Clinical trial NCT01400412: Bone, Immunologic, and Virologic Effects of a Antiretroviral Regimen
Official title: A Phase 2b, Double-Blind, Placebo-Controlled, Exploratory Randomized Trial to Determine the Bone, Immunologic, Virologic, and Neurocognitive Effects of a Novel Maraviroc-Containing Antiretroviral Regimen in Treatment-Naïve Patients Infected With R5-Tropic HIV-1
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1 Infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2011-07-22
Enrollment: 262
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 main purpose of this study was to compare the effects on bones of the following two drug combinations:

* maraviroc (MVC), emtricitabine (FTC), plus darunavir/ritonavir (DRV/r)
* tenofovir (TDF) plus emtricitabine (FTC) plus darunavir/ritonavir (DRV/r)

Additional study objectives were the following:

* To see how the drug combinations affect the brain and kidneys.
* To see how well the drug combinations lower the HIV viral load.
* To see how safe the drug combinations are, how well people are able to take the study drug combinations, and how well their immune systems respond to the study drugs.

Detailed description: There are now several HIV treatment options for a person with HIV infection who has not yet been treated. Most people who receive treatment and take their medications as directed have a good result. This is usually determined by measuring the amount of HIV in the blood (viral load). The best response is when HIV cannot be found (less than 50 copies/mL) in the blood. However, it has recently become clear that some people with HIV who are receiving effective HIV drugs continue to have more health problems than people without HIV infection. Sometimes, there is damage to organs in the body, including bone, kidneys, and the brain.

Eligibility criteria: Inclusion Criteria:

* HIV-1 infection
* No evidence of exclusionary resistance mutations defined as evidence of any major NRTI mutation according to the current IAS list of HIV-1 Resistance Mutations Associated with Drug Resistance, or any DRV RAMs (refer to the A5303 PSWP for a list of these mutations) on any genotype; or evidence of significant NRTI or DRV resistance on any phenotype performed at any time prior to study entry. NNRTI-associated resistance mutations were not exclusionary.
* ARV drug-naïve, defined as \</=10 days of ART at any time prior to study entry, except in the instances defined in section 4.1.3 of the protocol.
* R5-only tropism based on Trofile testing performed within 90 days prior to study entry.
* Screening HIV-1 RNA \>1000 copies/mL obtained within 90 days prior to study entry by any FDA-approved test for quantifying HIV-1 RNA at any laboratory that has a CLIA certification or its equivalent.
* Known hepatitis C virus (HCV) antibody status (performed at any laboratory that had a CLIA certification or its equivalent).
* Certain laboratory values obtained within 60 days prior to study entry, as defined in section 4.1.7 of the protocol.
* For women of reproductive potential, negative serum or urine pregnancy test with a sensitivity of ≤25 mIU/mL within 72 hours prior to study entry.
* Female subjects of reproductive potential, who were participating in sexual activity that could lead to pregnancy, must agree to use at least one reliable method of contraception (as defined in section 4.1.9.1 of the protocol) while receiving the study drugs and for 6 weeks after stopping the medications.
* Female subjects who were not of reproductive potential or whose male partner(s) had azoospermia were eligible to take study drugs without the use of contraceptives.
* Ability and willingness of subject or legal guardian/representative to give written informed consent.
* Willingness to undergo neuropsychological testing.
* DXA scan performed after confirmation of the subject's eligibility by Trofile testing but no more than 4 weeks prior to randomization.

Exclusion Criteria:

* Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry.
* New use of hormonal therapies within 6 months prior to study entry. (Stable therapy for ≥6 months was permitted.)
* New use of oral contraceptive pills (OCPs) in the past 3 months. (Stable therapy for ≥3 months was permitted.)
* Any oral, intravenous, or inhaled steroids within 30 days prior to study entry. (Intranasal steroids and topical corticosteroids were allowed.)
* Known allergy/sensitivity to study drugs or their formulations. (A history of sulfa allergy was not an exclusionary condition.)
* Known hypersensitivity to soy lecithin.
* Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or was clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry. (Oral candidiasis, vaginal candidiasis, mucocutaneous herpes simplex, and other minor illnesses (as judged by the site investigator) were not exclusionary conditions.)
* Requirement for any current medications that were prohibited with any study drugs. (Prohibited medications must be discontinued at least 30 days prior to entry. Refer to the A5303 PSWP for a list of prohibited medications.)
* The presence of decompensated cirrhosis.
* A history of or current, active HBV infection defined as positive hepatitis B surface antigen test (or positive HBV DNA in subjects with isolated HBcAb positivity, defined as negative HBsAg, negative HBsAb, and positive HBcAb) at screening.
* Current or prior use of biphosphonates, teriparatide, raloxifene, or denosumab.
* Weight \>300 lbs (exceeds weight limit of DXA scanners).
* History after 18 years of age of fracture of the spine, hip, wrist, or other site thought to be related to osteoporosis or bone fragility.
* Currently breastfeeding.
* Any active psychiatric illness including schizophrenia, severe depression, or severe bipolar affective disorder that, in the opinion of the investigator, could confound the analysis of the neurological examination or neuropsychological test results.
* Active drug or alcohol abuse that, in the investigator's opinion, could prevent compliance with study procedures or confound the analysis of study endpoints.
* Active brain infection (except for HIV-1), fungal meningitis, toxoplasmosis, central nervous system (CNS) lymphoma, brain neoplasm, or space-occupying brain lesion requiring acute or chronic therapy.

Primary outcomes:
measure: Percent Change From Baseline in Total Hip Bone Mineral Density (BMD)
timeFrame: Week 0, week 48
Secondary outcomes:
measure: Percent Change in Lumbar Spine Bone Mineral Density (BMD)
timeFrame: Week 0, week 48
measure: Change in CD4 Count From Baseline to Week 24
timeFrame: Week 0, week 24
measure: Change in CD4 Count From Baseline to Week 48
timeFrame: Week 0, week 48
measure: CD8+ T-cell Change From Baseline to Week 48
timeFrame: At weeks 0 and 48
measure: Percentage Change in Expression of CD38+/HLA-DR+ on CD4+ T Cells From Baseline to Week 48
timeFrame: At weeks 0 and 48
measure: Percentage Change in Expression of CD38+/HLA-DR+ on CD8+ T Cells From Baseline to Week 48
timeFrame: At weeks 0 and 48
measure: Percent Change in Expression of CD28+/CD57+ on CD8+ T Cells From Baseline to Week 48
timeFrame: At weeks 0 and 48
measure: Percent Change in Expression of CD57+ on CD8+ T Cells From Baseline to Week 48
timeFrame: At weeks 0 and 48
measure: Percent Change in Expression of CD28+ on CD8+ T Cells From Baseline to Week 48
timeFrame: At weeks 0 and 48
measure: Percent Change in Expression of RANKL+ on CD8+ T Cells From Baseline to Week 48
timeFrame: At weeks 0 and 48
measure: Change in Levels of IL-6 From Baseline to Week 48
timeFrame: At weeks 0 and 48
measure: Change in Level of IP-10 From Baseline to Week 48
timeFrame: At weeks 0 and 48
measure: Change in Levels of sCD163 From Baseline to Week 48
timeFrame: At weeks 0 and 48
measure: Change in Levels of sCD14 From Baseline
timeFrame: At weeks 0 and 48
measure: Change in Levels of D-dimer From Baseline
timeFrame: At weeks 0 and 48
measure: Cumulative Probability of Virologic Failure by Week 48
timeFrame: From study treatment initiation to week 48
measure: Number of Participants Who Experienced Bone Fractures
timeFrame: From study treatment initiation to week 48
measure: Number of Participants Who Died During the Study
timeFrame: From study treatment initiation to week 48
measure: Number of Participants Who Developed Grade 3 or 4 Primary Adverse Events
timeFrame: From study treatment initiation to week 48
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 31788 Alabama CRS
state: Alabama
city: Los Angeles
country: United States
facility: University of Southern California (1201)
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS (601)
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs (701)
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs (801)
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS (6101)
state: Colorado
city: Denver
country: United States
facility: University of Colorado Denver ATN CRS (33022)
state: Colorado
city: Washington
country: United States
facility: Georgetown University CRS (GU CRS) (1008)
state: District of Columbia
city: Washington
country: United States
facility: Children's National Med. Ctr. ATN CRS (33003)
state: District of Columbia
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS (901)
state: Florida
city: Tampa
country: United States
facility: Univ. of South Florida (USF) College of Medicine ATN CRS (33001)
state: Florida
city: Atlanta
country: United States
facility: The Ponce de Leon Center CRS (5802)
state: Georgia
city: Chicago
country: United States
facility: Northwestern University CRS (2701)
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS (2702)
state: Illinois
city: Baltimore
country: United States
facility: IHV Baltimore Treatment CRS (4651)
state: Maryland
city: Baltimore
country: United States
facility: 201 Johns Hopkins University CRS
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS (101)
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp. ACTG CRS (107)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington U CRS (2101)
state: Missouri
city: Camden
country: United States
facility: Cooper Univ. Hosp. CRS (31476)
state: New Jersey
city: New York
country: United States
facility: Columbia Physicians and Surgeons CRS (30329)
state: New York
city: Rochester
country: United States
facility: Trillium Health ACTG CRS (1108)
state: New York
city: Rochester
country: United States
facility: University of Rochester Adult HIV Therapeutic Strategies Network CRS (31787)
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs (3201)
state: North Carolina
city: Greensboro
country: United States
facility: Moses H. Cone Memorial Hospital CRS (3203)
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS (2401)
state: Ohio
city: Cleveland
country: United States
facility: Case CRS (2501)
state: Ohio
city: Cleveland
country: United States
facility: Metro Health CRS (2503)
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS (2301)
state: Ohio
city: Philadelphia
country: United States
facility: Hops. of Univ. of Pennsylvania CRS (6201)
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hospital ACTG CRS (2951)
state: Rhode Island
city: Memphis
country: United States
facility: St. Jude Children's Research Hosp. ATN CRS (33016)
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS (3652)
state: Tennessee
city: Dallas
country: United States
facility: Peabody Health Center CRS (31443)
state: Texas
city: Houston
country: United States
facility: Houston AIDS Research Team CRS (31473)
state: Texas
city: Houston
country: United States
facility: Texas Childrens Hospital ATN CRS (33018)
state: Texas
city: Seattle
country: United States
facility: University of Washington AIDS CRS (1401)
state: Washington
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS (5401)
Study officials:
affiliation: Northwestern University CRS
name: Babafemi Taiwo, MBBS, MD
role: STUDY_CHAIR
References:
citation: Taiwo BO, Chan ES, Fichtenbaum CJ, Ribaudo H, Tsibris A, Klingman KL, Eron JJ, Berzins B, Robertson K, Landay A, Ofotokun I, Brown T; AIDS Clinical Trials Group A5303 Study Team. Less Bone Loss With Maraviroc- Versus Tenofovir-Containing Antiretroviral Therapy in the AIDS Clinical Trials Group A5303 Study. Clin Infect Dis. 2015 Oct 1;61(7):1179-88. doi: 10.1093/cid/civ455. Epub 2015 Jun 9.