Clinical trial NCT01448707: 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
Official title: PROTEAse Inhibitor (DRV/Rtv) in Mono- or Triple Therapy in Suppressed HIV-1 Infected Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Human Immunodeficiency Virus (HIV) Infections
Acquired Immunodeficiency Syndrome (AIDS) Virus
Keywords: Darunavir (DRV)
TMC114
Prezista
HIV
virologic response
neurocognitive function
Lead sponsor: Janssen-Cilag International NV
Sponsor class: INDUSTRY
First posted: 2011-10-07
Enrollment: 274
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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 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

Primary outcomes:
measure: Virologic Response (Food Drug and Administration [FDA] Snapshot, Switch = Failure)
timeFrame: Week 48
Secondary outcomes:
measure: Virologic Response (Food Drug and Administration [FDA] Snapshot, Switch = Failure)
timeFrame: Week 96
measure: Virologic Response (FDA Snapshot, Switch Included)
timeFrame: Week 48 and 96
measure: Change From Baseline in Global Neurocognitive Performance z-Score
timeFrame: Baseline, Week 48 and 96
measure: Time to Loss of Virologic Response
timeFrame: Baseline up to Week 96 or early withdrawal
measure: Number of Participants Reporting Treatment-Emergent Phenotypic Drug Resistance
timeFrame: At Weeks 48 and 96
measure: Number of Participants Reporting Resistance Mutations With Confirmed Virologic Failure Who Have HIV RNA >400 Copies/mL and Genotype Resistance Results
timeFrame: Over 48 and 96 Weeks
Other outcomes:
Locations:
city: Graz
country: Austria
city: Wien
country: Austria
city: Antwerpen
country: Belgium
city: Brussels
country: Belgium
city: Bruxelles
country: Belgium
city: Gent
country: Belgium
city: Copenhagen
country: Denmark
city: Hvidovre N/A
country: Denmark
city: Bobigny
country: France
city: Bondy Cedex
country: France
city: Dijon
country: France
city: Paris Cedex 12
country: France
city: Paris
country: France
city: Berlin
country: Germany
city: Bonn
country: Germany
city: Frankfurt
country: Germany
city: Hannover
country: Germany
city: Köln
country: Germany
city: Budapest
country: Hungary
city: Dublin 9
country: Ireland
city: Galway
country: Ireland
city: Beer Sheva
country: Israel
city: Ramat-Gan
country: Israel
city: Tel-Aviv
country: Israel
city: Warszawa
country: Poland
city: Badalona
country: Spain
city: Barcelona
country: Spain
city: Cordoba
country: Spain
city: Granada
country: Spain
city: Madrid
country: Spain
city: Stockholm
country: Sweden
city: St Gallen
country: Switzerland
city: Zurich
country: Switzerland
city: Brighton
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
Study officials:
affiliation: Janssen-Cilag International NV
name: Janssen-Cilag International NV Clinical Trial
role: STUDY_DIRECTOR
References:
citation: 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.