There are 25 clinical trials

Clinical Trials

1 Hemochromatosis and Iron Overload Screening Study (HEIRS)

To determine the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of iron overload and hereditary hemochromatosis, in a multi-center, multiethnic, primary care-based sample of 100,000 adults. The study is conducted by the Division of Epidemiology and Clinical Applications of the NHLBI, the Division of Blood Diseases and Resources of the NHLBI, and the Ethical, Legal, and Social Implications (ELSI) Research Program of the NHGRI.

NCT00005541 Blood Disease Hemochromatosis Iron Overload

MeSH:Hematologic Diseases Hemochromatosis Iron Overload

HPO:Abnormality of blood and blood-forming tissues

Evidence suggests that early diagnosis and treatment can prevent disease manifestations and enable normal life expectancy The discovery of the HFE C282Y and H63D variants in the HLA gene region on chromosome 6 provides an opportunity for early and rapid genetic identification of individuals at risk for development of hereditary hemochromatosis. --- C282Y --- --- H63D ---

In order to obtain data on the prevalence of genetic factors in a routine care population, a random subgroup of approximately 20-40 percent of the 101,000 screenees will be genotyped for known variants, such as HFE C282Y and H63D, related to iron metabolism and overload. --- C282Y --- --- H63D ---

2 Studies of Phlebotomy Therapy in Hereditary Hemochromatosis

This study will evaluate the effectiveness of a test called MCV in guiding phlebotomy (blood drawing) therapy in patients with hemochromatosis an inherited disorder that causes too much iron to be absorbed by the intestine. The excess damages body tissues, most severely in the liver, heart, pancreas and joints. Because iron is carried in the hemoglobin of red blood cells, removing blood can effectively lower the body s iron stores. Patients with hemochromatosis undergo weekly phlebotomy treatments (1 pint per session) to deplete iron stores. This usually requires 10 to 50 treatments, after which blood is drawn every 8 to 12 weeks to prevent a re-build up of iron. A test that measures ferritin a protein involved in storing iron is commonly used to guide phlebotomy therapy in hemochromatosis patients. This study will compare the usefulness of the ferritin test with that of MCV, which measures red blood cell size, in guiding phlebotomy therapy. In addition, the study will 1) examine whether keeping iron levels low during maintenance therapy can help heal severe liver disease and improve arthritis in affected patients, and 2) design a system for making blood collected from hemochromatosis donors available for transfusion into other patients. Patients 15 years and older with diagnosed hemochromatosis or very high iron levels suggesting possible hemochromatosis may be eligible for this study. Candidates will have a history, physical evaluation, review of medical records and blood tests, and complete a symptoms questionnaire. Participants will have the following procedures: - Phlebotomy therapy every 1 to 2 weeks, depending on iron levels - Blood sample collection for blood cell counts and iron studies at every phlebotomy session - Blood sample collection (about 2 tablespoons) every 1 to 2 weeks after iron stores have been depleted - Phlebotomy every 8 to 12 weeks after iron stores are used up to prevent re-build up of excess iron With each blood donation that will be made available for transfusion to other patients, participants will answer the same health history screening questions and undergo the same blood tests given to all regular volunteer blood donors. These include screening for the HIV and hepatitis viruses and for syphilis. Patients who meet height and weight requirements may be asked to consider "double red cell" donations using apheresis. In this procedure, whole blood is collected through a needle placed in an arm vein, similar to routine phlebotomy. The blood then circulates through a machine that separates it into its components. The red cells are removed and the rest of the blood is returned to the body, either through the same needle or through a second needle in the other arm. Patients who have very high iron levels or an enlarged liver will be offered evaluation by the NIH Liver Service. Those judged to be at increased risk for cirrhosis may be advised to undergo a liver biopsy. If cirrhosis is found, the patient will be asked to consider a repeat biopsy after 3 to 5 years of continuous iron depletion to see if scarring has improved. Patients with arthritis will be offered evaluation by the NIH Arthritis Service and, depending on symptoms, may be advised to have X-ray studies or a joint biopsy.

NCT00007150 Hemochromatosis Procedure: Phlebotomy

MeSH:Hemochromatosis

- INCLUSION CRITERIA: Confirmed diagnosis of HH, defined by the following HFE genotypes: C282Y/C282 or C282Y/H63D. --- C282Y --- --- H63D ---

3 Treatment of Nonalcoholic Steatohepatitis With Pioglitazone

This study will evaluate the effectiveness of pioglitazone, a new diabetes medicine, on decreasing insulin resistance and improving liver disease in patients with nonalcoholic steatohepatitis (NASH). NASH is a chronic liver disease with unknown cause that involves fat accumulation and inflammation in the liver, leading to liver cirrhosis in 10 to 15 percent of patients and significant liver scarring in another 30 percent. Although similar to a condition that affects people who drink excessive amounts of alcohol, NASH occurs in people who drink only minimal or no alcohol. It is most often seen in patients with insulin resistance. Pioglitazone decreases insulin resistance and improves blood lipid (fat) levels, so that it may improve liver disease in NASH. Patients with NASH 18 years of age or older may be eligible for this study. Candidates will be screened with a medical history and physical examination and routine blood tests. They will see a dietitian for counseling on diet and weight reduction, if needed. They will stop taking any medications for liver disease and take a daily multivitamin pill. After 2 months, those eligible for participation will be enrolled in the study. Participants will be admitted to the Clinical Center for 2 to 3 days for a complete medical history, physical examination, blood tests, urinalysis, chest X-ray, electrocardiogram, abdominal ultrasound and a liver biopsy. After the diagnosis of NASH is confirmed, the following procedures will be performed: - Echocardiography - imaging test using sound waves shows the heart structure and function - Resting metabolic rate - measures amount of oxygen (and calories) used to maintain body functions at rest. While lying down, the patient wears a clear plastic hood over the head for 20 minutes while the amount of oxygen used is measured. - Magnetic resonance imaging (MRI) scans - shows the size of the liver and other organs. The patient lies on a table in a metal cylinder that contains a magnetic field (the scanner) for no more than 30 minutes while the organs are imaged. - Dual energy X-ray absorptiometry (DEXA) scan measures whole body composition, including amount of fat. The patient lies under an X-ray scanning machine for about 2 minutes. - Oral glucose tolerance test (OGTT) - measures blood sugar and insulin levels. The patient drinks a very sweet drink containing glucose (sugar), after which blood samples are collected at various intervals during the 3-hour test. The blood is drawn through a catheter (thin plastic tube) placed in the arm before the test begins. - Intravenous glucose tolerance test (IVGTT) - determines how the tissues respond to insulin and glucose. Glucose is injected into a vein, followed by a short infusion of insulin. Blood samples are collected through a catheter at various intervals during the 3-hour test. When the above procedures are completed, patients start taking pioglitazone by mouth once a day for 48 weeks, keeping track of the medication and any side effects. They will be seen at the clinic every 2 weeks for the first month and then every 4 weeks for the rest of the treatment period. The visits will include an interview and examination by a physician and blood draw for laboratory tests. Female patients will have a pregnancy test at each clinic visit. At the end of the treatment period patients will be admitted to the Clinical Center for a repeat medical evaluation that will include the procedures described above.

NCT00013598 Fatty Liver Nonalcoholic Steatohepatitis Drug: Pioglitazone

MeSH:Fatty Liver Non-alcoholic Fatty Liver Disease

HPO:Hepatic steatosis

Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D. --- C282Y --- --- H63D ---

4 Long-Term Treatment of Nonalcoholic Steatohepatitis With Pioglitazone

Nonalcoholic steatohepatitis (NASH) is a common liver disease that resembles alcoholic hepatitis but occurs in persons who drink little or no alcohol. The etiology of NASH is unclear, but it is commonly associated with diabetes, obesity, and insulin resistance. Several pilot studies, including a study of pioglitazone at the NIH Clinical Center (01-DK-0130), have shown that the insulin-sensitizing thiazolidinediones lead to decreases in serum alanine aminotransferase (ALT) levels and improved liver histology. Once therapy is stopped, however, ALT levels rapidly return to pre-treatment values. Inaddition we are currently enrolling patients with NASH in a pilot study of metformin therapy for 48-weeks, however our results in 3 patients thus far have not been very encouraging. In the current study, patients who have completed the pilot study of pioglitazone and have been off therapy for 48 weeks will be offered re-treatment for 3 years. We also propose to treat patients who have not had a satisfactory response to metformin with pioglitazone for the same duration. After a repeat medical and metabolic evaluation and liver biopsy, patients with moderate-to-severe NASH (activity score greater than or equal to 4) will restart pioglitazone at a dose of 15 mg daily. If after 48 weeks, ALT levels are not normal or improved to the degree identified during the pilot study, the dose will be increased to 30 mg daily at the end of 3 years, all patients will undergo repeat medical and metabolic evaluation and liver biopsy. The primary end point will be improvement in liver histology. Secondary end points will be improvements in insulin sensitivity, reduction in visceral fat, liver volume, and liver biochemistry. The aim of this study is to evaluate whether long-term pioglitazone therapy can safely achieve and maintain biochemical and histological improvements in NASH. ...

NCT00062764 Hepatitis Drug: Actos (Pioglitazone)

MeSH:Hepatitis Fatty Liver Non-alcoholic Fatty Liver Disease

HPO:Hepatic steatosis Hepatitis

Hemochromatosis as defined by presence of 3+ or 4 iron on liver biopsy stain and homozygosity for C282Y or compound heterozygosity for C282Y/H63D. --- C282Y --- --- H63D ---

5 Treatment of Nonalcoholic Steatohepatitis With Metformin

Nonalcoholic Steatohepatitis (NASH) is associated with progressive liver disease, fibrosis, and cirrhosis. Although the cause of NASH is unknown, it is often associated with obesity, type 2 diabetes, and insulin resistance. At present, there are no approved treatments for NASH patients, but an experimental approach has focused on improving their insulin sensitivity. Metformin is one of the most commonly used medications for the treatment of diabetes. The purpose of this study is to determine whether the medical problems of NASH patients, specifically liver damage, improves when their insulin sensitivity is enhanced with metformin. The study will last 3 to 5 years and will enroll up to 30 patients. Participants will undergo a complete medical examination, a series of lab tests, and a liver biopsy. They will then start taking a single 500-mg tablet of metformin once a day for 2 weeks, then the same dosage twice a day for 2 more weeks, if they tolerate the first dosage. The dosage will increase to 1,000 mg twice a day for the remaining 44 weeks of the study. After 1 year, participants will undergo a repeat medical examination and liver biopsy.

NCT00063232 Hepatitis Drug: Metformin

MeSH:Hepatitis Fatty Liver Non-alcoholic Fatty Liver Disease

HPO:Hepatic steatosis Hepatitis

7. Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D. --- C282Y --- --- H63D ---

6 Characterization of Cardiac Function in Subjects With Hereditary Hemochromatosis Who Are New York Heart Association Functional Class I

This study will examine the effect of iron buildup in the hearts of patients with hereditary hemochromatosis (HH), a genetic disease that causes the body to accumulate excess amounts of iron. The excess iron can damage the heart, liver, pancreas, skin, and joints. Generally, early treatment with phlebotomy (periodic removal of a unit of blood), and in some cases chelation (using a drug to remove iron from the body) slows down organ damage in HH patients. This study will try to elucidate the effect of iron buildup in the heart and determine if phlebotomy and chelation help keep the heart healthy. Patients with HH and healthy volunteers 21 years of age and older may be eligible for this study. (Normal volunteers will provide normal values of heart function that will be used to verify abnormalities detected in HH patients.) Patients must have a gene abnormality of Hfe gene Cys282Try homozygote. They may or may not be receiving treatment for HH and they must have no heart symptoms or serious organ damage due to HH. Candidates will be screened with a medical history and physical examination, blood tests, electrocardiogram (EKG), Holter EKG (24-hour EKG monitoring, see description below), and chest x-ray. Participants will undergo the following tests and procedures over 2 to 5 days: - Exercise test: The participant exercises on a treadmill while wearing a mouthpiece, which is used to measure how much oxygen is used. Electrodes placed on the chest and arms monitor the heartbeat during the test. - Echocardiography: This ultrasound test uses sound waves to take pictures. A small probe is held against the chest to allow a technician to take pictures of the heart and assess its function. A drug called Optison may be injected in an arm vein if needed to enhance the ultrasound images. - Exercise stress echocardiography: The participant exercises on a stationary bike while heart function is measured with an echocardiogram, EKG, and blood pressure cuff. - 24-hour Holter EKG: The participant wears a small machine that records heart rhythm continuously for 24 hours. The recorder is connected by cables to electrodes placed on the chest. - Magnetic resonance imaging: This test uses a magnetic field and radio waves to obtain detailed images of the heart and blood vessels. The participant lies flat on a table that slides inside the scanner, which is a large hollow tube. All tests are performed once in normal volunteers and in patients who have received standard treatment for HH. Untreated patients repeat the tests 6 months after beginning phlebotomy or chelation. Additional time points for these tests might be added if further evaluation is needed.

NCT00068159 Hereditary Hemochromatosis

MeSH:Hemochromatosis

No symptoms suggestive of heart disease or any other medical conditions, negative Hfe genotyping for Cys282Tyr or His63Asp with normal ferritin and iron saturation. --- Cys282Tyr --- --- His63Asp ---

7 A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Twice-Weekly Peginterferon Alpha 2a and Ribavirin Induction Therapy for Chronic Hepatitis C in Patients Who Are Coinfected With HIV-1

This study will evaluate the safety and effectiveness of combination therapy with peginterferon alpha-2a and ribavirin for treating hepatitis C virus (HCV) infection in HIV-infected patients. Peginterferon alpha with ribavirin is the therapy of choice for people with HCV alone. Peginterferon alpha-2a is a compound that results from attaching a polyethylene glycol molecule to interferon alpha-2a. This compound stays in the blood longer than unmodified interferon alpha-2a, causing a higher blood concentration and thus maintaining greater activity against the hepatitis C virus. HIV-infected patients 18 years of age and older with chronic hepatitis C infection and a viral load greater than 2000 copies/mL may be eligible for this 2-1/2 year study. Candidates are screened with a medical history and physical examination, blood and urine tests, eye examination, chest x-ray, electrocardiogram (EKG), liver ultrasound, and pregnancy test in women who are able to become pregnant. If a recent liver biopsy is not available, this test is done to determine the type and severity of liver disease. The patient is given a sedative before the procedure. Then, the skin in the area over the biopsy site is numbed with a local anesthetic and a needle is inserted rapidly into and out of the liver to obtain a small tissue sample. The patient remains in the hospital overnight for monitoring. Participants begin treatment with injections under the skin of peginterferon alpha-2a and ribavirin pills by mouth on study day 0. Peginterferon is given either once or twice a week for 4 weeks and then once a week for 44 weeks. Ribavirin is given daily. In addition, patients continue to take all other medications prescribed by their doctor. Clinic visits are scheduled for the following procedures: - Days 1, 3, 4, 7, 10 and weeks 2, 3, and 4 - Blood tests for safety measures and to measure blood levels of HIV and HCV. - Weeks 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 - Blood and urine tests to determine the side effects of treatment and its effect on the HCV infection. In addition, eye examinations are done every 3 months, and pregnancy and thyroid function tests are done several times during the treatment period. - Week 48 or end of treatment - Treatment stops after 48 weeks. At this time, or earlier for those who do not complete the 48 weeks, patients return to the clinic for a chest x-ray, EKG, blood tests, and abdominal ultrasound. Patients are hospitalized for a repeat liver biopsy. - Weeks 52, 56, 64 and 72 - Blood and urine tests to determine the side effects of treatment and its effect on the HCV infection, and a urine pregnancy test in women.

NCT00085917 Hepatitis C HIV Infections Drug: Double dose pegylated interferon with weight based Ribavirin Drug: standard dose pegylated interferon alfa -2a and ribavirin

MeSH:Hepatitis A Hepatitis C Hepatitis

HPO:Hepatitis

- Hemochromatosis or secondary iron overload as defined by (1) an elevated serum ferritin or an iron saturation (serum iron/IBC X 100%) of greater than 50% and (2) presence of 3+ or more stainable Iron on liver biopsy according to the study pathologist or a history of previous phlebotomy for Iron overload will undergo HFE genetic counseling and those with a positive HFE genetic test demonstrating homozygosity for C282Y and H63D are not eligible. --- C282Y --- --- H63D ---

Those who have compound heterozygosity to C282Y and H63D are also not eligible. --- C282Y --- --- H63D ---

8 S-Adenosyl Methionine for Symptomatic Treatment of Primary Biliary Cirrhosis

This study will examine the effect of S-adenosyl methionine (SAMe) on itching and fatigue in patients with primary biliary cirrhosis, a disease of the small bile ducts in the liver. Ursodiol, the only currently available treatment for biliary cirrhosis, does not cure the disease, and many people continue to have symptoms or liver test abnormalities despite treatment. SAMe is a naturally occurring substance found in most cells of the body. The highest levels of the substance are produced by the liver, where it helps to rid the body of toxins and breakdown products of metabolism. Studies in Europe suggest that SAMe may help to: 1) decrease the fatigue and itching that are common in persons with liver problems, and 2) decrease levels of liver enzymes in the blood, suggesting that it may decrease the amount of liver injury. Patients 21 years of age or older with primary biliary cirrhosis who are taking ursodiol and have symptoms of itching or fatigue may be eligible for this study. Candidates are screened with a medical history, physical examination, review of medical records, routine blood tests, and a symptoms rating scale. Participants stop all medications for itching 4 weeks before starting the study, but continue to take ursodiol during the 42-week trial. On entering the study, patients are assigned to take either SAMe or placebo tablets twice a day for 12 weeks. While taking the medications, they are followed in the clinic every 2 weeks for the first month and then every 4 weeks to fill out symptoms questionnaires and have a short medical evaluation and blood tests. At the end of 12 weeks, treatment is interrupted for a 2-week "wash-out" period, after which patients begin a 12-week crossover treatment; that is, patients who were taking SAMe are switched to placebo, and those who were taking placebo are switched to SAMe. After completing the second 12-week treatment course, patients come to the clinic at 4, 8, and 12 weeks to fill out symptoms questionnaires and have a medical evaluation and blood tests. At the last visit, patients are told which type of tablet they received during the two courses of treatment. SAMe is available without prescription in many forms as an over-the-counter medication.

NCT00125281 Liver Cirrhosis, Biliary Drug: S-adenosyl-methionine (SAMe) capsules

MeSH:Liver Cirrhosis Liver Cirrhosis, Biliary Fibrosis

HPO:Biliary cirrhosis Cirrhosis Hepatic fibrosis

Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D. --- C282Y --- --- H63D ---

Patients with iron saturation indices of greater than 45% and serum ferritin levels of greater than 300 ng/ml for men and greater than or equal to 250 ng/ml for women will undergo genetic testing for C282Y and H63D. --- C282Y --- --- H63D ---

9 Iron Depletion Therapy for Patients With Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease

The purpose of this study is to find out whether lowering the amount of iron in the body will result in less resistance to insulin and improved liver function in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease. This may result in better diabetes control and/or a decrease in the amount of liver fat.

NCT00230087 Non-Alcoholic Fatty Liver Disease Diabetes Mellitus Procedure: blood donation

MeSH:Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease Diabetes Mellitus

HPO:Abnormality of the liver Decreased liver function Diabetes mellitus Elevated hepatic transaminase Hepatic steatosis

- Hemoglobin HbA1c level ≤ 8 % - Serum ALT levels ≥1.3 x ULN - Between 18-65 years of age Exclusion Criteria - Hereditary hemochromatosis or hepatic iron overload defined as any of the following: - 2+ iron on hepatic iron staining - Hepatic Iron Index ≥ 1.9 - C282Y homozygous or C282Y/H63D compound heterozygous HFE genotype - Use of insulin or thiazolidinediones for the treatment of diabetes - Use of anti-NASH drugs (thiazolidinediones, vitamin E, UDCA, SAM-e, betaine, milk thistle, gemfibrozil, anti-TNF therapies, probiotics) - Serum ferritin <50μg/L - Serum transferrin-iron saturation <10 % - Hemoglobin <10 mg/L - Hematocrit <38 % - Voluntary blood donation or therapeutic phlebotomy within the previous twelve months (except routine lab tests) - Pregnant or lactating women - Prior history of coronary artery disease, myocardial infarction, exertional dyspnea or chronic chest pain at rest. - Evidence of myocardial infarction as determined by an ECG Inclusion Criteria - Histological evidence of NAFLD and enrollment in NASH CRN Database Study - Type 2 DM treated with diet or a stable dose of non-insulin sensitizing oral hypoglycemic agents for > 3 mo. --- C282Y --- --- H63D ---

- Hemoglobin HbA1c level ≤ 8 % - Serum ALT levels ≥1.3 x ULN - Between 18-65 years of age Exclusion Criteria - Hereditary hemochromatosis or hepatic iron overload defined as any of the following: - 2+ iron on hepatic iron staining - Hepatic Iron Index ≥ 1.9 - C282Y homozygous or C282Y/H63D compound heterozygous HFE genotype - Use of insulin or thiazolidinediones for the treatment of diabetes - Use of anti-NASH drugs (thiazolidinediones, vitamin E, UDCA, SAM-e, betaine, milk thistle, gemfibrozil, anti-TNF therapies, probiotics) - Serum ferritin <50μg/L - Serum transferrin-iron saturation <10 % - Hemoglobin <10 mg/L - Hematocrit <38 % - Voluntary blood donation or therapeutic phlebotomy within the previous twelve months (except routine lab tests) - Pregnant or lactating women - Prior history of coronary artery disease, myocardial infarction, exertional dyspnea or chronic chest pain at rest. - Evidence of myocardial infarction as determined by an ECG Non-Alcoholic Fatty Liver Disease Diabetes Mellitus Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease Diabetes Mellitus Nonalcoholic fatty liver disease (NAFLD) is a common liver disease in the United States. --- C282Y --- --- H63D ---

10 Effects of S-Adenosyl Methionine (SAMe) on Viral and Cell Signaling Response to Combination Therapy for Chronic Hepatitis C

This study will examine the effectiveness of S-adenosyl methionine (SAMe) in combination with peginterferon and ribavirin for treating hepatitis C virus. One out of three patients with hepatitis C develops cirrhosis of the liver, which can lead to liver failure or liver cancer. SAMe is a nutritional supplement that is made naturally in all cells of the body and acts to improve how the body handles stress. In laboratory experiments with liver cells, SAMe decreases the injury caused by liver toxins and improves the ability of interferon to block hepatitis C virus. Patients 18 years of age and older with hepatitis C infection who did not respond successfully to prior treatment with interferon and ribavirin or peginterferon and ribavirin may be eligible for this study. Participants receive the following treatment: - Peginterferon (given by injection) and ribavirin (taken by mouth) for 2 weeks - Washout period (no medications) for 4 weeks - SAMe (taken by mouth) for 2 weeks - Peginterferon, ribavirin and SAMe for 12-48 weeks, depending on patient response to treatment. Participants have a thorough physical evaluation before beginning treatment and again at the study's end. After starting treatment, patients return for clinic visits and blood tests weekly for the first several weeks, then less frequently (at 2-week, then 4-week and 8-week intervals until up to 72 weeks) to monitor symptoms, drug side effects, hepatitis C virus levels, liver enzyme levels and immune responses to hepatitis C. ...

NCT00475176 Chronic Hepatitis C Drug: Peginterferon alfa-2a Drug: Ribavirin Drug: S-adenosyl methionine for Chronic Liver Disease

MeSH:Hepatitis A Hepatitis C Hepatitis C, Chronic Hepatitis Hepatitis, Chronic

HPO:Chronic active hepatitis Chronic hepatitis Hepatitis

- Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D. --- C282Y --- --- H63D ---

Patients with iron saturation indices of greater than 45% and serum ferritin levels of greater than 300 ng/ml for men and greater than 250 ng/ml for women will undergo genetic testing for C282Y and H63D. --- C282Y --- --- H63D ---

11 An Open Label Non-Randomized Trial to Assess Safety and Tolerability of Alb-Interferon Alfa 2b Every Two Weeks With Ribavirin Among HIV/HCV Coinfected Individuals

This study will determine if Albumin-linked interferon (Albinterferon alfa-2b) every 2 weeks is safe and tolerated by patients infected by both hepatitis C virus (HCV) and human immunodeficiency virus (HIV). This is a new medication developed for HCV. It may help the immune system fight infections, especially those caused by viruses. Albinterferon alfa-2b appears quite similar to other interferons, in side effects and action in controlling HCV. Patients ages 18 and older who are infected with HCV genotype 1, are HIV positive, are infected with HCV, and have evidence of HCV-induced liver disease; and who are not pregnant or breast feeding may be eligible for this study. Many visits to NIH over a 76-week period are required. There will be collection of blood and urine, pregnancy test, and tests of HCV in the blood. A liver biopsy is required before start of the study if patients have not had one within 1 year. Another is done at the end of 72 weeks. An eye exam is done before start of the study and repeated later. An optional procedure called automated pheresis is done at the study beginning. Researchers can study patients' immunity to control HCV. Blood is drawn through a needle in an arm vein and spun in a machine to separate the desired blood component. Remaining blood is returned to the patient. Patients will receive Albinterferon alfa-2b at a dose of 900 mcg every 2 weeks for 48 weeks, by injection under the skin. Ribavirin is given at 1,000 mg or 1,200 mg by mouth twice daily, depending on a patient's weight. Side effects of Albinterferon alfa-2b are fatigue, headache, joint and muscle pain, and sleeplessness. The major side effect of ribavirin is anemia. Visits ranging from week 3 to 44 will determine the safety of Albinterferon alfa-2b and ribavirin and to see effects on reducing the HCV viral load. For weeks 48, 52, 56, 64, 72, and 76, patients will return for a clinic visit and blood tests. At week 72, an abdominal ultrasound and liver biopsy are done. Week 76 includes discussion of biopsy results.

NCT00489385 HIV Infections HCV Drug: Albinterferon Drug: Ribavirin Drug: Albuferon

MeSH:HIV Infections

Those subjects with, or a history of previous phlebotomy for iron overload will undergo HFE genetic counseling and those with a positive HFE genetic test demonstrating homozygosity for C282Y and H63D are not eligible. --- C282Y --- --- H63D ---

Those who have compound heterozygosity to C282Y and H63D are also not eligible. --- C282Y --- --- H63D ---

12 Therapeutic Effect of Erythrocyte Apheresis as Compared to Full Blood Phlebotomy in Patients With Hereditary Hemochromatosis

Primary hemochromatosis is the most frequent hereditary condition in Scandinavia. The condition may result in serious organ damage which can be prevented by therapy, but only few patients develop such organ damage. The optimal treatment, therefore, is still a matter of discussion Prevention of organ damage has traditionally been accomplished by drawing of full blood (phlebotomy), which has to be frequently repeated during the initial phase and then continued indefinitely as a maintenance treatment. The removed amount of iron may be increased two- or threefold for each procedure by using modern equipment for selective removal of red blood cells (red cell apheresis). Possible drawbacks of this technique may be higher costs, prolonged time for each therapeutic procedure, and certain requirements to the patients. The possible advantages are the reduced number of therapeutic procedures and less strain for the patient. No larger, randomized study has been published in order to determine which method should be preferred. This study is a controlled trial in which participating patients are asked to be randomized to red cell apheresis or traditional phlebotomy. Each group will be followed by means of well-defined assessments in order to explore possible advantages and disadvantages of each method in order to establish what type of treatment should be recommended.

NCT00509652 Hemochromatosis Procedure: Arm 1: Erythrocyte apheresis Procedure: Arm 2: Whole blood phlebotomy

MeSH:Hemochromatosis

Inclusion Criteria: 1. Diagnosis - Individuals who art homozygous for C282Y or H63D or "compound heterozygous" for these tow variants and have ferritin levels higher than 300 micrograms/L or transferrin saturation higher than 50%. --- C282Y --- --- H63D ---

- Individuals heterozygous for C282Y or H63D if ferritin levels higher than 500 micrograms/L or transferrin saturation higher than 50%. --- C282Y --- --- H63D ---

Exclusion Criteria: 1. Contra-indications to either treatment modality 2. Patients who are not able to co-operate 3. Lack of informed consent Inclusion Criteria: 1. Diagnosis - Individuals who art homozygous for C282Y or H63D or "compound heterozygous" for these tow variants and have ferritin levels higher than 300 micrograms/L or transferrin saturation higher than 50%. --- C282Y --- --- H63D ---

Inclusion criteria 1. Diagnosis 1. Individuals who art homozygous for C282Y or H63D or "compound heterozygous" for these tow variants and have ferritin levels higher than 300 micrograms/L or transferrin saturation higher than 50%. --- C282Y --- --- H63D ---

2. Individuals heterozygous for C282Y or H63D if ferritin levels higher than 500 micrograms/L or transferrin saturation higher than 50%. --- C282Y --- --- H63D ---

13 Effect of Iron Depletion by Phlebotomy Plus Lifestyle Changes vs. Lifestyle Changes Alone on Liver Damage in Patients With Nonalcoholic Fatty Liver Disease With Increased Iron Stores

Patients will be randomized to lifestyle changes alone or lifestyle changes associated with iron depletion. Iron depletion will be achieved by removing 350 cc of blood every 10-15 days according to baseline hemoglobin values and venesection tolerance, until ferritin < 30 ng/ml and transferrin saturation < 25%. Weekly phlebotomies will be allowed for carriers of the C282Y HFE mutation. Smaller phlebotomies (250 cc) will be allowed for carriers of beta-thalassaemia trait. Maintenance phlebotomies (as much as required) will then be instituted to keep iron stores depleted (ferritin < 50 ng/ml and transferrin saturation < 25%, MCV <85 fl). Before starting treatment, patients will undergo ECG, and in the presence of hyperglycemia or hypertension also echocardiography (see exclusion criteria). Change in diabetes medication dosage or start of new therapy will be allowed for HbA1C values <6% or ≥ 7%. According to accepted criteria, previously untreated patients should be treated with metformin. If possible, newly diagnosed hypertension should be treated with Ace-inhibitors.

NCT00658164 Nonalcoholic Fatty Liver Disease Other: Iron depletion treatment

MeSH:Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease

HPO:Abnormality of the liver Decreased liver function Elevated hepatic transaminase Hepatic steatosis

*Hemochromatosis, as defined by homozygosity for the C282Y HFE mutation or compound heterozygosity for C282Y/H63D mutations or Hepatic Iron Index ≥ 1.9. --- C282Y --- --- H63D ---

14 A Phase III, Randomized Study of the Effects of Parenteral Iron, Oral Iron, or No Iron Supplementation on the Erythropoietic Response to Darbepoetin Alfa for Cancer Patients With Chemotherapy-Associated Anemia

RATIONALE: Darbepoetin alfa may cause the body to make more red blood cells. Red blood cells contain iron that is needed to carry oxygen to the tissues. It is not yet known whether giving darbepoetin alfa (DA) together with intravenous iron or oral iron is more effective than giving darbepoetin alfa together with a placebo in treating anemia caused by chemotherapy. PURPOSE: This randomized phase III trial is studying giving darbepoetin alfa together with iron to see how well it works compared with giving darbepoetin alfa together with a placebo in treating anemia caused by chemotherapy in patients with cancer.

NCT00661999 Anemia Leukemia Lymphoma Lymphoproliferative Disorder Multiple Myeloma and Plasma Cell Neoplasm Precancerous Condition Unspecified Adult Solid Tumor, Protocol Specific Biological: darbepoetin alfa Dietary Supplement: ferrous sulfate Drug: sodium ferric gluconate complex in sucrose Other: placebo

MeSH:Lymphoma Leukemia Multiple Myeloma Neoplasms, Plasma Cell Precancerous Conditions Anemia Lymphoproliferative Disorders

HPO:Anemia Leukemia Lymphoma Lymphoproliferative disorder Multiple myeloma

DISEASE CHARACTERISTICS: - Diagnosis of a non-myeloid cancer (other than non-melanomatous skin cancer) - Receiving or scheduled to receive chemotherapy (biological agents, such as small molecules/tyrosine kinase inhibitors and antibody-based therapies, are allowed) - Has chemotherapy-related anemia (hemoglobin < 11 g/dL) - No anemia known to be secondary to gastrointestinal bleeding or hemolysis - No anemia known to be secondary to vitamin B12 or folic acid deficiency + Vitamin B12 and folic acid deficiency must be ruled out if the mean corpuscular volume (MCV) is > 100 fL - No anemia secondary to chemotherapy-induced myelodysplastic syndromes - No primary hematologic disorder causing moderate to severe anemia (e.g., congenital dyserythropoietic anemia, homozygous hemoglobin S disease or compound heterozygous sickling states, or thalassemia major) - Carriers for these disease states are eligible - No first-degree relative with primary hemochromatosis (unless the patient has undergone HFE genotyping and was found to have at least one wild-type allele, while the proband in the family demonstrated to have either the common C282Y or H63D mutation) PATIENT CHARACTERISTICS: - ECOG performance status 0-2 - Ferritin > 20 mcg/L (i.e., not obviously iron deficient) - ALT or AST < 5 times upper limit of normal - Alert, mentally competent, and able to sign informed consent - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 3 months after completion of study treatment - Willing or able to be randomized and undergo study treatment - Willing or able to fill out quality-of-life forms - No uncontrolled hypertension (i.e., systolic blood pressure [BP] ≥ 180 mm Hg or diastolic BP ≥ 100 mm Hg) - No history of uncontrolled cardiac arrhythmias - No pulmonary embolism or deep venous thrombosis within the past year (unless the patient is on anticoagulation therapy and planning to continue it during study participation) - No known hypersensitivity to darbepoetin alfa, erythropoietin, mammalian cell-derived products, iron, or human albumin - No seizures within the past 3 months - No gastrointestinal conditions expected to cause significant impairment of oral iron, such as untreated celiac disease or amyloidosis involving the gut - Patients with celiac disease who are adhering to a gluten-free diet are eligible PRIOR CONCURRENT THERAPY: - See Disease Characteristics - More than 3 months since prior darbepoetin alfa, epoetin alfa, or any investigational forms of erythropoietin (e.g., gene-activated erythropoietin or novel erythropoiesis-stimulating protein) - More than 1 year since prior peripheral blood stem cell or bone marrow transplantation - More than 2 weeks since prior red blood cell transfusions - More than 14 days since prior major surgery - No prior gastrectomy or resection of > 100 cm of small intestine - Not planning to undergo stem cell or bone marrow transplantation within the next 6 months DISEASE CHARACTERISTICS: - Diagnosis of a non-myeloid cancer (other than non-melanomatous skin cancer) - Receiving or scheduled to receive chemotherapy (biological agents, such as small molecules/tyrosine kinase inhibitors and antibody-based therapies, are allowed) - Has chemotherapy-related anemia (hemoglobin < 11 g/dL) - No anemia known to be secondary to gastrointestinal bleeding or hemolysis - No anemia known to be secondary to vitamin B12 or folic acid deficiency + Vitamin B12 and folic acid deficiency must be ruled out if the mean corpuscular volume (MCV) is > 100 fL - No anemia secondary to chemotherapy-induced myelodysplastic syndromes - No primary hematologic disorder causing moderate to severe anemia (e.g., congenital dyserythropoietic anemia, homozygous hemoglobin S disease or compound heterozygous sickling states, or thalassemia major) - Carriers for these disease states are eligible - No first-degree relative with primary hemochromatosis (unless the patient has undergone HFE genotyping and was found to have at least one wild-type allele, while the proband in the family demonstrated to have either the common C282Y or H63D mutation) PATIENT CHARACTERISTICS: - ECOG performance status 0-2 - Ferritin > 20 mcg/L (i.e., not obviously iron deficient) - ALT or AST < 5 times upper limit of normal - Alert, mentally competent, and able to sign informed consent - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 3 months after completion of study treatment - Willing or able to be randomized and undergo study treatment - Willing or able to fill out quality-of-life forms - No uncontrolled hypertension (i.e., systolic blood pressure [BP] ≥ 180 mm Hg or diastolic BP ≥ 100 mm Hg) - No history of uncontrolled cardiac arrhythmias - No pulmonary embolism or deep venous thrombosis within the past year (unless the patient is on anticoagulation therapy and planning to continue it during study participation) - No known hypersensitivity to darbepoetin alfa, erythropoietin, mammalian cell-derived products, iron, or human albumin - No seizures within the past 3 months - No gastrointestinal conditions expected to cause significant impairment of oral iron, such as untreated celiac disease or amyloidosis involving the gut - Patients with celiac disease who are adhering to a gluten-free diet are eligible PRIOR CONCURRENT THERAPY: - See Disease Characteristics - More than 3 months since prior darbepoetin alfa, epoetin alfa, or any investigational forms of erythropoietin (e.g., gene-activated erythropoietin or novel erythropoiesis-stimulating protein) - More than 1 year since prior peripheral blood stem cell or bone marrow transplantation - More than 2 weeks since prior red blood cell transfusions - More than 14 days since prior major surgery - No prior gastrectomy or resection of > 100 cm of small intestine - Not planning to undergo stem cell or bone marrow transplantation within the next 6 months Anemia Leukemia Lymphoma Lymphoproliferative Disorder Multiple Myeloma and Plasma Cell Neoplasm Precancerous Condition Unspecified Adult Solid Tumor, Protocol Specific Lymphoma Leukemia Multiple Myeloma Neoplasms, Plasma Cell Precancerous Conditions Anemia Lymphoproliferative Disorders OBJECTIVES: Primary * To compare the effects of IV iron, oral iron, or placebo in combination with darbepoetin alfa on the hematopoietic response rate, defined as a hemoglobin increment of ≥ 2.0 g/dL from baseline or achievement of hemoglobin of ≥ 11 g/dL in the absence of red blood cell transfusions (RBC) in the preceding 28 days of the treatment period, in cancer patients with chemotherapy-associated anemia. --- C282Y --- --- H63D ---

DISEASE CHARACTERISTICS: - Diagnosis of a non-myeloid cancer (other than non-melanomatous skin cancer) - Receiving or scheduled to receive chemotherapy (biological agents, such as small molecules/tyrosine kinase inhibitors and antibody-based therapies, are allowed) - Has chemotherapy-related anemia (hemoglobin < 11 g/dL) - No anemia known to be secondary to gastrointestinal bleeding or hemolysis - No anemia known to be secondary to vitamin B12 or folic acid deficiency + Vitamin B12 and folic acid deficiency must be ruled out if the mean corpuscular volume (MCV) is > 100 fL - No anemia secondary to chemotherapy-induced myelodysplastic syndromes - No primary hematologic disorder causing moderate to severe anemia (e.g., congenital dyserythropoietic anemia, homozygous hemoglobin S disease or compound heterozygous sickling states, or thalassemia major) - Carriers for these disease states are eligible - No first-degree relative with primary hemochromatosis (unless the patient has undergone HFE genotyping and was found to have at least one wild-type allele, while the proband in the family demonstrated to have either the common C282Y or H63D mutation) PATIENT CHARACTERISTICS: - ECOG performance status 0-2 - Ferritin > 20 mcg/L (i.e., not obviously iron deficient) - ALT or AST < 5 times upper limit of normal - Alert, mentally competent, and able to sign informed consent - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 3 months after completion of study treatment - Willing or able to be randomized and undergo study treatment - Willing or able to fill out quality-of-life forms - No uncontrolled hypertension (i.e., systolic blood pressure [BP] ≥ 180 mm Hg or diastolic BP ≥ 100 mm Hg) - No history of uncontrolled cardiac arrhythmias - No pulmonary embolism or deep venous thrombosis within the past year (unless the patient is on anticoagulation therapy and planning to continue it during study participation) - No known hypersensitivity to darbepoetin alfa, erythropoietin, mammalian cell-derived products, iron, or human albumin - No seizures within the past 3 months - No gastrointestinal conditions expected to cause significant impairment of oral iron, such as untreated celiac disease or amyloidosis involving the gut - Patients with celiac disease who are adhering to a gluten-free diet are eligible PRIOR CONCURRENT THERAPY: - See Disease Characteristics - More than 3 months since prior darbepoetin alfa, epoetin alfa, or any investigational forms of erythropoietin (e.g., gene-activated erythropoietin or novel erythropoiesis-stimulating protein) - More than 1 year since prior peripheral blood stem cell or bone marrow transplantation - More than 2 weeks since prior red blood cell transfusions - More than 14 days since prior major surgery - No prior gastrectomy or resection of > 100 cm of small intestine - Not planning to undergo stem cell or bone marrow transplantation within the next 6 months DISEASE CHARACTERISTICS: - Diagnosis of a non-myeloid cancer (other than non-melanomatous skin cancer) - Receiving or scheduled to receive chemotherapy (biological agents, such as small molecules/tyrosine kinase inhibitors and antibody-based therapies, are allowed) - Has chemotherapy-related anemia (hemoglobin < 11 g/dL) - No anemia known to be secondary to gastrointestinal bleeding or hemolysis - No anemia known to be secondary to vitamin B12 or folic acid deficiency + Vitamin B12 and folic acid deficiency must be ruled out if the mean corpuscular volume (MCV) is > 100 fL - No anemia secondary to chemotherapy-induced myelodysplastic syndromes - No primary hematologic disorder causing moderate to severe anemia (e.g., congenital dyserythropoietic anemia, homozygous hemoglobin S disease or compound heterozygous sickling states, or thalassemia major) - Carriers for these disease states are eligible - No first-degree relative with primary hemochromatosis (unless the patient has undergone HFE genotyping and was found to have at least one wild-type allele, while the proband in the family demonstrated to have either the common C282Y or H63D mutation) PATIENT CHARACTERISTICS: - ECOG performance status 0-2 - Ferritin > 20 mcg/L (i.e., not obviously iron deficient) - ALT or AST < 5 times upper limit of normal - Alert, mentally competent, and able to sign informed consent - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 3 months after completion of study treatment - Willing or able to be randomized and undergo study treatment - Willing or able to fill out quality-of-life forms - No uncontrolled hypertension (i.e., systolic blood pressure [BP] ≥ 180 mm Hg or diastolic BP ≥ 100 mm Hg) - No history of uncontrolled cardiac arrhythmias - No pulmonary embolism or deep venous thrombosis within the past year (unless the patient is on anticoagulation therapy and planning to continue it during study participation) - No known hypersensitivity to darbepoetin alfa, erythropoietin, mammalian cell-derived products, iron, or human albumin - No seizures within the past 3 months - No gastrointestinal conditions expected to cause significant impairment of oral iron, such as untreated celiac disease or amyloidosis involving the gut - Patients with celiac disease who are adhering to a gluten-free diet are eligible PRIOR CONCURRENT THERAPY: - See Disease Characteristics - More than 3 months since prior darbepoetin alfa, epoetin alfa, or any investigational forms of erythropoietin (e.g., gene-activated erythropoietin or novel erythropoiesis-stimulating protein) - More than 1 year since prior peripheral blood stem cell or bone marrow transplantation - More than 2 weeks since prior red blood cell transfusions - More than 14 days since prior major surgery - No prior gastrectomy or resection of > 100 cm of small intestine - Not planning to undergo stem cell or bone marrow transplantation within the next 6 months Anemia Leukemia Lymphoma Lymphoproliferative Disorder Multiple Myeloma and Plasma Cell Neoplasm Precancerous Condition Unspecified Adult Solid Tumor, Protocol Specific Lymphoma Leukemia Multiple Myeloma Neoplasms, Plasma Cell Precancerous Conditions Anemia Lymphoproliferative Disorders OBJECTIVES: Primary * To compare the effects of IV iron, oral iron, or placebo in combination with darbepoetin alfa on the hematopoietic response rate, defined as a hemoglobin increment of ≥ 2.0 g/dL from baseline or achievement of hemoglobin of ≥ 11 g/dL in the absence of red blood cell transfusions (RBC) in the preceding 28 days of the treatment period, in cancer patients with chemotherapy-associated anemia. --- C282Y --- --- H63D --- --- C282Y --- --- H63D ---

15 A Phase II Trial of the Safety and Efficacy of Iron Reduction by Phlebotomy in Recipients of Hematopoietic Stem Cell Transplants

Hypothesis: The reduction of total body iron by phlebotomy will be safe and feasible in the post-HSCT setting Iron overload is common after hematopoietic stem cell transplantation. It is associated with chronic liver disease, with increased rates of infection and decreased survival. Eligible, consenting patients will have once monthly phlebotomy procedures (500ml) for 12 months. SAFETY: At each visit, patients will have a comprehensive assessment prior to starting and after completing the phlebotomy. This assessment will include determination of pain at phlebotomy site, local infection and an assessment of symptoms of anemia including presyncope, fatigue and dyspnea. The patient's pulse, blood pressure, respiratory rate and temperature will also be determined before and following the phlebotomy. EFFICACY: Iron stores will be measured serially in each patient. Measurements will be performed prior to the start of phlebotomy, and at 6 months and 12 months following the start of the series of 12 phlebotomies. These evaluations will be undertaken regardless of the number of phlebotomies which the patient actually undergoes. Iron stores will be estimated by measuring serum ferritin and transferrin saturation levels. Total body iron will be estimated from hepatic and cardiac iron concentration as measured by magnetic resonance imaging (MRI). Gandon et al. (12) described a non-invasive technique using MRI to measure hepatic iron stores. Iron is a paramagnetic substance which causes local magnetic field inhomogeneities leading to dephasing and signal loss in MRI. Gradient echo sequences are most susceptible to their effects because they do not use a 180° refocusing pulse, unlike conventional spin-echo sequences. Gandon et al. used multiple gradient echo sequences, compared the signal in liver to adjacent muscle and used this ratio to correlate with hepatic iron levels measured on tissue biopsy samples using spectrophotometric analysis. Multiple sequences were used because the nomogram comparing the L/M signal ratio is linear over only a small concentration of tissue iron.

NCT00689182 Iron Overload Procedure: monthly phlebotomy x 12 months

MeSH:Iron Overload

Serum samples will also be collected at baseline to screen for the most common mutations of the HFE gene (C282Y mutation and H63D mutation) as hereditary hemochromatosis is common in the general population and may contribute to iron overload in HSCT recipients. --- C282Y --- --- H63D ---

16 The Effect of the Dietary Supplement Protandim on Non-Alcoholic Steatohepatitis: A Randomized, Double Blind, Placebo-Controlled Study

The purpose of this study is to evaluate the effect of Protandim on the degree of liver injury after one year of supplementation. Protandim is a nutritional supplement composed of the following 5 botanical extracts: Bacopa Moniera extract, Milk Thistle extract, Ashwagandha powder, Green tea, and Turmeric extract. Protandim is commercially available and can be purchased without a prescription. Our findings could lead to a better understanding of the role of oxidative stress and antioxidant therapy in NASH and may ultimately help improve patient care. Hypothesis #1: Protandim will lead to a significant improvement in NAS compared to placebo. Hypothesis #2: Protandim will lead to a significant decrease in serum markers of oxidative stress and liver chemistry tests. Hypothesis #3: Protandim will lead to decreased levels of TNF- α compared to placebo.

NCT00977730 Non-Alcoholic Steatohepatitis Dietary Supplement: Protandim Dietary Supplement: Placebo

MeSH:Fatty Liver Non-alcoholic Fatty Liver Disease

HPO:Hepatic steatosis

7. Iron overload/hemochromatosis, as defined by the following: elevated transferrin saturation (greater than 45 percent) OR serum ferritin (> 300 microg/L in men or >200 microg/L in women), with one of the following: 1) presence of 3+ or 4+ stainable iron on liver biopsy (if obtained); or 2) Hemochromatosis gene testing showing homozygosity for C282Y or compound heterozygosity for C282Y/H63D (if obtained). --- C282Y --- --- H63D ---

17 Impact of Host Iron Status and Iron Supplement Use on Growth and Viability of the Erythrocytic Stage of Plasmodium Falciparum

The purpose of this study is to perform laboratory based studies to determine if the growth and development of the malaria parasite is effected by iron status of its host (the person infected with the malaria parasite). Iron deficiency affects over 500 million people including many pregnant women and children from areas of the world that are plagued by malaria. Some population based studies have suggested that iron deficiency protects people from getting malaria and this has raised questions about the wisdom of public health policies that provide universal iron supplementation in countries where malaria is common. We will use red blood cells and sera from patients with iron deficiency anemia, hereditary hemochromatosis and normal individuals who are taking iron supplements to look at this question in a very systematic way. This study should provide information for or against a possible mechanism by which iron deficiency may affect the malaria parasite. The results will contribute to efforts to develop evidence-based public health policies on iron supplementation policies in malaria-endemic areas. There are three different types of individuals involved in this study (1) people with iron deficiency anemia who will be taking iron supplementation (2) people without iron deficiency anemia who will be taking iron supplementation and (3) people with a condition called hereditary hemochromatosis who have an excess of iron in their bodies.

NCT01027663 Iron Deficiency Anemia Malaria Dietary Supplement: Iron Supplement

MeSH:Malaria Anemia, Iron-Deficiency

HPO:Iron deficiency anemia

From the genotype standpoint, only patients homozygous for the C282Y and H63D mutations and those that are compound heterozygotes for C282Y/H63D will be enrolled. --- C282Y --- --- H63D ---

From the genotype standpoint, only patients homozygous for the C282Y and H63D mutations and those that are compound heterozygotes for C282Y/H63D will be enrolled. --- C282Y --- --- H63D --- --- H63D ---

18 Effects of Phlebotomy on Insulin Sensitivity in Insulin Resistance-associated Hepatic Iron Overload Patients

The purpose of this study is to evaluate efficacy of phlebotomy on insulin sensitivity as evaluated by euglycemic-hyperinsulinic clamp in insulin resistance-associated hepatic iron overload patients.

NCT01572818 Insulin Resistance Iron Overload Procedure: phlebotomy Behavioral: dietary and lifestyle counseling

MeSH:Insulin Resistance Iron Overload

HPO:Insulin resistance

Inclusion Criteria: - Age between 18 and 70 years - Ferritin between 450 and 1000 µg/L - Hepatic iron overload proved by MRI (CHF >36 µmol/g) - Body mass index > 25 kg/m² - Fasting glycemia <1,26 g/L - HbA1c < 6,5% - Signed written and informed consent Exclusion Criteria: - Other causes of hyperferritinemia: - Inflammatory syndrome (CRP >10 mg/L) or inflammatory, immune or malignant diseases - Hyperferritinemia-cataract syndrome (familial cataract or personal history of cataract before 50 years old) - Low ceruloplasmin level - Porphyria (cutaneous signs) - Haemochromatosis established by the genotype (C282Y homozygous or C282Y/H63D coumpound heterozygous genotypes) - Contraindication of phlebotomy - Haemoglobin <13,5 g/dL (threshold established by the Etablissement Français du Sang) - Heart failure or coronary heart diseases - Hepatic failure, renal (GFR <50mL/min) or respiratory insufficiency (chronic dyspnea) - Poor venous system - Viral, immune, genetic, vascular, malignant or toxic chronic hepatic disease - Alcohol consumption more than 21 doses per week during 5 years or more - Type 1 or type 2 diabetes - Oral anti-diabetic, corticoids or immune suppressor drugs - Hepatic severe disease - Claustrophobia, having a pace-maker or intracerebral clips - Subjects deprived of their liberty by judicial or administrative decision, subjects that are not affiliated to social security or topics exclusion period of a previous study Inclusion Criteria: - Age between 18 and 70 years - Ferritin between 450 and 1000 µg/L - Hepatic iron overload proved by MRI (CHF >36 µmol/g) - Body mass index > 25 kg/m² - Fasting glycemia <1,26 g/L - HbA1c < 6,5% - Signed written and informed consent Exclusion Criteria: - Other causes of hyperferritinemia: - Inflammatory syndrome (CRP >10 mg/L) or inflammatory, immune or malignant diseases - Hyperferritinemia-cataract syndrome (familial cataract or personal history of cataract before 50 years old) - Low ceruloplasmin level - Porphyria (cutaneous signs) - Haemochromatosis established by the genotype (C282Y homozygous or C282Y/H63D coumpound heterozygous genotypes) - Contraindication of phlebotomy - Haemoglobin <13,5 g/dL (threshold established by the Etablissement Français du Sang) - Heart failure or coronary heart diseases - Hepatic failure, renal (GFR <50mL/min) or respiratory insufficiency (chronic dyspnea) - Poor venous system - Viral, immune, genetic, vascular, malignant or toxic chronic hepatic disease - Alcohol consumption more than 21 doses per week during 5 years or more - Type 1 or type 2 diabetes - Oral anti-diabetic, corticoids or immune suppressor drugs - Hepatic severe disease - Claustrophobia, having a pace-maker or intracerebral clips - Subjects deprived of their liberty by judicial or administrative decision, subjects that are not affiliated to social security or topics exclusion period of a previous study Insulin Resistance Iron Overload Insulin Resistance Iron Overload The main objective of this study is to evaluate in patients with HSD effects of treatment with phlebotomy rules with lifestyle and dietary rules versus lifestyle modifications alone on peripheral insulin resistance (assessed by hyperinsulinemic clamp). --- C282Y --- --- H63D ---

Inclusion Criteria: - Age between 18 and 70 years - Ferritin between 450 and 1000 µg/L - Hepatic iron overload proved by MRI (CHF >36 µmol/g) - Body mass index > 25 kg/m² - Fasting glycemia <1,26 g/L - HbA1c < 6,5% - Signed written and informed consent Exclusion Criteria: - Other causes of hyperferritinemia: - Inflammatory syndrome (CRP >10 mg/L) or inflammatory, immune or malignant diseases - Hyperferritinemia-cataract syndrome (familial cataract or personal history of cataract before 50 years old) - Low ceruloplasmin level - Porphyria (cutaneous signs) - Haemochromatosis established by the genotype (C282Y homozygous or C282Y/H63D coumpound heterozygous genotypes) - Contraindication of phlebotomy - Haemoglobin <13,5 g/dL (threshold established by the Etablissement Français du Sang) - Heart failure or coronary heart diseases - Hepatic failure, renal (GFR <50mL/min) or respiratory insufficiency (chronic dyspnea) - Poor venous system - Viral, immune, genetic, vascular, malignant or toxic chronic hepatic disease - Alcohol consumption more than 21 doses per week during 5 years or more - Type 1 or type 2 diabetes - Oral anti-diabetic, corticoids or immune suppressor drugs - Hepatic severe disease - Claustrophobia, having a pace-maker or intracerebral clips - Subjects deprived of their liberty by judicial or administrative decision, subjects that are not affiliated to social security or topics exclusion period of a previous study Inclusion Criteria: - Age between 18 and 70 years - Ferritin between 450 and 1000 µg/L - Hepatic iron overload proved by MRI (CHF >36 µmol/g) - Body mass index > 25 kg/m² - Fasting glycemia <1,26 g/L - HbA1c < 6,5% - Signed written and informed consent Exclusion Criteria: - Other causes of hyperferritinemia: - Inflammatory syndrome (CRP >10 mg/L) or inflammatory, immune or malignant diseases - Hyperferritinemia-cataract syndrome (familial cataract or personal history of cataract before 50 years old) - Low ceruloplasmin level - Porphyria (cutaneous signs) - Haemochromatosis established by the genotype (C282Y homozygous or C282Y/H63D coumpound heterozygous genotypes) - Contraindication of phlebotomy - Haemoglobin <13,5 g/dL (threshold established by the Etablissement Français du Sang) - Heart failure or coronary heart diseases - Hepatic failure, renal (GFR <50mL/min) or respiratory insufficiency (chronic dyspnea) - Poor venous system - Viral, immune, genetic, vascular, malignant or toxic chronic hepatic disease - Alcohol consumption more than 21 doses per week during 5 years or more - Type 1 or type 2 diabetes - Oral anti-diabetic, corticoids or immune suppressor drugs - Hepatic severe disease - Claustrophobia, having a pace-maker or intracerebral clips - Subjects deprived of their liberty by judicial or administrative decision, subjects that are not affiliated to social security or topics exclusion period of a previous study Insulin Resistance Iron Overload Insulin Resistance Iron Overload The main objective of this study is to evaluate in patients with HSD effects of treatment with phlebotomy rules with lifestyle and dietary rules versus lifestyle modifications alone on peripheral insulin resistance (assessed by hyperinsulinemic clamp). --- C282Y --- --- H63D --- --- C282Y --- --- H63D ---

19 Ezetimibe Versus Placebo in the Treatment of Non-alcoholic Steatohepatitis

The purpose of the study is to see if the drug ezetimibe is a potential treatment for Nonalcoholic Steatohepatitis(NASH).

NCT01766713 Non Alcoholic Steatohepatitis Drug: Ezetimibe

MeSH:Fatty Liver Non-alcoholic Fatty Liver Disease

HPO:Hepatic steatosis

7. Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D. --- C282Y --- --- H63D ---

20 Deferasirox Versus Venesection in Patients With Hemochromatosis and for Treatment of Transfusional Siderosis in Myelodysplastic Syndrome: Diagnostics and New Biomarkers.

Hypothesis: Deferasirox can be used as a therapeutic agent to deplete the liver, heart and bone marrow of excess iron in patients with iron overload caused by myelodysplastic syndrome (MDS) and hemochromatosis (HC. Assess the effect of new serum biomarkers (NTBI and hepcidin) and MRI as indicators of iron overload and their usefulness to monitor iron depletion treatment. Study the effect of iron overload and iron depletion on intracellular signal transduction, trace metals concentrations in serum and urine and markers of oxidative stress in blood cells and urine.

NCT01892644 Hemochromatosis Myelodysplastic Syndromes Drug: Deferasirox Other: Venesection Drug: Deferasirox

MeSH:Preleukemia Myelodyspla Myelodysplastic Syndromes Hemochromatosis Iron Overload Syndrome

HPO:Myelodysplasia

The most common are the classic C282Y and H63D point mutations of the hemochromatosis protein HFE, which disturbs its interaction with the transferrin receptor 1, the first step in the hepcidin signal cascade. --- C282Y --- --- H63D ---

21 Sitagliptin Versus Placebo in the Treatment of Non-alcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), the progressive form of liver disease that can lead to cirrhosis and liver-related mortality in persons who drink little or no alcohol. NAFLD is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis. NASH is benign in many affected individuals but can cause progressive liver injury and, indeed, may be the major cause of cryptogenic cirrhosis1. Currently, there is no FDA approved treatment for NAFLD. Weight loss and exercise are the recommended but often difficult maintain these lifestyle changes in the long term and therefore therapeutic agents have been investigated. In this study, we propose to treat 50 patients with NAFLD and diabetes with either sitagliptin or placebo for 24 weeks. After an initial evaluation for insulin sensitivity and MRI liver fat distribution, patients will receive either 100 mg/day of sitagliptin or placebo. Patients will be monitored at regular intervals for symptoms of liver disease, side effects of sitagliptin and serum biochemical and metabolic indices. At the end of 24-weeks, patients will have a repeat medical evaluation, liver MRI and an optional liver biopsy. Pre and post treatment MRI-derived liver fat content and insulin sensitivity will be compared. The primary end point of successful therapy will be improvement in hepatic steatosis measured by MRI. Secondary end points will be improvement in insulin sensitivity and liver biochemistry.

NCT01963845 Non-alcoholic Fatty Liver Disease Drug: Sitagliptin Drug: Placebo

MeSH:Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease

HPO:Abnormality of the liver Decreased liver function Elevated hepatic transaminase Hepatic steatosis

- Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D. --- C282Y --- --- H63D ---

22 Aramchol Versus Placebo in the Treatment of HIV-associated Nonalcoholic Fatty Liver Disease and Lipodystrophy: A Randomized, Double-blinded, Allocation-concealed, Placebo-controlled Clinical Trial

A subset of patients with NAFLD that have not been extensively studied are those infected with human immunodeficiency virus (HIV). Currently, there is no FDA approved treatment for NAFLD or NASH. Additionally, there have been no significant clinical trials for HIV patients with NAFLD and there are no approved treatment options. We plan to conduct a randomized, double-blinded, placebo-controlled clinical trial to examine the efficacy of 600 mg of Aramchol daily (including 200 mg tablet and 400 mg tablet) versus identical placebo given over 12 weeks to improve HIV-associated hepatic steatosis as measured by a validated and accurate magnetic resonance imaging (MRI)-based technique.

NCT02684591 Nonalcoholic Fatty Liver Disease HIV Drug: Aramchol Drug: Placebo

MeSH:Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease Lipodystrophy

HPO:Abnormality of the liver Decreased liver function Elevated hepatic transaminase Hepatic steatosis Lipodystrophy

Evidence of another form of liver disease: Hepatitis B as defined as presence of hepatitis B surface antigen (HBsAg), Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA in serum, Autoimmune hepatitis as defined by anti-nuclear antibody (ANA) of 1:160 or greater and liver histology consistent with autoimmune hepatitis or previous response to immunosuppressive therapy, Autoimmune cholestatic liver disorders as defined by elevation of alkaline phosphatase and anti-mitochondrial antibody of greater than 1:80 or liver histology consistent with rimary biliary cirrhosis or elevation of alkaline phosphatase and liver histology consistent with sclerosing cholangitis, Wilsons disease as defined by ceruloplasmin below the limits of normal and liver histology consistent with Wilsons disease Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than normal and liver histology consistent with alpha-1-antitrypsin deficiency hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D, Drug-induced liver disease as defined on the basis of typical exposure and history,Bile duct obstruction as shown by imaging studies. --- C282Y --- --- H63D ---

23 Iron Supplement Effect Over Immune System and Neurobehavioral Child Development.

Objective: To evaluate the effect of Iron supplement with two different amounts (one in the higher limit and another in the lower limit of the suggested amount) according to the presence of mutations in the HFE gene in the physical, immune and neurobehavioral development in the 6 to 12 moth toddlers. Methodology: Subjects: 340 toddlers coming from Paediatric Serves of Sant Joan Hospital. Methods: At 6 and 12 months it done clinical history, food registry, biochemist determinations: haemoglobin, iron, transferrin, ferritin, reactive C protein and immune response (IL4, IL10, IL6 IFN, IgA, IgM, IgG, IgE). Mutations in the HFE gene: C282Y, H63D, S65D and hepcidin gene. Mental, psychomotor and behavioual development (Bayley Scales of Infant Development 2on Edition: 1993). We evaluate the level of language and communication (MacArthur), regulation and sensory process (Infant Toddler Symptom Checklist), familiar and environment surroundings (Scale Health General Parental Stress Index).

NCT02690675 Neurodevelopmental Disorders Lactation Dietary Supplement: Iron fortified formula milk

MeSH:Neurodevelopmental Disorders

Mutations in the HFE gene: C282Y, H63D, S65D and hepcidin gene. --- C282Y --- --- H63D ---

24 Effectiveness of Adaptation of the Dose of Iron Supplementation in Pregnancy on Maternal-child Health. Randomized Clinical Trial (ECLIPSES)

Currently, there is no consensus regarding iron supplementation dose that is most beneficial for maternal and offspring health during gestation. This deficit, or excess, of iron prejudices the mother-child wellbeing. Therefore the hypotheses are that an iron supplementation adapted to values of hemoglobin at the start of the pregnancy will would be more effective in preventing iron deficiency, without increasing the risk of hemoconcentration by the end of pregnancy. This would be helped optimize mother-child health status. The aims of the study are to determine the highest level of effectiveness of iron supplementation adapted to hemoglobin (Hb) levels in early pregnancy, which would be optimum for mother-child health. To accomplish this objective a Randomized Clinical Trial (RCT) triple-blinded was designed. The study is structured as a RCT with 2 strata, depending on the Hb levels before week 12 of gestation. Stratum 1: If Hb from 110 to 130 g/L, randomly assigned at week 12 to receive iron supplement of 40 or 80 mg/d. Stratum 2: If Hb >130 g/L, randomly assigned at week 12 to receive iron supplement of 40 or 20 mg/d. This study will be conducted in non-anemic pregnant women at early gestation stage, and their subsequent newborns. The data recollected to mothers will be: socio-economic data, clinical history, food item frequency, lifestyle and emotional state, and adherence to iron supplement prescription. In addition, biochemical measured will be Hemoglobin, serum ferritin, C reactive protein, cortisol, and alterations in the HFE gene (C282Y, H63D). In children, the data collected will be: ultrasound fetal biometry, anthropometric measurements, and temperament development Should conclusive outcomes be reached, the study would indicate the optimal iron supplementation dose required to promote maternal and infant health. These results would contribute towards developing guidelines for good clinical practice.

NCT03196882 Anemia Ferropenic Risk of Hemoconcentration (Iron Levels Risk of Hemoconcentration (Iron Levels > Risk of Hemoconcentration (Iron Levels >130g/L) Drug: 40mg/day of iron Drug: 20mg/day of iron Drug: 80mg/day of iron

MeSH:Anemia Anemia, Iron-Deficiency

HPO:Anemia Iron deficiency anemia

In addition, biochemical measured will be Hemoglobin, serum ferritin, C reactive protein, cortisol, and alterations in the HFE gene (C282Y, H63D). --- C282Y --- --- H63D ---

Presence or absence of polymorphisms: C282Y and H63D. --- C282Y --- --- H63D ---

Units on a scale (score).. H63D polymorphisms of HFE gene. --- H63D ---

25 Non Alcoholic Fatty Liver Disease and Coronary Heart Disease in Type 2 Diabetes Patients

To assess the feasibility in diabetics in a primary care setting of screening for NAFLD and advanced fibrosis, by using non-invasive magnetic resonance imaging (MRI) to estimate the hepatic proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE) to estimate hepatic stiffness.

NCT04462081 Nonalcoholic Steatohepatitis

MeSH:Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease Heart Diseases Coronary Disease Coronary Artery Disease Myocardial Ischemia

HPO:Abnormality of the liver Coronary artery atherosclerosis Decreased liver function Elevated hepatic transaminase Hepatic steatosis Myocardial infarction

- Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D. --- C282Y --- --- H63D ---

HPO Nodes