A Phase 2B Multicenter, Randomized, Comparative Trial Of UK-453,061 Versus Etravirine In Combination With Darunavir/Ritonavir And A Nucleos(t)Ide Reverse Transcriptase Inhibitor For The Treatment Of Antiretroviral Experienced HIV-1 Infected Subjects With Evidence Of NNRTI Resistant HIV-1

A Phase 2b Multicenter, Randomized, Comparative Trial Of Uk-453,061 Versus Etravirine In Combination With Darunavir/Ritonavir And A Nucleotide/Nucleoside Reverse Transcriptase Inhibitor For The Treatment Of Antiretroviral Experienced Hiv-1 Infected Subjects With Evidence Of Nnrti Resistant Hiv-1

This is a 96 week study to determine if UK- 453,061 in combination with Darunavir /ritonavir and a Nucleos(t)ide Reverse Transcriptase inhibitor is as efficacious, safe and tolerable as etravirine in combination with Darunavir /ritonavir and a Nucleos(t)ide Reverse Transcriptase inhibitor in HIV-1 infected patients who have been previously treated with antiretroviral drugs and have NNRTI resistance mutations.

Study Overview

• Status: Terminated
• Conditions: HIV-1
• Intervention / Treatment: Drug: UK-453,061 Dose 1; Drug: UK-453,061 Dose 2; Drug: Etravirine

Detailed Description

The trial was terminated on 12 April, 2012 due to lack of efficacy at the Week 24 analysis. The decision to terminate the trial was not based on any safety concerns.

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • PR
    • Curitiba, PR, Brazil, 80240-280
      • Instituto A.Z. de Pesquisa e Ensino
  • RJ
    • Nova Iguacu, RJ, Brazil, 26030-381
      • Hospital Geral de Nova Iguaçu
  • RS
    • PoA, RS, Brazil, 91350-200
      • Hospital Nossa Senhora da Conceicao
  • SP
    • Campinas, SP, Brazil, 13015-080
      • Instituto de Infectologia Campinas
    • Sao Paulo, SP, Brazil, 04121-000
      • Centro de Referência e Treinamento DST/AIDS
    • Sao Paulo, SP, Brazil, 04231-030
      • Hospital Heliopolis
• Germany
  • Koeln, Germany, 50937
    • Klinikum der Universitaet zu Koeln, Klinik I fuer Innere Medizin
• Italy
  • Bologna, Italy, 40138
    • Unita' Operativa Malattie Infettive
  • Roma, Italy, 00184
    • U.O.S. Immunologia Clinica
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre
  • Kelantan
    • Kota Bharu, Kelantan, Malaysia, 15586
      • Hospital Raja Perempuan Zainab II
• Poland
  • Szczecin, Poland, 71-455
    • Oddzial do Leczenia HIV
  • Warszawa, Poland, 01-201
    • SPZOZ Wojewodzki Szpital Zakazny
• Portugal
  • Coimbra, Portugal, 3000-075
    • Hospitais da universidade de Coimbra
  • Lisboa, Portugal, 1169-050
    • Centro Hospitalar de Lisboa - Zona Central - Hospital Santo António Capuchos
  • Lisboa, Portugal, 1349-019
    • Centro Hospitalar de Lisboa Ocidental, EPE.
  • Porto, Portugal, 4200-319
    • Hospital Sao Joao
  • Porto, Portugal, 4369-004
    • Hospital de Joaquim Urbano
• Puerto Rico
  • Bayamon, Puerto Rico, 00959
    • Innovative Care PSC
  • Ponce, Puerto Rico, 00717-1563
    • Ararat Research Center
  • Rio Piedras, Puerto Rico, 00935
    • University of Puerto Rico - Medical Sciences Campus - Puerto Rico Medical Center
  • San Juan, Puerto Rico, 00909
    • HOPE Clinical Research
  • San Juan, Puerto Rico, 00935
    • UPR-CTU Pharmacy
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 1818
      • Soweto Clinical Trials Centre
    • Johannesburg, Gauteng, South Africa, 2193
      • University of Witwatersrand
  • Johannesburg
    • Soweto, Johannesburg, South Africa, 2013
      • Chris Hani Baragwanath Hospital
  • Kwazulu-natal
    • Dundee, Kwazulu-natal, South Africa, 3000
      • Dr. J Fourie Medical Centre
    • Durban, Kwazulu-natal, South Africa, 4001
      • 203 Maxwell Centre
  • Western CAPE
    • Cape Town, Western CAPE, South Africa, 7780
      • Willowmead Medical Center
    • Cape Town, Western CAPE, South Africa, 7925
      • Desmond Tutu HIV Foundation
• Spain
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitari Germans Trias i Pujol
• Taiwan
  • Kaohsiung County, Taiwan, 82445
    • Department of Infectious Disease, E-Da Hospital
  • Taipei, Taiwan
    • Veterans General Hospital - Taipei
• Ukraine
  • Donetsk, Ukraine, 83045
    • Donetsk Regional Center of AIDSs prophylaxis and control
  • Lugansk, Ukraine, 91045
    • Lugansk Regional Center of AIDS prophylaxis and control
  • Vinnitsa District, Vinnitsa Region
    • Berezyna, Vinnitsa District, Vinnitsa Region, Ukraine, 23222
      • Vinnitsa Regional center for AIDS Prevention and Control
• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XU
    • Western General Hospital
  • Edinburgh, United Kingdom, EH3 9HA
    • Royal Infirmary GUM Clinic
  • London, United Kingdom, Nw3 2QG
    • Royal Free Hospital
  • EAST Sussex
    • Brighton, EAST Sussex, United Kingdom, BN2 1ES
      • Brighton and Sussex University Hospitals NHS Trust
  • Greater Manchester
    • Crumpsall, Greater Manchester, United Kingdom, M8 5RB
      • North Manchester General Hospital
• United States
  • California
    • Los Angeles, California, United States, 90028
      • Jeffrey Goodman Special Care Clinic
    • Los Angeles, California, United States, 90069
      • Office of Anthony Mills, MD, Inc.
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • Sacramento, California, United States, 95814
      • CARES
    • San Francisco, California, United States, 94121
      • San Francisco Veterans Affairs Medical Center
  • Florida
    • Miami, Florida, United States, 33133
      • The Kinder Medical Group
    • Miami, Florida, United States, 33137
      • Care Resource
    • Orlando, Florida, United States, 32803
      • Orlando Immunology Center
    • Pensacola, Florida, United States, 32504
      • Infectious Diseases Associates of Northwest Florida, PA
    • Tampa, Florida, United States, 33602
      • Hillsborough County Health Department
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • AIDS Research Consortium of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Ruth M. Rothstein CORE Center
  • New York
    • East Meadow, New York, United States, 11554
      • Nassau University Medical Center
    • Mount Vernon, New York, United States, 10550
      • Greiger Clinic
  • North Carolina
    • Huntersville, North Carolina, United States, 28078
      • Rosedale Infectious Diseases
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0405
      • University of Cincinnati Medical Center
  • Texas
    • Bellaire, Texas, United States, 77401
      • Saint Hope Foundation - Bellaire Clinic
    • Conroe, Texas, United States, 77301
      • Saint Hope Foundation - Conroe Clinic
    • Dallas, Texas, United States, 75204
      • Nicholaos C. Bellos, MD, PA
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas
    • Stafford, Texas, United States, 77477
      • Saint Hope Foundation - Stafford Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female at least 18 years of age available for a follow-up period of at least 96 weeks.
• HIV 1 RNA viral load of greater then 500 copies/mL.
• Negative urine pregnancy test.

Exclusion Criteria:

• Suspected or documented active, untreated HIV-1 related opportunistic infection or other condition requiring acute therapy at the time of randomization.
• Subjects with acute Hepatitis B and/or C within 30 days of randomization.
• Previous use of Darunavir or etravirine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Comparator	Drug: Etravirine; Etravirine 200 mg BID + one optimized NRTI + darunavir/ritonavir.
Experimental: UK- 453,061 Dose One	Drug: UK-453,061 Dose 1; UK 453,061 750 mg QD + one optimized NRTI + darunavir/ritonavir.
Experimental: UK- 453,061 Dose Two	Drug: UK-453,061 Dose 2; UK 453,061 1000 mg QD + one optimized NRTI + darunavir/ritonavir.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Human Immunodeficiency Virus Type 1 Ribonucleic Acid (HIV-1 RNA) Levels Less Than (<) 50 Copies/Milliliter (mL) at Week 24	Plasma HIV-1 RNA level was determined by the Roche Amplicor HIV-1 Monitor standard assay (version 1.5).	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With HIV-1 RNA Levels <50 Copies/mL at Week 48 and 96	Plasma HIV-1 RNA level was determined by the Roche Amplicor HIV-1 Monitor standard assay (version 1.5).	Weeks 48, 96
Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL at Week 24, 48 and 96	Plasma HIV-1 RNA level was determined by the Roche Amplicor HIV-1 Monitor standard assay (version 1.5).	Week 24, 48, 96
Change From Baseline in log10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96	Plasma HIV-1 RNA level was determined by the Roche Amplicor HIV-1 Monitor standard assay (version 1.5). For the log10 scale, all the HIV-1 RNA levels were log10 transformed prior to the average calculations. Baseline value calculated as average of measurements collected prior to and including Day 1 pre-dose.	Baseline, Week 24, 48, 96
Time-Averaged Difference (TAD) in log10 Transformed HIV-1 RNA Levels at Week 24, 48 and 96	TAD was calculated as (area under the curve of HIV-1 RNA levels [log10 copies/mL] from baseline to the time point of interest divided by time period in weeks) minus baseline HIV-1 RNA level (log10 copies/mL). Baseline value calculated as average of measurements collected at prior to and including Day 1 pre-dose. Due to early termination of the study decision was made not to derive TAD results for Week 96.	Week 24, 48, 96
Percentage of Participants With Response as Determined by the Time to Loss of Virologic Response (TLOVR50) Algorithm at Week 24, 48 and 96	TLOVR50 response (50 denotes lower limit of quantification [LLOQ] of assay=50 copies/mL): compliment to TLOVR50 failure. TLOVR50 failure based on observed HIV-1 RNA levels and failure events (death; permanent discontinuation of drug; lost to follow-up; new ARV drug; met treatment failure [TF] criteria). TF: an increase of at least (>=)3 times the baseline plasma HIV-1 RNA level at Week 2 or thereafter; failure to achieve HIV-1 RNA level <50 copies/mL at Week 24; starting at Week 2, an increase in HIV-1 RNA level to detectable levels (>50 copies/mL); HIV-1 RNA <1 log10 decrease from baseline at Week 4 or thereafter. TF were confirmed by second measurement >=14 days after first. Baseline value was calculated as the average of the measurements collected prior to and including Day 1 pre-dose.	Week 24, 48, 96
Change From Baseline in Cluster of Differentiation 4 (CD4+) Absolute Lymphocyte Counts at Week 24, 48 and 96	Blood samples for immunological status assessed by CD4+ lymphocyte count. Baseline value was calculated as the average of the measurements collected prior to and including Day 1 pre-dose.	Baseline, Week 24, 48, 96
Change From Baseline in Cluster of Differentiation 4 (CD4+) Percentage Lymphocyte Counts at Week 24, 48, 96	Blood samples for immunological status assessed by CD4+ lymphocyte count. Baseline value was calculated as the average of the measurements collected prior to and including Day 1 pre-dose.	Baseline, Week 24, 48, 96
Number of Participants With Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) Resistance-Associated Mutations (RAMs) and/or Phenotypic Susceptibility at Time of Treatment Failure Through Week 48	Genotypic and phenotypic resistance to NNRTIs based on International Acquired Immunodeficiency Syndrome (AIDS) Society, United States of America (IAS-USA) RAM guidelines were evaluated using Monogram Biosciences PhenoSenseGT Assay at Baseline. This was then repeated for all participants with HIV-1 viral load >500 copies/mL at treatment failure, up to Week 48.	Baseline through Week 48
Number of Participants With Laboratory Test Abnormalities	Laboratory analysis included blood chemistry, hematology and urinalysis.	Baseline up to Week 48 or early termination
Population Pharmacokinetics (PK) of Lersivirine	Data for this Outcome Measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules.	Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48
Lersivirine Success Percentage With Reference to Median Minimum Observed Plasma Concentration (Cmin)	Simple quartile exposure analysis of success rate (viral load <50 copies/mL) versus median Cmin assesses the exposure response relationship. Percentage of participants with HIV-1 RNA level <50 copies/mL at median Cmin quartile were planned to be reported.	Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48

Collaborators and Investigators

• Sponsor: Pfizer

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2009
• Primary Completion (Actual): October 18, 2012
• Study Completion (Actual): October 18, 2012

Study Registration Dates

• First Submitted: January 15, 2009
• First Submitted That Met QC Criteria: January 15, 2009
• First Posted (Estimate): January 16, 2009

Study Record Updates

• Last Update Posted (Actual): December 4, 2018
• Last Update Submitted That Met QC Criteria: November 7, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: HIV-1 NNRTI Treatment Experienced; may have Protease inhibitor experience
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Etravirine
• Other Study ID Numbers: A5271022; 2007-004392-19 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No