Clinical trial NCT00035932: Atazanavir (BMS-232632) in Combination With Ritonavir or Saquinavir, and Lopinavir/Ritonavir, Each With Tenofovir and a Nucleoside in Subjects With HIV
Official title: Phase III Open Label Atazanavir (BMS-232632) in Combination With Ritonavir or Saquinavir, and Lopinavir/Ritonavir, Each With Tenofovir and a Nucleoside in Subjects With HIV
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2002-05-08
Enrollment: 571
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to learn how well atazanavir (ATV) works in combination with ritonavir (RTV) or saquinavir (SQV) with tenofovir (TDF) and a nucleoside to reduce the viral load of treatment experienced subjects with human immunodeficiency virus (HIV). There is a comparison arm with lopinavir (LPV)/RTV and TDF and a nucleoside.


Eligibility criteria: Inclusion Criteria:

* Virologic failure to 2 or more highly active antiretroviral therapy (HAART) regimens that, in total, have included at least one drug from all approved classes protease inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors (PI, NNRTI, NRTI):

  1. Currently on a failing HAART regimen with 2 qualifying plasma viral load measurements (hospital/clinic value within 4 weeks of screening with viral load equivalent to =\>1,000 c/mL on the Roche Amplicor\[TM\] and central lab measurements of =\>1,000 c/mL (Roche Amplicor\[TM\]) within 4 weeks of randomization
  2. Cluster of Differentiation 4 (CD4) cell count =\>50 cells/mm3 obtained within 4 weeks prior to randomization
* =\>16 years of age (or minimum age as determined by local regulations or as legal requirements dictate);
* History of prior virologic response to at least one HAART regimen, defined as a 1.0 log10 decline or a decline in viral load to \<400 c/mL by Roche Amplicor or \<500 c/mL by Chiron Quantiplex branched DNA (bDNA) assay
* Both females of child bearing potential and males must utilize effective barrier contraception to reduce transmission of sexually transmitted disease, including human immunodeficiency virus (HIV). Other contraception in addition to barrier methods is permitted; interaction between atazanavir and oral contraceptives has not been studied.
* Subjects must be able to provide written informed consent;
* Subjects should be available for follow-up for a period of at least 48 weeks
* Baseline laboratory values measured within 2 weeks prior to initiating study drugs as follows:

  1. serum creatine \<1.5 times the upper limit of normal (ULN)
  2. total serum lipase \<1.4 times the ULN
  3. liver enzymes alanine aminotransferase (AST), aspartate aminotransferase (ALT) \<3 times the ULN
  4. total serum bilirubin \<1.5 times the ULN

Exclusion Criteria:

* Prior use (=\>3 days) of atazanavir, TVF or LPV/RTV; if history of SQV, then must be phenotypically sensitive
* the current failing antiretroviral regimen must have been administered for at least eight weeks at he initiation of screening and must not include both a PI and NNRTI
* Presence of a newly diagnosed HIV-related opportunistic infection or any medical requiring acute therapy at the time of enrollment
* Proven or suspected acute hepatitis in the 30 days prior to study entry. Subjects with chronic hepatitis are eligible provided that their liver function enzymes (ALT/AST) are \<3 x ULN
* Previous therapy with agents with significant systemic myelosuppressive, neurotoxic, pancreatoxic, hepatoxic or cytotoxic potential within 3 months of study start or the expected need for such therapy at the time of enrollment of therapy with methadone or ribavirin/interferons or treatment with neurotoxic drugs or drugs that affect Cytochrome P450 3A4 (CYP3A4).
* Active alcohol or substance use sufficient, in the Investigator's opinion, to prevent adequate compliance with study therapy or to increase the risk of developing pancreatitis or chemical hepatitis
* Intractable diarrhea (=\> 6 loose stools/day for at least 7 days consecutive days) within 30 days prior to study entry
* Pregnancy or breast-feeding
* History of hemophilia
* Presence of cardiomyopathy
* Any one of the following:

  1. Heart rate-corrected QT (QTc) interval \>450 msec on the screening electrocardiogram (EKG)
  2. Heart rate \<40 beats per minute (bpm)
  3. Pause length \>3 seconds seen on EKG
  4. Clinical symptoms potentially related to heart block
  5. Third degree heart block
* History of acute or chronic pancreatitis
* If choosing 2'-3' dideoxyinosine (ddI) or 2',3'-didehydro-3'-deoxythymidine (d4T) as the NRTI: History or signs and symptoms of bilateral peripheral neuropathy =\> Grade 2 at the time of screening
* Inability to tolerate oral medications
* Any other clinical conditions or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for study or unable to comply with the dosing requirements.

Primary outcomes:
measure: Mean Change From Baseline in HIV Ribonucleic Acid (RNA) at Week 24
timeFrame: Baseline, Week 24
measure: Mean Change From Baseline in HIV RNA at Week 48
timeFrame: Baseline, Week 48
measure: Mean Change From Baseline in HIV RNA at Week 96
timeFrame: Baseline, Week 96
Secondary outcomes:
measure: Mean Change From Baseline in HIV RNA at Week 2
timeFrame: Baseline, Week 2
measure: Participants Achieving Virologic Half Log Suppression (Limit of Quantification [LOQ] = 400 c/mL) at Week 24 (Overall and by Protease Inhibitor [PI] Sensitivity)
timeFrame: Baseline, Week 24
measure: Participants Achieving Virologic Half Log Suppression (LOQ = 400 c/mL) at Week 48, (Overall and by PI Sensitivity)
timeFrame: Baseline, Week 48
measure: Participants Achieving Virologic Half Log Suppression (LOQ = 400 c/mL) at Week 96
timeFrame: Baseline, Week 96
measure: Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 24
timeFrame: Week 24
measure: Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 24, by PI Sensitivity
timeFrame: Baseline, Week 24
measure: Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 48
timeFrame: Week 48
measure: Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 48, by PI Sensitivity
timeFrame: Baseline, Week 48
measure: Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 96
timeFrame: Week 96
measure: Participants Achieving Treatment Response (LOQ = 400 c/mL) Without Prior Failure at Week 24
timeFrame: Week 24
measure: Participants Achieving Treatment Response (LOQ = 400 c/mL) Without Prior Failure at Week 48
timeFrame: Week 48
measure: Participants Achieving Treatment Response (LOQ = 400 c/mL) Without Prior Failure at Week 96
timeFrame: Week 96
measure: Participants Achieving Treatment Response (LOQ = 50 c/mL) Without Prior Failure at Week 24
timeFrame: Week 24
measure: Participants Achieving Treatment Response (LOQ = 50 c/mL) Without Prior Failure at Week 48
timeFrame: Week 48
measure: Participants Achieving Treatment Response (LOQ = 50 c/mL) Without Prior Failure at Week 96
timeFrame: Week 96
measure: Change From Baseline in CD4 Cell Count at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in CD4 Cell Count at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in CD4 Cell Count at Week 96
timeFrame: Baseline, Week 96
measure: Correlation of ATV Minimum Plasma Concentration (Cmin), Inhibitory Quotient (IQ), and Number of Protease Inhibitor (PI) Mutations at Baseline With HIV RNA Change From Baseline at Week 24
timeFrame: Baseline, Week 24
measure: Correlation of ATV Minimum Plasma Concentration (Cmin), Inhibitory Quotient (IQ), and Number of Protease Inhibitor (PI) Mutations at Baseline With HIV RNA Change From Baseline at Week 48
timeFrame: Baseline, Week 48
measure: Correlation of ATV Minimum Plasma Concentration (Cmin) Inhibitory Quotient (IQ), and Number of PI Mutations at Baseline and CD4 Cell Count Change From Baseline at Week 24
timeFrame: Baseline, Week 24
measure: Correlation of ATV Minimum Plasma Concentration (Cmin) Inhibitory Quotient (IQ), and Number of PI Mutations at Baseline and CD4 Cell Count Change From Baseline at Week 48
timeFrame: Baseline, Week 48
measure: Lipid Mean Percent Change From Baseline at Week 24
timeFrame: Baseline, Week 24
measure: Lipid Mean Percent Change From Baseline at Week 48
timeFrame: Week 48
measure: Lipid Mean Percent Change From Baseline at Week 96, Observed Values
timeFrame: Week 96
measure: Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) Through Week 48
timeFrame: From Enrollment through Week 48
measure: Most Common AEs and AEs of Interest Through Week 48
timeFrame: From Enrollment to Week 48
measure: Fasting Glucose Mean Change From Baseline at Week 24
timeFrame: Baseline, Week 24
measure: Fasting Glucose Mean Change From Baseline at Week 48
timeFrame: Week 48
measure: Grade 3/4 Laboratory Abnormalities Through Week 48
timeFrame: From Enrollment to Week 48
measure: Fridericia-corrected QT (QTcF) Interval and Change From Baseline by Analysis Time Point
timeFrame: Baseline, Week 4 predose, 2-3 hours postdose, 6-12 hours postdose, Week 12, Week 24, Week 48
measure: PR Interval and Change From Baseline by Analysis Time Point
timeFrame: Baseline, Week 4 predose, 2-3 hours postdose, 6-12 hours postdose, Week 12, Week 24, Week 48
measure: Adherence to Regimen Though Week 48 Based on MACS the Multicenter AIDS Cohort Study (MACS) Adherence Questionnaire
timeFrame: Baseline, Week 24, Week 48
measure: Mean Score of European Quality of Life-5 Dimensions (EQ-5D) Health Index Score at Baseline, Mid-Study (Week 24), and Final (Week 48)
timeFrame: Baseline, Week 24, Week 48
measure: Mean Score of European Quality of Life-5 Dimensions (EQ-5D) Visual Analog Scale (VAS) at Baseline, Mid-Study (Week 24), and Final (Week 48)
timeFrame: Baseline, Week 24, Week 48
measure: Number of Participants Utilizing Resources for Managing Lipid Elevation
timeFrame: Baseline, Week 24, Week 48
measure: Mean ATV, RTV and SQV Minimum Concentration (Cmin) Values
timeFrame: collected at the pre-dose time point after receiving atazanavir for at least four weeks
measure: HIV IC50 at Week 24
timeFrame: Week 24
measure: Inhibitory Quotient at Week 24
timeFrame: Baseline, Week 24
measure: Inhibitory Quotient at Week 48
timeFrame: Baseline, Week 48
measure: HIV RNA Level - Treated Subjects With Evaluable Cmins at Week 24
timeFrame: Baseline, Week 24
measure: HIV RNA Level - Treated Subjects With Evaluable Cmins at Week 48
timeFrame: Baseline, Week 48
Other outcomes:
Locations:
city: San Francisco
country: United States
state: California
city: Torrance
country: United States
state: California
city: Boulder
country: United States
state: Colorado
city: Altamonte Springs
country: United States
state: Florida
city: Ft Lauderdale
country: United States
state: Florida
city: Ft Lauderdale
country: United States
state: Florida
city: Miami Beach
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Decatur
country: United States
state: Georgia
city: Honolulu
country: United States
state: Hawaii
city: Boise
country: United States
state: Indiana
city: Wichita
country: United States
state: Kansas
city: Louisville
country: United States
state: Kentucky
city: New Orleans
country: United States
state: Louisiana
city: Brookline
country: United States
state: Massachusetts
city: Fall River
country: United States
state: Massachusetts
city: East Orange
country: United States
state: New Jersey
city: Newark
country: United States
state: New Jersey
city: Buffalo
country: United States
state: New York
city: Manhasset
country: United States
state: New York
city: New York
country: United States
state: New York
city: Rochester
country: United States
state: New York
city: Huntersville
country: United States
state: North Carolina
city: Winston Salem
country: United States
state: North Carolina
city: Winston-Salem
country: United States
state: North Carolina
city: Akron
country: United States
state: Ohio
city: Dallas
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: