Treatment Simplification by Darunavir/Ritonavir 800/100 mg Once a Day Versus a Triple Combination Therapy With Darunavir/Ritonavir

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.

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00458302

Acronym

MONET

Enrollment

256

Registered

2007-04-10

Start date

2007-06-30

Completion date

2011-01-31

Last updated

2012-12-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Acquired Immunodeficiency Syndrome Virus, AIDS Virus, HIV Infections, Human Immunodeficiency Virus

Keywords

HIV, Monotherapy, Darunavir, Protease inhibitor, Early pre-treated, Undetectable, Treatment Experienced

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.

Interventions

DRUGdarunavir (DRV, TMC114)

800 mg qd (2 x 400 mg tablet) + 2 NRTI for 144 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Virological Response [Per Protocol (PP) - Time to Loss of Virologic Response (TLOVR), < 50 Copies/ml, Week 48]	Week 48	Virological response is defined as the number of patients in the PP population with a plasma viral load \< 50 HIV RNA copies/ml at Week 48. Treatment failure was defined as two consecutive HIV RNA levels ≥ 50 copies/mL, or discontinuation of randomised treatment (known as TLOVR). In addition, any switch in background nucleoside reverse transcriptase inhibitors (NRTIs) equaled failure\* (referred to as a Switch Equals Failure analysis). \*Discontinuations and rechallenge with NRTIs are taken into account until Week 48

Secondary

Measure	Time frame	Description
Virological Response [Per Protocol (PP), TLOVR - Switch Equals Failure, < 50 Copies/ml, Week 144]	Week 144	Virological response is defined as the number of patients in the PP population with a plasma viral load \< 50 HIV RNA copies/ml at Week 144. Treatment failure was defined as two consecutive HIV RNA levels ≥ 50 copies/mL, or discontinuation of randomised treatment (known as TLOVR). In addition, any switch in background nucleoside reverse transcriptase inhibitors (NRTIs) equaled failure\* (referred to as a Switch Equals Failure analysis). \*Discontinuations and rechallenge with NRTIs are taken into account until Week 144
Virological Response [Intent To Treat (ITT), TLOVR - All Switches Included, < 50 Copies/ml, Week 144]	Week 144	Virological response is defined as the number of patients in the ITT population with a plasma viral load \< 50 HIV RNA copies/ml at Week 144. Treatment failure was defined as two consecutive HIV RNA levels ≥ 50 copies/mL, or discontinuation of randomised treatment (known as TLOVR). All switches included means that all data even after any changes of treatment were kept. \*Discontinuations and rechallenge with NRTIs are taken into account until start of Week 144 window.
Virological Response [Per Protocol (PP), TLOVR - Switch Equals Failure, <200 Copies/ml, Week 144]	week 144	Virological response is defined as the number of patients in the PP population with a plasma viral load \< 200 HIV RNA copies/ml at Week 144. Treatment failure was defined as two consecutive HIV RNA levels ≥ 50 copies/mL, or discontinuation of randomised treatment (known as TLOVR). In addition, any switch in background nucleoside reverse transcriptase inhibitors (NRTIs) equaled failure\* (referred to as a Switch Equals Failure analysis). \*Discontinuations and rechallenge with NRTIs are taken into account until Week 144
Resistance Determinations	at each visit from baseline to week 144	Number of patients with resistance mutations at any time point when a patient had a viral load \> 50 copies/mL after randomization.
Mean Change From Baseline in CD4+ Cell Count	at week 4, 12, 24, 36, 48, 60, 72, 84, 96, 112, 128, 144	The mean change in CD4+ cell count from baseline was calculated with a last observation carried forward method; i.e. the last observed value was carried forward, irrespective of the reason for discontinuation.
Virological Response [Intent To Treat (ITT) - TLOVR, < 50 Copies/ml, Week 48]	Week 48	Virological response is defined as the number of patients in the ITT population with a plasma viral load \< 50 HIV RNA copies/ml at Week 48. Treatment failure was defined as two consecutive HIV RNA levels ≥ 50 copies/mL, or discontinuation of randomised treatment (known as TLOVR). In addition, any switch in background nucleoside reverse transcriptase inhibitors (NRTIs) equaled failure\* (referred to as a Switch Equals Failure analysis). \*Discontinuations and rechallenge with NRTIs are taken into account until start of Week 48 window
Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Cognitive Function Subscale	at baseline, week 48, 96 and 144	The FAHI cognitive function subscale. Each item is assessing the impact of HIV on cognitive function on a scale from 0 (not at all) to 5 (very much).
Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Emotional Well-Being Subscale	at baseline, week 48, 96 and 144	The FAHI emotional well-being subscale. Each item is assessing the impact of HIV on emotional well-being on a scale from 0 (not at all) to 5 (very much).
Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Functional and Global Well-Being Subscale	at baseline, week 48, 96 and 144	The FAHI functional and global well-being subscale. Each item is assessing the impact of HIV on functional and global well-being on a scale from 0 (not at all) to 5 (very much).
Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Physical Well-Being Subscale	at baseline, week 48, 96 and 144	The FAHI physical well-being subscale. Each item is assessing the impact of HIV on physical well-being on a scale from 0 (not at all) to 5 (very much).
Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Social Well-Being Subscale	at baseline, week 48, 96 and 144	The FAHI social well-being subscale. Each item is assessing the impact of HIV on physical well-being on a scale from 0 (not at all) to 5 (very much).
Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Total Score	at baseline, week 48, 96 and 144	The FAHI is a validated health-related quality of life questionnaire. The questionnaire consist of 44 items and includes 5 functional scales (physical, social, emotional, functional and global well-being and cognitive function). Each item is assessing the impact of HIV on a scale from 0 (not at all) to 5 (very much).

Countries

Austria, Belgium, Denmark, Germany, Hungary, Israel, Portugal, Russia, Spain, Switzerland, United Kingdom

Participant flow

Recruitment details

xxxxx

Participants by arm

Arm	Count
DRV/r+2NRTIs 800 mg qd (2 x 400 mg tablet) + 2 NRTI for 144 weeks	129
DRV/r 800 mg qd (2 x 400 mg tablet) monotherapy for 144 weeks	127
Total	256

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	4	14
Overall Study	Inc/Exc Criteria Not Met	1	1
Overall Study	Lost to Follow-up	2	0
Overall Study	Other	4	2
Overall Study	Pregnancy	2	1
Overall Study	Protocol Violation	0	2
Overall Study	Study Termination By Sponsor	1	0
Overall Study	Withdrawal by Subject	6	4

Baseline characteristics

Characteristic	DRV/r	DRV/r+2NRTIs	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	2 Participants	1 Participants	3 Participants
Age, Categorical Between 18 and 65 years	125 Participants	128 Participants	253 Participants
Age Continuous	43.4 years STANDARD_DEVIATION 9.14	44.1 years STANDARD_DEVIATION 9.74	43.7 years STANDARD_DEVIATION 9.43
CD4+ cell count (absolute count)	571.0 cells/µl	579.0 cells/µl	573.5 cells/µl
plasma viral load > 1000	2 participants	0 participants	2 participants
plasma viral load 400-1000	0 participants	0 participants	0 participants
plasma viral load < 50	118 participants	125 participants	243 participants
plasma viral load 50-400	7 participants	4 participants	11 participants
Region of Enrollment AUSTRIA	7 participants	9 participants	16 participants
Region of Enrollment BELGIUM	12 participants	12 participants	24 participants
Region of Enrollment DENMARK	14 participants	14 participants	28 participants
Region of Enrollment GERMANY	14 participants	14 participants	28 participants
Region of Enrollment HUNGARY	5 participants	6 participants	11 participants
Region of Enrollment ISRAEL	7 participants	1 participants	8 participants
Region of Enrollment ITALY	5 participants	11 participants	16 participants
Region of Enrollment POLAND	20 participants	9 participants	29 participants
Region of Enrollment PORTUGAL	7 participants	7 participants	14 participants
Region of Enrollment RUSSIAN FEDERATION	2 participants	9 participants	11 participants
Region of Enrollment SPAIN	24 participants	24 participants	48 participants
Region of Enrollment SWITZERLAND	1 participants	1 participants	2 participants
Region of Enrollment UNITED KINGDOM	9 participants	12 participants	21 participants
Sex: Female, Male Female	28 Participants	22 Participants	50 Participants
Sex: Female, Male Male	99 Participants	107 Participants	206 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	98 / 129	103 / 127	201 / 256
serious Total, serious adverse events	14 / 129	14 / 127	28 / 256

Outcome results

Primary

Virological Response [Per Protocol (PP) - Time to Loss of Virologic Response (TLOVR), < 50 Copies/ml, Week 48]

Virological response is defined as the number of patients in the PP population with a plasma viral load \< 50 HIV RNA copies/ml at Week 48. Treatment failure was defined as two consecutive HIV RNA levels ≥ 50 copies/mL, or discontinuation of randomised treatment (known as TLOVR). In addition, any switch in background nucleoside reverse transcriptase inhibitors (NRTIs) equaled failure\* (referred to as a Switch Equals Failure analysis). \*Discontinuations and rechallenge with NRTIs are taken into account until Week 48

Time frame: Week 48

Population: PP population: all randomised patients who took study drug, and who did not deviate from the protocol.This excludes 10 patients with major protocol deviations.

Arm	Measure	Value (NUMBER)
DRV/r+2NRTIs	Virological Response [Per Protocol (PP) - Time to Loss of Virologic Response (TLOVR), < 50 Copies/ml, Week 48]	108 participants
DRV/r	Virological Response [Per Protocol (PP) - Time to Loss of Virologic Response (TLOVR), < 50 Copies/ml, Week 48]	106 participants

Comparison: Assuming a virologic response rate of 90% at 48 weeks for both treatment arms, 111 patients were required per treatment arm to establish non-inferiority of DRV/r versus triple regimen with a maximum allowable difference of 12%, with a one-sided significance level of p=0.025 and 80% power. To account for a maximum of 10% major protocol violations that would be excluded from the on-protocol analysis, 125 patients were recruited in each treatment arm, so 250 patients in total.95% CI: [-10.1, 6.8]

Secondary

Change From Baseline in Health-Related Quality of Life - FAHI Questionnaire Cognitive Function Subscale

The FAHI cognitive function subscale. Each item is assessing the impact of HIV on cognitive function on a scale from 0 (not at all) to 5 (very much).

Time frame: at baseline, week 48, 96 and 144