Second-line Treatment of HIV-1 With Ritonavir Boosted Atazanavir or Darunavir With an Optimized NRTI Backbone (SUPPRESS)

An Open-Label Phase 3B Study in HIV-Infected Individuals With Viremia on or After Their First-Line Non-Nucleoside Reverse Transcriptase Inhibitor or Integrase Inhibitor-Based Regimen and Starting a Second-Line Regimen Consisting of ATV/RTV or DRV/RTV With an Optimized NRTI Backbone

The purpose of this study is to determine the proportion of subjects with HIV-1 RNA < 50 c/mL at Week 48 in patients who failed their first line therapy containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) or an integrase inhibitor

Study Overview

• Status: Withdrawn
• Conditions: HIV
• Intervention / Treatment: Drug: Atazanavir; Drug: Ritonavir; Drug: Optimized NRTI backbone; Drug: Darunavir

Detailed Description

Allocation: Randomization will be stratified

• ATV = Atazanavir
• DRV = Darunavir
• RTV = Ritonavir

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Southwest Center For Hiv/Aids
    • Phoenix, Arizona, United States
      • Southwest Center For Hiv/Aids
  • Arkansas
    • Little Rock, Arkansas, United States, 72207
      • Health For Life Clinic Pllc
  • California
    • Los Angeles, California, United States, 90069
      • Anthony M. Mills Md Inc
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
    • San Francisco, California, United States, 94109
      • Metropolis Medical Pc
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Hospital
  • Michigan
    • Berkley, Michigan, United States
      • Be Well Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63139
      • Southampton Health Center
    • Saint Louis, Missouri, United States
      • Southampton Health Center
  • New Jersey
    • Hillsborough, New Jersey, United States, 08844
      • I.D. Care Associates
    • Newark, New Jersey, United States, 07102
      • Saint Michael's Medical Center
  • New York
    • Bronx, New York, United States, 10468
      • James J Peters VAMC
    • Bronx, New York, United States
      • Infectious Disease Clinic & AI

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Signed informed consent.

• HIV-1 infected patients with viremia (VL ≥ 500/mL) on or after their first NNRTI or INI-based cART regimen and meeting one of the two criteria below:.

  i) On 1st line Non-nucleoside reverse transcriptase inhibitor (NNRTI) or Integrase inhibitor (INI)-based Combination antiretroviral therapy (cART) with HIV-1 RNA ≥ 500 c/ML after being on the same therapy for at least 12 weeks.

ii) Off 1st line NNRTI or INI-based Combination antiretroviral therapy (cART) for at least 2 weeks after having been on antiviral therapy for at least 4 weeks and who are non-compliant and off first line cART without a history of virologic failure with resistance, with a : HIV-1 RNA ≥ 500 c/ML.

• Fully sensitive genotype and phenotype report for Atazanavir/Ritonavir (clinical cut-off of 5.2) and Darunavir/Ritonavir (clinical cut-off ranging from 10 to 90).
• At least one NRTI other than Lamivudine (3TC) or emtricitabine (FTC) with full sensitivity (one "active" NRTI) by genotype and phenotype, ie, PhenoSense Genotype (GT), report must provide a "sensitive" net assessment of susceptibility. An NRTI or PI (reported with or without ritonavir) with a "partially sensitive" net assessment will not be considered "fully sensitive".
• Mentally able to participate in the study.
• Men and women ≥ 18 years old.
• Women of child bearing potential who engage in vaginal intercourse and who are not clinically sterilized must use highly effective methods of birth control during the study.

Exclusion Criteria

- Screening HIV genotype showing presence at baseline of any of the following Protease inhibitor (PI) Mutation Patterns associated with genotypic resistance to Atazanavir sulfate/ Ritonavir or Darunavir/Ritonavir will lead to exclusion:.

i) Subjects with any darunavir associated mutations* at baseline (*V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V).

ii) Subjects with a major mutation to Atazanavir sulfate consisting of N88S.

iii) Subjects with more than 3 of any of the following Atazanavir sulfate related mutations:D30N, M36I/V, M46I/L/T, I54V/L/T/M/A, A71V/T/I/G, G73S/A/C/T, V77I, V82A/F/T/S/I, I84V/A, N88D or L90M.

- Subjects with < 1 fully active NRTI on PhenoSense report, other than lamivudine and emtricitabine.

• Diagnosed with active tuberculosis.
• Chronic hepatitis B infection.
• Hepatitis C-positive patients who are not clinically stable or need treatment during the study period.
• Acute hepatitis in the 30 days prior to study entry.
• Any gastrointestinal disease or surgical procedure that may impact the absorption of study drug.
• Intractable diarrhea within 30 days prior to study entry.
• Presence of a newly diagnosed Human immunodeficiency virus (HIV)-related opportunistic infection or any medical condition requiring acute therapy at the time of enrollment.
• Subject's with Cushing's syndrome.
• Untreated hypothyroidism or hyperthyroidism.
• Recent therapy with agents with significant systemic myelosuppressive, neurotoxic, pancreatotoxic, hepatotoxic or cytotoxic potential within 3 months of study start.
• Subject's with obstructive liver disease.
• Active alcohol or illegal substance use.
• Inability to swallow capsules.
• Active peripheral neuropathy.
• Presence of cardiomypathy or any significant cardiovascular disease.
• Known, clinically significant cardiac conduction system disease.

• Physical and Laboratory Test Findings:.

  i) Moderate to severe hepatic insufficiency.

ii) Screening laboratory values as follows:.

A. T4 < 4mcg/dL or >11mcg/dL and/or Thyroid-stimulating hormone (TSH) <0.5mU/L or >5.0mU/L.

B. Calculated creatinine clearance < 60 cc/min.

C. Hemoglobin < 8.0 g/dL.

D. Total serum lipase ≥ 1.4 times the upper limit of normal (ULN).

E. Liver enzymes [Aspartate transaminase (AST), Alanine transaminase (ALT)] ≥ 5 times the ULN.

F. Alkaline phosphatase > 5 times the ULN.

G. Platelets < 50,000 cells/mm3.

H. Positive blood screen for hepatitis B surface antigen (HBsAg).

I. Total serum bilirubin ≥ 1.5 times the ULN.

- Allergies and Adverse Drug Reaction:.

i) Previously demonstrated hypersensitivity to any of the components of atazanavir or the other experimental agents in this study.

ii) Darunavir contains a sulfonamide moiety. Darunavir should be used with caution in patients with a known sulfonamide allergy.

iii) History of allergy to atazanavir, ritonavir, or darunavir.

iv) History of allergy to NRTIs included as NRTI backbone options in this study.

v) History of clinically relevant severe drug reaction.

- Sex and Reproductive Status:.

i) Women with a positive pregnancy test on enrollment prior to study drug administration.

ii) Women who become pregnant during the study will be taken off-protocol.

iii) Women using a prohibited contraceptive method.

iv) Women who are breastfeeding.

- Other Exclusion Criteria.

i) Prisoners or subjects who are involuntarily incarcerated.

ii) Subjects who are compulsorily detained for treatment of wither a psychiatric or physical illness.

- Other protocol-defined Inclusion/Exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: ATV/RTV 300/100 mg QD + optimized NRTI backbone	Drug: Atazanavir; Capsule, Oral, 300 mg, Once daily (QD), 48 weeks; Other Names: REYATAZ®; Drug: Ritonavir; Tablet, Oral, 100 mg, Once daily (QD), 48 weeks; Other Names: NORVIR®; Drug: Optimized NRTI backbone; tablet/capsule, Noninvestigational products i.e. NRTI backbone will be administered according to their respective package inserts for 48 weeks NRTI backbone are: - Abacavir (300 mg), Tenofovir (300 mg), Didanosine (250 mg or 400 mg), Stavudine (30 mg or 40 mg), Emtricitabine (200 mg), Lamivudine (300 mg), Zidovudine (300 mg), EPZICOM® (600 mg Ziagen® + 300 mg Lamivudine), COMBIVIR® (150 mg Lamivudine + 300 mg Zidovudine) The following NRTI combinations are prohibited in this study: Didanosine + Stavudine; Zidovudine + Stavudine; Lamivudine + Emtricitabine
Experimental: Arm 2: DRV/RTV 800/100 mg QD + optimized NRTI backbone	Drug: Ritonavir; Tablet, Oral, 100 mg, Once daily (QD), 48 weeks; Other Names: NORVIR®; Drug: Optimized NRTI backbone; tablet/capsule, Noninvestigational products i.e. NRTI backbone will be administered according to their respective package inserts for 48 weeks NRTI backbone are: - Abacavir (300 mg), Tenofovir (300 mg), Didanosine (250 mg or 400 mg), Stavudine (30 mg or 40 mg), Emtricitabine (200 mg), Lamivudine (300 mg), Zidovudine (300 mg), EPZICOM® (600 mg Ziagen® + 300 mg Lamivudine), COMBIVIR® (150 mg Lamivudine + 300 mg Zidovudine) The following NRTI combinations are prohibited in this study: Didanosine + Stavudine; Zidovudine + Stavudine; Lamivudine + Emtricitabine; Drug: Darunavir; Oral, Two 400 mg Tablets, Once daily (QD), 48 weeks; Other Names: PREZISTA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of subjects with Human immunodeficiency virus 1 (HIV-1) Ribonucleic Acid (RNA) < 50 c/mL	At Week 48

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of subjects with HIV-1 RNA < 50 c/mL	At week 24
Change from baseline in CD4 cell count	Baseline (Week 0) and at week 48
Incidence rates of serious adverse event (SAEs) and adverse events (AEs) leading to discontinuation	up to week 48
Incidence rates of antiretroviral resistance measured by newly emergent genotypic substitutions and phenotypic resistance to study drugs for virologic failure	up to week 48
Proportion of subjects with HIV-1 RNA < 50 c/mL at Week 48 by baseline M184V presence or absence	Week 48

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2012
• Primary Completion (Estimated): August 31, 2014
• Study Completion (Estimated): August 31, 2014

Study Registration Dates

• First Submitted: May 22, 2012
• First Submitted That Met QC Criteria: May 23, 2012
• First Posted (Estimated): May 24, 2012

Study Record Updates

• Last Update Posted (Actual): December 19, 2023
• Last Update Submitted That Met QC Criteria: December 17, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Darunavir; Atazanavir Sulfate
• Other Study ID Numbers: AI424-493; 2011-006186-18 (EudraCT Number)