Clinical trial NCT00458302: Treatment Simplification by Darunavir/Ritonavir 800/100 mg Once a Day Versus a Triple Combination Therapy With Darunavir/Ritonavir
Official title: A Randomised, Controlled, Open-label Trial to Compare the Efficacy, Safety and Tolerability of a Treatment Simplification by Darunavir/Ritonavir (DRV/r) 800/100 mg O.D. vs a Triple Combination Therapy With DRV/r in HIV-1 Infected Patients With Undetectable Plasma HIV-RNA on Their Current Treatments.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
AIDS Virus
Human Immunodeficiency Virus
Acquired Immunodeficiency Syndrome Virus
Keywords: HIV
Monotherapy
Darunavir
Protease inhibitor
Early pre-treated
Undetectable
Treatment Experienced
Lead sponsor: Janssen-Cilag International NV
Sponsor class: INDUSTRY
First posted: 2007-04-10
Enrollment: 256
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 the study is to compare the efficacy, safety and tolerability of darunavir/ritonavir 800/100 mg once a day (O.D.) as a monotherapy versus a triple combination therapy containing 2 nucleosides and darunavir/ritonavir in 250 HIV-1 infected patients who have been on Highly Active Antiretroviral Therapy (HAART) and have plasma viral load below 50 copies/ml for at least 24 weeks.

Detailed description: This study is randomised (patients are assigned different treatments based on chance), controlled, open-label trial to compare the efficacy, safety and tolerability of darunavir/ritonavir (DRV/r) 800/100 mg once a day (O.D.) as a monotherapy versus a triple combination therapy containing 2 nucleosides and DRV/r in 250 HIV-1 infected patients. Patients will be considered eligible if they have not changed any antiretroviral drugs for at least 8 weeks prior to screening and have documented evidence of plasma viral load (or plasma HIV-1 RNA) \< 50 copies/mL for at least 24 weeks prior to being screened. The trial will consist of a screening period up to 4 weeks, a 48-week treatment period, followed by a 4-week follow-up (FU) period. The primary objective is to demonstrate non-inferiority in efficacy of DRV/r versus the triple combination therapy containing DRV/r, with respect to confirmed virologic response, defined as plasma HIV-1 RNA \< 50 copies/mL at 48 weeks.Patients will be assigned a study medication based on a 1:1 ratio to either switch to a triple combination therapy containing 2 nucleosides and DRV/r 800/100 mg O.D, or initiate monotherapy with DRV/r 800/100 mg O.D. Patients in the triple combination arm who are already on 2 nucleosides prior to randomisation may remain on these or switch them at baseline. Patients randomised to the monotherapy arm will discontinue Highly Active Antiretroviral Therapy (HAART) at baseline and commence DRV/r 800/100 mg O.D. A Data and Safety Monitoring Board (DSMB) has been commissioned for this study. The role of the DSMB is to review the progress of the trial and the accumulating data to detect evidence of early safety issues for the patients while the trial is ongoing. An interim analysis will be performed after 24 weeks of treatment. The results of the Week 24 analysis will be used to determine whether long-term follow-up to 72 and 96 weeks will be done. The protease inhibitor (PI) component of the regimen cannot be changed until the end of the treatment period and the nucleoside reverse transcriptase inhibitors (NRTIs) cannot be modified until the end of the treatment period with the following exception: single antiretroviral (ARV) substitutions will be allowed for tolerability/toxicity reasons, as long as this can be linked to an adverse event (AE) or an serious adverse event (SAE). After withdrawal of the patient from the trial, changes in the ARV regimen are allowed after the assessments of the withdrawal visit have been performed.

Temporary interruption of all ARVs will be allowed in the event of suspected toxicity, as long as the temporary interruption is associated with and can be linked to an AE or a SAE. For the control arm, the nucleoside analogues could be re-optimized at baseline or on study, and all approved ARVs allowed. However, PIs other than DRV/r are not allowed during the treatment period. Patients who cannot resume study medication will have to be withdrawn. A physical examination will be done at protocol-scheduled visits and vital signs will be monitored at each study visit. In addition, at each study visit, every patient will be asked about the occurrence of or change to AEs since they were last seen by the investigator. Laboratory samples for haematology and serum chemistry will be drawn and the results determined and transmitted to the investigator. Urinalysis will be performed. Pregnancy test will be done at each visit for female participants of child-bearing potential. The primary endpoint will be the proportion with virologic response, defined as a confirmed plasma HIV-1 RNA \< 50 copies/mL at Week 48.The study hypothesis is that DRV/r monotherapy will be as effective as a triple combination regimen and will be well tolerated in this early pre-treated HIV-1 patients. Two 400mg tablets of darunavir once daily orally within 30 minutes after completion of a meal for 48 weeks.

Eligibility criteria: Inclusion Criteria:

* Patients with documented HIV-1 infection
* Patients currently receiving HAART for at least 24 weeks
* Plasma viral load \< 50 copies/mL for at least 24 weeks prior to screening (two results must be documented)
* Patients taking the same antiretroviral combination for at least 8 weeks before screening
* Patients and physician's preference to change the current HAART regimen for reasons of simplification and/or toxicity
* CD4 \> 100/mm3 at the start of HAART and \> 200/mm3 at screening.

Exclusion Criteria:

* No history of virological failure defined as two consecutive plasma HIV-1 RNA \> 500 copies/mL while on previous or current antiretroviral therapy
* No history of any primary PI mutations as defined by the IAS-USA guidelines 2006
* No patients co-infected with hepatitis B
* No pregnant or breastfeeding women
* No active clinically significant disease or life threatening disease or findings during screening of medical history or physical examination that, in the investigator's opinion, would compromise the patient's safety or outcome of the study.

Primary outcomes:
measure: Virological Response [Per Protocol (PP) - Time to Loss of Virologic Response (TLOVR), < 50 Copies/ml, Week 48]
timeFrame: Week 48
Secondary outcomes:
measure: Virological Response [Intent To Treat (ITT) - TLOVR, < 50 Copies/ml, Week 48]
timeFrame: Week 48
measure: Virological Response [Per Protocol (PP), TLOVR - Switch Equals Failure, < 50 Copies/ml, Week 144]
timeFrame: Week 144
measure: Virological Response [Intent To Treat (ITT), TLOVR - All Switches Included, < 50 Copies/ml, Week 144]
timeFrame: Week 144
measure: Virological Response [Per Protocol (PP), TLOVR - Switch Equals Failure, <200 Copies/ml, Week 144]
timeFrame: week 144
measure: Mean Change From Baseline in CD4+ Cell Count
timeFrame: at week 4, 12, 24, 36, 48, 60, 72, 84, 96, 112, 128, 144
measure: Resistance Determinations
timeFrame: at each visit from baseline to week 144
measure: Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Total Score
timeFrame: at baseline, week 48, 96 and 144
measure: Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Cognitive Function Subscale
timeFrame: at baseline, week 48, 96 and 144
measure: Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Emotional Well-Being Subscale
timeFrame: at baseline, week 48, 96 and 144
measure: Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Functional and Global Well-Being Subscale
timeFrame: at baseline, week 48, 96 and 144
measure: Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Physical Well-Being Subscale
timeFrame: at baseline, week 48, 96 and 144
measure: Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Social Well-Being Subscale
timeFrame: at baseline, week 48, 96 and 144
Other outcomes:
Locations:
city: Wien
country: Austria
city: Antwerpen
country: Belgium
city: Bruxelles
country: Belgium
city: Aarhus
country: Denmark
city: Copenhagen
country: Denmark
city: Hvidovre
country: Denmark
city: Odense
country: Denmark
city: Berlin
country: Germany
city: Frankfurt
country: Germany
city: Hamburg
country: Germany
city: Hannover
country: Germany
city: Kÿln N/A
country: Germany
city: Budapest
country: Hungary
city: Jerusalem
country: Israel
city: Tel Aviv
country: Israel
city: Tel Hashomer
country: Israel
city: Lisbon
country: Portugal
city: Porto
country: Portugal
city: Moscow
country: Russian Federation
city: Saint-Petersburg
country: Russian Federation
city: Barcelona N/A
country: Spain
city: Barcelona
country: Spain
city: Donostia Guipuzcoa
country: Spain
city: Granada
country: Spain
city: Madrid
country: Spain
city: Valladolid N/A
country: Spain
city: St Gallen
country: Switzerland
city: London
country: United Kingdom
Study officials:
affiliation: Janssen-Cilag International NV
name: Janssen-Cilag International NV Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Arribas JR, Horban A, Gerstoft J, Fatkenheuer G, Nelson M, Clumeck N, Pulido F, Hill A, van Delft Y, Stark T, Moecklinghoff C. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS. 2010 Jan 16;24(2):223-30. doi: 10.1097/QAD.0b013e3283348944.