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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00001082

Collaborator

(none)

505

Enrollment

Locations

Arms

Duration (Months)

33.7

Patients Per Site

1.1

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Cytomegalovirus Infections HIV Infections	Drug: Levocarnitine Drug: Adefovir dipivoxil Drug: Adefovir dipivoxil placebo	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

505 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Care Provider)

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

Study Start Date :

Dec 1, 1996

Actual Primary Completion Date :

Jan 1, 1999

Actual Study Completion Date :

Aug 1, 1999

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Participants will receive adefovir dipivoxil and L-carnitine	Drug: Levocarnitine 500 mg tablet taken orally daily Other Names: 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 Names: L-carnitine Drug: Adefovir dipivoxil placebo Oral placebo tablet taken daily

Arm

Intervention/Treatment

Experimental: 1

Participants will receive adefovir dipivoxil and L-carnitine

Drug: Levocarnitine

500 mg tablet taken orally daily

Other Names:

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 Names:

L-carnitine

Drug: Adefovir dipivoxil placebo

Oral placebo tablet taken daily

Outcome Measures

Primary Outcome Measures

Morbidity [Throughout study]

Eligibility Criteria

Criteria

Ages Eligible for Study:

13 Years and Older

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Community Consortium / UCSF	San Francisco	California	United States	94110
2	Denver CPCRA / Denver Public Hlth	Denver	Colorado	United States	80204
3	Washington Reg AIDS Prog / Dept of Infect Dis	Washington	District of Columbia	United States	20422
4	AIDS Research Consortium of Atlanta	Atlanta	Georgia	United States	30308
5	AIDS Research Alliance - Chicago	Chicago	Illinois	United States	60657
6	Louisiana Comm AIDS Rsch Prog / Tulane Univ Med	New Orleans	Louisiana	United States	70112
7	Wayne State Univ - WSU/DMC / Univ Hlth Ctr	Detroit	Michigan	United States	48201
8	Henry Ford Hosp	Detroit	Michigan	United States	48202
9	Southern New Jersey AIDS Cln Trials / Dept of Med	Camden	New Jersey	United States	08103
10	North Jersey Community Research Initiative	Newark	New Jersey	United States	07103
11	Partners in Research / New Mexico	Albuquerque	New Mexico	United States	87131
12	Harlem AIDS Treatment Grp / Harlem Hosp Ctr	New York	New York	United States	10037
13	The Research and Education Group	Portland	Oregon	United States	97210
14	Philadelphia FIGHT	Philadelphia	Pennsylvania	United States	19107
15	Richmond AIDS Consortium / Div of Infect Diseases	Richmond	Virginia	United States	23298