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The Safety and Effectiveness of Adefovir Dipivoxil in the Treatment of HIV-Infected Patients

Primary Purpose

Cytomegalovirus Infections, HIV Infections

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Levocarnitine
Adefovir dipivoxil
Adefovir dipivoxil placebo
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cytomegalovirus Infections focused on measuring Cytomegalovirus Infections, Antiviral Agents, CD4 Lymphocyte Count, Prodrugs, Survival, Adenine

Eligibility Criteria

13 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria Concurrent Medication: Allowed: Chronically administered concomitant therapies for HIV and opportunistic diseases, including chemotherapy for cutaneous Kaposi's sarcoma, must be on these therapies for at least 30 days prior to study entry. Short courses of oral antibiotics or other therapies given for a limited period of 3 weeks. Episodic use of IV acyclovir or oral acyclovir > 1g/day for treatment of acute illness is permitted at the clinician's discretion. Patients must have: A working diagnosis of HIV infection based on the patient's medical history, behavioral history, clinical signs and symptoms, or results of other laboratory tests. CD4+ cell count <= 100 cells/mm3 within 60 days prior to randomization (OR, AS PER AMENDMENT 8/7/97, a CD4+ cell count that is both > 100 and <= 200 cells/mm3 within 60 days prior to randomization and a documented nadir CD4+ cell count <= 50 cells/ mm3 at any time prior to randomization). Reasonably good health. Life expectancy of at least 6 months. Access to a refrigerator for the storage of adefovir dipivoxil. Signed informed consent from parent or legal guardian for patients less than 18 years of age. AS PER AMENDMENT 8/7/97: CMV serology (IgG) positive (CMV bDNA cohort and CMV-virology cohort). Exclusion Criteria Co-existing Condition: Patients with the following symptoms and conditions are excluded: Evidence of active CMV disease at screening. Conditions that would require use of medications listed in Exclusion Concurrent Medications. Concurrent Medication: Excluded: Any investigational anti-CMV agent. Adenine arabinoside (vidarabine). Amantadine hydrochloride (Symmetrel). Cidofovir (Vistide). CMV hyperimmune globulin. Cytosine arabinoside (cytarabine). Famciclovir. Foscarnet (phosphonoformic acid). Ganciclovir (Cytovene). GW 1263W94 (Benzamidazole). Idoxuridine. Intravenous acyclovir. ISIS 2922 (Anti-sense). Lobucavir. MSL109. Oral acyclovir > 1 g/day. Valacyclovir. Patients with the following prior conditions are excluded: History of CMV end-organ disease. Prior Medication: Excluded within 2 weeks of randomization: Any investigational anti-CMV agent. Adenine arabinoside (vidarabine). Amantadine hydrochloride (Symmetrel). Cidofovir (Vistide). CMV hyperimmune globulin. Cytosine arabinoside (cytarabine). Famciclovir. Ganciclovir (Cytovene). GW 1263W94 (Benzamidazole). Idoxuridine. Intravenous acyclovir. ISIS 2922 (Anti-sense). Lobucavir. MSL109. Oral acyclovir > 1 g/day. Valacyclovir. Excluded within 60 days prior to study entry: Foscarnet.

Sites / Locations

  • Community Consortium / UCSF
  • Denver CPCRA / Denver Public Hlth
  • Washington Reg AIDS Prog / Dept of Infect Dis
  • AIDS Research Consortium of Atlanta
  • AIDS Research Alliance - Chicago
  • Louisiana Comm AIDS Rsch Prog / Tulane Univ Med
  • Wayne State Univ - WSU/DMC / Univ Hlth Ctr
  • Henry Ford Hosp
  • Southern New Jersey AIDS Cln Trials / Dept of Med
  • North Jersey Community Research Initiative
  • Partners in Research / New Mexico
  • Harlem AIDS Treatment Grp / Harlem Hosp Ctr
  • The Research and Education Group
  • Philadelphia FIGHT
  • Richmond AIDS Consortium / Div of Infect Diseases

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

1

2

Arm Description

Participants will receive adefovir dipivoxil and L-carnitine

Participants will receive adefovir dipivoxil placebo and L-carnitine.

Outcomes

Primary Outcome Measures

Morbidity

Secondary Outcome Measures

Full Information

First Posted
November 2, 1999
Last Updated
September 28, 2013
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00001082
Brief Title
The Safety and Effectiveness of Adefovir Dipivoxil in the Treatment of HIV-Infected Patients
Official Title
A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Adefovir Dipivoxil (Bis-POM PMEA) in Prolonging Survival of HIV-Infected Individuals With a CD4+ Cell Count of <= 100/mm3 or With a CD4+ Cell Count Both > 100 and <= 200/mm3 and a Nadir CD4+ Cell Count of <= 50/mm3
Study Type
Interventional

2. Study Status

Record Verification Date
September 2013
Overall Recruitment Status
Completed
Study Start Date
December 1996 (undefined)
Primary Completion Date
January 1999 (Actual)
Study Completion Date
August 1999 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

Brief Summary
To evaluate the safety and efficacy of adefovir dipivoxil in prolonging survival of patients with advanced HIV disease. In CMV prophylaxis substudy: To evaluate the efficacy of adefovir dipivoxil in preventing the development of CMV end-organ disease in patients with advanced HIV coinfected with CMV. The optimal treatment for HIV infection and the prevention of CMV disease has not been identified. Currently available antiretroviral therapies are hampered by both significant toxicities and the development of resistance. In addition, agents for preventing CMV disease, such as oral ganciclovir, are complicated by poor bioavailability and decreased compliance secondary to toxicities. Moreover, discordant results have been reported regarding the effectiveness of oral ganciclovir for preventing CMV disease. There is a need for newer agents with anti-HIV and anti-herpesvirus activity that have good pharmacokinetic and safety profiles and that will be well tolerated by patients. Adefovir dipivoxil is an oral pro-drug of PMEA, a nucleoside analog with activity against a broad spectrum of retroviruses and herpesviruses, including important human pathogens, such as HIV-1, HIV-2 and CMV. Due to its anti-HIV and anti-herpesvirus activity, adefovir dipivoxil may be able to decrease the incidence of opportunistic herpesvirus infections and prolong survival in patients with advanced HIV infection.
Detailed Description
The optimal treatment for HIV infection and the prevention of CMV disease has not been identified. Currently available antiretroviral therapies are hampered by both significant toxicities and the development of resistance. In addition, agents for preventing CMV disease, such as oral ganciclovir, are complicated by poor bioavailability and decreased compliance secondary to toxicities. Moreover, discordant results have been reported regarding the effectiveness of oral ganciclovir for preventing CMV disease. There is a need for newer agents with anti-HIV and anti-herpesvirus activity that have good pharmacokinetic and safety profiles and that will be well tolerated by patients. Adefovir dipivoxil is an oral pro-drug of PMEA, a nucleoside analog with activity against a broad spectrum of retroviruses and herpesviruses, including important human pathogens, such as HIV-1, HIV-2 and CMV. Due to its anti-HIV and anti-herpesvirus activity, adefovir dipivoxil may be able to decrease the incidence of opportunistic herpesvirus infections and prolong survival in patients with advanced HIV infection. All patients will be enrolled within the first 18 months of the study. They will be randomized to 1 of 2 groups. Group 1 will be comprised of 1080 patients and will receive adefovir dipivoxil plus L-carnitine and group 2 will be comprised of 1080 patients and will receive a placebo plus L-carnitine. At least the first 400 patients enrolled (200 in each group) will comprise the safety-HIV virology cohort. These patients will have more frequent follow up visits, additional laboratory evaluations, and more intensive safety data information during the first 6 months. NOTE: At least 850 patients who are infected with CMV are followed for the development of CMV end-organ disease in a CMV prophylaxis substudy. AS PER AMENDMENT 8/7/97: All patients are enrolled in the primary study and randomized to the treatment or placebo regimen. Within the primary study, patients meeting specified criteria may be enrolled in one or more of the following cohorts: Safety-HIV virology cohort (at least the first 400 patients enrolled in the study regardless of CMV status). CMV bDNA cohort (those patients in the safety-HIV virology cohort who are CMV-positive). CMV-virology cohort (the first 400 patients in the CMV bDNA cohort enrolled at sites able to obtain CMV urine cultures). All patients who are CMV-positive are enrolled in the CMV prophylaxis substudy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cytomegalovirus Infections, HIV Infections
Keywords
Cytomegalovirus Infections, Antiviral Agents, CD4 Lymphocyte Count, Prodrugs, Survival, Adenine

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare Provider
Allocation
Randomized
Enrollment
505 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
Participants will receive adefovir dipivoxil and L-carnitine
Arm Title
2
Arm Type
Experimental
Arm Description
Participants will receive adefovir dipivoxil placebo and L-carnitine.
Intervention Type
Drug
Intervention Name(s)
Levocarnitine
Other Intervention Name(s)
L-carnitine
Intervention Description
500 mg tablet taken orally daily
Intervention Type
Drug
Intervention Name(s)
Adefovir dipivoxil
Intervention Description
120 mg tablet taken orally daily
Intervention Type
Drug
Intervention Name(s)
Adefovir dipivoxil placebo
Intervention Description
Oral placebo tablet taken daily
Primary Outcome Measure Information:
Title
Morbidity
Time Frame
Throughout study

10. Eligibility

Sex
All
Minimum Age & Unit of Time
13 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Concurrent Medication: Allowed: Chronically administered concomitant therapies for HIV and opportunistic diseases, including chemotherapy for cutaneous Kaposi's sarcoma, must be on these therapies for at least 30 days prior to study entry. Short courses of oral antibiotics or other therapies given for a limited period of 3 weeks. Episodic use of IV acyclovir or oral acyclovir > 1g/day for treatment of acute illness is permitted at the clinician's discretion. Patients must have: A working diagnosis of HIV infection based on the patient's medical history, behavioral history, clinical signs and symptoms, or results of other laboratory tests. CD4+ cell count <= 100 cells/mm3 within 60 days prior to randomization (OR, AS PER AMENDMENT 8/7/97, a CD4+ cell count that is both > 100 and <= 200 cells/mm3 within 60 days prior to randomization and a documented nadir CD4+ cell count <= 50 cells/ mm3 at any time prior to randomization). Reasonably good health. Life expectancy of at least 6 months. Access to a refrigerator for the storage of adefovir dipivoxil. Signed informed consent from parent or legal guardian for patients less than 18 years of age. AS PER AMENDMENT 8/7/97: CMV serology (IgG) positive (CMV bDNA cohort and CMV-virology cohort). Exclusion Criteria Co-existing Condition: Patients with the following symptoms and conditions are excluded: Evidence of active CMV disease at screening. Conditions that would require use of medications listed in Exclusion Concurrent Medications. Concurrent Medication: Excluded: Any investigational anti-CMV agent. Adenine arabinoside (vidarabine). Amantadine hydrochloride (Symmetrel). Cidofovir (Vistide). CMV hyperimmune globulin. Cytosine arabinoside (cytarabine). Famciclovir. Foscarnet (phosphonoformic acid). Ganciclovir (Cytovene). GW 1263W94 (Benzamidazole). Idoxuridine. Intravenous acyclovir. ISIS 2922 (Anti-sense). Lobucavir. MSL109. Oral acyclovir > 1 g/day. Valacyclovir. Patients with the following prior conditions are excluded: History of CMV end-organ disease. Prior Medication: Excluded within 2 weeks of randomization: Any investigational anti-CMV agent. Adenine arabinoside (vidarabine). Amantadine hydrochloride (Symmetrel). Cidofovir (Vistide). CMV hyperimmune globulin. Cytosine arabinoside (cytarabine). Famciclovir. Ganciclovir (Cytovene). GW 1263W94 (Benzamidazole). Idoxuridine. Intravenous acyclovir. ISIS 2922 (Anti-sense). Lobucavir. MSL109. Oral acyclovir > 1 g/day. Valacyclovir. Excluded within 60 days prior to study entry: Foscarnet.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brosgart C
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Fisher E
Official's Role
Study Chair
Facility Information:
Facility Name
Community Consortium / UCSF
City
San Francisco
State/Province
California
ZIP/Postal Code
94110
Country
United States
Facility Name
Denver CPCRA / Denver Public Hlth
City
Denver
State/Province
Colorado
ZIP/Postal Code
80204
Country
United States
Facility Name
Washington Reg AIDS Prog / Dept of Infect Dis
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20422
Country
United States
Facility Name
AIDS Research Consortium of Atlanta
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30308
Country
United States
Facility Name
AIDS Research Alliance - Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60657
Country
United States
Facility Name
Louisiana Comm AIDS Rsch Prog / Tulane Univ Med
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112
Country
United States
Facility Name
Wayne State Univ - WSU/DMC / Univ Hlth Ctr
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Henry Ford Hosp
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Southern New Jersey AIDS Cln Trials / Dept of Med
City
Camden
State/Province
New Jersey
ZIP/Postal Code
08103
Country
United States
Facility Name
North Jersey Community Research Initiative
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07103
Country
United States
Facility Name
Partners in Research / New Mexico
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87131
Country
United States
Facility Name
Harlem AIDS Treatment Grp / Harlem Hosp Ctr
City
New York
State/Province
New York
ZIP/Postal Code
10037
Country
United States
Facility Name
The Research and Education Group
City
Portland
State/Province
Oregon
ZIP/Postal Code
97210
Country
United States
Facility Name
Philadelphia FIGHT
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
Richmond AIDS Consortium / Div of Infect Diseases
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States

12. IPD Sharing Statement

Citations:
Citation
Fisher E, Brosgart C, Cohn D, Chaloner K, Pulling C, Alston B, Schmetter B, El-Sadr W. Placebo (PLC)-controlled, multicenter trial of adefovir dipivoxil (ADV) in patients (pt) with HIV disease. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:160 (abstract no 491)
Results Reference
background
Citation
Brosgart C, Fisher E, Pulling C, Chaloner K, Cohn D, Elsadr W, Verheggen R, Schmetter B, Alston B. Prevalence of asymptomatic CMV retinitis (CMVR) in AIDS patients. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:152 (abstract no 453)
Results Reference
background
Citation
Fisher E, Brosgart C, Cohn D, Chaloner K, Pulling C, Schmetter B, Alston B, El-Sadr W. Safety of adefovir dipivoxil (ADV) and incidence of proximal renal tubular disorder (PRTD) in a placebo (PLC)-controlled trial in patients (pt) with advanced HIV disease. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:195 (abstract no 678)
Results Reference
background
Citation
Brosgart C, Pulling C, Chaloner K, Fisher E, Coakley D, Diggins M, Ivannidis J. Serum carnitine levels in AIDS patients with advanced HIV disease from the CPCRA 039 trial. Int Conf AIDS. 1998;12:1094 (abstract no 60508)
Results Reference
background

Learn more about this trial

The Safety and Effectiveness of Adefovir Dipivoxil in the Treatment of HIV-Infected Patients

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