STANFORD UNIVERSITY - Research Informed Consent Form Protocol Director: Minnie Sarwal, MD
Protocol Title: A Multicenter, Randomized, Prospective, Open-Label Trail of Rituximab in the Treatment of Progressive IgA Nephropathy
IRB Approval Date: March 23, 2010 IRB Expiration Date: March 22, 2011
Subject’s name: ______
Please check one of the following:
_____ You are an adult subject in this study.
_____ You are the parent or guardian granting consent for a minor subject in this study.
This information applies to the subject. If the subject is a minor, "you" refers to "your child".
Are you participating in any other research studies? _____ yes _____no
Introduction
You are asked to be in a research study of the drug Rituximab to treat people with IgA Nephropathy (IgAN). Before you decide to join the study, it is important you read and understand this explanation of the study. This informed consent describes the procedures, the drugs, and your role in this study. Please read it carefully. Ask Dr. Sarwal any questions you have. You must sign this informed consent to join the study.
Your participation in this study is entirely voluntary.
Your decision whether or not to join will not affect your medical care. If you decide to be in the study, you are free to take back your consent at any time. You may stop being in this study without affecting you or your medical care. If you decide to terminate your participation in this study, you should notify Dr. Sarwal at (650) 723-7903.
This study is looking to enroll 54 IgAN patients at 6 centers in the United States. Stanford University hopes to enroll 12 patients.
PURPOSE AND BACKGROUND
IgAN is a kidney disease that causes blood and protein in the urine. It can lead to kidney failure. Treatment options include:
· Angiotensin Converting Enzyme inhibitors (ACEi) – a blood pressure drug, it protects kidney function. The most common drug used to treat IgAN is Lisinopril, an ACEi.
· Angiotensin II Receptor Antagonist/Blocker (ARB) ) – a blood pressure drug, it protects kidney function. This is used with or instead of ACEi to control blood pressure.
· Corticosteroids – for example, prednisone – a steroid that reduces inflammation.
· Omega-3 Fish Oil Supplements (FOS) with high concentrations of Eicosapentanoic Acid (EPA) and Docosahexanoic Acid (DHA)
Rituximab is a drug that is approved to treat non-Hodgkin's lymphoma – cancers of the immune system. It has also been used to treat other illnesses related to the immune system. It may be able to prevent IgA cells from damaging your kidney. We hope that Rituximab will slow the disease progression of IgAN.
In this study, we are comparing treatment of IgAN with:
· Rituximab, ACE and/or ARB and FOS verses
· ACE and/or ARB and FOS alone.
Who Can Be In The Study?
Patients with IgAN, protein in the urine and high blood pressure are eligible for this study.
Pregnant or lactating women cannot be in the study. Pregnancy tests will be done on all women before and during the study. Women of childbearing age may be in this study only if they agree to use two reliable methods of birth control or practice abstinence during this study. Anyone who becomes pregnant during the study will be taken out of the study.
Duration of study involvment
Your participation in this study will last about 13 months.
PROCEDURES
Screening:
If you have had an IgAN positive kidney biopsy in the last 3 months, you can be screened for this study. Screening involves a physical exam, blood and urine lab tests, a chest x-ray and electrocardiogram. This is all part of standard care for your kidney disease.
Randomization:
If you qualify for the study and you wish to join, you will be randomized to Rituximab therapy or no Rituximab. This is similar to the tossing of a coin. You have a 50% chance of receiving Rituximab.
Study Procedures:
All patients in this study will take ACE and/or ARB and FOS by mouth every day for 13 months. This is standard treatment for IgAN patients.
All patients in this study will have 4 clinic visits at 3, 6, 9 and 13 months after starting the study. You will have a physical exam. These visits are standard care for your disease. Study blood and urine lab tests will be done at, 6 and 13.
If you are randomized to Rituximab, you will get Rituxmab infusions 4 times: on study days 1, 15, 168 and 182. You will need to come to the hospital as an out-patient. Rituximab goes into your body slowly through and IV line – a needle in your arm. The first infusion will take about 8 hours. 1 week after the first infusion, you will have a blood test. The next 3 infusions should take about 6 hours each.
At month 13, your doctor may want you to have another kidney biopsy. This will also be part of your standard of care, but we will include the results in our study.
Patients who do not get Rituximab and who do not see an improvement in their disease at the end of the study will be offered treatment with Rituximab when they complete the study.
Study Procedures:
Tests or Procedures / Screening Period / Study WEEK0 / 2 / 13 / 25 / 27 / 37 / 54
Physical Exam/Medical history / x / x / x / x / x
Kidney Biopsy / x / x
Standard Lab Draw/ Urine Tests / x / x / x / x / x
Rituximab Infusion if you are in this group / X / X / X / X
Study Blood Draw / x / x / x
Tissue sampling for genetic testing and future research
You may choose to be in a tissue storage component of this research study. We are collecting extra blood – 1 tablespoon – at study months 0, , 6 and 13. It will be used to do genetic testing. You may also choose to have a piece of your kidney biopsy stored for genetic testing. Urine will also be stored for future research along with blood and biopsy samples.
As part of the analysis on your samples, the investigators (may/will) do genetic testing. Genetic research is research that studies genes, including gene characteristics and gene versions that are transmitted by parents to children. Genetic research may include looking at information, such as personal appearance and biochemistry, gene sequences, genetic landmarks, individual and family medical histories, reactions to medications and responses to treatment. Genetic research raises certain questions about informing you of any results. Possible risks of knowing results include: anxiety; other psychological distress; and the possibility of insurance and job discrimination. Sometimes patients have been required to furnish information from genetic testing for health insurance, life insurance, and/or a job. A Federal law, the Genetic Information Nondiscrimination Act of 2008 (GINA), generally makes it illegal for health insurance companies, group health plans, and employers with 15 or more employees to discriminate against you based on your genetic information. A possible risk of not knowing includes being unaware of the need for treatment. These risks can change depending on the results of the research and whether there is a treatment or cure for a particular disease.
1. Introduction. Research using tissues is an important way to understand human disease and/or the role genes play in disease. There are several things you should know before allowing your tissues to be studied. Your tissues will be stored using the unique study code assigned to you in the study. This code will not reveal your identity. Generally, results from the research conducted on your stored tissues will not be released to you, even if they could be of some benefit. There are several things you should know before allowing your tissues to be studied:
2. Subject Identification. If you agree to participate in this part of the study, your tissues will be stored under a unique identifier number. Only Dr. Sarwal and the research coordinator will have access to your personal information. Your name or other public identifiers will not be included with any data shared with other investigators.
3. Risks. This sample storage study does not involve any physical health risks. Research using tissues is an important way to understand human disease and/or the role genes play in disease. There are several things you should know before allowing your tissues to be studied. Your tissues will be stored under a unique identifier name that will not reveal your identity.
4. Right to Withdraw. You have the right to refuse to allow your tissues to be studied now or saved for future study. You may withdraw from this study at any time. Once the sample is taken it will be unlinked from your name. This will protect your identity and preserve anonymity. However, once you donate the sample you will not be able to withdraw your tissues from the from the research project because the samples will not be traceable.
Even with special precautions, there is no absolute protection against discrimination on the basis of disease or genetic information. For this reason, the investigator will use the results of this study as research only and not include them in your medical record.
5. Use in Commercial Development of Products. Tissue research may result in new products, tests or discoveries. In some instances, these may have potential commercial value. However, donors of tissues do not retain any property rights to the materials. Therefore you would not share in any financial benefits from these products, tests or discoveries.
Your blood and urine will be stored in a locked freezer at Stanford University before being shipped to Mayo clinic for processing. All personal information will be removed from the samples before storing.
YES / NODo you agree to donate blood samples to be saved for future research?
Do you agree to donate a piece of your kidney biopsy to be
saved for future research?
Do you agree to donate urine to be saved for future research?
Subject Name / Subject Signature / Date
Relationship to Subject
STUDY MEDICATIONS
All patients will take ACE at a dose that gives a blood pressure of 125/75 for adults and the 95th percentile of age, height and gender for children. If you don’t respond well to the ACE, you may get an ARB (Angiotensin Receptor Blocker) to treat your blood pressure.
All patients will take FOS at a dose of 3.6g EPA/day. The dose will be modified appropriately for children.
If you are randomized to Rituximab, you will get 1000mg of Rituximab 4 times. It will be given through a needle in your arm at a rate of 50mg/hour. If this goes well, the rate of infusion will be increased 50mg/hour every 30 minutes to a maximum of 400mg/hour as tolerated. Rituximab doses for pediatric patients will be 375mg/m2.
The next 3 Rituximab infusions will be at an initial rate of 100 mg/hour, and increased by 100 mg/hour every 30 minutes to a maximum of 400 mg/hour as tolerated. Rituximab doses for pediatric patients will be 375mg/m2 and infused over 4-6 hours according to the discretion of the co-investigator at that site.
potential risks and discomforts
ACE: (Lisinopril) may cause: headache, dizziness, decreased kidney function, cough, rash, difficulty sleeping, muscle cramps, loss of taste and a lowering of white blood cells. Lisinopril has been associated with a low incidence of facial swelling. It may have risks that we don’t know about.
No female who may be pregnant should join the study. Lisinopril may damage a developing fetus. If there is a chance of pregnancy at study entry or any other time during the study, a pregnancy test must be performed. All sexually active females should use some form of birth control during the study.
ARB: (Losartan/Candesartan) may cause: Muscle cramps, back or leg pain, dizziness, nasal congestion, sinusitis. It may have risks that we don’t know about.
FOS: (OMACORÒ) have no significant side effects at the doses used in this study but may leave a bad taste in your mouth.
Rituximab: (RITUXAN): The most common side effects are infusion-related symptoms, particularly with the first Rituximab infusion. These symptoms include flu-like symptoms, fever, shivering, nausea, swelling, headache, shortness of breath, facial swelling and low blood pressure. We may stop your ACE/ARB 12 hours prior to the infusion. Chest pain, irregular heart rhythm and dizziness, have occurred in patients treated with Rituximab. Patients with a history of cardiac disease will be monitored closely. In rare instances, severe and fatal infusion-related reactions have occurred.
The FDA has recently issued a warning of a new safety concern regarding Rituximab. In rare instances, some patients treated with Rituximab have developed progressive multifocal leukoencephalopathy (PML), a fatal viral infection of the central nervous system. Patients who are being treated or have been treated with Rituximab who experience any major changes in vision, balance, or coordination, or who experience confusion, should promptly call their doctor. Patients at risk for serious infusion reactions have: cancer, high white blood cell counts, heart or lung disease. There is some preliminary data to support that this is related to the overall extent of immunosuppression received by the patient and may not be attributable to a single drug. We will thus closely monitor all our patients who receive increased immunosuppression for treatment of their disease, including the use of Rituxan in this study.
Potential Benefits
We hope that your kidney condition will improve in this study, but it may not. People in the future will benefit from knowing whether Rituximab helps patients with IgAN.