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

• ClinicalTrials.gov Identifier: NCT00110305
• Recruitment Status: Completed
• First Posted: May 6, 2005
• Results First Posted: October 28, 2013
• Last Update Posted: June 25, 2014
• Sponsor: Tibotec Pharmaceuticals, Ireland
• Information provided by (Responsible Party): Tibotec Pharmaceuticals, Ireland

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Human Immunodeficiency Virus Type 1	Drug: TMC278 25 mg; Drug: TMC278 75 mg; Drug: TMC278 150 mg; Drug: Efavirenz; Drug: Non-nucleoside reverse transcriptase inhibitor (NRTIs)	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 368 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase IIb Randomized, Partially Blinded, Dose-Finding Trial of TMC278 in Antiretroviral-Naive HIV-1 Infected Subjects
• Study Start Date: June 2005
• Actual Primary Completion Date: December 2011
• Actual Study Completion Date: December 2011

Arms and Interventions

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: Combivir; Truvada
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: TMC278 75 mg; TMC278 75 mg (1 X 25 mg + 1 X 50 mg) tablets 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: Combivir; Truvada
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: TMC278 150 mg; TMC278 150 mg (1 X 50 mg + 1 X 100 mg) tablets 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: Combivir; Truvada
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: 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.; 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: Combivir; Truvada

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: Week 48 ]
   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.

Secondary Outcome Measures :

1. 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 [ Time Frame: Week 96 ]
   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.
2. Number of Participants With Virologic Response at Week 96 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis [ Time Frame: Week 96 ]
   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.
3. 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 [ Time Frame: Week 240 ]
   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.
4. Number of Participants With Virologic Response at Week 240 (Viral Load Less Than 50 Copies Per mL) - Snapshot Analysis [ Time Frame: Week 240 ]
   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.
5. 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 [ Time Frame: Week 240 ]
   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.
6. Change From Baseline in CD4+ Cell Count (Absolute) at Week 96 [ Time Frame: Baseline (Day 1 of Week 0) to 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.
7. Change From Baseline in CD4+ Cell Count (Relative) at Week 96 [ Time Frame: Baseline (Day 1 of Week 0) to 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.
8. Change From Baseline in CD4+ Cell Count (Absolute) at Week 240 [ Time Frame: Baseline (Day 1 of Week 0) to 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.
9. Change From Baseline in CD4+ Cell Count (Relative) at Week 240 [ Time Frame: Baseline (Day 1 of week 0) to 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.
10. Number of Participants With Virologic Failure for the Resistance Determinations by Developing Mutations: First Available On-Treatment Genotypic Data After Failure [ Time Frame: Week 240 ]
    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).
11. Area Under the Plasma Concentration Time Curve From Time 0 to 24 Hours (AUC24h) for TMC278 [ Time Frame: Up to Week 96 ]
    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.
12. Trough Plasma Concentration (Ctrough) for TMC278 [ Time Frame: Up to Week 96 ]
    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.
13. 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 [ Time Frame: Up to Week 96 ]
    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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, California

Beverly Hills, California, United States

United States, District of Columbia

Washington, District of Columbia, United States

United States, Florida

Orlando, Florida, United States

Tampa, Florida, United States

United States, Georgia

Atlanta, Georgia, United States

United States, New York

Stony Brook, New York, United States

United States, North Carolina

Winston-Salem, North Carolina, United States

United States, Texas

Addison, Texas, United States

United States, Washington

Seattle, Washington, United States

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 Cedex 10, France

Paris Cedex 12, France

Paris, 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 N/A, Russian Federation

Moscow, 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

Sponsors and Collaborators

Tibotec Pharmaceuticals, Ireland

Investigators

• Study Director: Tibotec Pharmaceuticals, Ireland Clinical Trial; Tibotec Pharmaceuticals, Ireland

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Tibotec Pharmaceuticals, Ireland
• ClinicalTrials.gov Identifier: NCT00110305
• Obsolete Identifiers: NCT00980837
• Other Study ID Numbers: CR006760; TMC278-C204 ( Other Identifier: Tibotec Pharmaceuticals, Ireland ); R278474-C204 ( Other Identifier: Tibotec Pharmaceuticals, Ireland )
• First Posted: May 6, 2005
• Results First Posted: October 28, 2013
• Last Update Posted: June 25, 2014
• Last Verified: June 2014

Keywords provided by Tibotec Pharmaceuticals, Ireland:

Human Immunodeficiency Virus Type 1; Human immunodeficiency virus (HIV); Antiretroviral; Antiviral; ARV; TMC278; Efavirenz; Combivir; Truvada; Zidovudine; Lamivudine; Tenofovir disoproxil fumarate; Emtricitabine

Additional relevant MeSH terms:

Acquired Immunodeficiency Syndrome; HIV Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Efavirenz; Reverse Transcriptase Inhibitors; Rilpivirine; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers