Clinical trial NCT00515827: Effect of Addition of Raltegravir (MK-0518) to PI- or NNRTI-Based ART Regimens in HIV Infected Subjects With Undetectable Viral Load
Official title: A Double-Blind, Randomized, Pilot Study to Measure the Effect of Treatment Intensification With a Potent Integrase Inhibitor, Raltegravir (MK-0518), on the Level of Persistent Plasma Viremia Below 50 Copies/ml in Subjects on Protease Inhibitor- or Non-Nucleoside Reverse Transcriptase Inhibitor-Containing Regimens
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Treatment Experienced
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2007-08-14
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in vitro activity against HIV-1 strains including those resistant to currently available antiretroviral drugs. The purpose of this study is to assess the effectiveness of raltegravir in further reducing viral load in HIV infected patients that have already achieved viral suppression below the level of detection of standard viral load assays when added to antiretroviral therapy (ART).

Detailed description: Although ART has reduced the morbidity and mortality from HIV-1 infection, most individuals who stop ART experience rapid viral rebound. Effective ART can suppress viral load to less than 50 copies/ml; however, current treatment regimens cannot completely eliminate the infection. The primary purpose of this study was to assess the ability of the HIV-1 integrase inhibitor, raltegravir, to reduce viral load when added to ART regimens of HIV-1 infected patients who have achieved viral suppression to less than 50 copies/ml.

The study lasted 24 weeks. Participants were randomly assigned to one of two arms. Participants in Arm A were administered raltegravir in addition to their usual ART regimen from study entry until Week 12. At Week 12, subjects halted raltegravir use and received a placebo until Week 24. Participants in Arm B were administered the placebo in addition to their usual ART regimen from study entry until Week 12. At Week 12, subjects halted the placebo and received raltegravir until Week 24. A real-time polymerase chain reaction (PCR) single copy assay (SCA) capable of detecting 1 copy of HIV RNA was used to assay viral load. The cross-over design allowed assessment of the effect of intensification with raltegravir between the two arms at Weeks 10/12 and every participant enrolled in the study receiving raltegravir for 12 weeks. Primary analysis focused on weeks 10/12 measurement and with no washout period, typical analysis of cross-over design was not intended.

All participants had scheduled visits at Weeks 0, 2, 4, 10, 12, 14, 16, 22, and 24. A targeted physical exam occurred at all visits. Blood and urine collection occurred at selected visits. A medical/medication assessment occurred at trial entry. Drug dispensing and an adherence questionnaire occurred at some visits. A pregnancy test occurred at select visits. Participants' background ART medications were not provided by the study.

Eligibility criteria: Inclusion Criteria:

* HIV-1 Infection
* ART for at least 12 months prior to study entry that includes at least two NRTIs and either an NNRTI or a ritonavir-boosted PI
* No change in ART regimen for at least 3 months prior to study entry
* CD4 count of 200 or more at screening
* Viral load below the limit of quantification of an ultrasensitive assay for at least 6 months prior to study entry
* Viral load less than 50 copies/ml using Roche Amplicor HIV-1 RNA Ultrasensitive assay within 60 days of study entry
* All viral load assays obtained within 6 months prior to study entry lower than limits of quantification on all tests
* Pre-ART viral load level greater than 100,000 copies/ml
* Detectable viral load of 1 copy or more on the screening SCA
* Available pre-study entry plasma sample for SCA viral load determination
* Absolute neutrophil count of 750/mm3 or more
* Hemoglobin of 9 g/dL or more for female subjects and 10 g/dL or more for male subjects
* Platelet count of 50,000/mm3 or more
* Calculated creatinine clearance of 30 ml/min or more
* AST, ALT, and alkaline phosphate less than or equal to 5 x ULN
* Total bilirubin less than or equal to 2.5 x ULN. If subject is taking indinavir or atazanavir at screening, total bilirubin must be less than or equal to 5 x ULN.
* Negative serum or urine pregnancy test within 48 hours prior to study entry for females with reproductive potential
* Willing to use acceptable means of contraception

Exclusion Criteria:

* Previous documented virologic failure on an antiretroviral regimen
* Unstable clinical condition that would preclude the subject from undergoing study procedures
* Use of immunosuppressive medications within 60 days prior to study entry. Participants using inhaled or nasal steroids are not excluded.
* Opportunistic infection within 60 days prior to study entry
* Allergy or sensitivity to components of study drug
* Active drug or alcohol abuse
* Serious illness requiring systemic treatment within 60 days prior to study entry
* Receipt of non-HIV vaccination within 30 days prior to study entry
* Receipt of any HIV vaccines
* Plan to change background ART within 24 weeks after study entry
* Pregnant or breastfeeding

Primary outcomes:
measure: HIV-1 RNA Level
timeFrame: At Weeks 10 and 12
Secondary outcomes:
measure: Change in HIV-1 RNA Level
timeFrame: At pre-entry, entry, weeks 10 and 12
measure: Change in Total CD4 Cell Count
timeFrame: At pre-entry, entry, and week 12
measure: Change in Total CD8 Cell Count
timeFrame: At pre-entry, entry, and week 12
measure: Change in CD4+/CD38+/HLA-DR+ Percent
timeFrame: At pre-entry, entry, and week 12
measure: Change in CD8+/CD38+/HLA-DR+ Percent
timeFrame: At pre-entry, entry, and week 12
measure: Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From First Day of Treatment to Week 12
timeFrame: From first day of treatment to week 12
measure: Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From Week 12 to Week 24
timeFrame: From week 12 to week 24
measure: Number of Participants Who Discontinued Study Drug
timeFrame: From first day of treatment to week 12
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Palo Alto
country: United States
facility: Stanford CRS
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: New York
country: United States
facility: Cornell CRS
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: New York
country: United States
facility: Columbia P&S CRS
state: New York
city: New York
country: United States
facility: Harlem ACTG CRS
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS
state: North Carolina
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS
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: Massachusetts General Hospital
name: Rajesh T Gandhi, MD
role: STUDY_CHAIR
affiliation: University of North Carolina, Chapel Hill
name: Joseph J Eron Jr., MD
role: STUDY_CHAIR
affiliation: University of Pittsburgh Medical Center
name: John W Mellors, MD
role: STUDY_CHAIR
References:
citation: Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, Gonzalez CJ, Chen J, Harvey CM, Isaacs RD; Protocol 005 Team. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007 Apr 14;369(9569):1261-1269. doi: 10.1016/S0140-6736(07)60597-2.
citation: Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, Azrolan N, Iwamoto M, Wagner JA, Wenning LA. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos. 2007 Sep;35(9):1657-63. doi: 10.1124/dmd.107.016196. Epub 2007 Jun 25.
citation: Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT, Cooper DA, Liporace R, Schwartz R, Isaacs R, Gilde LR, Wenning L, Zhao J, Teppler H. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006 Dec 15;43(5):509-15. doi: 10.1097/QAI.0b013e31802b4956.
citation: Gandhi RT, Zheng L, Bosch RJ, Chan ES, Margolis DM, Read S, Kallungal B, Palmer S, Medvik K, Lederman MM, Alatrakchi N, Jacobson JM, Wiegand A, Kearney M, Coffin JM, Mellors JW, Eron JJ; AIDS Clinical Trials Group A5244 team. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med. 2010 Aug 10;7(8):e1000321. doi: 10.1371/journal.pmed.1000321.
citation: Gandhi RT, Coombs RW, Chan ES, Bosch RJ, Zheng L, Margolis DM, Read S, Kallungal B, Chang M, Goecker EA, Wiegand A, Kearney M, Jacobson JM, D'Aquila R, Lederman MM, Mellors JW, Eron JJ; AIDS Clinical Trials Group (ACTG) A5244 Team. No effect of raltegravir intensification on viral replication markers in the blood of HIV-1-infected patients receiving antiretroviral therapy. J Acquir Immune Defic Syndr. 2012 Mar 1;59(3):229-35. doi: 10.1097/QAI.0b013e31823fd1f2.