A Study to Evaluate the Pharmacokinetic Profile (How the Body Absorbs, Distributes, Metabolizes and Eliminates a Drug) of TMC125 Plus Tenofovir/Emtricitabine Once Daily With or Without Darunavir/r Once Daily in Antiretroviral (ARV) Naive HIV-1 Patients (Patients Have Never Received ARV Treatment).

Study Overview
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Brief Summary
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The purpose of this study is to determine the pharmacokinetic profile of TMC125 400mg with tenofovir DF/emtricitabine FDC (fixed dose combination) 300/200mg all dosed once daily with and without darunavir/ritonavir 800/100 mg once daily in HIV-1 infected, antiretroviral (ARV) naÃ-ve patients (patients who have never received ARV treatment).

Detailed Description
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This is a multi-center, open-label (doctors and patients know which drug is being given), Phase IIa clinical trial to evaluate the pharmacokinetic (PK) profile, safety and tolerability of TMC125 dosed once daily with tenofovir/emtricitabine with and without darunavir/ritonavir in antiretroviral naive HIV-1 infected patients. There will be an optional open-label extension phase to evaluate effectiveness, safety and tolerability of continued tenofovir/emtricitabine with darunavir/ritonavir all dosed once daily for 48 weeks. This study will be conducted in the United States at up to 5 sites where 20 patients will initially receive TMC125 400mg with tenofovir DF/emtricitabine FDC 300/200 mg all dosed once daily for 14 days. On Day 15, a blood sample will be obtained and intensive TMC125 pharmacokinetic (PK) values and fasting lipids (check of total cholesterol, direct LDL, HDL, triglycerides) following a 10 hour fast (no eating) will be assessed. Patients will then add darunavir / ritonavir 800/100 mg once a day to the regimen for Days 15 - 29. On Day 29 intensive PK sampling for TMC125, darunavir and ritonavir will be performed and fasting lipids will be evaluated. On Day 29, patients will discontinue TMC125 and continue darunavir/ritonavir 800/100 mg and tenofovir DF/emtricitabine FDC 300/200 mg all dosed once daily. On Day 43, fasting lipids will be assessed. At this point, patients may enter the optional open-label extension phase of the study and continue treatment with darunavir/ritonavir 800mg/100 mg and tenofovir DF/emtricitabine FDC 300/200mg all dosed once daily through 48 total weeks of treatment. The study will consist of a total of 8 visits including 2 intensive PK visits. Within 4 weeks after the Screening Visit, the study site should have received all data to determine a patient's eligibility for the study. The Baseline Visit (Day 1) will be followed by a study visit on Day 8. An intensive PK visit will occur on Day 15. After modification of therapy on Day 15, a study visit will occur on Day 22. A second intensive PK visit will occur on Day 29. On Day 43 a study visit will occur at which point study therapy will be discontinued unless the patient elects to continue in the optional open label extension phase of the study. Patients electing to continue in the open-label extension will have 4 additional study visits at Week 12, 24, 36 and 48. All patients will be asked to return for a 4-week follow-up visit after the completion of study treatment. During the treatment period, the patient will be seen at regular visits during which the investigator will assess the patient's medical condition, any Adverse Events and study drug compliance. Laboratory evaluations for effectiveness and safety will be done at regular visits as well as blood pressure monitoring. All patients will receive TMC125 400 mg orally (by mouth) once daily. Tenofovir DF 300mg/emtricitabine 200mg will be dosed once daily orally as the fixed dose combination. Darunavir/ritonavir will be dosed 800/100 mg orally once daily. All doses should be administered following a meal.

Official Title
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A Multicenter Study to Evaluate the Pharmacokinetic Profile and Safety of TMC125 Plus Tenofovir DF/Emtricitabine All Dosed Once Daily With and Without Darunavir (PREZISTA™)/ Ritonavir Once Daily in Antiretroviral naïve HIV-1 Infected Subjects

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: TMC125; darunavir; ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented HIV-1 infection Naive to antiretroviral therapy (never received antiretroviral therapy prior to study) In the opinion of the investigator, have an indication for antiretroviral therapy Able to comply with the protocol requirements Exclusion Criteria: No previous or current use of antiretroviral medications (ARVs) for the treatment of HIV infection or hepatitis B/C infection with anti-HIV activity No evidence of antiretroviral resistance on current or past resistance assays No chronic hepatitis B and/or C co-infection No grade 3 or 4 laboratory abnormality as defined by National Institute of Allergy and Infectious Diseases Division of Acquired Immunodeficiency Syndrome (DAIDS) grading tables, or a calculated creatinine clearance (CLCr) < 50 mL/min. No known diabetes mellitus or hyperlipidemia requiring lipid-lowering therapy No acute viral hepatitis including, but not limited to A, B, or C.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 001<br>TMC125; darunavir; ritonavirTMC125 400mg once daily for 4 weeks; Darunavir-800mg once daily for 48 weeks; Ritonavir-100mg once daily for 48 weeks | Drug: TMC125; darunavir; ritonavir<br>* TMC125 400mg once daily for 4 weeks; Darunavir-800mg once daily for 48 weeks; Ritonavir-100mg once daily for 48 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Contributing to the Pharmacokinetic (PK) Evaluations: Cmin, Cmax, AUC24 & Css,av | At visit Days 14 & 28, samples were collected pre-dose and at 1, 2, 3, 4, 6, 9, and 12 hours post-dose. An additional sample was taken at 24 hours (Day 15 or 29 as applicable) post-dose. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Graded Laboratory Abnormalities (Worst Grade): Glucose-Hyperglycemia | Number of Participants with Treatment-Emergent Graded Laboratory Abnormalities (Worst Grade): Glucose-Hyperglycemia. Worst Grade is based on the National Institute of Allergy and Infectious Diseases Division of Acquired Immunodeficiency Syndrome (DAIDS) toxicity grading scale, 0,1,2,3,4 and 5 : None, Mild, Moderate, Severe, Life-threatening and Death. | Day 1 through 42 and Week 48 | 
| Number of Participants With Treatment-Emergent Graded Laboratory Abnormalities (Worst Grade): Glucose- Hypoglycemia | Number of participants with Treatment-Emergent Graded Laboratory Abnormalities (Worst Grade): Glucose- Hypoglycemia. Worst Grade is based on the DAIDS toxicity grading scale 0-5: No Toxicity-Death. | Day 1 through 42 and Week 48 | 
| Number of Participants With Treatment-Emergent Non-Graded Laboratory Abnormalities(Worst Abnormality): Glucose- Insulin | Number of participants with Treatment-Emergent Non-Graded Laboratory Abnormalities(Worst Abnormality): Glucose- Insulin. Normal Range: 3.0 - 27.0 ulU/mL | Day 1 through 42 and Week 48 | 
| Number of Participants With Treatment-Emergent Graded Laboratory Abnormalities (Worst Grade): Lipids- Total Cholesteral | Number of participants with Treatment-Emergent Graded Laboratory Abnormalities (Worst Grade): Lipids- Total Cholesteral. Worst Grade is based on the DAIDS toxicity grading scale, 0-5 : No Toxicity-Death. | Day 1 through 42 and Week 48 | 
| Number of Participants With Treatment-Emergent Non-Graded Laboratory Abnormalities(Worst Abnormality): Lipids- High-density Lipoprotein (HDL) | Number of participants with Treatment-Emergent Non-Graded Laboratory Abnormalities(Worst Abnormality): Lipids- High-density lipoprotein (HDL). Normal Range: 40 - 59 mG/dL 1.03 - 1.53 mmol/L | Day 1 through 42 and Week 48 | 
| Number of Participants With Treatment-Emergent Graded Laboratory Abnormalities(Worst Grade): Lipids- Low-density Lipoprotein (LDL) Direct | Number of participants with Treatment-Emergent Graded Laboratory Abnormalities(Worst Grade): Lipids- Low-density lipoprotein (LDL) Direct. Worst Grade is based on the DAIDS toxicity grading scale, 0-5 : No Toxicity-Death. | Day 1 through 42 and Week 48 | 
| Number of Participants With Treatment-Emergent Graded Laboratory Abnormalities(Worst Grade): Lipids- Triglycerides | Number of participants with Treatment-Emergent Graded Laboratory Abnormalities(Worst Grade): Lipids- Triglycerides. Worst Grade is based on the DAIDS toxicity grading scale, 0-5 : No Toxicity-Death. | Day 1 through 48 and Week 48 | 
| Virologic Response < 50 HIV-1 RNA Copies/mL (ITT-Observed Case) | Virologic Response < 50 HIV-1 RNA Copies/mL (ITT-Observed Case). | Day 8, 14, 22, 28, 42 and Week 48 | 
| Log10 Viral Load (HIV-1 RNA Copies/mL): Mean Changes From Baseline(ITT-Observed Case) | Log10 Viral Load (HIV-1 RNA copies/mL): Mean Changes From Baseline(ITT-Observed Case). | Baseline, Day 8, 14, 22, 28 & 42 and Week 48 | 
| CD4+ Cell Count (x 10^6 Cell/L): Baseline and Median Changes From Baseline (ITT-Observed Case) | CD4+ Cell Count (x 10^6 cell/L): Baseline and Median Changes From Baseline (ITT-Observed Case). | Baseline, Day 8, 14, 22, 28 & 42 ans Week 48 | 
| CD4+ Cell Count (Percent): Baseline and Median Changes From Baseline (ITT-Observed Case) |  | Baseline, Day 8, 14, 22, 28 & 42 and Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, AIDS, Immunodeficiency Virus, Human, PREZISTA, darunavir, TMC114, TMC125, Protease Inhibitor, Non-Nucleoside Reverse Transcriptase Inhibitor, Truvada, Treatment Naive