Clinical Trial:Studies of the Addition of Adefovir Dipivoxil to Lamivudine for the Treatment of Chronic Hepatitis B: A Randomized, Double-Blind, Placebo Controlled Study in HIV-Infected Patients and an Open-Label Study in HIV-Negative Subjects

[Guest guest]

Studies of the Addition of Adefovir Dipivoxil to Lamivudine for the

Treatment of Chronic Hepatitis B: A Randomized, Double-Blind, Placebo

Controlled Study in HIV-Infected Patients and an Open-Label Study in

HIV-Negative Subjects

This study is currently recruiting patients.

Sponsored by

National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

This is a randomized, placebo controlled study of the safety and efficacy

of the addition of adefovir to lamivudine for the treatment of chronic

hepatitis B in subjects with an hepatitis B virus (HBV) viral load of at

least one million copies/mL despite at least one year of lamivudine therapy.

Two patient populations will be separately enrolled: HIV-uninfected (40

subjects) and HIV-infected (40 subjects). Subjects will be randomly

allocated to receive adefovir 10 mg daily for one year or matching placebo.

At the end of one year, all patients may choose to receive open-label

adefovir. Patients may not have decompensated cirrhosis or other causes of

liver disease such as hepatitis C. Liver biopsies are performed prior to

study and at the end of one year. The purpose of the study is to evaluate

the safety and efficacy of lamivudine plus adefovir as compared with

continued lamivudine in these patient groups, to compare responses between

HIV-uninfected and HIV-infected subjects, and to obtain specimens for

studies of immune responses to HBV. HIV-infected patients will receive

lamivudine 150 mg bid plus adefovir 10 mg qd (or placebo) and HIV-uninfected

subjects will receive lamivudine 100 mg qd plus adefovir 10 mg qd (or

placebo). L-carnitine supplementation will be used only if low serum

carnitine levels are documented. Additionally, patients will have the option

of enrolling in a sub-study assessing the kinetics of viral load response to

study drug. Specimens will be stored for possible future determination of

adefovir levels and use in evaluating HBV and HIV resistance to Adefovir.

Patients discontinuing study drug, or not electing to receive open-label

adefovir, will be monitored for safety for at least an additional 24 weeks.

The primary study endpoint will be a comparison of the absolute HBV viral

load at Week 48 between the placebo and adefovir arms blocked by HIV

sero-status. Secondary endpoints include safety, liver pathology, and

transaminase level. Adefovir will be discontinued for toxicity; there will

be no dose reduction. A DSMB will oversee the trial for toxicity.

Condition Treatment or Intervention Phase

HIV Infections

Chronic Hepatitis B Drug: Adefovir Dipivoxil Phase III

MEDLINEplus related topics: AIDS; Hepatitis; Viral Infections

Study Type: Interventional

Further Study Details:

This clinical trial examines the addition of adefovir dipivoxil to a

lamivudine regimen for treating chronic hepatitis B infection. Two patient

populations will be separately recruited: HIV-infected (40 subjects) and

HIV-uninfected (20 subjects). HIV-infected patients will be enrolled in a

randomized, placebo controlled study of the safety and efficacy of the

addition of adefovir to lamivudine for the treatment of chronic hepatitis B

in subjects with an hepatitis B virus (HBV) viral load of at least one

million copies/mL despite at least one year of lamivudine therapy. A similar

population of HIV-uninfected subjects will be treated with open-label

adefovir 10 mg daily for one year. These HIV-negative subjects will serve as

a control group for immunological comparisons to the HIV-positive group

treated with adefovir. HIV-infected subjects will be randomly allocated to

receive adefovir 10 mg daily for one year or matching placebo. At the end of

one year, HIV-infected patients may choose to receive open-label adefovir,

and HIV-uninfected patients will have the option of continuing open-label

drug if they are responding to treatment. Patients may not have

decompensated cirrhosis or other causes of liver disease such as hepatitis

C. Liver biopsies are performed prior to study and at the end of one year.

The purpose of the study is to evaluate the safety and efficacy of

lamivudine plus adefovir as compared with continued lamivudine in

HIV-infected patients, to compare responses between HIV-uninfected and

HIV-infected subjects, and to obtain specimens for studies of immune

responses to HBV. HIV-infected patients will receive lamivudine 150 mg bid

plus adefovir 10 mg qd (or placebo) and HIV-uninfected subjects will receive

lamivudine 100 mg qd plus adefovir 10 mg qd . L-carnitine supplementation

will be used only if low serum carnitine levels are documented.

Additionally, patients will have the option of enrolling in a sub-study

assessing the kinetics of viral load response to study drug. Specimens will

be stored for possible future determination of adefovir levels and use in

evaluating HBV and HIV resistance to Adefovir. Patients discontinuing study

drug, or not electing to receive open-label adefovir in extension, will be

monitored for safety for at least an additional 24 weeks. The primary study

endpoint will be a comparison of the absolute HBV viral load at Week 48

between the placebo and adefovir HIV-positive patient groups, and for the

HIV-negative population, the comparison of absolute HBV viral at Week 48

versus baseline. Secondary endpoints include safety, liver pathology, and

transaminase level. Adefovir will be discontinued for toxicity; there will

be no dose reduction. A DSMB will oversee the trial for toxicity.

Eligibility

Genders Eligible for Study: Both

Criteria

Must be greater than or equal to 21 years of age.

Must be infected with HBV with HBV viral load greater than 1.0 x 10 (6)

copies/mL by Roche assay at screen.

Must be HBeAg positive.

May be HIV infected or uninfected.

If HIV infected:

1)CD4 must be greater than of equal to 100 and VL less than or equal to

10,000 at screen.

2) No antiretroviral changes 12 weeks prior to entry and no anticipated

changes 12 weeks into study.

Must have a physician(s) outside of NIH who will provide routine, as well

as HIV (if applicable) and liver specific, care.

Must be able to return to NIH for study visits.

Must be receiving lamivudine at a dose of at least 100 mg qd for greater

than or equal to one year prior to enrollment (with no dosing interruptions

of greater than 1 month total in the previous year and no interruption in

the 3 months prior to study entry).

Must have a serum creatinine less than 1.5 mg/dL.

Must have 1.2 less than or equal to ALT (SGPT) less than or equal to 7 X

ULN (current NIH lab values 49-287 U/L inclusive) at screen.

Must have direct bilirubin less than or equal to 1.0 mg/dL.

Must have a serum phosphorus greater than or equal to 2.2 mg/dL (normal

range NIH 2.3-4.3 mg/dL).

Must have a neutrophil count greater than or equal to 1000 cells/mm(3).

Must have platelets greater than or equal to 70,000/mm(3).

Must have PT less than or equal to 15 sec (NIH ULN 14.7 sec).

Must have a hemoglobin greater than or equal to 10 mg/dL.

Female subjects capable of pregnancy must use effective contraception

during the study. Effective contraception methods include abstinence,

surgical sterilization of either partner, barrier methods such as diaphragm,

condom, cap or sponge, or use of hormonal contraception. If HIV infected

using hormonal contraception, must be receiving an anti-HIV regimen that

will not alter the metabolism of hormonal contraception.

Must be willing and able to provide written informed consent.

Must be willing to undergo hepatic biopsy at the start and end of study.

The initial protocol biopsy will not be required if the subject can provide

pathologic slides from a biopsy performed within three months of the History

and Physical visit that are found by the Liver Disease Section and the NIH's

pathologist to be adequate for this study.

No prior use of ADV, tenofovir, or cidofovir.

No decompensated cirrhosis: Child-Pugh Class B or C cirrhosis; Class A

Score = 5 acceptable, Class A Score = 6 acceptable as long as not secondary

to encephalopathy or ascites.

No active serious systemic infections other than HIV or HBV.

No liver disease caused by reasons other than hepatitis B e.g., HCV, HDV,

's, hemochromatosis, autoimmune hepatitis (ANA greater than or equal

to 160) except history of drug-associated hepatitis with discontinuation of

causative agent.

No history of encephalopathy, varices, heart failure, or ascites.

No history of pancreatitis.

No new AIDS-defining event other than esophageal candidiasis diagnosed

within 1 month prior to baseline.

No treatment with immunomodulator drugs (interleukins, corticosteriods for

indications other than the tratment of adrenal insufficiency) in the 4 weeks

prior to baseline. G-CSF and epoetin use are permitted.

No anti-HBV therapy other than lamivudine (such as emtricitabine,

lobucavir, entecavir, HBIG, clevudine, MCC-478) with the exeception of

interferon alpha, famciclovir or foscarnet that ended more than 12 weeks

prior to screen.

No Hepatic mass suggestive of hepatocellular carcinoma.

No alpha fetoprotein greater than 200 ng/ml.

No evidence of gastrointestinal malabsorption or chronic nausea or

vomiting.

No current alcohol or substance abuse that potentially could interfere

with patient compliance.

No malignancy other than cutaneous Kaposi's sarcoma, skin cancer treated

by resection or HPV-associated carcinoma in situ or Bowen's disease in the 5

years prior to enrollment.

No history of clinically significant renal dysfunction within the previous

12 months prior to baseline.

No concomitant therapy with aminoglycosides, amphotericin B, cisplatinum,

IV pentamidine, vancomycin, systemic chemotherapeutic agents, probenecid or

other nephrotoxic agents.

No proteinuria greater than or equal to 3+.

No ANA greater than or equal to 1:160.

No positive PCR test for hepatitis C.

No antibodies to hepatitis D (delta hepatitis).

Females must not be pregnant or breast-feeding. Pregnancy test must be

negative within two weeks prior to dosing with adefovir or placebo.

No history of organ or bone marrow transplantation.

No systemic illness that will make it unlikely that the subject will be

able to return to NIH for the required study visits.

No seizure disorder.

Expected Total Enrollment: 100

Location and Contact Information

land

National Institute of Allergy and Infectious Diseases (NIAID), 9000

Rockville Pike Bethesda, land, 20892, United States; Recruiting

Patient Recruitment and Public Liaison Office 1-800-411-1222

prpl@...

TTY 1-866-411-1010

More Information

Detailed Web Page

Publications

The effects of lamivudine on replication of hepatitis B virus in

HIV-infected men

Lamivudine as initial treatment for chronic hepatitis b in the united states

Long-term therapy of chronic hepatitis B with lamivudine

Study ID Numbers 010239; 01-I-0239

Date study started August 22, 2001

Record last reviewed July 5, 2001

Last Updated July 5, 2001

NLM Identifier NCT00023153

ClinicalTrials.gov processed this record on 2001-12-26

[Guest guest]

Studies of the Addition of Adefovir Dipivoxil to Lamivudine for the

Treatment of Chronic Hepatitis B: A Randomized, Double-Blind, Placebo

Controlled Study in HIV-Infected Patients and an Open-Label Study in

HIV-Negative Subjects

This study is currently recruiting patients.

Sponsored by

National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

This is a randomized, placebo controlled study of the safety and efficacy

of the addition of adefovir to lamivudine for the treatment of chronic

hepatitis B in subjects with an hepatitis B virus (HBV) viral load of at

least one million copies/mL despite at least one year of lamivudine therapy.

Two patient populations will be separately enrolled: HIV-uninfected (40

subjects) and HIV-infected (40 subjects). Subjects will be randomly

allocated to receive adefovir 10 mg daily for one year or matching placebo.

At the end of one year, all patients may choose to receive open-label

adefovir. Patients may not have decompensated cirrhosis or other causes of

liver disease such as hepatitis C. Liver biopsies are performed prior to

study and at the end of one year. The purpose of the study is to evaluate

the safety and efficacy of lamivudine plus adefovir as compared with

continued lamivudine in these patient groups, to compare responses between

HIV-uninfected and HIV-infected subjects, and to obtain specimens for

studies of immune responses to HBV. HIV-infected patients will receive

lamivudine 150 mg bid plus adefovir 10 mg qd (or placebo) and HIV-uninfected

subjects will receive lamivudine 100 mg qd plus adefovir 10 mg qd (or

placebo). L-carnitine supplementation will be used only if low serum

carnitine levels are documented. Additionally, patients will have the option

of enrolling in a sub-study assessing the kinetics of viral load response to

study drug. Specimens will be stored for possible future determination of

adefovir levels and use in evaluating HBV and HIV resistance to Adefovir.

Patients discontinuing study drug, or not electing to receive open-label

adefovir, will be monitored for safety for at least an additional 24 weeks.

The primary study endpoint will be a comparison of the absolute HBV viral

load at Week 48 between the placebo and adefovir arms blocked by HIV

sero-status. Secondary endpoints include safety, liver pathology, and

transaminase level. Adefovir will be discontinued for toxicity; there will

be no dose reduction. A DSMB will oversee the trial for toxicity.

Condition Treatment or Intervention Phase

HIV Infections

Chronic Hepatitis B Drug: Adefovir Dipivoxil Phase III

MEDLINEplus related topics: AIDS; Hepatitis; Viral Infections

Study Type: Interventional

Further Study Details:

This clinical trial examines the addition of adefovir dipivoxil to a

lamivudine regimen for treating chronic hepatitis B infection. Two patient

populations will be separately recruited: HIV-infected (40 subjects) and

HIV-uninfected (20 subjects). HIV-infected patients will be enrolled in a

randomized, placebo controlled study of the safety and efficacy of the

addition of adefovir to lamivudine for the treatment of chronic hepatitis B

in subjects with an hepatitis B virus (HBV) viral load of at least one

million copies/mL despite at least one year of lamivudine therapy. A similar

population of HIV-uninfected subjects will be treated with open-label

adefovir 10 mg daily for one year. These HIV-negative subjects will serve as

a control group for immunological comparisons to the HIV-positive group

treated with adefovir. HIV-infected subjects will be randomly allocated to

receive adefovir 10 mg daily for one year or matching placebo. At the end of

one year, HIV-infected patients may choose to receive open-label adefovir,

and HIV-uninfected patients will have the option of continuing open-label

drug if they are responding to treatment. Patients may not have

decompensated cirrhosis or other causes of liver disease such as hepatitis

C. Liver biopsies are performed prior to study and at the end of one year.

The purpose of the study is to evaluate the safety and efficacy of

lamivudine plus adefovir as compared with continued lamivudine in

HIV-infected patients, to compare responses between HIV-uninfected and

HIV-infected subjects, and to obtain specimens for studies of immune

responses to HBV. HIV-infected patients will receive lamivudine 150 mg bid

plus adefovir 10 mg qd (or placebo) and HIV-uninfected subjects will receive

lamivudine 100 mg qd plus adefovir 10 mg qd . L-carnitine supplementation

will be used only if low serum carnitine levels are documented.

Additionally, patients will have the option of enrolling in a sub-study

assessing the kinetics of viral load response to study drug. Specimens will

be stored for possible future determination of adefovir levels and use in

evaluating HBV and HIV resistance to Adefovir. Patients discontinuing study

drug, or not electing to receive open-label adefovir in extension, will be

monitored for safety for at least an additional 24 weeks. The primary study

endpoint will be a comparison of the absolute HBV viral load at Week 48

between the placebo and adefovir HIV-positive patient groups, and for the

HIV-negative population, the comparison of absolute HBV viral at Week 48

versus baseline. Secondary endpoints include safety, liver pathology, and

transaminase level. Adefovir will be discontinued for toxicity; there will

be no dose reduction. A DSMB will oversee the trial for toxicity.

Eligibility

Genders Eligible for Study: Both

Criteria

Must be greater than or equal to 21 years of age.

Must be infected with HBV with HBV viral load greater than 1.0 x 10 (6)

copies/mL by Roche assay at screen.

Must be HBeAg positive.

May be HIV infected or uninfected.

If HIV infected:

1)CD4 must be greater than of equal to 100 and VL less than or equal to

10,000 at screen.

2) No antiretroviral changes 12 weeks prior to entry and no anticipated

changes 12 weeks into study.

Must have a physician(s) outside of NIH who will provide routine, as well

as HIV (if applicable) and liver specific, care.

Must be able to return to NIH for study visits.

Must be receiving lamivudine at a dose of at least 100 mg qd for greater

than or equal to one year prior to enrollment (with no dosing interruptions

of greater than 1 month total in the previous year and no interruption in

the 3 months prior to study entry).

Must have a serum creatinine less than 1.5 mg/dL.

Must have 1.2 less than or equal to ALT (SGPT) less than or equal to 7 X

ULN (current NIH lab values 49-287 U/L inclusive) at screen.

Must have direct bilirubin less than or equal to 1.0 mg/dL.

Must have a serum phosphorus greater than or equal to 2.2 mg/dL (normal

range NIH 2.3-4.3 mg/dL).

Must have a neutrophil count greater than or equal to 1000 cells/mm(3).

Must have platelets greater than or equal to 70,000/mm(3).

Must have PT less than or equal to 15 sec (NIH ULN 14.7 sec).

Must have a hemoglobin greater than or equal to 10 mg/dL.

Female subjects capable of pregnancy must use effective contraception

during the study. Effective contraception methods include abstinence,

surgical sterilization of either partner, barrier methods such as diaphragm,

condom, cap or sponge, or use of hormonal contraception. If HIV infected

using hormonal contraception, must be receiving an anti-HIV regimen that

will not alter the metabolism of hormonal contraception.

Must be willing and able to provide written informed consent.

Must be willing to undergo hepatic biopsy at the start and end of study.

The initial protocol biopsy will not be required if the subject can provide

pathologic slides from a biopsy performed within three months of the History

and Physical visit that are found by the Liver Disease Section and the NIH's

pathologist to be adequate for this study.

No prior use of ADV, tenofovir, or cidofovir.

No decompensated cirrhosis: Child-Pugh Class B or C cirrhosis; Class A

Score = 5 acceptable, Class A Score = 6 acceptable as long as not secondary

to encephalopathy or ascites.

No active serious systemic infections other than HIV or HBV.

No liver disease caused by reasons other than hepatitis B e.g., HCV, HDV,

's, hemochromatosis, autoimmune hepatitis (ANA greater than or equal

to 160) except history of drug-associated hepatitis with discontinuation of

causative agent.

No history of encephalopathy, varices, heart failure, or ascites.

No history of pancreatitis.

No new AIDS-defining event other than esophageal candidiasis diagnosed

within 1 month prior to baseline.

No treatment with immunomodulator drugs (interleukins, corticosteriods for

indications other than the tratment of adrenal insufficiency) in the 4 weeks

prior to baseline. G-CSF and epoetin use are permitted.

No anti-HBV therapy other than lamivudine (such as emtricitabine,

lobucavir, entecavir, HBIG, clevudine, MCC-478) with the exeception of

interferon alpha, famciclovir or foscarnet that ended more than 12 weeks

prior to screen.

No Hepatic mass suggestive of hepatocellular carcinoma.

No alpha fetoprotein greater than 200 ng/ml.

No evidence of gastrointestinal malabsorption or chronic nausea or

vomiting.

No current alcohol or substance abuse that potentially could interfere

with patient compliance.

No malignancy other than cutaneous Kaposi's sarcoma, skin cancer treated

by resection or HPV-associated carcinoma in situ or Bowen's disease in the 5

years prior to enrollment.

No history of clinically significant renal dysfunction within the previous

12 months prior to baseline.

No concomitant therapy with aminoglycosides, amphotericin B, cisplatinum,

IV pentamidine, vancomycin, systemic chemotherapeutic agents, probenecid or

other nephrotoxic agents.

No proteinuria greater than or equal to 3+.

No ANA greater than or equal to 1:160.

No positive PCR test for hepatitis C.

No antibodies to hepatitis D (delta hepatitis).

Females must not be pregnant or breast-feeding. Pregnancy test must be

negative within two weeks prior to dosing with adefovir or placebo.

No history of organ or bone marrow transplantation.

No systemic illness that will make it unlikely that the subject will be

able to return to NIH for the required study visits.

No seizure disorder.

Expected Total Enrollment: 100

Location and Contact Information

land

National Institute of Allergy and Infectious Diseases (NIAID), 9000

Rockville Pike Bethesda, land, 20892, United States; Recruiting

Patient Recruitment and Public Liaison Office 1-800-411-1222

prpl@...

TTY 1-866-411-1010

More Information

Detailed Web Page

Publications

The effects of lamivudine on replication of hepatitis B virus in

HIV-infected men

Lamivudine as initial treatment for chronic hepatitis b in the united states

Long-term therapy of chronic hepatitis B with lamivudine

Study ID Numbers 010239; 01-I-0239

Date study started August 22, 2001

Record last reviewed July 5, 2001

Last Updated July 5, 2001

NLM Identifier NCT00023153

ClinicalTrials.gov processed this record on 2001-12-26