Dolutegravir + Rilpivirine Switch Study (DORISS)

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the capacity of Dolutegravir + Rilpivirine vs. continued triple combination HAART to maintain plasma HIV RNA ≤ 50 copies/ml throughout 24 weeks in patients with plasma HIV RNA ≤ 50 copies/mL for at least 2 years under conventional HAART (2 NNRTI + 3rd agent). The main secondary objectives are the following: % of virologic success (plasma viral load ≤ 50 copies/mL) at W24 and W48 % of patients who maintain a plasma viral load ≤ 50 copies / ml from D0 to W48 % of virological failure defined by two consecutive plasma viral load > 50 copies/mL Profile of genotypic resistance in case of virological failure. The trial will be conducted according to the design below, in 3 steps: Step 1: enrollment of 80 patients (40 in each arm) Step 2: enrollment on hold until W16 data from the 40 patients enrolled in the intervention arm have been analyzed. Step 3: resumption and completion of enrollment if conditions for resuming enrollment at the end of step 2 are fulfilled, i.e. if the percentage of patients randomized to the intervention arm who have a plasma viral load ≤ 50 copies/mL from D0 to W16 is significantly > 70%, which translates in a maximum of 6 virologic failures.

Official Title
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Dolutegravir + Rilpivirine Switch Study (DORISS): Pilot and Noninferiority Trial Comparing Dolutegravir + Rilpivirine vs. Continued HAART (Highly Active Antiretroviral Therapy) in Patients With Plasma HIV RNA ≤ 50 Copies/mL for at Least 2 Years

Conditions
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HIV Infection, HAART-treated, Virologically Controlled

Intervention / Treatment
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* Drug: Arm 1 (intervention)
* Drug: Arm 2 (control)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years HIV-1 infection Treatment with suppressive triple HAART (2 NRTI + either 1 PI/r, or 1 NNRTI, or INI), unchanged for > 6 months, Intra-class substitution within past 6 months is not considered as a treatment change. Plasma HIV-RNA ≤ 50 copies/mL for > 2 years CD4 cell count > 350/mm3 for > 6 months No prior virologic failure under an NNRTI-containing or an INSTI-containing ART regimen No NNRTI mutation on pre-ART genotype (if no pre-ART genotype available: no NNRTI mutation on DNA genotype at screening) among the following: K101E/P, E138A/G/K/Q/R/S, V179L, Y181C/I/V, Y188L, H221Y, M230I/L/V, L100I + K103N/S, L100I +K103R +V179D. No mutation (either on pre-ART genotype or on DNA genotype at screening) among the following: T66K, G118R, V151L, S153F/Y, R263K, T66K + L74M, E92Q + N155H, Q148R +N155H, Q148H/K/R with at least one mutation of L74I or E138A/K/T or G140A/C/S Negative HBs Ag Informed consent form signed by patient and investigator A specific consent for the pharmacokinetic substudy will be signed by the 10 patients of the pilot phase of the trial who will be randomized to the Dolutegravir + Rilpivirine arm and will volunteer for this PK study Patient covered with health insurance Effective contraception Exclusion Criteria: HIV-2 infection Dialysis or severe renal failure (creatinine clearance < 30 ml/min) History of decompensated liver disease History of HIV-associated neurocognitive disorders AST or ALT > 5 x ULN Positive HBc Ac and negative HBs Ac Patient receiving a proton pump inhibitor that cannot be switched to another anti-secretory drug Current pregnancy or breastfeeding Patient involved in another research that precludes enrolment in another trial Patient under guardianship, or deprived of liberty by a court or administrative decision.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (intervention)<br>Dolutegravir 50 mg/d + Rilpivirine 25 mg/d qd orally (intake during a meal) | Drug: Arm 1 (intervention)<br>* Dolutegravir 50 mg/j + Rilpivirine 25 mg/j qd orally (intake during meal)<br>|
| Active Comparator: Arm 2 (control)<br>Continuation of existing HAART at the time of randomization | Drug: Arm 2 (control)<br>* Continuation of existing HAART at the time of randomization<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pilot phase: Percentage of patients with plasma viral load ≤ 50 copies HIV-RNA/ml from D0 (Day 0) to W16 (Week 16) |  | Week 16 | 
| Non-inferiority phase: Percentage of patients with plasma HIV RNA maintained ≤ 50 copies/mL throughout 24 weeks |  | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with plasma viral load ≤50 HIV RNA copies/mL at Week 24 and Week 48 |  | Week 48 | 
| Percentage of patients with plasma viral load ≤50 HIV RNA copies/mL from Day 0 to Week 48 |  | Week 48 | 
| Percentage of virologic failure, defined as 2 consecutive plasma HIV RNA > 50 copies/mL |  | Week 48 | 
| Measure of the profile of genotypic resistance in plasma in case of virologic failure |  | Week 48 | 
| Percentage of patients who discontinued or changed the strategy of the study |  | Week 48 | 
| Measure of the HIV-DNA between day 0 and week 48 | Evolution of the HIV-DNA between Day 0 and week 48 | W48 | 
| Measure of CD4 lymphocytes at week 24 compared to day 0 | Evolution of CD4 lymphocytes (average) at Week 24 compared to Day 0 | Week 24 | 
| Measure of CD4 lymphocytes at Week 48 compared to Day 0 | Evolution of CD4 lymphocytes (average) at Week 48 compared to Day0 | Week 48 | 
| Number of patients with adverse events of grade 2 to 4 | Adverse events : incidence, grade and relation to study medication of all adverse events, of grade 2 to 4 events | Week 48 | 
| Measure of changes in serum plasma lipid parameters at week 24 compared to Day 0 | Mean changes in serum plasma lipid parameters at Week 24 compared to Day 0 | Week 24 | 
| Measure of changes in serum lipid parameters at week 48 to Day 0 | Mean changes in serum plasma lipid parameters at Week 48 compared to Day 0 | Week 48 | 
| Measure of changes in fat mass distribution at week 24 compared to Day 0 | Changes in fat mass distribution at Week 24 compared to Day 0 | Week 24 | 
| Measure of changes in fat mass distribution at Week 48 compared to Day 0 | Changes in fat mass distribution at Week 48 compared to Day 0 | Week 48 | 
| Measure of adherence to treatment at Week 24 compared to Day 0 | Evolution of adherence to treatment at Week 24 compared to Day 0 assessed by a validated questionnaire | Week 24 | 
| Measure of adherence to treatment at Week 48 compared to Day 0 | Evolution of adherence to treatment at Week 48 compared to Day 0 assessed by a validated questionnaire | Week 48 | 
| Measure of patient satisfaction for their treatment at Day 0 | Assessment of patient satisfaction for their treatment at D0 by questionnaire | Day 0 | 
| Measure of patient satisfaction for their treatment at Week 24 | Assessment of patient satisfaction for their treatment at Week 24 by questionnaire | Week 24 | 
| Measure of patient satisfaction for their treatment at Week 48 | Assessment of patient satisfaction for their treatment at Week 48 by questionnaire | Week 48 | 
| Measure of changes in plasma biomarkers of inflammation (hs-CRP and IL-6) and immune activation (sCD14 , MCP -1, IP10 ) at Week 24 compared to Day 0 . | Changes in plasma biomarkers of inflammation (hs-CRP and IL-6) and immune activation (sCD14 , MCP -1, IP10 ) at Week 24 compared to Day 0 . | Week 24 | 
| Measure of changes in plasma biomarkers of inflammation (hs-CRP and IL-6) and immune activation (sCD14 , MCP -1, IP10 ) at Week 48 compared to Day 0 . | Changes in plasma biomarkers of inflammation (hs-CRP and IL-6) and immune activation (sCD14 , MCP -1, IP10 ) at Week 48 compared to Day 0 . | Week 48 | 
| Measure of plasma concentrations of Dolutegravir and Rilpivirine measured at Week 4 | Analysis PK (PharmacoKinetic) / PD (Pharmaodynamic) of plasma concentrations of Dolutegravir and Rilpivirine measured at Week 4 | Week 4 | 
| Measure of plasma concentrations of Dolutegravir and Rilpivirine measured at Week 24 | Analysis PK / PD of plasma concentrations of Dolutegravir and Rilpivirine measured at Week 24 | Week 24 | 
| Measure of the profile of genotypic resistance in plasma in case of virologic failure |  | Week 24 | 
| Percentage of virologic failure, defined as 2 consecutive plasma HIV RNA > 50 copies/mL |  | Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dolutegravir, Rilpivirine, PI- and NRTI- sparing ART regimen, switch study