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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00001082
First received: November 2, 1999
Last updated: September 28, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Cytomegalovirus Infections
HIV Infections
Drug: Levocarnitine
Drug: Adefovir dipivoxil
Drug: Adefovir dipivoxil placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Morbidity [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]

Enrollment: 505
Study Start Date: December 1996
Study Completion Date: August 1999
Primary Completion Date: January 1999 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Participants will receive adefovir dipivoxil and L-carnitine
Drug: Levocarnitine
500 mg tablet taken orally daily
Other Name: L-carnitine
Drug: Adefovir dipivoxil
120 mg tablet taken orally daily
Experimental: 2
Participants will receive adefovir dipivoxil placebo and L-carnitine.
Drug: Levocarnitine
500 mg tablet taken orally daily
Other Name: L-carnitine
Drug: Adefovir dipivoxil placebo
Oral placebo tablet taken daily

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:

  1. Safety-HIV virology cohort (at least the first 400 patients enrolled in the study regardless of CMV status).
  2. CMV bDNA cohort (those patients in the safety-HIV virology cohort who are CMV-positive).
  3. 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.

  Eligibility

Ages Eligible for Study:   13 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00001082

Locations
United States, California
Community Consortium / UCSF
San Francisco, California, United States, 94110
United States, Colorado
Denver CPCRA / Denver Public Hlth
Denver, Colorado, United States, 80204
United States, District of Columbia
Washington Reg AIDS Prog / Dept of Infect Dis
Washington, District of Columbia, United States, 20422
United States, Georgia
AIDS Research Consortium of Atlanta
Atlanta, Georgia, United States, 30308
United States, Illinois
AIDS Research Alliance - Chicago
Chicago, Illinois, United States, 60657
United States, Louisiana
Louisiana Comm AIDS Rsch Prog / Tulane Univ Med
New Orleans, Louisiana, United States, 70112
United States, Michigan
Henry Ford Hosp
Detroit, Michigan, United States, 48202
Wayne State Univ - WSU/DMC / Univ Hlth Ctr
Detroit, Michigan, United States, 48201
United States, New Jersey
Southern New Jersey AIDS Cln Trials / Dept of Med
Camden, New Jersey, United States, 08103
North Jersey Community Research Initiative
Newark, New Jersey, United States, 07103
United States, New Mexico
Partners in Research / New Mexico
Albuquerque, New Mexico, United States, 87131
United States, New York
Harlem AIDS Treatment Grp / Harlem Hosp Ctr
New York, New York, United States, 10037
United States, Oregon
The Research and Education Group
Portland, Oregon, United States, 97210
United States, Pennsylvania
Philadelphia FIGHT
Philadelphia, Pennsylvania, United States, 19107
United States, Virginia
Richmond AIDS Consortium / Div of Infect Diseases
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
Investigators
Study Chair: Brosgart C
Study Chair: Fisher E
  More Information

Publications:
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)
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)
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)
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)

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00001082     History of Changes
Other Study ID Numbers: CPCRA 039, 11589
Study First Received: November 2, 1999
Last Updated: September 28, 2013
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Cytomegalovirus Infections
Antiviral Agents
CD4 Lymphocyte Count
Prodrugs
Survival
Adenine

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
Communicable Diseases
Cytomegalovirus Infections
HIV Infections
Infection
DNA Virus Infections
Herpesviridae Infections
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Adefovir
Adefovir dipivoxil
Carnitine
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
Growth Substances
Micronutrients
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Reverse Transcriptase Inhibitors

ClinicalTrials.gov processed this record on October 29, 2014