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

Human Immunodeficiency Virus (HIV) Infections Clinical Trial

— PROTEA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01448707
• Other study ID #: CR018370
• Secondary ID: TMC114IFD3003201
• Status: Completed
• Phase: Phase 3
• First received: June 2, 2011
• Last updated: October 23, 2017
• Start date: March 15, 2012
• Est. completion date: March 18, 2015

Study information

• Verified date: October 2017
• Source: Janssen-Cilag International NV
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 274
• Est. completion date: March 18, 2015
• Est. primary completion date: June 11, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• Acquired Immunodeficiency Syndrome (AIDS) Virus
• HIV Infections
• Human Immunodeficiency Virus (HIV) Infections
• Immunologic Deficiency Syndromes

Intervention

Drug:
• Darunavir
Darunavir (DRV): type = exact number, unit = mg, number = 800, form = tablet, route = oral use
• Ritonavir
ritonavir (rtv): type = exact number, unit = mg, number = 100, form = tablet, route = oral use

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Janssen-Cilag International NV

Countries where clinical trial is conducted

Austria,  Belgium,  Denmark,  France,  Germany,  Hungary,  Ireland,  Israel,  Poland,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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