GRACE: A Study to Compare the Effectiveness, Safety and Tolerability of PREZISTA (Darunavir)/Ritonavir by Gender and Race When Administered With Other Antiretroviral Medications in Human Immunodeficiency Virus (HIV) Positive Women and Men.

Study Overview
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Brief Summary
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The purpose of this study is to evaluate any differences in the effectiveness, safety, and tolerability of PREZISTA (darunavir; DRV) 600 mg, administered with ritonavir (RTV) 100 mg twice a day on virologic response (defined as a viral load (VL) of < 50 copies/mL) over a 48-week treatment period in HIV-positive women and men. Additional antiretroviral (ARV) agents will also be administered and will be chosen by the Investigator based on resistance testing and prior treatment history (referred to as the Optimized Background Regimen (OBR)).

Detailed Description
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This is a multi-center, open-label (doctors and patients know which drug is being administered), Phase IIIb clinical trial to evaluate differences in effectiveness, safety, and tolerability of darunavir/ritonavir by sex and/or race over a 48-week treatment period. This study will be conducted in HIV positive women and men who have been treated previously with antiretroviral therapy. This study will enroll 70% women and will be conducted in the U.S., Puerto Rico, Mexico and Canada in approximately 420 patients who will receive darunavir 600 mg and ritonavir 100 mg twice daily. The primary objective of this study is to determine the percentage of patients who achieve virologic response, defined as a viral load (VL) of <50 copies/mL at week 48. Secondary study objectives include comparisons of endpoints between women and men as well as race across multiple parameters including but not limited to change in CD4 count from baseline to week 48, time to loss of virologic response (TLOVR), changes in metabolic parameters (blood chemistry), etc. Within 4 weeks after the Screening Visit (initial visit with investigator to determine eligibility), the Investigator should have received all data required to determine the patient's eligibility and will construct the individual Optimized Background Regimen (OBR) that will be used during the treatment period in combination with darunavir/ritonavir for those patients enrolled in the study. The OBR will consist of additional antiretroviral (ARV) agents that will also be administered during the study chosen by the Investigator and based on resistance testing and prior treatment history. The study Sponsor will provide the following ARV agents, that may be used as options for the OBR: TMC 125 (investigational non-nucleoside reverse transcriptase inhibitor; NNRTI); Truvada (tenofovir/emtricitabine); Viread (tenofovir); Emtriva (emtricitabine); Zidovudine. Other NRTIs (nucleoside reverse transcriptase inhibitors) or NNRTIs may be used at the discretion of the Investigator, but will not be provided by the Sponsor. The Baseline Visit (Day 1) will be followed by a 48-week treatment period during which patients will be evaluated at Weeks 4, 8, 12, 16, 24, 36, 48 and at a final Follow-Up Visit during Week 52. (total of 10 visits from Screening to final visit). At a number of visits throughout the study, blood samples will be obtained to assess defined laboratory values, safety parameters and to determine concentrations of study drugs darunavir, TMC125 (if applicable) and ritonavir). Patients will be assessed for change in CD4 count and HIV-RNA throughout the study. At each visit, vital signs will be assessed and patients will be asked about any untoward medical occurrences and these will be recorded as adverse events (AEs) and/or HIV-related events. Detailed definitions and reporting procedures for AEs will be provided as part of the protocol. Study patients will receive PREZISTA (darunavir) 600 mg boosted with 100 mg of ritonavir orally (by mouth) twice a day in combination with other antiretroviral drugs for 48 weeks.

Official Title
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GRACE: An Open-label, Multicenter Trial to Compare the Efficacy, Safety, and Tolerability of PREZISTA (Darunavir)/Ritonavir by Gender and Race, When Administered in Combination With an Individually Optimized Background Regimen Over a 48-week Treatment Period.

Conditions
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HIV, Infectious

Intervention / Treatment
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* Drug: darunavir
* Drug: ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented HIV infection Plasma HIV-RNA >= 1000 copies/mL Must be able to comply with protocol requirements Exclusion Criteria: No prior use of PREZISTA (darunavir), TMC125, enfuvirtide, or tipranavir No currently active AIDS defining illness, Category C conditions according to the Center for Disease Control [CDC] Classification System for HIV Infection (1993) with the following exceptions, which must be discussed with the Sponsor prior to enrollment: stable cutaneous Kaposi's Sarcoma, Wasting syndrome due to HIV infection Not currently using an investigational drug Not pregnant or breastfeeding No Grade 3 or 4 laboratory abnormality as defined by DAIDS (Division of AIDS, National Institute of Allergy and Infectious Diseases).

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>darunavir 600mg bid for 48 wks,ritonavir 100mg bid for 48 wks | Drug: darunavir<br>* 600mg bid for 48 wks<br>Drug: ritonavir<br>* 100mg bid for 48 wks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Viral Load (VL) < 50 HIV-1 RNA Copies/mL (Time to Loss of Virologic Response[TLOVR]) Subjects by Sex | TLOVR - responders/non-responders per FDA TLOVR response algorithm. A subject was considered a responder at that time point and that subsequent. A subject was considered a non-responder at a time point in the following situations: discontinued treatment at that time point, a rebound value at that time point and that subsequent or at that time point and that followed by treatment discontinuation, intermittent missing values were considered a response if the immediately preceding and following visits were a response, rebound at earlier time point, or any new, unplanned ARV except in tolerability | Week 48 | 
| Number of TLOVR Non-virologic Failure (VF) Censored - VL < 50 HIV-1 RNA Subjects by Sex | TLOVR non-virologic failure (VF) censored. This imputation method differs from the TLOVR algorithm, because subjects that dropped out for reasons other than virologic failure were censored from the time of discontinuation onwards. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of VL < 50 HIV-1 RNA Copies/mL (TLOVR) Subjects by Race | Intention to Treat population (ITT) | Week 48 | 
| Number of Etravirine-TMC125 (ETR) Subgroup- VL < 50 HIV-1 RNA Copies/mL (TLOVR) Subjects | The Etravirine-TMC125 (ETR Subgroup population was defined as all ITT subjects who took at least 1 dose of ETR) | Week 48 | 
| Descriptive Statistics of [TLOVR Non-virologic Failure (VF) Censored] - VL < 50 HIV-1 RNA by Race | TLOVR non-virologic failure (VF) censored. This imputation method differs from the TLOVR algorithm, because subjects that dropped out for reasons other than virologic failure were censored from the time of discontinuation onwards. | Week 48 | 
| Descriptive Statistics of ETR Subgroup [TLOVR Non-virologic Failure (VF) Censored] - VL < 50 HIV-1 RNA | The Etravirine-TMC125 (ETR Subgroup population was defined as all ITT subjects who took at least 1 dose of ETR) TLOVR non-virologic failure(VF) censored. This imputation method differs from the TLOVR algorithm, because subjects that dropped out for reasons other than virologic failure were censored from the time of discontinuation onwards. | Week 48 | 
| Descriptive Statistics of Change From Baseline in CD4+ Cell Count Using Observed Values | Observed obsevations have no imputation methods applied. | Baseline, Week 48 | 
| Descriptive Statistics of ETR Subgroup - Change From Baseline in CD4+ Cell Using Observed Values | The Etravirine-TMC125 (ETR Subgroup population was defined as all ITT subjects who took at least 1 dose of ETR) | Week 48 | 
| Descriptive Statistics of Change From Baseline in CD4+ Cell Count Using the Imputation Method of Last Observation Carried Forward (LOCF) | Last Observation Carried Forward (LOCF) imputation method applied. | Week 48 | 
| Descriptive Statistics of ETR Subgroup - Change From Baseline in CD4+ Cell Count Using the Imputation Method of LOCF | The Etravirine-TMC125 (ETR Subgroup population was defined as all ITT subjects who took at least 1 dose of ETR). The Last Observation Carried Forward (LOCF) imputation method was applied. | 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, Females, Women, PREZISTA, darunavir, TMC114, Protease Inhibitor