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 (PROTEA)

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

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.

Study Overview

• Status: Completed
• Conditions: Human Immunodeficiency Virus (HIV) Infections; Acquired Immunodeficiency Syndrome (AIDS) Virus
• Intervention / Treatment: Drug: Darunavir; Drug: Ritonavir

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 274
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
  • Wien, Austria
• Belgium
  • Antwerpen, Belgium
  • Brussels, Belgium
  • Bruxelles, Belgium
  • Gent, Belgium
• Denmark
  • Copenhagen, Denmark
  • Hvidovre N/A, Denmark
• France
  • Bobigny, France
  • Bondy Cedex, France
  • Dijon, France
  • Paris, France
  • Paris Cedex 12, France
• Germany
  • Berlin, Germany
  • Bonn, Germany
  • Frankfurt, Germany
  • Hannover, Germany
  • Köln, Germany
• Hungary
  • Budapest, Hungary
• Ireland
  • Dublin 9, Ireland
  • Galway, Ireland
• Israel
  • Beer Sheva, Israel
  • Ramat-Gan, Israel
  • Tel-Aviv, Israel
• Poland
  • Warszawa, Poland
• Spain
  • Badalona, Spain
  • Barcelona, Spain
  • Cordoba, Spain
  • Granada, Spain
  • Madrid, Spain
• Sweden
  • Stockholm, Sweden
• Switzerland
  • St Gallen, Switzerland
  • Zurich, Switzerland
• United Kingdom
  • Brighton, United Kingdom
  • London, United Kingdom
  • Manchester, United Kingdom

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Darunavir monotherapy; 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; Darunavir (DRV): type = exact number, unit = mg, number = 800, form = tablet, route = oral use; Drug: Ritonavir; ritonavir (rtv): type = exact number, unit = mg, number = 100, form = tablet, route = oral use
Active Comparator: Triple therapy containing darunavir; 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; Darunavir (DRV): type = exact number, unit = mg, number = 800, form = tablet, route = oral use; Drug: Ritonavir; ritonavir (rtv): type = exact number, unit = mg, number = 100, form = tablet, route = oral use

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Janssen-Cilag International NV

Publications and helpful links

General Publications

• Girard PM, Antinori A, Arribas JR, Ripamonti D, Bicer C, Netzle-Sveine B, Hadacek B, Moecklinghoff C. Week 96 efficacy and safety of darunavir/ritonavir monotherapy vs. darunavir/ritonavir with two nucleoside reverse transcriptase inhibitors in the PROTEA trial. HIV Med. 2017 Jan;18(1):5-12. doi: 10.1111/hiv.12386. Epub 2016 Jun 9.

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2012
• Primary Completion (Actual): June 11, 2014
• Study Completion (Actual): March 18, 2015

Study Registration Dates

• First Submitted: June 2, 2011
• First Submitted That Met QC Criteria: October 6, 2011
• First Posted (Estimate): October 7, 2011

Study Record Updates

• Last Update Posted (Actual): November 27, 2017
• Last Update Submitted That Met QC Criteria: October 23, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: HIV; Prezista; TMC114; neurocognitive function; Darunavir (DRV); virologic response
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Darunavir
• Other Study ID Numbers: CR018370; TMC114IFD3003 (Other Identifier: Janssen); 2011-001635-23 (EudraCT Number); PROTEA (Other Identifier: Janssen)