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

Phase 3

Completed

• Conditions: Cytomegalovirus Infections; HIV Infections
• Interventions: Drug: Levocarnitine; Drug: Adefovir dipivoxil placebo; Drug: Adefovir dipivoxil

• Registration Number: NCT00001082
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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:

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.

Study Timeline

• Study Start: 1996-12
• Primary Completion: 1999-01
• Study Completion: 1999-08
• Study First Submitted: 1999-11-02
• Study First Submitted QC: 2001-08-30
• Study First Posted: 2001-08-31
• Status Verified: 2013-09
• Last Update Submitted: 2013-09-28
• Last Update Posted: 2013-10-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 505

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2	Adefovir dipivoxil placebo	Participants will receive adefovir dipivoxil placebo and L-carnitine.
1	Adefovir dipivoxil	Participants will receive adefovir dipivoxil and L-carnitine
1	Levocarnitine	Participants will receive adefovir dipivoxil and L-carnitine
2	Levocarnitine	Participants will receive adefovir dipivoxil placebo and L-carnitine.

Primary Outcome Measures

Name	Time	Method
Morbidity	Throughout study

Trial Locations

Locations (15)

Community Consortium / UCSF; 🇺🇸 San Francisco, California, United States

Denver CPCRA / Denver Public Hlth; 🇺🇸 Denver, Colorado, United States

Washington Reg AIDS Prog / Dept of Infect Dis; 🇺🇸 Washington, District of Columbia, United States

AIDS Research Consortium of Atlanta; 🇺🇸 Atlanta, Georgia, United States

AIDS Research Alliance - Chicago; 🇺🇸 Chicago, Illinois, United States

Louisiana Comm AIDS Rsch Prog / Tulane Univ Med; 🇺🇸 New Orleans, Louisiana, United States

Wayne State Univ - WSU/DMC / Univ Hlth Ctr; 🇺🇸 Detroit, Michigan, United States

Henry Ford Hosp; 🇺🇸 Detroit, Michigan, United States

Southern New Jersey AIDS Cln Trials / Dept of Med; 🇺🇸 Camden, New Jersey, United States

North Jersey Community Research Initiative; 🇺🇸 Newark, New Jersey, United States

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