Dolutegravir + Rilpivirine Switch Study (DORISS) (DORISS)

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

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.

Study Overview

• Status: Withdrawn
• Conditions: HIV Infection; HAART-treated; Virologically Controlled
• Intervention / Treatment: Drug: Arm 1 (intervention); Drug: Arm 2 (control)

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Besançon, France, 25030
    • CHU Jean Minjoz
  • Bobigny, France, 93000
    • Hôpital Avicenne
  • Bondy, France, 93140
    • Hôpital Jean Verdier
  • Bordeaux, France, 33076
    • CHU de Bordeaux
  • Dijon, France, 21079
    • CHU de Dijon
  • La Roche sur Yon, France, 85925
    • CHD La Roche sur Yon
  • Le Kremlin Bicetre, France, 94275
    • CHU Kremlin Bicêtre
  • Levallois-perret, France, 92300
    • Hopital Perpetuel Secours
  • Nantes, France, 44093
    • CHU de Nantes
  • Paris, France, 75015
    • Hôpital Necker - Enfants Malades
  • Paris, France, 75908
    • Hopital Europeen Georges Pompidou
  • Paris, France, 75013
    • Hôpital La Pitié Salpêtrière
  • Paris, France, 75004
    • CHU Hôtel Dieu PARIS
  • Paris Cedex 10, France, 75475
    • Hôpital Saint louis
  • Paris cedex 18, France, 75877
    • CHU BICHAT - Claude Bernard
  • Rennes, France, 35000
    • CHU de Rennes - Hôpital Pontchaillou
  • Saint Denis, France, 93200
    • Ch Delafontaine
  • Saint Etienne, France, 42055
    • CHU Saint Etienne
  • Strasbourg, France, 67091
    • CHU de Strasbourg
  • Suresnes, France, 92150
    • Hôpital FOCH
  • Toulouse, France, 31059
    • CHU Toulouse
  • Tours Cedex 09, France, 37044
    • CHRU De Tours
  • VANDOEUVRE LES NANCY cedex, France, 54511
    • Chu de Nancy
  • Guadeloupe
    • Point-a-pitre, Guadeloupe, France, 97159
      • CHU Guadeloupe
  • Martinique
    • Fort de France, Martinique, France, 87261
      • CHU de Fort de France

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Nantes University Hospital

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Anticipated): October 1, 2017
• Study Completion (Anticipated): October 1, 2017

Study Registration Dates

• First Submitted: February 18, 2014
• First Submitted That Met QC Criteria: February 20, 2014
• First Posted (Estimate): February 24, 2014

Study Record Updates

• Last Update Posted (Estimate): August 28, 2015
• Last Update Submitted That Met QC Criteria: August 27, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: Dolutegravir; Rilpivirine; switch study; PI- and NRTI- sparing ART regimen
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: RC13_0322; 2013-003344-23 (EudraCT Number)