Carnosine in GWI

Carnosine in GWI Study Participant Login

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If you are interested in participating in our research, please contact:

1) Email: gwiresearch@georgetown.edu

2) Email: cfsresearch@georgetown.edu

3) Phone: 202-687-8231

Introduction

You are invited to consider participating in this study. The study is called Carnosine in Gulf War Illness, (GWI). Carnosine is a body chemical available over-the-counter as a dietary supplement. It may act as an antioxidant in your brain and muscles. The effects of this supplement will be compared to a placebo. We will look for changes in functional magnetic resonance imaging (fMRI; brain scans), questionnaires, activity, and other measurements. You can participate if you have GWI or Chronic Fatigue Syndrome (CFS), and if you have completed the CNDP1 in GWI study. Active duty military personnel cannot take part in this study.

Please take your time to make your decision. Discuss it with your family and friends. It is important that you read and understand several general principles that apply to all who take part in our studies:

1. a.Taking part in the study is entirely voluntary
   

2. b.Personal benefit to you may or may not result from taking part in the study, but knowledge may be gained from your participation that will benefit others
   

3. c.You may withdraw from the study at any time without any of the benefits you would have received normally being limited or taken away.
   

The purpose and nature of the study, possible benefits, risks, and discomforts, other options, your rights as a participant, and other information about the study are discussed below. Any new information discovered, at any time during the research, which might affect your decision to participate or remain in the study will be provided to you. You are urged to ask any questions you have about this study with the staff members who explain it to you. You are urged to take whatever time you need to discuss the study with your physician, hospital personnel and your family and friends. The decision to participate or not is yours. If you decide to participate, please sign and date where indicated at the end of this form. The principal investigator (person in charge of this research study) is James N. Baraniuk, M.D.

The research is being sponsored by the Department of Defense (DOD). DOD is called the sponsor. Georgetown University is being paid by the DOD to conduct this study with James N. Baraniuk, M.D. as the primary investigator.

This research study follows the directives of the U.S. Army Medical Research and Materiel Command (USAMRMC) Guidelines for Human Research (June 21, 2007) and its Guidelines for Investigators: Requirements for U.S. Army Medical Research and Materiel Command (USAMRMC) Headquarters Review and Approval of Research Involving Human Volunteers, Human Anatomical Substances, and/or Human Data under the guidance of the USAMRMC Human Research Protection Office (HRPO). As a volunteer, you must be aware that representatives of the USAMRMC have the authority to review research records. You have the right to decline to participate in this research study based on the Department of Defense source of funding.

You may NOT participate if you are Active Duty Military.

Why is the study being done?

You are being asked to participate in this study because you were enlisted in the military for at least 30 days during the period of the Persian Gulf War between August 1, 1990 and July 31, 1991, and you have developed Gulf War Illness (GWI). There are still many questions about the cause(s) of GWI. This study is being done to determine if the types of changes that may be causing you to have GWI, and to test a new treatment.

Reasons why you may not take part in this study (Exclusion Criteria)

You may not participate in this protocol if any of the following exclusion criteria apply to you:

1. 1.HIV / AIDS subjects will be excluded. This infection alters many of the tests that will be part of this study. Everyone will have an HIV test. If your HIV test is positive, Dr. Baraniuk and the study team will contact you immediately. You will be immediately referred to your local primary care physician, infectious disease or other medical facility for follow-up and to start treatment.
   

2. 2.Pregnant women will be excluded because of hormone effects and the fatigue that is common in pregnancy. Every woman will have a pregnancy test.
   

3. 3.Active duty military personnel
   

4. 4.Children will be excluded because they are not old enough to have participated in the Persian Gulf War.
   

5. 5.Incarcerated people (in jail) will be excluded because it is not fair to include them in this research study.
   

6. 6.Cognitive impairment (problems thinking; brain fog) can make it difficult to understand this informed consent form, the questionnaires, and how to perform other parts of this study. If you have problems like this, then you cannot be in this study. However, we recognize that problems concentrating, selecting the right word, and other issues are part of GWI. You will have an interview with Dr. Baraniuk who will decide if you can join the study or not. You will be able to take part if you have GWI but do not have another cause for a problem with thinking such as mental retardation, severe head injury, stroke, proven multiple sclerosis, melancholic suicidal major depression, schizophrenia, dementia, or other serious neurological cause. A Mini-Mental Status Examination will be administered. A cut-off score of ≥ 24 must be achieved to be part of this study.
   

7. 7.Neurological and Psychiatric Illnesses. Candidates with mental retardation, severe head injury, stroke, proven multiple sclerosis, melancholic suicidal major depression, schizophrenia, dementia, or other very serious neurological illness will be excluded.
   

8. 8.Brain Injury. Candidates will be excluded if they have had a severe head injury, intracranial bleeding, unconscious for more than 1 day (e.g. in a coma), seizure disorder, multiple sclerosis, dementia as in Alzheimer disease, the tremor and movement problems of Parkinson’s disease, or other nerve disorder.
   

9. 9.Metal Implants. All subjects with metal in their body will be excluded. This includes metal implants, prostheses, wires (e.g. CABG sternotomy closures), dental braces, plates, or screws in bones.
   

10. 10.Claustrophobia. All candidates with claustrophobia will be excluded. All candidates will tour the fMRI scanner during their Screening Visit. They may discover that they are claustrophobic in the narrow gantry, become anxious or agitated in this small space, or develop phonophobia from the noise. Candidates will be quizzed about these responses on their tour and those will positive responses will be excluded.
    

11. 11.Low Back Pain. Low back pain and other ailments that make it unable to remain still in the fMRI will be taken into consideration for exclusion.
    

12. 12.Heart, lung, kidney, arthritis, autoimmune, cancer, and other chronic illnesses. Major, chronic, severe illnesses will lead to exclusion. These will be illnesses where the underlying pathophysiology, medical or other treatment, and symptomatology will interfere with identification and assessment of GWI symptoms, or that may cause alterations in fMRI studies. Illnesses that may spontaneously flare during the treatment interval (e.g. Crohn’s disease, ischemic bowel disease, autoimmune, neoplastic, high blood pressure, angina, heart attack, stroke, or other illnesses), or that may require acute modifications in drug dosing, surgery or other disruptions in usual medical treatment will lead to exclusion. Subjects may participate if they have well controlled diabetes or thyroid disease. Dr. Baraniuk will make the decision of whether these illnesses are under appropriate control.
    

13. 13.Abnormal laboratory and questionnaire results. Everyone will complete questionnaires, have blood work and other tests. We have set limits for these studies of blood, kidney, liver, blood pressure, heart, psychological status, and other measures that will allow you to be recruited into the study (inclusion criteria). If your results are outside these limits (exclusion criteria), then Dr. Baraniuk will exclude you from the study. He and his study staff will help arrange for you to see your personal physician or another doctor to investigate abnormal test results.
    

14. 14.Refusal to have CNDP1 and other gene testing. Everyone who participates in this study will have a test of their CNDP1 gene. This is a genetic test of a very short piece of your body’s genetic material. We will determine if you have the usual short version or one of the long versions of this gene. This result will be important because we will test to see if people with the long version have different test results compared to those with the short version. Cheek swabs are used to obtain the genetic material. Samples will also be obtained so that other similar genetic tests can be done. These results will also be used to separate GWI from healthy control subjects to see if these gene changes are found more often in GWI than healthy veterans. We will also be testing other unique changes in genes that we think may be related to GWI. If there are differences in GWI compared to Healthy Veterans, then we may have new insights into what is going wrong in GWI, and possibly new ways to treat the illness. These tests will be confidential, so you will not know the results. There is not enough information from these tests to identify you based on this genetic testing. There is more information below about protections for you.
    

15. 15.Problems Drawing Blood. Some people have very small veins that make it difficult to maintain intravenous lines for fluid replacement, or for drawing blood for tests. If you have small veins, or if it is difficult for nurses and doctors to draw your blood, then you should tell Dr. Baraniuk and his staff. It may be better to save your veins rather than have multiple needle sticks during this voluntary study.
    

16. 16.English Language. The study will be conducted exclusively in English. Inability to read, comprehend, answer questionnaires, follow written and verbal instructions, or communicate with the study staff will lead to exclusion from the study.
    

The purpose of this study:

1. a.Determine if taking carnosine, an over-the-counter dietary supplement and common body chemical, has any benefits compared to a placebo treatment (no carnosine) in GWI.
   

2. b.Determine if carnosine is safe for GWI subjects to take.
   

3. c.Study the variations in symptoms and blood test results in the group of GWI subjects who are taking a placebo. This will help to use see if there are different subtypes of GWI subjects. This is very important since some treatments may be more effective in one subtype than another.
   

4. d.Compare functional magnetic resonance imaging (fMRI) results between the start of the study and the end (3 months) to determine if the carnosine had any benefits in the brain. You will have to lie flat in the narrow, noisy machine. This will be tested while you are resting, and while you taking 2 thinking problem solving tests, and by your brain responses to pressure on your thumb nail.
   

The magnet in the fMRI is very strong. You cannot take part if you have claustrophobia, cannot stand loud noises, or have any metal in your body. The magnet can pull on the metal in your body such as shrapnel, wires used in chest surgery, plates, pins and screws in bones. It can cause them to heat up to a painful level. The magnet will pull hair clips and pins out at 40 miles per hour. This is dangerous to you.

This clinical research project involves two different types of studies:

Observational Study:

To learn about the natural changes in the severity of GWI over time. The group of subjects taking the placebo study drug will provide important information about how different symptoms change over time.

Phase I Study:

1. 1.Test the safety of carnosine to see what good and bad effects occur of GWI volunteers.
   

2. 2.Determine if there are any significant differences in any of the tests after six months of treatment with carnosine compared to the placebo. If everyone taking carnosine shows improvements, then this drug may be useful for treating everyone with GWI.
   

3. 3.We predict that some volunteers who take the carnosine will benefit more than others. This may be determined by the results of the genetic tests. If the genetic test results predict a difference in the benefits of carnosine, then this will provide an important clue for understanding what causes GWI.
   

4. 4.Determine the benefits of carnosine, since this may provide clues into the causes of GWI.
   

5. 5.Determine if the fMRI can identify improvements in your brain and ability to perform different types of tests that may be caused by carnosine compared to placebo.
   

6. 6.Determine if carnosine has any bad side effects in GWI subjects.
   

Please advise the researchers of any medications you are taking. In addition, if you are taking any over-the-counter drugs or herbal supplements which you have obtained from the drug store, grocery store, etc., you should advise the researchers.

Why is this clinical research study design being used?

You are being asked to participate in this study because you were enlisted in the military for at least 30 days during the Persian Gulf War of August 1, 1990 to July 31, 1991, and you have developed GWI.

This is the second of two studies. You must have completed the first study CNDP1 in GWI in order to qualify for this treatment study, Carnosine in GWI.

This study will last just over three (3) months.

You will be randomized into one of the two study groups. Randomization means that you are put into a group by chance. It is like flipping a coin. The choice of which group you are placed in is done by a computer. You will receive either carnosine or a capsule that does not contain carnosine (placebo controlled study). Neither you nor Dr. Baraniuk and his study team will know which study drug you have been assigned to receive (double blind study).

It is essential that some volunteers take carnosine and others do not. We will measure the differences in test results between the carnosine and placebo treated groups. This comparison is important in order to determine if the carnosine has any beneficial effects at all, or has harmful effects in GWI subjects.

This research is being done because there is still a lot of confusion about the causes and long term effects experienced by veterans of the Persian Gulf War of 1990 to 1991. Most of the research studies have focused on differences in responses to questionnaires. We are taking a different approach by studying differences in genes, proteins and other tests. Some of these tests may be useful in the future for the diagnosis of GWI, assessing the severity of the condition, or choosing the best type of treatment(s).

fMRI (brain scans). You will be in the fMRI machine for about 1 hour at the start and at the end of the study. We will scan you brain to see if there are changes in the structure of the brain in GWI, and if any of these changes can become normal after taking carnosine. You will take memory tests and other thinking processes that may also improve after carnosine. There will be test of your tolerance to pain. This test involves applying different pressures to your thumb nail, and asking you how much pain you feel. Another test will measure the levels of carnosine-like chemicals in your brain that may play a vital role in preventing nerve damage. These chemicals are regulated by CNDP1, one of the genes we are measuring in everyone. It is possible that some people respond better than others depending on which version of the CNDP1 and possibly other genes they carry.

Long and Short Versions of the CNDP1 Gene. This carnosine treatment study is the direct result of our earlier GWI study. CNDP1 was found in the fluid around the brain of GWI subjects but was not detected in a healthy control group. We identified one specific, potential genetic difference in the gene for the protein CNDP1. This was testing in the CNDP1 in GWI study (IRB #2008-012). We propose that this genetic difference may be a risk factor for developing GWI. CNDP1 destroys an important antioxidant that your body makes. The antioxidant is called carnosine. It helps protect your brain, nerves and muscles from damage. There is a common short form of the gene for CNDP1, and a less common long version. The long version leads to rapid destruction of carnosine compared to the slower destruction with the short form of the CNDP1 gene. We think that GWI subjects will have more people with the long form of CNDP1 than the healthy veteran group. We will determine which version of the CNDP1 gene you possess in the CNDP1 in GWI study. In this study, we will look for differences in the treatment effects that may be related to the long or short version your CNDP1 gene. In addition, we will do other genetic tests to see if they are also associated with GWI.

We will also test for several sex hormone – related genes, and two that are related to high blood pressure, strokes, and problems with blood clotting. The alternative versions of these genes may be related to GWI.

Carnosine Treatment of GWI. We will compare the effects of carnosine and placebo in GWI subjects to see if carnosine treatment leads to any significant improvements in symptoms. It is possible that all of the carnosine subjects may improve, since a similar study in children with autism showed benefits compared to placebo. It is also possible that subjects with the long form of CNDP1 may benefit more than the rest of the GWI group. However, it is also possible that carnosine will have no benefits or may even be harmful in GWI. We must test this possibility.

Carnosine.

Carnosine protects your brain, muscles, and other tissues. Carnosine is broken down by CNDP1.  We propose that higher CNDP1 levels lead to tissue damage in GWI. Carnosine supplements may help prevent and reverse the damage.

Long-Term Changes.

It may take six months to see any benefits or harm of carnosine. Therefore it is critical that some people receive the placebo. The symptoms in the placebo treatment group will be critical for the success of this study. GWI subjects on placebo treatment will have the usual variations in symptom severity during the six month period. The benefits of carnosine can be seen only by comparison to the placebo group. Distinct subsets of GWI may be identified who need other types of treatments.

Genetic Study.

During each visit, we will scrape the insides of your cheeks and collect the white blood cells from your blood. We will do test on your genetic material (DNA) to find out which version of each of the different genes you have. We are also interested in genes are turned on or off in these cells. Differences between the start and finish of the study, and between the carnosine and placebo treated groups, will help us determine if carnosine was beneficial. The differences may also help identify potential causes of GWI.