A Clinical Trial Comparing the Efficacy of Darunavir/Ritonavir Monotherapy Versus a Triple Combination Therapy Containing Darunavir/Ritonavir and 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Patients With Undetectable Plasma HIV-1 RNA on Current Treatment

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy, safety and tolerability of darunavir/ritonavir 800/100 mg monotherapy with a triple combination therapy containing darunavir/ritonavir 800/100 mg and 2 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) in approximately 260 Human Immunodeficiency Virus-1 (HIV-1) infected patients who have been on Highly Active AntiRetroviral Therapy (HAART) medication and have a plasma Viral Load below 50 copies/mL for at least 48 weeks. Also the changes in neurocognitive function will be compared throughout the study.

Detailed Description
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This is phase IIIb, randomised (study medication is assigned by chance), open-label (both the patient and the study physician will know to which treatment group the patient is assigned) trial to compare the efficacy, safety and tolerability of darunavir/ritonavir (DRV/rtv) 800/100 mg once daily monotherapy with a triple combination therapy containing DRV/rtv 800/100 mg once daily and an investigator-selected background of 2 other anti-HIV drugs of the class nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs). The investigator-selected N[t]RTIs is a dual combination of either be abacavir (ABC), lamivudine (3TC), zidovudine (AZT), tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC). Approximately 260 HIV-1 infected patients, who have received HAART for at least 48 weeks, have not changed their treatment within the last 8 weeks, and who have documented evidence of plasma viral load (plasma HIV-1 RNA) below 50 copies/mL for at least 48 weeks prior to being screened, participate in the study. The study period includes a screening period of maximum 6 weeks, a 4-week run-in period, a 96 week treatment period, followed by a 4 weeks follow-up period. According to the original protocol, at the start of the 4-week run-in period all patients replaced their 3rd agent (non-nucleoside reverse transcriptase (NNRTI), protease inhibitor (PI) or integrase inhibitor) of the HAART medication with DRV/rtv and continued with the 2 N[t]RTIs. After 4 weeks the patient was randomly assigned (like flipping a coin) to either the monotherapy group or the triple therapy group. If assigned to the monotherapy group, the 2 N[t]RTIs were stopped and only DRV/rtv was continued. If assigned to the triple therapy group, DRV/rtv were continued together with 2 N[t]RTIs, which can be the same as already taken or are switched to new N[t]RTIs. Based on the primary efficacy analysis after Week 48, the protocol was amended such that subjects in the monotherapy arm who entered the study with a nadir CD4+ count of <200 cells/μL will also receive 2 N[t]RTIs (ie, triple therapy) as soon as possible. The main purpose of this study is to demonstrate that DRV/rtv monotherapy is as effective as a triple combination therapy containing DRV/rtv and 2N[t]RTIs. In addition, the study looks at overall safety and tolerability between the two treatment groups. During the study, patients' health are monitored by physical examination, checking of vital signs (blood pressure / pulse), and laboratory testing on blood and urine samples. Also blood samples are drawn to measure the antiviral effectiveness (i.e., decrease of the plasma viral load to a level <50 HIV-1 RNA copies/mL) and immunology assessments (to assess the body's immune system). A battery of neurocognitive function tests is performed during the study visits. A sub-study takes place in selected hospitals. Approximately 100 patients have 2 additional tests done, at the start of the run-in phase and after 48-weeks of randomisation. For this substudy a lumbar puncture (extraction of cerebrospinal fluid [CSF] from the spinal canal) for laboratory testing (antiviral effectiveness, pharmacokinetic analysis, biochemistry and immune markers) and an additional blood sample for pharmacokinetic analysis (to measure the drug level in blood) is taken. The study hypothesis is that, after 48 weeks of randomised treatment, DRV/rtv monotherapy is as effective as the triple therapy containing DRV/rtv plus 2 N[t]RTIs. Two 400 mg tablets of darunavir and one 100 mg tablet ritonavir are taken together once daily orally within 30 minutes after completion of a meal, for 100 weeks. The intake of the investigator-selected N[t]RTIs as according the local prescribing information.

Official Title
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PROTEAse Inhibitor (DRV/Rtv) in Mono- or Triple Therapy in Suppressed HIV-1 Infected Subjects

Conditions
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Human Immunodeficiency Virus (HIV) Infections, Acquired Immunodeficiency Syndrome (AIDS) Virus

Intervention / Treatment
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* Drug: Darunavir
* Drug: Ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection receiving HAART for at least 48 weeks Have at least 2 documented plasma HIV-1 RNA <50 copies/mL, and no HIV-1 RNA >=50 copies/mL in the 48 weeks prior to the screening Be taking the same antiretroviral (ARV) combination for at least 8 weeks before screening Have the preference, together with the physician, to change the current HAART regimen for reasons of simplification and/or toxicity Exclusion Criteria: Has a history of virologic failure defined as 2 consecutive plasma HIV-1 RNA >500 copies/mL while on previous or current antiretroviral therapy Has a history of any primary PI mutations Has clinical or laboratory evidence of significantly decreased hepatic function or decompensation, irrespective of liver enzyme levels (liver insufficiency) Is diagnosed with acute viral hepatitis at screening or before Baseline 1 Is co-infected with hepatitis B

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: Darunavir monotherapy<br>Darunavir (DRV) + ritonavir (rtv): 2 tablets DRV 400 mg should be taken together with 1 tablet rtv 100 mg within 30 minutes after a meal. Following the primary efficacy analysis after Week 48, patients who entered the study with a nadir CD4+ count of <200 cells/μL will also receive 2 N[t]RTIs (ie, triple therapy) as soon as possible | Drug: Darunavir<br>* Darunavir (DRV): type = exact number, unit = mg, number = 800, form = tablet, route = oral use<br>Drug: Ritonavir<br>* ritonavir (rtv): type = exact number, unit = mg, number = 100, form = tablet, route = oral use<br>|
| Active Comparator: Triple therapy containing darunavir<br>Darunavir (DRV) + ritonavir (rtv) + 2 N[t]RTIs: 2 tablets DRV 400 mg should be taken together with 1 tablet rtv 100 mg within 30 minutes after a meal in combination with 2 N[t]RTIs (an investigator-selected dual combination of either abacavir (ABC), lamivudine (3TC), zidovudine (AZT), tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC) | Drug: Darunavir<br>* Darunavir (DRV): type = exact number, unit = mg, number = 800, form = tablet, route = oral use<br>Drug: Ritonavir<br>* ritonavir (rtv): type = exact number, unit = mg, number = 100, form = tablet, route = oral use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virologic Response (Food Drug and Administration [FDA] Snapshot, Switch = Failure) | The percentage of participants who have plasma human immunodeficiency virus type-1 (HIV-1) ribonucleic acid (RNA) levels <50 copies/milliliters [mL] after 48 weeks of follow-up. Switch = Failure is defined as switch in background nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) not permitted by the trial protocol or plasma HIV-1 RNA assessment closest to target date of the analysis time point window (44-52 weeks) and next/confirmation of Plasma HIV-1 RNA in the analysis time point window above the threshold or discontinuation for any other reason. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virologic Response (Food Drug and Administration [FDA] Snapshot, Switch = Failure) | The percentage of participants who have plasma human immunodeficiency virus type-1 (HIV-1) ribonucleic acid (RNA) levels <50 copies/milliliters [mL] after 96 weeks of follow-up after switching to DRV/ritonavir(rtv) monotherapy versus triple therapy containing DRV/rtv. Switch = Failure is defined as switch in background nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) not permitted by the trial protocol. | Week 96 | 
| Virologic Response (FDA Snapshot, Switch Included) | The percentage of participants who have plasma human immunodeficiency virus type-1 (HIV-1) ribonucleic acid (RNA) levels <50 copies/milliliters [mL] after 48 and 96 weeks of follow-up after switching to DRV/ritonavir(rtv) monotherapy versus triple therapy containing DRV/rtv. Switch included is defined as all participants who discontinued randomized medication were followed up on their subsequent treatment. | Week 48 and 96 | 
| Change From Baseline in Global Neurocognitive Performance z-Score | Change in neurocognitive function of DRV/rtv monotherapy versus triple therapy containing DRV/rtv over 48 and 96 weeks. Neurocognitive function will be measured by Hopkins Verbal Learning Test (verbal learning and memory), Colour Trail Test (psychomotor speed and cognitive flexibility) and Grooved Pegboard Test (psychomotor speed and fine motor function). Higher values for change in z-score represent an improvement in Neurocognitive Performance (NP). | Baseline, Week 48 and 96 | 
| Time to Loss of Virologic Response | Time (in days) it takes to show loss of response per time to loss of virologic response (TLOVR) algorithm: confirmed HIV-1 RNA >= 50 copies/mL or premature discontinuation. | Baseline up to Week 96 or early withdrawal | 
| Number of Participants Reporting Treatment-Emergent Phenotypic Drug Resistance | The loss of treatment options of DRV/rtv monotherapy versus triple therapy containing DRV/rtv at Weeks 48 and 96, as defined by treatment-emergent phenotypic drug resistance. Drug resistance is classified as: 1) Confirmed HIV RNA >= 400 copies/mL, 2) Post-baseline phenotypic data and 3) Phenotypic resistance to any of the drug classes (NRTI, NNRTI, or PI). | At Weeks 48 and 96 | 
| Number of Participants Reporting Resistance Mutations With Confirmed Virologic Failure Who Have HIV RNA >400 Copies/mL and Genotype Resistance Results | The viral genotype of participants treated with DRV/rtv monotherapy versus triple therapy containing DRV/rtv over 48 and 96 weeks. Genotypic resistance (number of resistance mutations) at any time point when a participant had a confirmed plasma VL >400 copies/mL after randomization was performed per treatment group for the ITT population. Results were summarized based on individual treatment received: Darunavir resistance mutations, non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations, nucleoside reverse transcriptase inhibitor (NRTI) mutations, protease inhibitor (PI) resistance mutations, PR mutations, RT mutations, extended NNRTI mutations, primary PI mutations. | Over 48 and 96 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Darunavir (DRV), TMC114, Prezista, HIV, virologic response, neurocognitive function