caused by different bacteria. They are antibiotic agents. This means they stop bacteria from growing. Additionally, clarithromycin has beneficial effects on the immune system, while clofazimine is known to decrease inflammation and to protect nerve cells under certain conditions. These 3 antibiotics have also been given together in previous clinical studies to approximately 155 subjects suffering from Crohn’s disease. The studies showed that these 3 antibiotics may improve symptoms of Crohn’s disease. In this study, the three antibiotics will be combined as RHB-104 and administered to subjects with moderate to severe Crohn’s disease.


Approved 28Oct2016 Study Sponsor and Funding RedHill Biopharma Ltd., a pharmaceutical company, is the sponsor of this study. RedHill Biopharma Ltd. will pay your study doctor or the institution to cover costs for conducting the study at their clinic. Independent Review Board Copernicus Group Independent Review Board (IRB), designated by your study doctor, has reviewed and approved for this study to take place at DHAT Research Institute. The IRB is a group of scientists and non-scientists who review the ethics of research. The goal of the IRB is to protect the rights and welfare of study subjects. Overall Objective and Description of the Study The purpose of this study is to test whether RHB-104 is effective and safe in subjects with active Crohn’s disease when compared to placebo. Previous studies conducted with these antibiotics in Crohn's patients were not conclusive; it could not be determined that the antibiotics were effective or not. One of the potential causes of Crohn’s disease is thought to be a gastrointestinal infection by a specific type of bacterium called Mycobacterium avium paratuberculosis, also called MAP. This study may help to determine if the effect of RHB-104, a combination antibiotic therapy, could improve symptoms due to Crohn’s disease and explore a relationship between Crohn’s disease and MAP. The laboratory testing related to the identification of MAP is experimental and will be further investigated in this study. However, as MAP is a slow growing mycobacterium without a proven antibiotic treatment, and because this laboratory test to measure the presence of MAP is still experimental, improvement in symptoms of Crohn’s Disease will be considered a marker of RHB-104’s effectiveness in Crohn’s Disease against MAP, rather than a “positive” or “negative” MAP lab test result. Results of experimental MAP testing will not be disclosed to subjects. The study is a double-blind study. That means that neither you nor your doctor or his/her staff will know whether you receive the active drug RHB-104 or placebo. The placebo looks like RHB-104 but contains no active medication. If an emergency occurs, and it is important medically to know what treatment you received, then your study doctor and study staff can find out if you took the active drug or placebo. Whether you receive the active drug or placebo will be determined by chance alone (like flipping a coin). You will have a 50% chance to receive the active drug or placebo during the study. You will be asked to take the study drug (RHB-104 or placebo) for 52 weeks. The term “study drug” refers to both RHB-104 and placebo in this form. You will be asked to initially take 2 capsules of study drug every day for the first week and then 4 capsules every day during Week 2, 6 capsules every day in Week 3, 8 capsules every day in Week 4 and finally 10 capsules every day from Week 5 until the end of the study (up to Week 52). You will take half of the number of capsules in the morning and the other half in the evening with food at both times and will be reminded via phone of your change in dose for those weeks during which you do not have an onsite visit.


Approved 28Oct2016 Overall, your participation in this study will last about 60 weeks. You will need to visit the research site at least 15 times during the study. Note that if you complete 26 weeks of study drug administration but remain out of remission, defined as a Crohn’s Disease Activity Index (CDAI) >150, you may be eligible for an extension study in which you would receive the active treatment RHB-104 (open-label protocol RHB-104-04, pending regulatory acceptance). Minimal Study Requirements To qualify for this study:

• You must be able to read and then sign this consent form. • You must be between 18 and 75 years of age. • You must have moderate to severe symptoms of Crohn’s disease, involving the

small or large bowel, at the time of screening defined by a test/questionnaire called a Crohn’s Disease Activity Index (CDAI).

• You must have a history of Crohn’s disease diagnosed by endoscopy or radiography at least 6 months prior to the study.

• Women who are pregnant or nursing a child may not take part in the study. Women who are able to have children must have a negative urine pregnancy test at the beginning of this study.

• Women who are able to have children and men who are able to father children must agree with the study doctor on the type of birth control they will use during the entire study and for 6 weeks following the last dose of the study drug. One of the antibiotics in RHB-104 (rifabutin) may weaken the effect of hormonal contraceptives (birth control pills and hormone implants), therefore an effective contraceptive is required (i.e. barrier method with spermicide, or an intrauterine device/system [IUD/IUS], or a progestogen injection like Depo-Provera®).The effects of RHB-104 on pregnancy are not known.

• During the time that you will be enrolled in this study, you must agree not to participate in another study where you could receive another investigational study drug.

• You must not eat any foods or take medicines containing ‘”probiotics.” Yogurts with live active culture are permissible.

• You must currently be receiving either 5-acetyl salicylic acid (5-ASA) compounds, corticosteroids like prednisone, or immunomodulators like azathioprine, 6-mercaptopurine (6-MP) or methotrexate.

There may be reasons why you are not allowed to take part in this study. The study doctor or staff will discuss these with you. Below is a description of each study visit and the procedures that will be done over the course of the study. Procedures may be repeated to confirm or monitor results outside the accepted range.


Approved 28Oct2016 Detailed Description of the Clinical Research Study Procedures If the study doctor is not the primary doctor treating your Crohn’s disease, you may be asked to sign a release of medical records so additional information about your disease can be retrieved from your other doctor(s). At the first visit, you will have medical tests and examinations done. The study doctor will use these results to determine if you meet all of the requirements to participate in the study. This is called screening. Screening Visit (From 42 days to Day 7 before the first dose of study drug) The screening visit for this study includes:

• Discussion of study information and obtaining your signed consent to participate in the study.

• Recording of your demographic information and medical history. • Physical examination and vital signs (pulse, blood pressure, respiratory rate,

height, weight, temperature). As part of the physical examination, the study doctor will examine your eyes (uveitis assessment) and may ask you to see an eye doctor.

• You will be asked questions about your current prescription(s) and over-the-counter medications.

• The study coordinator will give you a diary card and explain the use of the CDAI diary and when/how to fill it out. You must bring the completed cards with you at your next visit.

• You will have an electrocardiogram (ECG) done. An ECG traces the electrical activity of the heart.

• Blood collection: Approximately 27 milliliters (mL) (or about 2 tablespoons) will be taken from a vein in your arm using a needle to check your general health, and to test for hepatitis B, hepatitis C, HIV and tuberculosis (TB). If your TB results suggest possible infection, you will be asked additional health questions.

o If you have positive test results for TB, HIV or hepatitis B or C, we will notify

you. We are required to notify state health authorities of positive results. If you do not want to be tested, you should not take part in this research study.

• Urine collection: You have to give a urine sample to test your general health, and

in female subjects, to verify that you are not pregnant. • Collection of stool samples to check for infection and inflammation.

In case the time between the blood draw and the Baseline visit is longer than 28 days, repeat blood sample (about 27 mL or 2 tablespoons) may be taken to repeat some laboratory tests. Scheduling and Preparation for the Colonoscopy You may be asked to have a colonoscopy for two possible reasons:


Approved 28Oct2016 1) To determine whether you have Crohn’s Disease with active inflammation, in the

event that your CD status cannot be confirmed with laboratory tests or with a recent colonoscopy report. This procedure is necessary to verify your eligibility to the study and will be scheduled during the screening period.

And/Or

2) To determine the severity of your Crohn’s Disease prior to and after 26 weeks of

treatment. Your decision to have or not have these optional procedures will not influence your ability to take part in this study. These procedures will be performed only at sites conducting this optional evaluation. Screening colonoscopies performed at these sites will be considered the pre-treatment procedure. If you agree, it will be scheduled at least 8 days before the baseline visit or at the baseline visit. Should you agree to have pretreatment colonoscopy performed, you must understand that you will be asked to have the procedure repeated after completion of 26 weeks of treatment with study drug so that the amount of healing, if any, can be measured.

If you agree to take part in the study and have a colonoscopy, your study doctor will review the preparation procedure and will schedule you to return for the colonoscopy and for later follow-up visits. You will be informed about the exact date and time of each expected visit. Colonoscopy Procedure Visit A colonoscopy is a procedure that involves inserting a flexible tube past your anus into the inside of your bowel or colon. If the colonoscopy is performed to verify whether you have active Crohn’s Disease, it will be done during the screening period, before confirming your eligibility for the study. If you agree to the optional colonoscopy, the procedure will be done before starting study treatment and after 26 weeks of administration with the study drug. A few days before the baseline visit, once your 7-Day CDAI diary is completed, you will have to prepare for the colonoscopy procedure. The colonoscopy will include the following steps:

1) Before Procedure • You will be asked to stop taking some medications that may prolong bleeding

(e.g., Aspirin, Motrin [ibuprofen], Advil [ibuprofen], Aleve [naproxen], Feldene [pyroxicam]) 7 days prior to the procedure.

• It is very important that your bowel be as clean as possible prior to the colonoscopy. Your doctor will inform you of which medications will be required for your bowel preparation. These medications could include GoLytely, Magnesium Citrate, suppositories, milk of magnesia, enemas, or a combination of these.


Approved 28Oct2016 • Your doctor will provide you with specific information regarding a special diet

that you will be requested to eat a couple of days prior to the procedure. This diet will limit your food intake to assist with the cleansing of your bowels.

2) During Procedure

• When you arrive for the colonoscopy, an intravenous (IV) line will be inserted into your vein. A medication will be given to you through the IV line to make you sleepy and forgetful about the procedure. This is called sedation. The injection may cause a local reaction. Bruising under the skin may occur, but should not cause permanent damage and is usually not painful.

• A flexible lighted tube will then be inserted through your anus and advanced into your colon. The colon will then be inflated with air to allow the study doctor to observe the lining of the colon. The colonoscopy will take approximately 30 to 60 minutes.

• If you agree to the optional procedure: o A video will be taken using the flexible lighted tube. This video will be used

to record the severity of your Crohn’s disease before and after study drug treatment.

• Biopsy samples may be collected; this is optional, and samples will only be

taken if you permit it. A biopsy is the removal of tissue for further evaluation. During the colonoscopy, up to 11 biopsies samples will be taken through the use of a special forceps that is presented through the flexible lighted tube. These samples will be sent for identification of MAP, culture for MAP, possible determination of antibiotic levels within the colon tissue, and stored for future analysis of MAP.

3) After Procedure

• Since you will be given a mild sedative, you will need to stay at your doctor’s office for 1 to 2 hours after the procedure. You will need to have someone else drive you home and under no circumstances can you drive yourself home after this procedure.

Risks Associated with a Colonoscopy

• There are risks involved associated with a colonoscopy. These risks include bleeding, perforation or hole in the wall of the colon, and infection. Complications occur in less than 1% (less than 1 out of 100 colonoscopies) as most patients have no complications from a colonoscopy.

• A perforation may require surgical repair and/or making a separate temporary opening that connects the cavity of the intestine through the abdominal wall to the outside through the skin, and is called a colostomy.

• Infection may require treatment with antibiotics. • Other risks associated with a colonoscopy procedure include: abdominal

bloating, gas in the colon, and discomfort. These risks occur in 1% to 25% (1 to 25 out of 100) of people who undergo a colonoscopy.


Approved 28Oct2016 Risks Associated with Sedation

• Sedation involves an unconscious state that may be associated with depressed breathing, injury to blood vessels, memory dysfunction/memory loss.

• Serious, but rare complication that can occur with all anesthetic methods include breathing and heart problems, drug reactions, cardiac arrest, brain damage or death.

• Your study doctor and or anesthesiologist will discuss risks specific to the type of anesthesia planned for your procedure.

You should immediately contact your doctor if you have any significant side effects or problems, regardless of whether you feel they are due to the colonoscopy. Your doctor will then decide if you should come to the clinic or hospital for further evaluation. Baseline Visit (Visit 1/Week 0) The Baseline visit will be done after the study doctor and staff have looked at results of screening tests and have confirmed that you are eligible for this study. All Study Visits Following the Screening Visit: Visits Weeks 0, 2, 4, 6, 8, 12, 16, 20, 26, 35, 44, 52 and 56 The following procedures will be done:

• Review of the inclusion/exclusion criteria. • Physical examination including looking at your eyes and measuring vital signs

(pulse, blood pressure, respiratory rate, temperature, height and weight). • You will be asked how you feel or if you have certain kinds of pains. • You will be asked questions about your current prescription and over-the-counter

medications. • Review of your diary (Crohn’s Disease Activity Index [CDAI]) (except Weeks 2, 6,

and 56). • Blood collection: Throughout this study, a total of approximately 246 mL (about

17 tablespoons) will be taken from a vein in your arm using a needle. The blood samples will be used for the following reasons:

o To check your general health. o To check markers of inflammation (all visits except Weeks 2, 4, 6 and 56). o To check for the presence of MAP (all visits except Weeks 2, 6 and 56). o To send for MAP culture - to see if MAP can be grown from the blood sample

(visits Week 0, 26 and 52 only).

• Blood collection to check blood levels of antibiotics: Throughout this study, a total of approximately 290 ml (about 20 tablespoons) will be taken from a vein in your arm using a needle. At all study visits except Weeks 0, 16 and 56, you must take your morning dose of study drug at the study site after blood samples have been drawn (at week 56 you will have already completed taking study drug). This is called a trough or low level of antibiotic concentration. At all study


Approved 28Oct2016 visits except Weeks 0, 16, 26 and 56, you will be asked to have repeat blood levels drawn up to 3 hours after your first dose that day and again 3-8 hours after your first dose that day. These are time periods after you have taken the antibiotic. You may return to the site for these additional blood tests.

• Urine collection: You will be asked to provide a urine sample to test your health and, in female subjects, to make sure you are not pregnant. Study medication will be dispensed (except for Week 52 when medication will be collected, and for the final visit Week 56).

After completion of the above procedures, at the Baseline Visit/Week 0, you will be asked to start administration with one of the two study drugs. The study coordinator will review with you how to take the study drug and you will be given a supply to take home. The study coordinator will give you diary cards and explain the use of the diaries and when/how to complete them. They must be filled out and you will need to bring with you your completed diary cards and study drug (used and unused drug containers) to every follow-up visit. It is also very important that, throughout the study, you discuss any difficulties or side effects that you experience with your study doctor or coordinator, whether or not you feel they are related to, or caused by the study drug. Visit Specific Procedures

• At Visits Weeks 0, 26 and 52 you will be asked to complete two additional questionnaires that evaluate the quality of your health and Crohn’s disease severity and symptoms (Inflammatory Bowel Disease Questionnaire (IBDQ)) and Short Form Health Survey (SF-36)

• At Visits Weeks 0, 2, 4 ,6 12, 26 and 52 an Electrocardiogram (ECG) will be performed.

• At Visits Weeks 0, 12, 26, and 52 you will be asked to collect stool samples to test for signs of inflammation and infection (Week 26 and 52 only).

• 3-4 days after Visit Week 26 colonoscopy with biopsy will be performed (only if you agreed to the optional procedure and had a colonoscopy done before the baseline visit). Biopsy samples will be sent for identification of MAP, culture for MAP, possible determination of antibiotic levels within the colon tissue, and stored for future analysis of MAP.

Frozen Blood Samples Six mL (about 1 tsp) of whole blood will be taken from a vein at the same time as other blood samples are taken at Visits Weeks 0, 4, 8, 12, 16, 20, 26, 35, 44, and 52. These blood samples may be used in the future to determine the presence of MAP in blood as well as establish a diagnostic test for MAP that may be licensed and commercially marketed. The samples will be frozen and stored at a U.S. based central laboratory for up to 10 years after study completion. Any remaining samples will be destroyed after 10 years. Each blood sample with be identified by the study participant number. Your name or any other personal information will not be included on the label. The study participant number can only be linked to you through your study doctor.


Approved 28Oct2016 Frozen Colon Biopsy Samples A biopsy sample from normal colonic tissue will be frozen and archived at each colonoscopy to determine the presence of MAP in colonic tissue prior to and after 26 weeks of treatment with study drug. These samples will be stored at a U.S. based central laboratory for up to 10 years after study completion. All remaining stored samples will be destroyed after 10 years. Each biopsy sample with be identified by the study participant number. Your name or any other personal information will not be included on the label. The study participant number can only be linked to you through your study doctor. Frozen Stool Samples One additional stool sample (1gm/cc) will be collected at screening, Visit Week 26, and Visit Week 52. These samples will be, frozen and stored at a U.S. based central laboratory for up to 10 years after study completion. All remaining samples will be destroyed after 10 years. These samples may be studied for potential analysis of the fecal microbiome – the microorganisms in your stool - at screening, and following 26 and 52 weeks of treatment with study drug. Each stool sample with be identified by the study participant number. Your name or any other personal information will not be included on the label. The study participant number can only be linked to you through your study doctor. Unscheduled Visit (Any time between the scheduled visits) Please contact the study site or return to your study doctor immediately if you do not feel well, develop new symptoms or side effects, or have questions regarding the study. Restrictions Please make sure you tell the study personnel about all medications you have taken recently, are taking now, or plan to take in the future, whether prescribed or bought over-the-counter. In the first 4 weeks of the study, when the dose of RHB-104 is gradually increased, it is recommended that you do not drive a car or operate hazardous machinery until you know how RHB-104 affects you. Risks, Stresses or Discomforts Participating in a clinical research study involves some unforeseeable risks and side effects that could occur. Your Crohn’s disease symptoms may worsen or remain the same during your participation in this study. Risks associated with RHB-104 In a clinical study of 102 subjects using a different formulation and dosage of RHB-104 vs. placebo, the most common treatment-related side effects included, tooth discoloration, skin discoloration, urine discoloration, abnormal liver function tests and joint pains. Vaginal yeast infection was more common in this group of subjects only in the first 16 weeks of the study when corticosteroids were given with the antibiotics.


Approved 28Oct2016 Skin, Tooth and Lens Discoloration Study drug may cause a discoloration of the skin from red to brownish-black, as well as discoloration of the front of the eye and inside eyelids, tears, sweat, sputum, urine, teeth, and stool. Discoloration of the skin is reversible but it may take several months or years to disappear after the conclusion of study therapy. Discoloration of soft contact lenses has been reported with the use of some of the components of RHB-104 and subjects may wish to wear glasses during the course of this study. Discoloration of intra-ocular lenses has also been reported. Eye Pain Inflammation of the eye called uveitis has also occurred with rifabutin, one of the drugs in RHB-104. Any pain, redness or diminished vision should be reported immediately to the study doctor. This is usually temporary but may be permanent in rare instances. Irregular Heart Beats Two of the antibiotics in RHB-104 (clarithromycin and clofazimine) may cause serious ECG changes. These changes include delayed conduction through the heart muscle and irregular beats. This risk may be increased when all the three components of RHB-104 are used in combination or with other drugs such as quinolones - a type of antibiotic like ciprofloxacin for example. These conditions are rare but potentially life-threatening and the reason that you will have frequent ECGs during this study. Subjects considered being at increased risk for such complications based on the ECG recorded at screening and medical history are not allowed to enter the trial. Some of the side effects seen by each of the drugs in RHB-104 are given below. Infection The increasing dose of RHB-104 given every week for the first 5 weeks of the study can potentially lead to blood levels of antibiotics which may not be effective against infection and which could lead to resistance of bacteria to antibiotics. Long-term use of any antibiotics including those in RHB-104 can increase the risk of developing a diarrheal infection called C. difficile. This condition may be severe or even life-threatening. You will be checked for this condition during the study and should alert your study doctor if you develop diarrhea. Liver Function Some of the components of RHB-104 may affect your liver function and may cause elevations in blood tests called liver function tests. This has been seen in patients receiving a fast dose increase reaching 5 capsules of RHB-104 twice a day within nine days. In this study, you will reach this dose on day 29. Elevation in liver function is usually reversible upon discontinuation of the medication. You will be closely monitored for this by frequent blood tests and will be withdrawn from the study in case of liver injury.


Approved 28Oct2016 Clarithromycin The most common side effects are:

• diarrhea, • nausea, • changes in taste, • abdominal pain/discomfort, • headache, • vomiting, • dry mouth, and • decreased appetite.

These are usually reversible upon discontinuation of the medication. On rare occasions, clarithromycin has caused changes in heart rhythm. You will be monitored for this during the study. Life-threatening rashes, although rare, have occurred with the use of clarithromycin. You will be monitored for this during the study. If you develop any symptoms of fever and skin rash, hives, pain or swelling in the throat, arm pits or groin, sore eyes or swelling of lips or tongue during the study, you should report it immediately to clinic staff. Rifabutin The most common side effects are:

• abdominal pain, • nausea, • vomiting, • upset stomach, • gas, • burping, • muscle pain, • rash, • change in color of urine, • changes in taste, and • changes in blood tests.

These are usually reversible upon discontinuation of the study drug. Rarely, this drug may decrease the number of cells responsible for fighting infection. You will be monitored for this by blood tests. If you develop fever or chills during the study, you should report them to the clinic staff.


Approved 28Oct2016 Inflammation of the eye has also been reported with the use of this drug and may cause pain, redness or diminished vision. This should be reported to the study doctor immediately. This is usually temporary but may be permanent in rare instances. Clofazimine The most common side effects are:

• darkening of skin and eye color, • dryness and itchiness of the skin and eyes, • rash, • abdominal pain, • diarrhea, • nausea, • upset stomach, • vomiting, • burning, • increased blood sugar, and • a change in the color of urine, feces, saliva and/or sweat.

These are usually reversible upon discontinuation of the study drug, but may be permanent. Patients should be advised that skin discoloration, although reversible, may take several months or years to disappear after the conclusion of therapy with clofazimine in particular. Rarely, this drug has caused serious abdominal conditions that may be life-threatening. If you feel any abdominal pain or have any stomach problems, you should report this immediately to the clinic staff. Riboflavin Riboflavin is a type of B vitamin that has been added to the placebo. There is no known toxicity from riboflavin, but it may similarly discolor urine as RHB-104. During the collection of blood samples, you may experience swelling, pain and/or bruising at the needle site. Although rare, localized clot formation and infections may occur. Lightheadedness and/or fainting may also occur during or shortly after the blood draw. Reproductive Risks RHB-104 has not been tested in pregnant women. The effects of this drug on an unborn fetus are not known at this time. Animal studies have shown negative/toxic effects on embryos and fetuses. If you suspect that you or your partner is pregnant while on the study, you must notify the study doctor immediately. You (or your embryo or fetus if you or your partner becomes pregnant) may have other not yet identified side effects during the time you participate in the study or years after receiving the drug. If you or your partner becomes pregnant, the pregnancy will be followed until its conclusion. Your partner will be asked to provide authorization for this follow-up.


Approved 28Oct2016 You or your partner should wait at least 6 weeks after stopping the study drug before becoming pregnant. In the event that you do become pregnant while on the study, the study drug will be immediately discontinued and your participation to the study will be stopped. The study doctor or your primary care physician will follow your pregnancy to term, and document the maternal and fetal outcomes. Alternative Therapies Rather than participating in this study, you may choose to receive other currently approved medication for Crohn’s disease, or you may choose to receive no treatment at all. Routine standard care for the treatment of Crohn’s disease involves disease-modifying drugs (such as treatment with mesalamine preparations [e.g., Salazopirin, Asacol, or Pentasa], steroids [e.g., prednisone], immunosuppressants [e.g., Imuran, Purinethol, or biologic agents e.g Remicade®]). Your study doctor will discuss alternative treatments available to you and disclose risks and benefits of these alternative treatments. Concomitant and Prohibited Medications During this study, you will be expected to continue medications you are currently taking including prednisone, 5-ASA, 6-MP, azathioprine, methotrexate, infliximab or adalimumab. Prednisone may be slowly reduced and eventually discontinued after Week 8 if directed by your study doctor. If your study doctor prescribes new treatments or changes your baseline doses/regimen, you may remain on study drug and continue to be assessed at all scheduled study visits. Certain medications are not allowed while taking part in this study. These include newly prescribed corticosteroids, antibiotics called quinolones, probiotics and certain biologic medications (e.g. Enbrel® [etanercept] Entyvio® (Vedolizumab), Cimzia® [certolizumab pegol] and Simponi® [golimumab recombinant Interleukin-1 (anakira - Kineret®), Tysabri® (natalizumab), cyclosporine, digoxin, estrogens and any other investigational agents. You should also refrain from drinking grapefruit juice during the study. If you experience intolerable signs and symptoms of Crohn’s disease, your study doctor will discontinue you from study drug and treat you per his/her direction. Some medications may change levels of the antibiotics administered in RHB-104 and may affect the ability of the study to assess the benefit of RHB-104. You will need to review all of your medications with the study investigator to determine if you may enroll in the study.


Approved 28Oct2016 Levels of certain medications may be elevated while taking part in this study. These include antidepressants - like Pamelor® (nortriptyline) or Zoloft® (sertraline), neuroleptics like Clozari® (clozapine), beta-blockers like Tenormin® (atenolol), antidiarrheals like Imodium® (loperamide), and antiarrhythmics like Mexitil® (mexiletine). If you are taking any of these types of medications, please discuss this with your personal physician and study doctor who should be aware of all medications you are currently taking. Potential Benefits If the study drug works to decrease the symptoms you experience from Crohn’s disease, you may benefit from taking part in this study. However, there is no guarantee that the study drug will be effective or that your symptoms will not get worse. Your participation in this study will help the investigators better understand the effectiveness of this new treatment for Crohn’s disease. This study might benefit others in the future. New Findings You will be informed in a timely manner of any relevant new information as it arises that may affect your willingness to continue your participation in this study (e.g. unexpected relevant adverse reactions observed in other subjects). If new information needs to be provided to you, then you will be given a revised consent form. Subject Compensation You will be reimbursed for expenses up to $50.00 for each study visit you complete for a possible total of up to $700.00. You will not be reimbursed for completing the colonoscopy. If you do not finish the entire study, the reimbursement you receive will depend on the number of scheduled visits you complete. The study staff can tell you more about when and how you will receive compensation. You will be reimbursed monthly. Payment for taking part in a research study may be considered taxable income. If this payment is more than $600.00 in any one calendar year, the study doctor or clinic will have to report this to the Internal Revenue Service (IRS). This will be reported using a 1099 (Miscellaneous Income) form. This form will be issued to you and a copy will be sent to the IRS. Costs The study drug, clinical evaluations, and medical testing will be provided at no charge to you, your private medical insurance (if any), or the public health insurance plan. Reasonable travel expenses to and from visits will be reimbursed. You and/or your government coverage or private health insurance company will be responsible for all other hospital or outpatient medical costs or expenses that occur due to any illness related to your routine medical care that is outside of the study requirements.


Approved 28Oct2016 Ownership All data and records provided by RedHill Biopharma Ltd. or generated during the study (other than a subject’s medical records/source documents) and all inventions discovered in the course of conducting the study are the property of RedHill Biopharma Ltd. The biological samples obtained may be used for the development of new therapies, diagnostic methods, medicines, treatments for disease, information and other developments which may be patented or otherwise have commercial value to RedHill Biopharma Ltd., researcher, study doctor or other third parties. By consenting to participate in this research you authorize the use of your sample for the research described above and you acknowledge that there are no plans to provide financial benefit or compensation to you should this occur. Confidentiality All information that you give will be kept strictly confidential. The information collected about you usually will not directly identify you (for example, by name, address, or social security number). Instead, a code number will be used for your information. Your records may be reviewed by:

• RedHill Biopharma Ltd. • People who work with the sponsor on the study • Government agencies, such as the FDA • Copernicus Group Independent Review Board (IRB)

These people may look at your records to make sure the study has been done the right way. They also want to make sure that your health information has been collected the right way, or for other reasons that are allowed under the law. If information about this study is published, you will not be identified. Study Information Website A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the study results. You can search this Web site at any time. In Case of Research-Related Injury In case of the occurrence of life threatening, disabling or other serious adverse events (including hospitalization), your study doctor should be contacted immediately at the following 24-hour emergency telephone/contact number. 24-hour contact number(s): 972-771-2222 All forms of medical diagnosis and treatment – whether routine or experimental – involve some risk of injury. In spite of all precautions, you might develop medical complications from participating in this study. If any injury occurs to you during the course of this study, as a direct result of the administration of the study drug, the study


Approved 28Oct2016 sponsor, RedHill Biopharma Ltd., agrees to pay all medical expenses necessary to treat such injury to the extent you are not provided coverage through either public or private medical insurance coverage, provided that you have followed the directions of your study doctor. Should research-related injury occur, please contact your study doctor. Study sponsor, RedHill Biopharma Ltd., has agreed to medical expenses necessary to treat an injury which occurs to you during the course of this study as a direct result of the administration of the study drug, as described above, and neither Digestive Health Associates of Texas, DHAT Research Institute nor principal investigator Harry E. Sarles, Jr., MD is responsible for payment of any such expenses. Please note that financial compensation is not routinely available from the study sponsor, RedHill Biopharma Ltd., for such things as lost wages, disability or discomfort due to injury. In addition, no financial compensation is available from Digestive Health Associates of Texas, DHAT Research Institute or principal investigator Harry E. Sarles, Jr., MD. Furthermore, please note that RedHill Biopharma Ltd. does not accept liability for any claims or damages:

(i) resulting from or associated with Crohn's disease; (ii) arising from existing illnesses other than the exacerbation of the same by the

treatment; (iii) arising from any consequence of your not carrying out the instructions in relation

to the use of the study drug; or (iv) resulting from the clinical study not achieving the requested result.

Furthermore, please note that Digestive Health Associates of Texas, DHAT Research Institute and principal investigator Harry E. Sarles, MD, do not accept any liability for any claims or any damages. It is the policy of Digestive Health Associates of Texas, DHAT Research Institute and principal investigator Harry E. Sarles, Jr., MD to provide neither financial compensation nor free medical treatment for research-related injury. You do not give up your legal rights by signing this form. Voluntary Participation and Right to Withdraw Your participation in this study is voluntary. You may refuse to participate in this study. You may end your participation in the study at any time without suffering any disadvantages. You are not required to give reasons. For your safety, if you withdraw, you will be asked to return for a visit after your last dose of study drug to undergo a physical examination and blood draw, and to review your symptoms, current medications and diary. Procedures will be performed as described under Visit Week 26 or Visit Week 52, depending on when you withdraw. In addition, you will be asked to


Approved 28Oct2016 return for a post-treatment assessment 4 weeks after your early termination to undergo procedures described above as Visit Week 56/Post Treatment Visit. If you choose not to take part or to stop at any time, your decision will not affect your future medical care and will involve no loss of benefits to which you are otherwise entitled. Removal from the Study Your participation may be stopped if you:

• do not follow the study doctor’s instructions • do not take the study drug as prescribed • do not return on time for scheduled doctor’s appointments • do not follow the study procedures • develop a medical condition during the study that increases your medical risk • become pregnant • need a treatment or medication that is not allowed on the study or that may

interfere with the study treatment If you are withdrawn from the study, you will not be able to continue taking the study drug. For your safety, you will be asked to undergo a physical examination and blood draw, to complete a questionnaire and to review your symptoms, current medications and diary. In addition, the sponsor of this study, RedHill Biopharma Ltd., the FDA or the IRB may terminate your participation at any time. Questions Please request an additional consultation with your study doctor or the individual signing this form if you have further questions. Take the time to understand this written information and the verbal explanations and information given to you by the doctor signing this form. You can also consult your own doctor. You have the right to have all of your questions answered about the study. If you have further questions about this study, or if you think you have an injury or illness from the study drug, you should contact the principal investigator, whose contact information is located on the first page of this consent form. You should contact the study doctor first if you have questions, complaints, or concerns about the study. Please call Copernicus Group IRB at 1-888-303-2224 if:

• You want to talk to someone other than the study doctor or study staff. • You have a hard time reaching the study doctor or study staff.


Approved 28Oct2016 • You have questions about your rights as a research subject.

Please visit the Copernicus Group IRB website www.cgirb.com for more information about research studies and the role of a research subject.


Approved 28Oct2016 CONSENT

Consent to Hepatitis and HIV Testing Yes No I consent to having my blood tested for hepatitis B, hepatitis C and HIV. ______________________ ____________________ _______________ Name of Patient Signature of Patient Date (print name; to be completed by patient) Consent to Optional Colonoscopy The risks and benefits of colonoscopy have been explained to me. Yes No I consent to undergoing the optional colonoscopy, with biopsy and video capture, prior to treatment and at Visit Week 26. ______________________ ____________________ _______________ Name of Patient Signature of Patient Date (print name; to be completed by patient)

Rev. 28Oct2016 Page 20 of 25 Version 6.1.0

Approved 28Oct2016 Subject’s Statement of Consent to Participate in the Study A Phase III Randomized, Double Blind, Placebo-controlled, Multicenter, Parallel Group Study to Assess the Efficacy and Safety of Fixed-dose Combination RHB-104 in Subjects with Moderately to Severely Active Crohn’s Disease I have been informed by the person whose signature is given below, about the nature of the study with RHB-104, as well as what effects and possible advantages and possible side effects or risks to expect. I will receive a signed and dated copy of this Informed Consent Form. I have had sufficient opportunity to ask questions and do not have any further questions at the moment. My participation in this study is voluntary. I may end my participation in the study at any time without suffering any disadvantages. I am not required to give reasons for my decision. I have been told that I have not given up any legal rights. During my participation, I will accept and follow the instruction of the study doctor. I will receive a copy of this signed informed consent form. I voluntarily agree to take part in this research study. ______________________ ____________________ _______________ Name of Subject Signature of Subject Date (print name; to be completed by subject) Individual Obtaining Consent The information about the study was described to the subject in a language he/she understood. I have provided an explanation of the above investigational study and have encouraged the subject to request additional information regarding this study and possible alternatives. A copy of this signed and dated consent form will be given to the subject. ______________________ ____________________ _______________ Name of the Individual Signature of the Individual Date Obtaining Consent Obtaining Consent (print name; to be completed by the individual obtaining consent)


Approved 28Oct2016 Investigator Statement I certify that the research study has been explained to the above subject by me or a member of my research staff (to whom I have delegated the authority for this procedure), including the purpose, the procedures, the possible risks and benefits associated with the participation in this research study as well as alternative therapies that are available. Any questions raised have been answered to the subject’s satisfaction. ______________________ ____________________ _______________ Name of the Principal Signature of the Principal Date Investigator Investigator (print name; to be completed by the Principal Investigator)


Approved 28Oct2016

HIPAA AUTHORIZATION The United States government has issued a privacy rule to protect the privacy rights of patients. This rule was issued under a law called the Health Insurance Portability and Accountability Act of 1996 (HIPAA). The Privacy Rule is designed to protect the confidentiality of your personal health information. The document you are reading, called an “Authorization,” describes your rights and explains how your health information will be used and disclosed (shared). As part of this study, the study doctor and his/her team at the research facility will keep confidential study records of your participation in the study. Your participation in this study will also be documented in your medical records. These study records will include personal information that you provide including your age (month and year of birth), sex, etc., as well as the results of procedures and tests, information about your response to study treatments, and other medical information relating to your participation in the study. The records identifying you will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the study are published, your identity will remain confidential. If you sign this Authorization, you will be agreeing to the disclosures described below:

a. Your study records will be assigned a code number by the study team and you will not be identified by name in the study records that are sent to RedHill Biopharma Ltd. (RHB) and its corporate affiliates and qualified representatives hired by those entities. However, RHB and its corporate affiliates and their representatives will have the right to see your complete study records, including your name when viewed at the research facility. Personnel at RHB and its corporate affiliates and their representatives will visit the research facility to review both your study records and medical records and check on the conduct of the study.

b. Some or all of your test results and other information will be transferred to and processed electronically, analyzed and evaluated by both RHB and its corporate affiliates and their representatives. These results and information may also be reported to various government regulatory agencies including Health Canada, the United States Food and Drug Administration (FDA) as well as the Ministry of Health in Israel or regulatory agencies in other countries.


Approved 28Oct2016

c. Your study records and medical records may also be reviewed by Copernicus Group Independent Review Board (IRB), which protects the rights of subjects in a research study.

d. The research facility and will review and use your study records only for the purposes of this study. They will keep your identity confidential and, except for the disclosures described above, will not disclose your study records to other parties unless it is required by law.

e. Any reports or articles that are written about the study and its results will never identify you by name.

f. Your study records will be kept at this research facility indefinitely following completion of the study. You will not have the right to review your records while the research is in progress. However, you have the right to review your records after the research has been completed and to request corrections of errors if necessary.

Your personal health information may be further shared by the groups above. If shared by them, the information will no longer be covered by the Privacy Rule. However, these groups are committed to keeping your personal health information confidential. You have the right to cancel this Authorization at any time by giving written notice to the study doctor, informing them that you are cancelling your authorization to use and disclose medical information. Please send your written cancellation notice to the address on page one of this form if you make this decision. If you cancel this Authorization to use and disclose your medical information, you will not be permitted to continue your participation in the study. However, if you drop out of the study and do decide to cancel your authorization to use and disclose your medical information, the information that has already been collected in your study record may continue to be used and disclosed as described above. No new information will be obtained for study purposes unless the information concerns an adverse event (a bad effect) related to the study. If an adverse event occurs, your entire medical record may be reviewed. All information that has already been collected for study purposes, and any new information about an adverse event related to the study, will be sent to the study sponsor.


Approved 28Oct2016

If you withdraw from the study but do not withdraw your Authorization, new personal health information may be collected until this study ends. This Authorization does not have an expiration date. If you do not withdraw this Authorization in writing, it will remain in effect indefinitely. Your study doctor will keep this Authorization for at least 6 years. You may not participate in this study nor can your study records be used or disclosed by the research facility for research purposes unless you sign this Authorization. If you do not sign this Authorization, you cannot take part in this research study or receive study-related treatment. If you withdraw this Authorization in the future, you will no longer be able to take part in this study. Your decision to withdraw your Authorization or not to take part will not involve any penalty or loss of access to treatment or other benefits to which you are entitled. AUTHORIZATION I authorize the release of my medical records and personal health information related to this study to the sponsor and its representatives, the Copernicus Group Independent Review Board, the FDA, and other regulatory agencies as described above. I have been told that I will receive a signed and dated copy of this Authorization for my records. Printed Name of Subject Signature of Subject Date


Documents

INFORMED CONSENT FORM AND HIPAA · PDF fileINFORMED CONSENT FORM AND HIPAA AUTHORIZATION . ... RedHill Biopharma Ltd. ... Crohn’s Disease will be considered a marker of RHB-104’s