TMC278-TiDP6-C209: A Clinical Trial in Treatment Naive HIV-1 Patients Comparing TMC278 to Efavirenz in Combination With Tenofovir + Emtricitabine.

A Phase III, Randomized, Double-blind Trial of TMC278 25 mg q.d. Versus Efavirenz 600mg q.d. in Combination With a Fixed Background Regimen Consisting of Tenofovir Disoproxil Fumarate and Emtricitabine in Antiretroviral-naive HIV-1 Infected Subjects.

The purpose of this trial is to compare the effectiveness, safety and tolerability of TMC278 given at a dose of 25 mg once daily versus efavirenz (EFV) at a dose of 600 mg once daily, when combined with a fixed background regimen consisting of emtricitabine (FTC) + tenofovir disoproxil fumarate (TDF), in HIV-1 infected patients who have not yet taken any anti-HIV drugs. The following evaluations will be done: antiviral activity, immunologic changes, and viral geno-/phenotype evolution, relationship of Pharmacokinetics (PK) and PK/Pharmacodynamics, medical resource utilization and treatment adherence.

Study Overview

• Status: Completed
• Conditions: HIV Infections; HIV-1; Human Immunodeficiency Virus Type 1
• Intervention / Treatment: Drug: Efavirenz; Drug: TMC278

Detailed Description

Over the past decade, anti-human immunodeficiency virus (HIV) drugs have been introduced sequentially for use in the clinic. Currently, patients are routinely being treated with 3 or 4 drug combinations including nucleoside/tide analogue reverse transcriptase inhibitors (NRTIs/NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and/or fusion inhibitors. New potent antiretroviral (ARV) compounds that work in people whose HIV-1 virus is resistant to available drugs are urgently needed. This is a Phase III, randomized (study medication is assigned by chance), double-blind (neither the study physician nor the patient knows the name of the study assigned medication), double-dummy, active-controlled trial to compare the effectiveness, safety, and ability to tolerate TMC278 versus efavirenz (EFV). The study will last for 104 weeks which includes a screening period of 4 weeks, a 96-week treatment period, followed by a 4 week follow-up period. Patients will be randomly assigned to TMC278 or to efavirenz, either of these treatments will be in combination with two other anti-HIV drugs (2 NRTIs: emtricitabine (FTC) + tenofovir (TDF)). TDF/FTC will be administered as a fixed dose combination if available. The hypothesis to be provided in this study is that the investigational drug TMC278 will perform just like efavirenz (EFV) in terms of antiviral effectiveness (i.e., suppressing of the plasma viral load to a level < 50 HIV-1 RNA (ribonucleic acid) copies/mL) in ARV-naïve HIV-infected patients. During the trial, patients' health will be monitored by physical examination, interview to assess health and well being, and laboratory testing on blood and urine samples. Experimental Group: One tablet of TMC278 25 mg once daily plus one tablet of placebo once daily that looks just like efavirenz (EFV) plus tenofovir/emtricitabine; Control Group: One tablet of Placebo once daily that looks just like TMC278 plus EFV 600 mg once daily plus tenofovir/emtricitabine.

• Study Type: Interventional
• Enrollment (Actual): 694
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
  • Cordoba, Argentina
  • Guernica, Argentina
• Australia
  • Darlinghurst, Australia
  • Melbourne, Australia
  • Perth, Australia
  • Surry Hills, Australia
• Austria
  • Innsbruck, Austria
  • Vienna, Austria
  • Wien, Austria
• Brazil
  • Curitiba, Brazil
  • Nova Iguacu, Brazil
  • Rio De Janeiro, Brazil
  • Salvador, Brazil
  • Sao Paulo, Brazil
• Canada
  • Ontario
    • Ottawa, Ontario, Canada
    • Toronto, Ontario, Canada
  • Quebec
    • Montreal, Quebec, Canada
• Denmark
  • Copenhagen, Denmark
  • Hvidovre N/A, Denmark
  • Odense N/A, Denmark
• France
  • Loire, France
  • Lyon, France
  • Paris, France
  • Paris Cedex 10, France
  • Paris Cedex 12, France
  • Tourcoing, France
  • Villejuif Cedex, France
• Mexico
  • Ciudad De Mexico, Mexico
  • Zapopan, Mexico
• Netherlands
  • Rotterdam, Netherlands
• Portugal
  • Amadora, Portugal
  • Lisboa, Portugal
  • Portimao, Portugal
  • Porto, Portugal
• Puerto Rico
  • San Juan, Puerto Rico
• Romania
  • Bucuresti, Romania
  • Iasi, Romania
  • Timisoara, Romania
• Russian Federation
  • Krasnodar, Russian Federation
  • St Petersburg, Russian Federation
• South Africa
  • Bloemfontein, South Africa
  • Cape Town, South Africa
  • Durban N/A, South Africa
  • Houghton, Johannesburg, South Africa
  • Johannesburg, South Africa
  • Pretoria N/A, South Africa
• Spain
  • Alicante, Spain
  • Barcelona, Spain
  • Madrid, Spain
• Sweden
  • Göteborg, Sweden
  • Malmö, Sweden
  • Stockholm, Sweden
• Taiwan
  • Kaohsiung, Taiwan
  • Kaohsiung County, Taiwan
  • Tainan, Taiwan
  • Taipei, Taiwan
• Thailand
  • Bangkok, Thailand
  • Chiang Mai, Thailand
  • Khon Kaen, Thailand
• United Kingdom
  • Birmingham, United Kingdom
  • Brighton, United Kingdom
  • London, United Kingdom
• United States
  • Alabama
    • Birmingham, Alabama, United States
  • Arizona
    • Phoenix, Arizona, United States
  • California
    • Beverly Hills, California, United States
    • Los Angeles, California, United States
    • Newport Beach, California, United States
    • Sacramento, California, United States
  • District of Columbia
    • Washington, District of Columbia, United States
  • Florida
    • Fort Lauderdale, Florida, United States
    • Miami, Florida, United States
    • Tampa, Florida, United States
    • Vero Beach, Florida, United States
    • West Palm Beach, Florida, United States
  • Georgia
    • Macon, Georgia, United States
  • Illinois
    • Chicago, Illinois, United States
  • Maryland
    • Baltimore, Maryland, United States
  • New Jersey
    • Newark, New Jersey, United States
  • New York
    • Albany, New York, United States
    • Buffalo, New York, United States
    • New York, New York, United States
  • North Carolina
    • Chapel Hill, North Carolina, United States
    • Durham, North Carolina, United States
    • Winston Salem, North Carolina, United States
  • Ohio
    • Akron, Ohio, United States
    • Cincinnati, Ohio, United States
    • Columbus, Ohio, United States
  • Oregon
    • Portland, Oregon, United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
  • South Carolina
    • Columbia, South Carolina, United States
  • Texas
    • Austin, Texas, United States
    • Dallas, Texas, United States
  • Washington
    • Seattle, Washington, United States
  • Wisconsin
    • Milwaukee, Wisconsin, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient with documented HIV-1 infection
• Patient has never been treated with a therapeutic HIV vaccine or an ARV drug prior to screening
• Patient's HIV-1 plasma viral load at screening is > 5,000 HIV-1 RNA copies/mL (assayed by RNA PCR standard specimen procedure)
• Patient's virus is sensitive to TDF and FTC
• Patient agrees not to start ART (antiretroviral treatment) before the baseline visit

Exclusion Criteria:

• Previous use of ANY ARV drug for ANY length of time
• Any documented evidence of NNRTI resistance associated mutations in patient's HIV
• Category C AIDS defining illness, except: stable Kaposi Sarcoma, wasting syndrome if not progressive
• Pneumocystis carinii pneumonia (PCP) that is considered not cured
• Active TB
• Allergy or hypersensitivity to study or background ARTs
• Specific grade 3 or 4 toxicity
• Kidney impairment: calculated creatinine clearance <50 ml/min

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Efavirenz; Efavirenz 600mg once daily for 96 weeks	Drug: Efavirenz; 600mg once daily for 96 weeks
Experimental: TMC278; TMC278 25 mg tablet once daily for 96 weeks	Drug: TMC278; 25 mg tablet once daily for 96 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 48	Virological response is defined as confirmed plasma viral load less than (<) 50 human immunodeficiency virus-1 (HIV-1) (ribonucleic acid [RNA]) copies/milliliter (ml) at Week 48. The TLOVR algorithm was used to derive response. Response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders after discontinuation. Resuppression after confirmed virologic failure was considered as failure. Virologic Failure includes participants who were rebounder (confirmed viral load >= 50 copies/ml after being responder) or who were never suppressed (no confirmed viral load <50 copies/ml).	Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 48	The analysis is based on the last observed viral load (VL) data within the Week 48 window. Virologic response is defined as a VL<50 copies/ml (observed case). Missing VL was considered as non-response. Virologic Failure includes subjects who had VL>=50 copies/ml in the Wk48 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a VL>=50 copies/ml and subjects who had a switch in background regimen that was not permitted by the protocol.	Week 48
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <50 Copies/ml) at Week 96		Week 96
The Number of Participants With Virological Response (Intent-to-Treat - Snapshot, <50 Copies/ml) at Week 96		Week 96
Number of Participants With Virological Response (Observed, <50 Copies/ml) at Last On-Treatment Visit (Post-Week 96).	Virological response is defined as (observed) plasma viral load less than 50 human immunodeficiency virus-type 1 (HIV-1) ribonucleic acid (RNA) copies per ml at the last on-treatment visit (post-Week 96).	Variable, ranging from 3 months up to maximum 15 months for TMC278 and 12 months for Efavirenz after the 96-week visit
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/ml) at Week 48		Week 48
Number of Participants With Virological Response (Intent-to-Treat - Time to Loss of Virologic Response [TLOVR], <400 Copies/ml) at Week 96		Week 96
Mean Change From Baseline to Week 48 and Week 96 in Absolute and Relative CD4+ Cell Counts (Using Imputed Data)	Change from baseline in CD4+ cell count was imputed in case of missing values: in case of premature discontinuation, data were imputed with the baseline value after discontinuation (i.e. change=0, Non-Completer [NC] = Failure); otherwise last observation carried forward was applied.	Baseline, Week 48, and Week 96
Number of Participants With Virologic Failure for the Resistance Determination by Emerging Resistance Associated Mutations: First Available On-Treatment Genotypic Data After Failure	Virologic failure for the resistance determinations was defined as lack of virologic response (never having had 2 consecutive plasma viral load <50 copies/mL) and plasma viral load increase of >=0.5 log 10 copies/mL above nadir (i.e., never suppressed), or confirmed loss of virologic response (2 consecutive plasma viral load >=50 copies/mL after having had 2 consecutive plasma viral load <50 copies/mL; i.e., rebounder), or discontinued with a last observed on-treatment plasma viral load >=50 copies/mL after having had 2 consecutive plasma viral load <50 copies/mL. For this study, treatment-emergent reverse transcriptase (RT) resistance associated mutations (RAMs) occurring in at least 2 virologic failures (for at least one treatment group) for the following lists are presented: i) Extended list of Non-nucleoside reverse transcriptase inhibitor (NNRTI RAMs) ii) IAS-USA list of Nucleoside/tide reverse transcriptase inhibitor (N[t]RTI RAMs).	Week 96

Collaborators and Investigators

• Sponsor: Tibotec Pharmaceuticals, Ireland

Publications and helpful links

General Publications

• Rimsky L, Van Eygen V, Hoogstoel A, Stevens M, Boven K, Picchio G, Vingerhoets J. 96-Week resistance analyses of rilpivirine in treatment-naive, HIV-1-infected adults from the ECHO and THRIVE Phase III trials. Antivir Ther. 2013;18(8):967-77. doi: 10.3851/IMP2636. Epub 2013 May 28.
• Nelson M, Amaya G, Clumeck N, Arns da Cunha C, Jayaweera D, Junod P, Li T, Tebas P, Stevens M, Buelens A, Vanveggel S, Boven K; ECHO and THRIVE Study Groups. Efficacy and safety of rilpivirine in treatment-naive, HIV-1-infected patients with hepatitis B virus/hepatitis C virus coinfection enrolled in the Phase III randomized, double-blind ECHO and THRIVE trials. J Antimicrob Chemother. 2012 Aug;67(8):2020-8. doi: 10.1093/jac/dks130. Epub 2012 Apr 24.
• Molina JM, Cahn P, Grinsztejn B, Lazzarin A, Mills A, Saag M, Supparatpinyo K, Walmsley S, Crauwels H, Rimsky LT, Vanveggel S, Boven K; ECHO study group. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011 Jul 16;378(9787):238-46. doi: 10.1016/S0140-6736(11)60936-7.

Study record dates

Study Major Dates

• Study Start: May 1, 2008
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: October 4, 2007
• First Submitted That Met QC Criteria: October 4, 2007
• First Posted (Estimate): October 8, 2007

Study Record Updates

• Last Update Posted (Estimate): March 29, 2016
• Last Update Submitted That Met QC Criteria: March 1, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: HIV-1; AIDS; Treatment Naive; Antiretroviral; TMC278-C209; Non-nucleoside reverse transcriptase inhibitor; TMC278-TiDP6-C209
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Efavirenz; Rilpivirine
• Other Study ID Numbers: CR002689; TMC278-TIDP6-C209 (Other Identifier: Tibotec Pharmaceuticals, Ireland)