Bone, Immunologic, and Virologic Effects of a Antiretroviral Regimen

HIV-1 Infection Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01400412
• Other study ID #: ACTG A5303
• Secondary ID: 1U01AI068636
• Status: Completed
• Phase: Phase 2
• Start date: January 17, 2012
• Est. completion date: June 2014

Study information

• Verified date: January 2018
• Source: AIDS Clinical Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 262
• Est. completion date: June 2014
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• HIV-1 Infection

Intervention

Drug:
• Darunavir
Darunavir was administered orally once a day as two 400 mg tablets with food. When the 800 mg formulation tablet became available, it was substituted for the two 400 mg tablet.
• Ritonavir
Ritonavir was administered orally together with darunavir as one 100 mg tablet once daily with food.
• Tenofovir disoproxil fumarate
Tenofovir disoproxil fumarate was administered orally as one 300 mg tablet once a day.
• Emtricitabine
Emtricitabine was administered orally once a day as one 200 mg capsule.
• Placebo for Tenofovir disoproxil fumarate
Placebo for tenofovir disoproxil fumarate was administered orally once a day as one tablet.
• Placebo for Maraviroc
Placebo for maraviroc was administered orally once a day as one tablet.
• Maraviroc
Maraviroc was administered orally once a day as one 150 mg tablet.

Locations

Country	Name	City	State
Puerto Rico	Puerto Rico-AIDS CRS (5401)	San Juan
United States	The Ponce de Leon Center CRS (5802)	Atlanta	Georgia
United States	University of Colorado Hospital CRS (6101)	Aurora	Colorado
United States	201 Johns Hopkins University CRS	Baltimore	Maryland
United States	IHV Baltimore Treatment CRS (4651)	Baltimore	Maryland
United States	31788 Alabama CRS	Birmingham	Alabama
United States	Brigham and Women's Hosp. ACTG CRS (107)	Boston	Massachusetts
United States	Massachusetts General Hospital ACTG CRS (101)	Boston	Massachusetts
United States	Cooper Univ. Hosp. CRS (31476)	Camden	New Jersey
United States	Unc Aids Crs (3201)	Chapel Hill	North Carolina
United States	Northwestern University CRS (2701)	Chicago	Illinois
United States	Rush Univ. Med. Ctr. ACTG CRS (2702)	Chicago	Illinois
United States	Univ. of Cincinnati CRS (2401)	Cincinnati	Ohio
United States	Case CRS (2501)	Cleveland	Ohio
United States	Metro Health CRS (2503)	Cleveland	Ohio
United States	The Ohio State Univ. AIDS CRS (2301)	Columbus	Ohio
United States	Peabody Health Center CRS (31443)	Dallas	Texas
United States	University of Colorado Denver ATN CRS (33022)	Denver	Colorado
United States	Moses H. Cone Memorial Hospital CRS (3203)	Greensboro	North Carolina
United States	Houston AIDS Research Team CRS (31473)	Houston	Texas
United States	Texas Childrens Hospital ATN CRS (33018)	Houston	Texas
United States	UCLA CARE Center CRS (601)	Los Angeles	California
United States	University of Southern California (1201)	Los Angeles	California
United States	St. Jude Children's Research Hosp. ATN CRS (33016)	Memphis	Tennessee
United States	Univ. of Miami AIDS CRS (901)	Miami	Florida
United States	Vanderbilt Therapeutics CRS (3652)	Nashville	Tennessee
United States	Columbia Physicians and Surgeons CRS (30329)	New York	New York
United States	Hops. of Univ. of Pennsylvania CRS (6201)	Philadelphia	Pennsylvania
United States	The Miriam Hospital ACTG CRS (2951)	Providence	Rhode Island
United States	Trillium Health ACTG CRS (1108)	Rochester	New York
United States	University of Rochester Adult HIV Therapeutic Strategies Network CRS (31787)	Rochester	New York
United States	Washington U CRS (2101)	Saint Louis	Missouri
United States	Ucsd, Avrc Crs (701)	San Diego	California
United States	Ucsf Aids Crs (801)	San Francisco	California
United States	University of Washington AIDS CRS (1401)	Seattle	Washington
United States	Univ. of South Florida (USF) College of Medicine ATN CRS (33001)	Tampa	Florida
United States	Children's National Med. Ctr. ATN CRS (33003)	Washington	District of Columbia
United States	Georgetown University CRS (GU CRS) (1008)	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
AIDS Clinical Trials Group	National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change From Baseline in Total Hip Bone Mineral Density (BMD)	The primary endpoint is the percent change in bone mineral density (BMD) at total hip (as measured by DXA scan) from baseline (week 0) to week 48.	Week 0, week 48
Secondary	Percent Change in Lumbar Spine Bone Mineral Density (BMD)	The percent change in bone mineral density (BMD) at lumbar spine (as measured by DXA scan) from baseline (week 0) to week 48.	Week 0, week 48
Secondary	Change in CD4 Count From Baseline to Week 24	Change in CD4 count from baseline (week 0) to week 24	Week 0, week 24
Secondary	Change in CD4 Count From Baseline to Week 48	Change in CD4 count from baseline (week 0) to week 48	Week 0, week 48
Secondary	CD8+ T-cell Change From Baseline to Week 48	CD8+ T-cell change from baseline to week 48	At weeks 0 and 48
Secondary	Percentage Change in Expression of CD38+/HLA-DR+ on CD4+ T Cells From Baseline to Week 48	percentage change is define as [ (week 48 - week 0) / week 0 ] * 100%	At weeks 0 and 48
Secondary	Percentage Change in Expression of CD38+/HLA-DR+ on CD8+ T Cells From Baseline to Week 48	percentage change is defined as [ (week 48 - week 0) / week 0 ] * 100%	At weeks 0 and 48
Secondary	Percent Change in Expression of CD28+/CD57+ on CD8+ T Cells From Baseline to Week 48	percentage change is define as [ (week 48 - week 0) / week 0 ] * 100%	At weeks 0 and 48
Secondary	Percent Change in Expression of CD57+ on CD8+ T Cells From Baseline to Week 48	percentage change is define as [ (week 48 - week 0) / week 0 ] * 100%	At weeks 0 and 48
Secondary	Percent Change in Expression of CD28+ on CD8+ T Cells From Baseline to Week 48	percentage change is define as [ (week 48 - week 0) / week 0 ] * 100%	At weeks 0 and 48
Secondary	Percent Change in Expression of RANKL+ on CD8+ T Cells From Baseline to Week 48	percentage change is defined as [ (week 48 - week 0) / week 0 ] * 100%	At weeks 0 and 48
Secondary	Change in Levels of IL-6 From Baseline to Week 48	Change in levels of Interleukin 6 (IL-6) from baseline to week 48	At weeks 0 and 48
Secondary	Change in Level of IP-10 From Baseline to Week 48	Change in level of Interferon gamma-induced protein 10 (IP-10) from baseline to week 48	At weeks 0 and 48
Secondary	Change in Levels of sCD163 From Baseline to Week 48	Change in levels of soluble CD163 from baseline to week 48	At weeks 0 and 48
Secondary	Change in Levels of sCD14 From Baseline	Change in levels of soluble CD14 from baseline	At weeks 0 and 48
Secondary	Change in Levels of D-dimer From Baseline	Change in levels of D-dimer from baseline	At weeks 0 and 48
Secondary	Cumulative Probability of Virologic Failure by Week 48	Confirmed virologic failure is defined as confirmed plasma HIV-1 RNA levels > 1000 copies/mL at or after week 16 and before week 24, or confirmed HIV-1 RNA levels> 200 copies/mL at or after week 24. Participants who discontinued the study with an unconfirmed virologic failure (HIV-1 RNA > 1000 copies at 16 weeks or HIV-1 RNA level > 200 copies/mL at or after week 24) are considered as virologic failures at the study visit week of the unconfirmed value. Time to virologic failure is defined as the time from study entry to the planned visit week of the initial failure.; Product-limit estimates for the survival function were used to estimate the cumulative probability of virologic failure over time and its corresponding 95% confidence interval for each treatment group.	From study treatment initiation to week 48
Secondary	Number of Participants Who Experienced Bone Fractures	Number of participants who experienced bone fractures during the study	From study treatment initiation to week 48
Secondary	Number of Participants Who Died During the Study	Number of participants who died during the study	From study treatment initiation to week 48
Secondary	Number of Participants Who Developed Grade 3 or 4 Primary Adverse Events	Grade 3 or 4 primary adverse events includes primary signs/symptoms, primary laboratory abnormalities, or primary diagnoses.; See DAIDS AE Grading Table Version 1.0, Dec 2004 (Clarification, Aug 2009)	From study treatment initiation to week 48