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)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Janssen-Cilag International NV
ClinicalTrials.gov Identifier:
NCT01448707
First received: June 2, 2011
Last updated: February 1, 2016
Last verified: January 2016
  Purpose
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.

Condition Intervention Phase
Human Immunodeficiency Virus (HIV) Infections
Acquired Immunodeficiency Syndrome (AIDS) Virus
Drug: Darunavir
Drug: Ritonavir
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: PROTEAse Inhibitor (DRV/Rtv) in Mono- or Triple Therapy in Suppressed HIV-1 Infected Subjects

Resource links provided by NLM:


Further study details as provided by Janssen-Cilag International NV:

Primary Outcome Measures:
  • Virologic Response (Food Drug and Administration [FDA] Snapshot, Switch = Failure) [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Virologic Response (Food Drug and Administration [FDA] Snapshot, Switch = Failure) [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    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.

  • Virologic Response (FDA Snapshot, Switch Included) [ Time Frame: Week 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Global Neurocognitive Performance z-Score [ Time Frame: Baseline, Week 48 and 96 ] [ Designated as safety issue: No ]
    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).

  • Time to Loss of Virologic Response [ Time Frame: Baseline up to Week 96 or early withdrawal ] [ Designated as safety issue: No ]
    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.

  • Number of Participants Reporting Treatment-Emergent Phenotypic Drug Resistance [ Time Frame: At Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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).

  • Number of Participants Reporting Resistance Mutations With Confirmed Virologic Failure Who Have HIV RNA >400 Copies/mL and Genotype Resistance Results [ Time Frame: Over 48 and 96 Weeks ] [ Designated as safety issue: No ]
    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.


Enrollment: 274
Study Start Date: March 2012
Study Completion Date: March 2015
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01448707

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Sponsors and Collaborators
Janssen-Cilag International NV
Investigators
Study Director: Janssen-Cilag International NV Clinical Trial Janssen-Cilag International NV
  More Information

Responsible Party: Janssen-Cilag International NV
ClinicalTrials.gov Identifier: NCT01448707     History of Changes
Other Study ID Numbers: CR018370  TMC114IFD3003  2011-001635-23  PROTEA 
Study First Received: June 2, 2011
Results First Received: October 30, 2015
Last Updated: February 1, 2016
Health Authority: Belgium: Ministry of Social Affairs, Public Health and the Environment

Keywords provided by Janssen-Cilag International NV:
Darunavir (DRV)
TMC114
Prezista
HIV
virologic response
neurocognitive function

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Ritonavir
Darunavir
Reverse Transcriptase Inhibitors
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on August 24, 2016