A Study to Compare Effectiveness and Safety of Darunavir/Ritonavir (DRV/Rtv) 800mg/100mg Once Daily Versus DRV/Rtv 600mg/100mg Twice Daily in Early Treatment-Experienced HIV-1 Infected Patients (ODIN)

Study Overview
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Brief Summary
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The purpose of this study is to test if being treated with darunavir/ritonavir (DRV/rtv) 800/100 mg daily is as effective as being treated with DRV/rtv 600/100 mg twice daily, in early antiretroviral (ARV)-experienced patients when given along with selected optimized background regimen (OBR).

Detailed Description
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This is a randomized (the study medication is assigned by chance), open-label (all people know the identity of the intervention) study in which 590 patients will be randomly assigned to receive either DRV/rtv 800/100 mg daily or DRV/rtv 600/100 mg twice daily along with the selected OBR. An OBR will consist of at least 2 nucleoside reverse transcriptase inhibitors (NRTIs) selected by the investigator. The study will include a 4 week screening period, 48-weeks of treatment period and 4-weeks of follow-up. The study will also consists of extension phase after Week 48: in regions where DRV is not yet commercially available or reimbursed by the health care system, patients who complete the 48 weeks of treatment with DRV/rtv and who continue to benefit from this treatment, will have the opportunity to continue DRV treatment as a 600 mg twice daily dosage until DRV is reimbursed and available via the public and/or private health care system or until its development is discontinued. Safety evaluation will consists of adverse events (including specific toxicities), clinical laboratory tests, vital signs, electrocardiogram, physical and skin examination.

Official Title
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A Randomized, Open-label Trial to Compare the Efficacy, Safety and Tolerability of DRV/Rtv (800mg/100mg) q.d Versus DRV/Rtv (600mg/100mg) b.i.d in Early Treatment-experienced HIV-1 Infected Subjects

Conditions
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Human Immunodeficiency Virus - Type 1

Intervention / Treatment
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* Drug: Darunavir (DRV)
* Drug: Ritonavir (rtv)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with documented human immunodeficiency virus - Type 1 (HIV-1) infection Patients with a viral load greater than 1,000 HIV-1 ribonucleic acid (RNA) copies/mL Stable highly active antiretroviral therapy (HAART) regimen for at least 12 weeks at screening In the investigator's opinion, non-nucleoside reverse transcriptase inhibitors (NNRTIs) are not a valid treatment option, because of the patient's antiretroviral (ARV) treatment history, ARV resistance testing, medication-taking behavior, safety and tolerability concerns, or other patient-related factors Prescreening or/and screening plasma HIV-1 RNA greater than 1,000 copies/mL on HAART regimen at screening Exclusion Criteria: Presence of any currently active conditions that fit the definition of the World Health Organization (WHO) Clinical Stage 4, with the following exceptions: stable cutaneous kaposi's sarcoma (ie, no internal organ involvement other than oral lesions) that is unlikely to require any form of systemic therapy during the study time period, wasting syndrome Patients for whom an investigational ARV is part of the current regimen, with the following exceptions if applicable (depending on local regulatory approval): tenofovir, emtricitabine Previous or current use of enfuvirtide (ENF), tipranavir and/or DRV Life expectancy of less than 12 months Pregnant or breast-feeding females Any active clinically significant disease (eg, tuberculosis [TB], cardiac dysfunction, pancreatitis, acute viral infections) or findings during screening of medical history or physical examination that, in the investigator's opinion, would compromise the patient's safety or outcome of the study

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DRV/rtv 800/100 mg once daily<br>Two 400 mg darunavir (DRV) ie, TMC114 tablets + one 100 mg ritonavir (rtv) capsule once daily. | Drug: Darunavir (DRV)<br>* DRV/rtv 800/100 mg once daily group: 2 tablets of 400 mg of DRV administered orally once daily. DRV/rtv 600/100 mg twice daily group: 1 tablet of 600 mg DRV administered orally twice daily.<br>* Other names: TMC114;Drug: Ritonavir (rtv)<br>* DRV/rtv 800/100 mg once daily group: One capsule of 100 mg of ritonavir administered orally once daily. DRV/rtv 600/100 mg twice daily group: One capsule of 100 mg of ritonavir administered orally twice daily.<br>* Other names: rtv;|
| Experimental: DRV/rtv 600/100 mg twice daily<br>One 600 mg TMC114 tablet + one 100 mg capsule of rtv twice daily. | Drug: Darunavir (DRV)<br>* DRV/rtv 800/100 mg once daily group: 2 tablets of 400 mg of DRV administered orally once daily. DRV/rtv 600/100 mg twice daily group: 1 tablet of 600 mg DRV administered orally twice daily.<br>* Other names: TMC114;Drug: Ritonavir (rtv)<br>* DRV/rtv 800/100 mg once daily group: One capsule of 100 mg of ritonavir administered orally once daily. DRV/rtv 600/100 mg twice daily group: One capsule of 100 mg of ritonavir administered orally twice daily.<br>* Other names: rtv;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological Response at Week 48 (Number of Participants With Plasma Viral Load Less Than 50 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 after discontinuation. 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. | 48 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virologic Response at Week 48 (Viral Load Less Than 400 Copies/mL) | Number of participants with confirmed plasma viral load less than 400 copies/mL at Week 48. | 48 weeks | 
| Change in log10 Viral Load From Baseline at Week 48 |  | 48 weeks | 
| Time to Reach First Virologic Response | Time (in weeks) to achieve viral load less than 50 copies/mL by the participants. | 48 weeks | 
| Time to Loss of Virologic Response | Time taken to lose the virologic response ie, plasma viral load less than 50 copies/mL by participants. | 48 weeks | 
| Time-averaged Difference (DAVG) of log10 Plasma Viral Load Over 48 Weeks |  | 48 weeks | 
| Change in CD4+ Cell Count From Baseline | CD4+ cell count was calculated using the Last Observation Carried Forward (LOCF) algorithm. | 48 Weeks | 
| Change From Baseline in Total Functional Assessment of HIV Infection (FAHI) Score | The FAHI is a 44-item questionnaire and incorporates 5 functional scales (physical well-being, emotional well-being/living with HIV, functional and global well-being, social well-being, and cognitive functioning). Each scale included several questions (all 5 scales include total 44 questions). For each question, participants gave a score of either 0 (not at all), 1 (a little bit), 2 (somewhat), 3 (quite a bit) and 4 (very much). Total FAHI imputed score is calculated by adding scores for each question. The range of total FAHI score is 0 to 176. Higher scores indicate worsening. | 48 weeks | 
| Percentage of Participants Adherent/Non-adherent to ARV as Determined by Modified Medication Adherence Self Report Inventory (M-MASRI) Questionnaire at Week 48 | Self-reported adherence to the ARV medications was measured. The M-MASRI asks participants to report the number of doses taken, as well as the number of doses taken during the last 30 days prior to the study visit by means of a horizontal visual analogue scale (VAS) that generates a self-rated percentage of doses of all the ARV medications taken during the past 30 days. | 48 weeks | 
| Area Under the Curve From the Time of Study Medication Administration Upto 24 Hour Postdose (AUC24h) of DRV and Rtv | Pharmacokinetic parameter AUC24h was assessed from the time of study medication administration upto 24 hour postdose. Population Pharmacokinetic Estimates of DRV and rtv were evaluated. | 0 hour predose and 1 hour post dose measured at Weeks 4 and 24. Any time point measured at Weeks 8 and 48. | 
| Predose Plasma Concentration (C0h) of DRV and Rtv. | Pharmacokinetic parameter C0h was assessed. Population Pharmacokinetic Estimates of DRV and rtv were evaluated. | 0 hour predose and 1 hour post dose measured at Weeks 4 and 24. Any time point measured at Weeks 8 and 48 | 
| Number of Participants Developing Mutations at Endpoint | Development of Mutations in Virologic Failures (Plasma Viral Load less than 50 Copies/mL) at endpoint. | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human immunodeficiency virus - type 1, HIV-1 Infection, TMC-114, Darunavir, Ritonavir