Clinical trial NCT00038272: A Study of DAPD Alone Versus DAPD Plus MMF for Treatment of HIV Infection
Official title: A Phase I/II Randomized, Double-Blind, Placebo-Controlled Pilot Study of Beta-D-2,6-diaminopurine Dioxolane (DAPD) Versus DAPD Plus Mycophenolate Mofetil (MMF) in Treatment-Experienced Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Placebos
Drug Therapy, Combination
Anti-HIV Agents
Mycophenolate Mofetil
2,6-diaminopurine dioxolane
Treatment Experienced
DAPD
MMF
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2002-05-30
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, efficacy, and side effects of beta-D-2,6-diaminopurine dioxolane (DAPD) compared to DAPD plus mycophenolate mofetil (MMF) when these drugs are added to the anti-HIV treatment regimens of people infected with HIV.

Some studies have shown that DAPD and MMF can help fight HIV. However, neither DAPD nor MMF has been approved by the Food and Drug Administration for treating HIV infection. This study will help doctors decide if DAPD and MMF are good drugs for treating HIV.

Detailed description: The antiretroviral potency of DAPD varies among antiretroviral-experienced patients. In vitro studies indicate that the potency of DAPD can be markedly increased by the addition of MMF. Preliminary data indicate that MMF is well tolerated in patients with advanced HIV-1 disease. However, there is currently no clinical data on the activity of DAPD combined with MMF. This study will be the first to evaluate the addition of DAPD and MMF to a patient's current antiretroviral therapy.

At study entry, patients will be randomly assigned to one of two blinded treatment arms. Arm A receives DAPD plus MMF placebo in addition to their current regimen, while Arm B receives DAPD plus MMF in addition to their current regimen. All patients remain on their current antiretroviral regimen through Week 2. After Week 2, patients who virologically respond are encouraged to remain on blinded study treatment through Week 24. Patients who do not virologically respond are unblinded.

After unblinding, patients who were not receiving MMF may add it to their antiretroviral regimen. Response to the addition of open-label MMF is assessed after 2 weeks. Resistance to antiretroviral agents, including DAPD, will be assessed following any virologic failure occurring after Week 2. All patients have the option of optimizing their background antiretroviral regimen at Week 2, based on the results of a pre-entry resistance assay; enfuvirtide will be made available for background therapy optimization through Week 48.

Patients who are still receiving DAPD alone or DAPD plus MMF at Week 48 and who are still responding virologically may choose to continue the study drug(s) and be followed for up to an additional 48 weeks. Throughout the study, HIV-1 RNA levels, CD4 cell counts, and study drug levels will be monitored regularly. Eye exams will be done at several study visits. Only DAPD, MMF, and MMF placebo will be supplied by this study; patients must obtain the rest of their treatment regimen through their doctor. Patients who discontinue treatment before the end of study will need to come in for a follow-up visit 4 weeks after discontinuation and may need to attend future follow-up visits at 8-week intervals, as determined by the investigator.

Eligibility criteria: Inclusion Criteria for Step 1:

* HIV infected
* Triple-class antiretroviral treatment, as determined by the site investigator and as defined by all of the following: a) exposure to 2 or more nucleotide reverse transcriptase inhibitors (NRTIs) for at least 3 months each; b) exposure to 2 or more non-boosted protease inhibitors (PIs) for at least 3 months each, or exposure to a dual PI regimen for at least 3 months; and c) exposure to at least 1 non-nucleotide reverse transcriptase inhibitor (NNRTI) for at least 3 months.
* CD4 cell count of at least 50 cells/mm3 within 45 days prior to study entry
* Viral load of 2000 copies/ml or more within 45 days prior to study entry
* On current antiretroviral treatment regimen for at least 30 days prior to study entry. If current treatment includes abacavir, abacavir must be discontinued at least 30 days prior to study entry.
* Willing to use acceptable methods of contraception

Exclusion Criteria for Step 1:

* Pregnant or breastfeeding
* Allergy or sensitivity to the study drugs and their formulations
* Diabetes mellitus
* Cataracts or any measurable loss of vision due to lens opacity
* Best-corrected visual acuity worse than 20/200
* Certain drugs or vaccines within 30 days prior to study entry
* History of any of the following: kidney disease; serious illness within 14 days prior to study entry; end organ cytomegalovirus infection; Kaposi's sarcoma; cataracts; active herpetic infection or peptic ulcer disease within 12 months; or malabsorption, severe chronic diarrhea, or inability to eat 1 or more meals a day because of chronic nausea, emesis, or abdominal/mouth and throat discomfort
* Current alcohol or drug abuse that would interfere with adherence to study requirements

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Palo Alto
country: United States
facility: Stanford CRS
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Sacramento
country: United States
facility: Univ. of California Davis Med. Ctr., ACTU
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Honolulu
country: United States
facility: Univ. of Hawaii at Manoa, Leahi Hosp.
state: Hawaii
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS
state: Maryland
city: Minneapolis
country: United States
facility: University of Minnesota, ACTU
state: Minnesota
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: New York
country: United States
facility: Beth Israel Med. Ctr., ACTU
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS
state: Pennsylvania
city: Philadelphia
country: United States
facility: Univ. of Pennsylvania Health System, Presbyterian Med. Ctr.
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Pitt CRS
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
Study officials:
affiliation: Division of Infectious Diseases, University of Texas Southwestern Medical Center
name: David Margolis, MD
role: STUDY_CHAIR
References:
citation: Chapuis AG, Paolo Rizzardi G, D'Agostino C, Attinger A, Knabenhans C, Fleury S, Acha-Orbea H, Pantaleo G. Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo. Nat Med. 2000 Jul;6(7):762-8. doi: 10.1038/77489.
citation: Coull JJ, Turner D, Melby T, Betts MR, Lanier R, Margolis DM. A pilot study of the use of mycophenolate mofetil as a component of therapy for multidrug-resistant HIV-1 infection. J Acquir Immune Defic Syndr. 2001 Apr 15;26(5):423-34. doi: 10.1097/00126334-200104150-00004.
citation: Gulick RM. New antiretroviral drugs. Clin Microbiol Infect. 2003 Mar;9(3):186-93. doi: 10.1046/j.1469-0691.2003.00570.x.
citation: Rizzardi GP, Lazzarin A, Pantaleo G. Potential role of immune modulation in the effective long-term control of HIV-1 infection. J Biol Regul Homeost Agents. 2002 Jan-Mar;16(1):83-90.