Enfuvirtide/Current Protease Inhibitor Switch to PREZISTA (Darunavir)/Ritonavir + TMC125 in HIV Patients With Enfuvirtide Side Effects.

Study Overview
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Brief Summary
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The purpose of this study is to examine the safety, tolerability, and effectiveness of darunavir/ritonavir combined with TMC125 when current protease inhibitor(s), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI(s)) and enfuvirtide are replaced by darunavir/ritonavir and TMC125 in HIV positive patients who can no longer tolerate enfuvirtide and are experiencing viral suppression. Other antiviral drugs in the regimen are to remain unchanged.

Detailed Description
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This is a multi-center, open-label (doctors and patients know which drug is being given), Phase IIIb clinical trial to evaluate the effectiveness, safety and tolerability of the combination of PREZISTA (darunavir)/ritonavir and TMC125 when substituted for enfuvirtide, current protease inhibitor(s) and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI(s)) in antiretroviral resistant patients with viral suppression but who are intolerant of enfuvirtide. This study will be conducted in the U.S. at up to 5 sites where 40 patients will receive PREZISTA (darunavir) /ritonavir twice daily (600/100mg) and TMC125 (200 mg) twice daily over a 48-week treatment period. The study will consist of a total of 11 patient visits. At the screening visit (Week -1 to -6) blood will be collected from patients to determine eligibility. Once all data are available to determine the eligibility of the patient, the baseline visit will be scheduled and trial treatment initiated at this visit. The Baseline Visit (Day 1) will be followed by a 48-week treatment period. The patient will be evaluated at Weeks 2, 4, 8, 12, 16, 24, 36, and 48. Patients will be asked to return for a 2-week follow up visit at Week 50. Treatment will include PREZISTA (darunavir) /ritonavir and TMC125 plus continued nucleosides. The patient must continue all existing nucleosides in their background regimen for the duration of the study. 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 efficacy and safety will be done at regular visits. Study patients will receive oral (by mouth) PREZISTA (darunavir) 600 mg and 100 mg of ritonavir twice a day in combination with TMC125 200mg orally twice a day for 48 weeks.

Official Title
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Open Label Phase 3b, 48 wk Pilot Study of the Antiviral Efficacy and Tolerability of Combination of PREZISTA/r and TMC125 When Substituted for Enfuvirtide, Current Protease Inhibitor(s) and NNRTI(s) in Antiretroviral Resistant Patients With Viral Suppression But Who Are Intolerant of Enfuvirtide.

Conditions
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HIV

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 positive History of drug resistance or antiretroviral failure while receiving each of three drug classes: Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) and (protease inhibitors) PIs On a PI containing regimen with enfuvirtide with HIV viral load (VL) < 400 copies/mL for 6 months or longer Continuously using the same PI regimen for 4 months prior to Screening Decline to continue enfuvirtide or their physician recommends discontinuation due to injection site reactions that persist despite optimal technique and training with available methods of administration or loss of sites for injection due to tissue nodules and hardening. Exclusion Criteria: No use of any drug contraindicated in the current US package insert for PREZISTA (darunavir) or in the investigators brochure for TMC125 No prior or current therapy with PREZISTA (darunavir) or TMC125 No prior genotypic results demonstrating 3 or more darunavir resistance-associated mutations associated with diminished response to darunavir (V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V or L89V). Patients with > 3 darunavir resistance-associated mutations with available darunavir phenotypes, may be enrolled if the resistance phenotype demonstrates: Fold Change (FC) <10 to darunavir by PhenoSense GT (Monogram Biosciences) or FC <10 to darunavir by Antivirogram (Virco, BVBA) or FC <3.4 to darunavir by vircoTYPE (Virco BVBA) AST or ALT >5 times ULN Calculated CrCl < 30 ml/min.

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; RitonavirTMC125-200mg two times a day for 48 weeks; Darunavir -200mg two times a day for 48 weeks; Ritonavir-100mg two times a day for 48 weeks; | Drug: TMC125, Darunavir; Ritonavir<br>* TMC125-200mg two times a day for 48 weeks; Darunavir -200mg two times a day for 48 weeks; Ritonavir-100mg two times a day for 48 weeks;<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Who Maintain Plasma HIV Viral Load Measurements < 400 Copies/ml at 2, 4, 8, 12, 16, 24, 36 and 48 Weeks After Switching to DRV/r and ETR, Missing Equals Failure. |  | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Who Have Viral Load Measurements <50 Copies/ml at 2, 4, 8, 12, 16, 24, 36 and 48 Weeks After Switching to DRV/r and ETR, Missing Equals Failure. |  | 48 weeks | 
| CD4+ Cell Count (x 10^6 Cell/L): Baseline and Median Changes From Baseline at 4, 8, 12, 16, 24, 36 and 48 Weeks. |  | Week 48 | 
| CD4+ Cell Count (x 10^6 Cell/L): Baseline and Mean Changes From Baseline at 4, 8, 12, 16, 24,36 and 48 Weeks. |  | Week 48 | 
| Median Change From Baseline in Triglycerides at Week 48. |  | Week 48 | 
| Median Change From Baseline in Total Cholesterol at Week 48. |  | Week 48 | 
| Median Change From Baseline in LDL Cholesterol at Week 48. |  | Week 48 | 
| Median Change From Baseline in HDL Cholesterol. |  | Week 48 | 
| Median Change From Baseline in Total Cholesterol (TC) / High Denisty Lipoprotein (HDL) Ratio at Week 48. |  | Week 48 | 
| Median Change From Baseline in Glucose at Week 48. |  | 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, enfuvirtide, Treatment Experienced