Pilot Study of a Raltegravir Based NRTI Sparing Regimen

The recruitment status of this study is unknown because the information has not been verified recently.
Verified February 2012 by Yale University.
Recruitment status was  Recruiting
Sponsor:
Collaborators:
Bristol-Myers Squibb
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Michael J Kozal, Yale University
ClinicalTrials.gov Identifier:
NCT00814879
First received: December 18, 2008
Last updated: February 28, 2012
Last verified: February 2012
  Purpose

This pilot study will provide data on the safety and efficacy of the combination of Raltegravir (RAL) 400mg BID + Atazanavir (ATV) 300 mg BID in Antiretroviral (ARV)-experienced subjects that have a suppressed HIV viral load on a Ritonavir (RTV) boosted Protease Inhibitor (PI) based regimen who are then switched to a regimen of RAL 400mg BID +ATV 300mg BID.


Condition Intervention
Acquired Immune Deficiency Syndrome
AIDS
Human Immunodeficiency Virus
HIV Infections
Drug: Raltegravir
Drug: Atazanavir
Other: Standard treatment regimen

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Randomized, Open-Label Study Comparing the Safety and Efficacy of a Raltegravir Based NRTI Sparing Regimen

Resource links provided by NLM:


Further study details as provided by Yale University:

Primary Outcome Measures:
  • Virologic Failure: Primary comparisons is regimen a. versus b. for the proportion of patients remaining <50 copies HIV RNA/ml at week 48. [ Time Frame: 48 Weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Proportion of patients with < 400 copies HIV RNA/mL at week 48; Change in CD4+ cell count at weeks 24 and 48; proportion of patients with new HIV disease progression event; changes in fasted lipid and glycemic parameters changes in renal function [ Time Frame: 48 weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 60
Study Start Date: December 2008
Estimated Study Completion Date: January 2013
Estimated Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: a.
N(t)RTI(s) based backbone & PI/r
Other: Standard treatment regimen
N(t)RTI(s) based backbone plus ritonavir boosted PI
Experimental: b.
Raltegravir (RAL) 400mg BID + atazanavir (ATV) 300 mg BID
Drug: Raltegravir
400 mg BID
Other Name: Isentress
Drug: Atazanavir
300 mg BID
Other Name: Reyataz

Detailed Description:

The purpose of this pilot study is to compare the virological efficacy, as measured by the proportion of patients with plasma HIV-RNA below the limit of detection (<50 copies/mL), of two ARV regimens; patients are randomized to remain on regimens containing N(t)RTI(s) + PI/r or switch to Raltegravir + ATV but without N(t)RTI(s).

Study Arms:

  1. N(t)RTI(s) based backbone + PI/r
  2. Raltegravir (RAL) 400mg BID + atazanavir (ATV) 300 mg BID

Antiretroviral (ARV) treatment guidelines currently recommend ARV regimens containing a Nucleos(t)ide Reverse Transcriptase Inhibitors [N(t)RTI(s)] based backbone with a Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI) or ritonavir boosted Protease Inhibitor (PI/r).(1) However, significant toxicity has been associated with N(t)RTI(s) and PI/r containing regimens. N(t)RTI(s) can cause lipoatrophy, lipid elevations, renal toxicity, neuropathy and lactic acidosis.(1) These toxicities have required clinicians and HIV-infected individuals to use alternative ARV regimens that do not use N(t)RTI(s). PIs are known to cause gastrointestinal side effects, dyslipidemia, and fat maldistribution (lipodystrophy).(1) The DHHS HIV treatment guidelines recommend that PIs should be given with a low dose of ritonavir (RTV). RTV is a PI that has an inhibitory effect on cytochrome P-450 3A4 isoenzyme which metabolizes most PIs. The addition of RTV serves as a pharmacokinetic "booster" by increasing PI drug concentrations.(1) However, RTV is known to increase PI side effects, elevate lipid levels and has significant drug-drug interactions with many medications given to HIV+ individuals.(1) These RTV drug interactions can complicate the medical care of an HIV-infected individual.

Raltegravir (RAL) is a recently FDA approved antiretroviral agent that inhibits HIV replication by blocking the integration of HIV proviral DNA into the host cell chromosomal DNA. RAL does not exhibit cross resistance to other ARV classes and thus has been initially used in HIV-infected individuals that are infected with drug resistant HIV strains. Recently published data on the use of RAL(2,3)in HIV-infected subjects with known ARV drug resistance or those without ARV drug resistance4 demonstrates that RAL is a potent agent, suppressing HIV viral loads in the majority of subjects and having excellent CD4 cell responses.(2-4) RAL is metabolized through glucuronidation by the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) enzyme pathway.(5)ATV is a known inhibitor of this enzyme pathway. ATV will increase RAL levels,(5) however, the current DHHS HIV treatment guidelines do not recommend a change in the dose of RAL if given with ATV as persons receiving ATV and RAL have demonstrated good tolerability of the combination and low side effect profiles.(1-3,5)

The availability of RAL provides an opportunity to examine alternative ARV strategies that may be equally efficacious and less toxic than those currently recommended in HIV treatment guidelines. Such combinations might include RAL+ATV regimen without a concomitant N(t)RTI(s) based backbone and/or the inclusion of RTV. However, there is little data available to date regarding such a combination. HIV care providers have already begun to use the combination of RAL+ unboosted ATV as the patients they care for are intolerant of RTV or have had major side effects/toxicity with N(t)NRTIs. More investigation is required to determine if RAL+ATV is an efficacious and safe alternative to RTV boosted PI based ARV strategies. Before a RAL based strategy that does not include N(t)RTIs or RTV can be compared to other ARV class strategies for long-term efficacy outcomes, preliminary data on a RAL+ATV based regimen is needed. This pilot study will provide data on the safety and efficacy of the combination of RAL 400mg BID + ATV 300 mg BID in ARV-experienced subjects that have a suppressed HIV viral load on a RTV boosted PI based regimen who are then switched to a regimen of RAL 400mg BID +ATV 300mg BID.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV-1 positive
  • On stable ARV-therapy for a minimum of 4 months with a HIV viral load of < 50 copies
  • Currently on a N(t)RTI(s) based backbone + PI/r
  • No prior history of PI drug resistance (by historical genotype or phenotype)
  • Aged > 18 years of age
  • Written informed consent
  • Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized.

Exclusion Criteria:

  • Prior exposure to Raltegravir or Elvitegravir
  • A detectable HIV viral load >50 copies within the last 4 months
  • An ARV change within the last 4 months
  • History of PI drug resistance
  • Prior virologic failure on an ATV containing regimen
  • Prior history of intolerance to ATV
  • Pregnant or nursing mothers
  • Pre-existing grade 3 or above laboratory toxicity except for lipids:
  • Absolute neutrophil count (ANC) < 750 cells/mL.
  • Hemoglobin < 8.0 g/dL.
  • Platelet count < 50 000 cells/mL.
  • AST, ALT and alkaline phosphatase > 5 x ULN.
  • Serum bilirubin > 5 x ULN.
  • calculated creatinine clearance of <50mL/min/1.73m2
  • Patients with chronic active hepatitis B infection defined by positive serum Hbs antigen
  • Use of any prohibited medications and/or the use of proton pump inhibitors in ATV plus RAL containing regimens)
  • Patients with current alcohol or illicit substance use that in judgment of investigator makes study adherence unlikely
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00814879

Contacts
Contact: Laurie J Andrews, RN MPH 203-785-3557 laurie.andrews@yale.edu
Contact: Cyndi Frank, RN MBA 203-785-6939 cyndi.frank@yale.edu

Locations
United States, Connecticut
Yale University School of Medicine Recruiting
New Haven, Connecticut, United States, 06504
Contact: Laurie J Andrews, RN MPH    203-785-3557    laurie.andrews@yale.edu   
Principal Investigator: Michael J Kozal, MD         
Saint Raphael Healthcare System Not yet recruiting
New Haven, Connecticut, United States, 06511
Principal Investigator: Sharon Weissman, MD         
Waterbury Hospital Not yet recruiting
Waterbury, Connecticut, United States, 06721
Principal Investigator: Steven I Aronin, MD FACP         
VA CT Healthcare Systems Not yet recruiting
West Haven, Connecticut, United States, 06516
Principal Investigator: Michael J Kozal, MD         
Sponsors and Collaborators
Yale University
Bristol-Myers Squibb
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Michael J Kozal, MD Yale University
  More Information

No publications provided

Responsible Party: Michael J Kozal, Professor of Medicine, Yale University
ClinicalTrials.gov Identifier: NCT00814879     History of Changes
Other Study ID Numbers: 0811004448, Yale-No Nukes
Study First Received: December 18, 2008
Last Updated: February 28, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Yale University:
Acquired Immune Deficiency Syndrome
AIDS
Anti-Infective Agents
Antiretroviral
Antiviral Agents
Atazanavir
Human Immunodeficiency Virus
HIV
HIV Protease Inhibitors
NRTI
Nucleoside Reverse Transcriptase Inhibitors
Raltegravir
Resistance
treatment experienced

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Immunologic Deficiency Syndromes
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immune System Diseases
Atazanavir
Anti-Infective Agents
HIV Protease Inhibitors
Reverse Transcriptase Inhibitors
Therapeutic Uses
Pharmacologic Actions
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on April 15, 2014