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Protocol Details

The Hep C Antiviral Long-Term Tx Against Cirrhosis (HALT-C) Trial: A Randomized Controlled Trial to Evaluate the Safety & Efficacy of Long-Term Peginterferon Alpha2A for Tx of Chronic Hep C in Patients Who Failed to Respond to Previous Interferon Therapy

This study is NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

00-dk-0186

Sponsoring Institute

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Recruitment Detail

Type: Completed Study; data analyses ongoing
Gender: Male & Female
Min Age: 18
Max Age: N/A

Referral Letter Required

No

Population Exclusion(s)

Children

Special Instructions

Currently Not Provided

Keywords

Prevention;
Hepatocellular Carcinoma;
Complications;
Natural History;
Fibrosis

Recruitment Keyword(s)

Hepatitis C

Condition(s)

Hepatitis C;
Liver Cirrhosis

Investigational Drug(s)

Pegylated Interferon alfa2a and ribavirin

Investigational Device(s)

None

Intervention(s)

Drug: Pegylated Interferon alfa2a and ribavirin

Supporting Site

National Institute of Diabetes and Digestive and Kidney Diseases

This study will test whether long-term antiviral therapy with interferon can prevent liver disease from progressing in patients with chronic hepatitis C infection a long-lasting viral infection affecting the liver. About 1,200 patients in 10 centers across the United States will be enrolled in this study to determine the best treatment for patients with advanced scarring of the liver who do not respond to short-term interferon therapy. These patients are at the greatest risk of going developing liver cirrhosis, liver failure or liver cancer.

Patient 18 years of age or older with hepatitis C and advanced scarring who have not responded to previous interferon treatment, either with or without ribavirin, may be eligible for this study. Candidates will be screened with a medical history and physical examination, questionnaires on drug and alcohol use, mood and quality of life, blood tests, liver ultrasound and, if needed, a liver biopsy (removal of a small sample of liver tissue for microscopic evaluation).

All patients enrolled in the study will receive interferon injections under the skin once a week and ribavirin by mouth twice a day for 24 weeks. At periodically scheduled clinic visits, patients will fill out a questionnaire about symptoms and have blood tests and vital signs taken. They will have a physical exam and gastrointestinal and liver exam every 12 weeks and will complete questionnaires on general health and mood at weeks 12 and 20. After 24 weeks, patients will be examined for evidence of virus in their blood and will be divided into responders (no virus detected in the blood) and non-responders (virus is detected in the blood).

Responders will continue the same treatment for another 24 weeks. At the end of treatment, they will be followed periodically for another 24 weeks with undergo physical examinations, gastrointestinal and liver exams, and blood collection to assess disease progress and side effects of treatment. A small portion of blood will be stored for future testing to identify factors that affect the progress of liver disease and development of liver cancer. This may include genetic testing.

Non-responders will be randomly divided into two groups for the next phase of the study long-term maintenance therapy that will continue for an additional 3 1/2 years. One group will receive interferon alone; the other will receive no treatment. Every 3 months during treatment and 6 months after maintenance the maintenance phase ends, patients will undergo the following procedures:

1. Physical examination and gastrointestinal and liver exam (every visit).

2. Blood sample collection to monitor disease progress and treatment side effects (every visit). A small portion of blood will be stored for future testing to identify factors that affect the progress of liver disease and development of liver cancer. These may include genetic testing.

3. Questionnaires about general health and daily activities (every 6 months).

4. Ultrasound examinations of the liver (yearly).

5. Liver biopsy (2 years and 4 years after the start of the first phase of the study).

6. Endoscopy (between week 22 and week 26 and at 4 years). This test uses a thin flexible tube with a light at the tip to examine the esophagus (food pipe) for abnormal veins called varices, which can rupture and bleed. If varices are found, another examination will be done at 24 months.

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Eligibility

INCLUSION CRITERIA:

Age at entry at least 18 years.

HCV-RNA positive or serology positive for HCV antibody by a second generation or higher assay.

Lead-in patients must have had previous treatment with any interferon preparation (standard or pegylated interferon), utilized either alone or in combination with ribavirin, administered at a minimum dose of 3 mU three times weekly or its equivalent, for at least 12 weeks. No interferon, ribavirin, or amantadine treatment in the 2 months prior to screen visit # 1.

Lead-in patients: Documented non-response to the most recent adequate course of interferon therapy, as defined above. Non-response will be defined as follows:

a. A positive test for HCV RNA after at least treatment week 12 of adequate interferon therapy while still being treated, or within one week of discontinuing the most recent adequate course of interferon;

b. If virologic measurements were not performed or are unavailable from the most recent adequate treatment, serum ALT must have been elevated within 6 months of onset and at anytime during 4 weeks prior to or 1 week after stopping this prior adequate course of interferon therapy;

c. If elevated serum ALT's or positive HCV-RNA laboratory test are not available, a clinic note documenting non-response will suffice.

A positive test for HCV RNA, by the Core Virology Laboratory, at the time of screening to enter the study.

Lead-in patients must satisfy the following biopsy criteria:

a. Patients selected to enter the HALT-C Lead-In Phase, must have had a liver biopsy performed at least 2 months following the last course of interferon and within 12 months prior to the baseline visit, demonstrating at least Ishak stage 3 fibrosis as judged by the clinical center pathologist;

b. Patients with a history of Ishak stage 3 or higher fibrosis, who subsequently have fibrosis scored as Ishak 2 can also be enrolled. Both biopsies must be read by the local HALT-C pathologist using the Ishak fibrosis scoring system. The most recent Ishak fibrosis score will be used for determination of the study outcome.

Express patients: Documented adequate pegylated interferon and ribavirin for at least 24 weeks may be substituted for the Lead-in Phase of the study provided the following criteria are met:

A. Adequate drug dosing is defined as follows:

1) Intent to treat with

a. peginterferon alfa-2a 180 mcg/wk or peginterferon alfa-2b 1.5 mcg/kg/wk

AND

b. 800 mg daily of ribavirin (minimum);

2). Dose adjustment is dependent on patient s tolerance to the drug(s) and is at the discretion of the treating physician.

B. A positive HCV-RNA obtained at least 20 weeks after the start of the adequate course of treatment with pegylated interferon with ribavirin and before Screening for HALT-C. This test may be obtained either on or off treatment.

C. A pre-treatment liver biopsy which is available and has been performed within 18 months of randomization or a liver biopsy which is performed at least 8 weeks after the end of treatment and no more than 24 weeks prior to randomization. Slides from the biopsy must demonstrate at least Ishak stage 3 fibrosis as judged by the clinical center pathologist and then must be read centrally before randomization.

D. Patients with a history of Ishak stage 3 or higher fibrosis, who subsequently have fibrosis scored as Ishak 2 can also be enrolled as Express patients. Both biopsies must be read by the local HALT-C pathologist using the Ishak fibrosis scoring system. The most recent Ishak fibrosis score will be used for determination of the study outcome.

A willingness by all women of child bearing potential to utilize adequate contraception during the Main Trial study. Use of adequate contraception is not mandated during the extension trial since no medication is being offered.

A willingness by all men to utilize adequate contraception during the time they are treated with interferon-ribavirin combination therapy and for 6 months thereafter.

EXCLUSION CRITERIA:

Liver histology which, in the opinion of the study pathologist, is consistent with: Any other co-existent cause of chronic liver disease defined as follows:

Hepatitis B surface antigen (HBsAg) positive within the past 12 months.

Autoimmune hepatitis as defined by the following criteria:

1. A titer for anti-nuclear antibody of 1:160 or greater;

And either 2 or 3:

2. Liver histology, in the opinion of the study pathologist, consistent with auto-immune hepatitis; and/or

3. Previous response to immunosuppressive therapy.

Autoimmune cholestatic liver disorders as defined by the presence of all of the following criteria:

1. A persistent elevation in serum alkaline phosphatase.

2. A titer for anti-nuclear or anti-mitochondrial antibodies of greater than 1:160 or 1:40 respectively;

3. Liver histology, in the opinion of the study pathologist, that is consistent with either primary biliary cirrhosis or sclerosing cholangitis.

Wilson's disease are as defined by both of the following criteria:

1. A value for ceruloplasmin below the limits of normal.

2. Liver histology which, in the opinion of the study pathologist, is consistent with Wilson s disease.

Alpha-1-antitrypsin deficiency as defined by both of the following criteria:

1. A serum value for alpha-1 antitrypsin less than normal;

2. Liver histology which, in the opinion of the study pathologist, is consistent with alpha-1-antitrypsin deficiency.

Hemochromatosis or secondary iron overload as defined by 1 and 2 below:

1. An elevated value for serum ferritin or an iron saturation (serum iron/IBC x 100%) of greater than 50% and

2. Presence of 3+ or 4+ stainable iron on liver biopsy according to the study pathologist or a history of previous phlebotomy for iron overload.

All patients meeting the above criteria must undergo HFE genetic counseling. Patients with an HFE genetic test demonstrating homozygosity for C282Y or compound heterozygosity, i.e. C282Y +/- and H63D -/+ are not eligible.

Patients who do not have the HFE genotypes just described may be entered into the study after first undergoing phlebotomy therapy to remove hepatic iron and then undergoing repeat liver biopsy demonstrating less than 3+ hepatic iron.

Any patients who have had HFE genetic test demonstrating homozygosity for C282Y or compound heterozygosity, i.e. C282Y +/- and H63D-/+ are not eligible.

Steatophepatitis (alcohol or non-alcoholic), defined as severe histologic changes to include all of the following 3 criteria:

1. Steatosis (marked);

2. Mallory bodies (many);

3. Zone 3 pericellular fibrosis (extensive).

Drug-induced liver disease.

A Child-Turcotte-Pugh score of greater than or equal to 7 points or any history of ascites, or any history of hepatic encephalopathy, or current evidence of ascites.

Any documented history of bleeding from either esophageal or gastric varices.

A platelet count of less than 50,000/mm(3). Pre-treatment or screening platelet count values may be used by the Express Group for eligibility requirements.

A neutrophil count of less than 1,000/mm(3). Pre-treatment or screening platelet count values may be used by the Express Group for eligibility requirements.

A hematocrit of less than 33% or hemoglobin less than 11 gm/dL. Pre-treatment or screening platelet count values may be used by the Express Group for eligibility requirements.

An alpha-fetoprotein of greater than 200 ng/mL for Lead-in patients, and an AFP of greater than 1000 for Express patients.

Evidence of a hepatic mass lesion by either ultrasound, CT or MR scan that is suspicious for hepatocellular carcinoma.

Renal insufficiency defined by a serum creatine greater than 1.5 mg/dL.

A positive test for HIV confirmed by Western blot obtained within the past 12 months.

Diabetes that, in the opinion of the investigator, is not controlled by diet, an oral hypoglycemic agent, and/or insulin.

Patients with hemophilia.

Patients who have received an organ, limb or bone marrow transplant.

Patients who require the use of certain chronic medications such as immunosuppressive medications (corticosteroids, methotrexate, azathioprine) or coumadin should be off medications for six months or longer before being screened.

Patients with active systemic autoimmune disorders such as rheumatoid arthritis, systemic lupus, etc.

Patients who have had a malignancy diagnosed and/or treated within the past 5 years, except for localized squamous or basal cell cancers treated by local excision, and those who have been adequately treated and have an excellent chance of cancer-free survival, in the opinion of the oncologist.

Patients with serious cardiac, cerebrovascular or pulmonary disease that, in the opinion of the investigator would preclude treatment with interferon and/or ribavirin.

Patients with underlying hematologic abnormalities that, in the opinion of the investigator, would preclude treatment with interferon.

Patients with a history of seizure disorder that has not been well-controlled by anti-seizure medications within the past 2 years.

Women who are pregnant or breast feeding.

Male partners of women who are pregnant or breast feeding.

Patients with active alcohol abuse within the past 12 months.

Patients who have used illicit drugs (e.g., heroin, cocaine, angel dust, etc.) within the past 2 years.

Patients with a history of any one of the following:

1. Suicide attempt or hospitalization for depression within the past 5 years.

2. Any current (within 6 months) severe or poorly-controlled psychiatric disorder (e.g., depression, schizophrenia, bipolar illness, obsessive-compulsive disorder, severe anxiety, personality disorder).

3. The following patients must be assessed and followed (if recommended) by a psychiatrist or other mental health professional:

a. Patients who have had a suicide attempt and/or hospitalization for depression more than 5 years ago.

b. Patients who have had a severe or poorly-controlled psychiatric disorder (e.g., depression, schizophrenia, bipolar illness, obsessive-compulsive disorder, severe anxiety, personality disorder) more than 6 months ago but less than 5 years ago.

Patients who have been intolerant to previous interferon therapy.

Patients who are unable to provide informed consent.

Patients who are unable or unwilling to undergo three liver biopsies over 4 years for assessment of hepatic histology during this trial.

Patients with a serum bilirubin above 2.5 mg/dL, except for:

1. A patient with Gilbert's syndrome, in the opinion of the investigator or

2. An Express patient being treated with ribavirin.

Patients participating in another clinical trial can be screened 6 months after the end of study drug.

Any other condition which, in the opinion of the investigator, would make the subject unsuitable for enrollment, or could interfere with the subject participating in or completing the protocol.

Lead-in Patients: Documented virologic response (undetectable HCV-RNA) within 4 weeks prior to or 6 months after discontinuing the most recent adequate course of interferon.

Patients who have undergone liver transplantation.


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Citations:

Epidemiology of hepatitis c

Epidemiology of the hepatitis c virus

Hepatitis c: the clinical spectrum of disease

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Contacts:

Principal Investigator

Referral Contact

For more information:

Marc G. Ghany, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
BG 10 RM 9C432A
10 CENTER DR
BETHESDA MD 20814
(301) 402-5115
mg228m@nih.gov

Elenita Rivera, R.N.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institutes of Health
Building 10
Room 8E
10 Center Drive
Bethesda, Maryland 20892
(301) 496-3531
erivera@cc.nih.gov

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

prpl@mail.cc.nih.gov

Clinical Trials Number:

NCT00006164

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