A Study of TMC278 in Human Immunodeficiency Virus Type 1 Infected Patients, Who Are Not Treated With Antiretroviral Medicines

A Phase IIb Randomized, Partially Blinded, Dose-Finding Trial of TMC278 in Antiretroviral-Naive HIV-1 Infected Subjects

The purpose of this study is to evaluate the dose-response relationship of antiviral activity after 48 weeks treatment with 3 different dose regimens of TMC278.

Study Overview

• Status: Completed
• Conditions: Human Immunodeficiency Virus Type 1
• Intervention / Treatment: Drug: TMC278 25 mg; Drug: Non-nucleoside reverse transcriptase inhibitor (NRTIs); Drug: TMC278 75 mg; Drug: TMC278 150 mg; Drug: Efavirenz

Detailed Description

This is a randomized (the study medication is assigned by chance), active controlled (participants are assigned to either a recognized effective treatment or the study medication) study. This study consists of 3 phases: screening phase (4 weeks), treatment phase (96 weeks), and follow up phase (4 weeks). In the treatment phase, participants will be randomly assigned to 1 of the 4 treatment groups: (1) TMC278 25 mg, (2) TMC278 75 mg, (3) TMC278 150 mg, or (4) efavirnez (control group); along with investigator selected 2 non-nucleoside reverse transcriptase inhibitor (NRTIs) until Week 96. TMC278 will be assigned by double-blinded fashion (participant and investigator are not aware of the TMC278 dose what participants will receive) and efavirnez will be assigned by open-label fashion (all people know what treatment participants will receive). After Week 96, 3 optional open-label (all people know the identity of the intervention) extension periods will be conducted to collect long term safety and effectiveness data of TMC278. 3 optional extension periods are: first optional extension period (all participants will receive TMC278 75 mg + 2 NRTIs from Week 96 to Week144); second optional extension period (all participants will receive TMC278 25 mg + 2 NRTIs from Week 144 to Week 240); and third optional extension period (all participants will receive TMC278 25 mg + 2 NRTIs from Week 240 until TMC278 is commercially available). Participants on efavirenz group will have the option to continue on efavirenz + 2 NRTIs until the total treatment duration of 240 weeks. Safety evaluations will include assessment of adverse events, clinical laboratory tests, electrocardiogram, physical examination, and vital signs which will be monitored throughout the study. The maximum duration of the study will be 104, 152, or 248 weeks, plus the optional third extension period.

• Study Type: Interventional
• Enrollment (Actual): 368
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
  • Rosario, Argentina
• Austria
  • Wien, Austria
• Brazil
  • Campinas, Brazil
  • Curitiba, Brazil
  • Pinheiros, Brazil
  • Rio De Janeiro, Brazil
  • Sao Paulo, Brazil
• China
  • Beijing, China
• France
  • Paris, France
  • Paris Cedex 10, France
  • Paris Cedex 12, France
  • Tourcoing, France
• Germany
  • Berlin, Germany
  • Freiburg, Germany
  • Köln, Germany
  • München, Germany
• Mexico
  • Ciudad De Mexico, Mexico
• Puerto Rico
  • San Juan, Puerto Rico
• Russian Federation
  • Kazan, Russian Federation
  • Moscow, Russian Federation
  • Moscow N/A, Russian Federation
  • Nizhny Novgorod, Russian Federation
  • Saint-Petersburg, Russian Federation
  • St Petersburg, Russian Federation
  • Volgograd, Russian Federation
• South Africa
  • Bloemfontein, South Africa
  • Cape Town, South Africa
  • Johannesburg, South Africa
• Thailand
  • Bangkok, Thailand
  • Chiang Mai, Thailand
  • Khon Kaen, Thailand
• Uganda
  • Kampala, Uganda
• United Kingdom
  • London, United Kingdom
  • Manchester, United Kingdom
• United States
  • California
    • Beverly Hills, California, United States
  • District of Columbia
    • Washington, District of Columbia, United States
  • Florida
    • Orlando, Florida, United States
    • Tampa, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
  • New York
    • Stony Brook, New York, United States
  • North Carolina
    • Winston-Salem, North Carolina, United States
  • Texas
    • Addison, Texas, United States
  • Washington
    • Seattle, Washington, United States

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Documented human immunodeficiency virus type 1 (HIV-1) infection
• Never been treated with an antiretroviral (ARV) treatment or therapeutic HIV vaccine, or received less than or equal to 2 weeks treatment prior to screening with an nucleoside reverse transcriptase inhibitors
• HIV-1 plasma viral load above 5000 HIV-1 RNA copies per milliliter, at screening
• Cortisol of at least 550 nano moles per liter (19.9 microgram per deciliter) at screening
• Sensitivity to investigator selected nucleosides, at screening

Exclusion Criteria:

• Currently having active Acquired Immunodeficiency Syndrome (AIDS) defining illness
• Known or suspected acute (primary) HIV-1 infection
• Any current or history of adrenal disorder, and an acute hepatitis A, B, or C infection
• Documented genotypic evidence of Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) resistance at screening
• Pregnant or breastfeeding females
• Not agree to protocol-defined effective use of contraception

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TMC278 25 mg; Participants will receive TMC278 25 mg once daily up to Week 96. Later on, participants will receive TMC278 75 mg once daily up to Week 144 and then TMC278 25 mg once daily up to Week 240.	Drug: TMC278 25 mg; TMC278 25 mg tablet will be administered once daily.; Drug: Non-nucleoside reverse transcriptase inhibitor (NRTIs); Investigator selected 2 NRTIs: (1) Zidovudine and lamivudine (Combivir) and (2) tenofovir disoproxil fumarate and emtricitabine (Truvada) will be administered as per the package inserts, along with the TMC278 during the study period.; Other Names: Truvada; Combivir
Experimental: TMC278 75 mg; Participants will receive TMC278 75 mg once daily up to Week 144. Later on, participants will receive TMC278 25 mg once daily up to Week 240.	Drug: Non-nucleoside reverse transcriptase inhibitor (NRTIs); Investigator selected 2 NRTIs: (1) Zidovudine and lamivudine (Combivir) and (2) tenofovir disoproxil fumarate and emtricitabine (Truvada) will be administered as per the package inserts, along with the TMC278 during the study period.; Other Names: Truvada; Combivir; Drug: TMC278 75 mg; TMC278 75 mg (1 X 25 mg + 1 X 50 mg) tablets will be administered once daily.
Experimental: TMC278 150 mg; Participants will receive TMC278 150 mg once daily up to Week 96. Later on, participants will receive TMC278 75 mg once daily up to Week 144 and then TMC278 25 mg once daily up to Week 240.	Drug: Non-nucleoside reverse transcriptase inhibitor (NRTIs); Investigator selected 2 NRTIs: (1) Zidovudine and lamivudine (Combivir) and (2) tenofovir disoproxil fumarate and emtricitabine (Truvada) will be administered as per the package inserts, along with the TMC278 during the study period.; Other Names: Truvada; Combivir; Drug: TMC278 150 mg; TMC278 150 mg (1 X 50 mg + 1 X 100 mg) tablets will be administered once daily.
Active Comparator: Efavirenz; Participants will receive efavirenz 600 mg once daily up to Week 96. Later on, participants will have an option to continue on efavirenz until Week 144 or until Week 240.	Drug: Non-nucleoside reverse transcriptase inhibitor (NRTIs); Investigator selected 2 NRTIs: (1) Zidovudine and lamivudine (Combivir) and (2) tenofovir disoproxil fumarate and emtricitabine (Truvada) will be administered as per the package inserts, along with the TMC278 during the study period.; Other Names: Truvada; Combivir; Drug: Efavirenz; Efavirenz 600 mg (1 x 600 mg tablet or 3 x 200 mg capsules, depending on formulation locally available) will be administered once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Virologic Response at Week 48 (Viral Load Less Than 50 Copies Per mL) - as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm	The TLOVR algorithm was used to derive response, ie, response and loss of response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders. Participants with intermittent missing viral load values were considered responders if the preceeding and succeeding visits indicated response. In all other cases, intermittent values were imputed with nonresponse. Resuppression after confirmed virologic failure was considered as failure in this algorithm.	Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm	The TLOVR algorithm was used to derive response, ie, response and loss of response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders. Participants with intermittent missing viral load values were considered responders if the preceeding and succeeding visits indicated response. In all other cases, intermittent values were imputed with nonresponse. Resuppression after confirmed virologic failure was considered as failure in this algorithm.	Week 96
Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis	The analysis is based on the last observed viral load data within the Week 96 window. Virologic response is defined as a viral load less than 50 copies/mL. Missing viral load was considered as non-response.	Week 96
Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm	The TLOVR algorithm was used to derive response, ie, response and loss of response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders. Participants with intermittent missing viral load values were considered responders if the preceeding and succeeding visits indicated response. In all other cases, intermittent values were imputed with nonresponse. Resuppression after confirmed virologic failure was considered as failure in this algorithm.	Week 240
Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis	The analysis is based on the last observed viral load data within the Week 240 window. Virologic response is defined as a viral load less than 50 copies/mL. Missing viral load was considered as non-response.	Week 240
Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 400 Copies/mL) - as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm	The TLOVR algorithm was used to derive response, ie, response and loss of response needed to be confirmed at 2 consecutive visits and participants who permanently discontinued were considered nonresponders. Participants with intermittent missing viral load values were considered responders if the preceeding and succeeding visits indicated response. In all other cases, intermittent values were imputed with nonresponse. Resuppression after confirmed virologic failure was considered as failure in this algorithm.	Week 240
Change From Baseline in CD4+ Cell Count (Absolute) at Week 96	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 (Day 1 of Week 0) to Week 96
Change From Baseline in CD4+ Cell Count (Relative) at Week 96	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 (Day 1 of Week 0) to Week 96
Change From Baseline in CD4+ Cell Count (Absolute) at Week 240	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 (Day 1 of Week 0) to Week 240
Change From Baseline in CD4+ Cell Count (Relative) at Week 240	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 (Day 1 of week 0) to Week 240
Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure	Virologic failure for the resistance determinations was defined as a viral load greater than 0.5 log10 copies /mL above the nadir with a minimum of 500 copies/mL. For this study, treatment-emergent mutations (for at least one treatment) are presented as Resistance associated mutation (RAMs): i) Non-nucleotide reverse transcriptase inhibitor (NNRTI) RAMs, ii) Nucleoside/tide reverse transcriptase inhibitor (N[t]RTI RAMs).	Week 240
Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) for TMC278	For each participant, a single value for area under the plasma concentration-time curve from time of administration up to 24 hours post dosing (AUC24h) of TMC278 was estimated from a population pharmacokinetic model, based on all samples collected throughout the trial up to Week 96.	Up to Week 96
Trough Plasma Concentration (Ctrough) for TMC278	For each participant, a single value for trough (i.e. predose) plasma concentration (Ctrough) of TMC278 was estimated from a population pharmacokinetic model, based on samples collected throughout the trial up to Week 96.	Up to Week 96
Number of Participants With Virologic Response (Viral Load Less Than 50 Copies Per mL) - as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm, by Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) Quartiles	Quartile 1, 2, 3 and 4 of AUC24h means the quartile with the lowest 25%, 26-50%, 51-75% and the highest 25% of AUC24h values, respectively, irrespective of the different doses of TMC278. For each participant, a single value for area under the plasma concentration-time curve from time of administration up to 24 hours post dosing (AUC24h) of TMC278 was estimated from a population pharmacokinetic model, based on all samples collected throughout the trial up to Week 96. Virologic response was calculated by time to loss of virologic response (TLOVR) algorithm.	Up to Week 96

Collaborators and Investigators

• Sponsor: Tibotec Pharmaceuticals, Ireland

Publications and helpful links

General Publications

• Pozniak AL, Morales-Ramirez J, Katabira E, Steyn D, Lupo SH, Santoscoy M, Grinsztejn B, Ruxrungtham K, Rimsky LT, Vanveggel S, Boven K; TMC278-C204 Study Group. Efficacy and safety of TMC278 in antiretroviral-naive HIV-1 patients: week 96 results of a phase IIb randomized trial. AIDS. 2010 Jan 2;24(1):55-65. doi: 10.1097/QAD.0b013e32833032ed.

Study record dates

Study Major Dates

• Study Start: June 1, 2005
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: May 5, 2005
• First Submitted That Met QC Criteria: May 5, 2005
• First Posted (Estimate): May 6, 2005

Study Record Updates

• Last Update Posted (Estimate): June 25, 2014
• Last Update Submitted That Met QC Criteria: June 11, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: Lamivudine; Efavirenz; Truvada; Zidovudine; Antiviral; Antiretroviral; Emtricitabine; Tenofovir disoproxil fumarate; ARV; Human immunodeficiency virus (HIV); Human Immunodeficiency Virus Type 1; TMC278; Combivir
• 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; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; 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; Reverse Transcriptase Inhibitors; Efavirenz; Rilpivirine
• Other Study ID Numbers: CR006760; TMC278-C204 (Other Identifier: Tibotec Pharmaceuticals, Ireland); R278474-C204 (Other Identifier: Tibotec Pharmaceuticals, Ireland)