Antiretroviral Treatment Taken 4 Days Per Week Versus Continuous Therapy 7/7 Days Per Week in HIV-1 Infected Patients

HIV Infections Clinical Trial

— QUATUOR  

Official title:

Randomized, Open-label and Multicentric Trial Evaluating the Non-inferiority of Antiretroviral Treatment Taken 4 Consecutive Days Per Week Versus Continuous Therapy 7/7 Days Per Week in HIV-1 Infected Patients With Controlled Viral Load Under Antiretroviral Therapy

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03256422
• Other study ID #: ANRS 170 - QUATUOR
• Status: Active, not recruiting
• Phase: Phase 3
• First received: August 9, 2017
• Last updated: February 2, 2018
• Start date: September 7, 2017
• Est. completion date: December 2020

Study information

• Verified date: August 2017
• Source: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The trial is an open-label, multicenter, prospective, randomized trial in 2 parallel groups, evaluating at W48, the non-inferiority of antiretroviral treatment taken 4 consecutive days a week versus continuous therapy, in HIV infected patients with controlled viral load for at least 12 months and stable antiretroviral treatment since 4 months.

Description:

Open-label, multicenter, prospective, randomized trial in 2 parallel groups, evaluating at W48, the non-inferiority of antiretroviral treatment taken 4 consecutive days a week versus continuous therapy, in HIV infected patients with controlled viral load for at least 12 months and stable antiretroviral treatment since 4 months. The non-inferiority margin (delta) is 5%. The randomization will be stratified according to the family of the third antiretroviral agent (II, PI, and NNRTI). A minimum of 200 patients will be included in the integrase inhibitor strata to provide a sufficient power to assess the efficacy of strategy in this population.

At W48, all patients with virological success in the continuous therapy group will switch to the 4/7 days therapy.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 640
• Est. completion date: December 2020
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• HIV-1 infection, coinfection HIV-1/HIV-2 possible

• Age=18 years old

• Current therapy unchanged for the last 4 months

• Receiving tritherapy with 2 nucleoside reverse transcriptase inhibitor+protease inhibitors or 2 nucleoside reverse transcriptase inhibitor+non-nucleoside reverse transcriptase inhibitors or 2 nucleoside reverse transcriptase inhibitor+integrase inhibitors.

Allowed treatment drugs are :

1. nucleoside analogs : tenofovir (TDF ou TAF), emtricitabine, abacavir, lamivudine 2. protease inhibitors : lopinavir/r, darunavir/r ou atazanavir/r 3. Non nucleoside reverse transcriptase inhibitors : efavirenz, rilpivirine ou etravirine 4. integrase inhibitors : dolutegravir, elvitegravir/cobicistat ou raltegravir

• Viruses susceptible to all antiretroviral drugs present in the ongoing tritherapy (AC11-ANRS algorithm).

1. If a genotype is available in the patient medical history; viruses must be susceptible to all ongoing antiretroviral drugs

2. If no RNA genotype available, a genotype will be performed on DNA at screening and will not have to show any resistance to the ongoing antiretroviral drugs

• Viral load (VL) < 50 cp/mL in the past year, with at least 3 VL measurements including screening; only one episode of viral blip < 200 copies/mL is authorized in the last year

• CD4 T cells > 250/mm3 at the screening visit

• Estimated glomerular filtration rate > 60 mL/min (Chronic Kidney Disease - Epidemiology Collaboration method)

• Transaminases : aspartate aminotransférase et alanine aminotransférase < 3N

• Haemoglobin > 10 g/dL

• Platelets > 100 000/mm3

• For women of childbearing age, negative pregnancy test at screening; agree to use mechanical contraception during the study

• Social security system coverage

• Informed consent form signed by patient and investigator

Exclusion Criteria:

• Infection by HIV-2

• Chronic and active Viral B Hepatitis with positive antigen HBs

• Chronic and active Viral C Hepatitis with treatment expected in the next 98 weeks

• Concomitant treatment using interferon, interleukins, any other immune-therapy or chemotherapy, antivitaminK for patients on ARVT using a booster

• Concomitant prophylactic or curative treatment for an opportunistic infection

• All conditions (use of alcohol, drugs, etc.) judged by the investigator to possibly interfere with study protocol compliance, observance and/or study treatment tolerance

• Pregnant or breast feeding women

• Subjects under "sauvegarde de justice" (judicial protection due to temporarily and slightly diminished mental or physical faculties), or under legal guardianship

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Treatment discontinuation
• Receiving tritherapy. Allowed treatment drugs are : nucleoside analogs : tenofovir (TDF ou TAF), emtricitabine, abacavir, lamivudine protease inhibitors : lopinavir/r, darunavir/r ou atazanavir/r non nucleoside reverse transcriptase inhibitors : efavirenz, rilpivirine ou etravirine integrase inhibitors : dolutegravir, elvitegravir/cobicistat ou raltegravir

Locations

Country	Name	City	State
France	Centre hospitalier Victor Dupouy	Argenteuil
France	Hôpital Henri Duffaut	Avignon
France	CHRU Jean Minjoz	Besançon
France	Avicenne	Bobigny
France	Jean Verdier	Bondy
France	Hôpital Pellegrin	Bordeaux
France	Hôpital Saint-André	Bordeaux
France	Hôpital Ambroise Paré	Boulogne-Billancourt
France	Hôpital de la Côte de Nacre	Caen
France	Hôpital Louis Pasteur	Chartres
France	Antoine Beclère	Clamart
France	Hôpital Gabriel Montpied	Clermont-Ferrand
France	Centre hospitalier sud francilien	Corbeil-Essonnes
France	CHI de Créteil	Créteil
France	Hôpital Henri Mondor	Créteil
France	Hôpital du Bocage	Dijon
France	Hôpital La Meynard Zobda Quitman	Fort-de-France	Martinique
France	Hôpital Raymond Poincaré	Garches
France	Hôpital Michallon	Grenoble
France	Bicêtre	Kremlin Bicêtre
France	CHD de la Roche Sur Yon	La Roche-sur-Yon
France	Centre Hospitalier du Mans	Le Mans
France	Institut hospitalier franco-britannique	Levallois-Perret
France	Hôpital Dupuytren	Limoges
France	Hôpital de la Croix Rousse	Lyon
France	Hôpital Edouard Herriot	Lyon
France	Hôpital Européen	Marseille
France	Hôpital Sainte Marguerite	Marseille
France	Hôpital Gui de Chauliac	Montpellier
France	Hôpital Emile Müller	Mulhouse
France	Hôpital de l'Hôtel Dieu	Nantes
France	Hôpital de l'Archet	Nice
France	Hôpital Carémeau	Nîmes
France	Hôpital de La Source	Orléans
France	Hôpital Bichat	Paris
France	Hôpital de l'Hôtel Dieu	Paris
France	Hôpital Européen Georges Pompidou	Paris
France	Hôpital Necker	Paris
France	Hôpital Pitié-Salpêtrière	Paris
France	Hôpital Saint-Antoine	Paris
France	Hôpital Saint-Louis	Paris
France	Hôtel-Dieu	Paris
France	Lariboisière	Paris
France	Tenon	Paris
France	Centre Hospitalier de Perpignan	Perpignan
France	CHU Pointe-à-Pitre	Pointe-à-Pitre	Guadeloupe
France	Centre Hospitalier René Dubos	Pontoise
France	Centre hospitalier Annecy Genevois	Pringy
France	Hôpital Robert Debré	Reims
France	Hôpital Pontchaillou	Rennes
France	Centre Hospitalier de Saint-Brieuc	Saint-Brieuc
France	Hôpital Delafontaine	Saint-Denis
France	Hôpital Nord	Saint-Étienne
France	Centre Hospitalier Général de Saint Nazaire	Saint-Nazaire
France	Hôpital Civil	Strasbourg
France	Hôpital Foch	Suresnes
France	Hôpital La Grave	Toulouse
France	Hôpital Purpan	Toulouse
France	Hôpital Gustave Dron	Tourcoing
France	Hôpital Bretonneau	Tours
France	Hôpital de Brabois	Vandoeuvre les Nancy cedex
France	Hôpital André Mignot	Versailles
France	Centre Hospitalier Intercommunal	Villeneuve-Saint-Georges

Sponsors (3)

Lead Sponsor	Collaborator
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)	IMEA Leon M'Ba Foundation, Unit 1136 INSERM, Faculty of medecine, University Pierre and Marie Curie

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients with therapeutic success at Week 48.	To evaluate after 48 weeks the therapeutic success of a weekly strategy of 4 consecutive days on treatment followed by 3 days off treatment, defined by : absence of virological failure : a measure of the viral load will be done, this measure have to be < 50 cp/mL. If it's > 50 cp/mL, a second measure will be done at 2 to 4 weeks apart. If it's still > 50 cp/mL, it's a virological failure; no discontinuation or modification of the study strategy for more than 30 consecutive days.	Week 48
Secondary	Proportion of patients with therapeutic success at Week 96	To evaluate after 96 weeks the therapeutic success of a weekly strategy of 4 consecutive days on treatment followed by 3 days off treatment, defined by : absence of virological failure : a measure of the viral load will be done, this measure have to be < 50 cp/mL. If it's > 50 cp/mL, a second measure will be done at 2 to 4 weeks apart. If it's still > 50 cp/mL, it's a virological failure; no discontinuation or modification of the study strategy for more than 30 consecutive days.	Week 96
Secondary	Virological success	The HIV-1 viral load at week 48 must be inferior to 50 copies/mL	Week 48 and Week 96
Secondary	Number of virological " blips "	viral load > 50 copies/mL followed by a control value = 50 cp/mL	between Week 0 and Week 48, and between Week 0 and Week 96
Secondary	Percentage of patients with a viral load signal detected	(subgroup of patients tested with Roche-Taqman, threshold<20 copies/mL)	between Week 0 and Week 48 and Week 0 and Week 96
Secondary	Proportion of patients with acquisition of drugs resistance mutations in case of virological failure detected by Sanger and by next generation sequencing		Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96 (if it's necessary)
Secondary	Frequency of minority resistant variants archived in DNA at Week 0 and their impact on virological failure (2 consecutive VL> 50 copies / mL) and on the acquisition of drugs resistance mutations		Week 0
Secondary	Evolution of ultra sensitive viral load and total DNA in the peripheral blood mononuclear cells at Week 0, Week 24, Week 48 and Week 96; evolution of viral genotypic sequence between Week 0, Week 48 and Week 96 (subgroup of 120 patients)	Immuno-viro-pharmacological sub-study of 120 patients	between Week 0, Week 48 and Week 96
Secondary	Description of the factors associated with virological rebound (viral load >50 cp/mL).	(viral load >50 cp/mL).	Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96 (if it's necessary)
Secondary	Evolution of T cluster of differentiation 4 and cluster of differentiation 8 cells count, and T cluster of differentiation 4 /cluster of differentiation 8 ratio	Measurement of T cluster of differentiation 4 cell count, T cluster of differentiation 8 cell count, and T cluster of differentiation 4 /T cluster of differentiation 8 ratio	from Week-4 to Week 48 and Week 96
Secondary	Evolution of fasting metabolic parameters	Measurement of total cholesterol total, LDL-C, HDL-C, Triglycerides and glycemia	until Week 48 and Week 96
Secondary	Evolution of inflammation and immune activation parameters	Measurement of sCD14, sCD163, IP-10, C-reactive protein, interleukin-6 et D-dimerus, soluble TNF receptor 1, soluble TNF receptor 2 Immuno-viro-Pharmacological Sub-study in 120 patients	from Week 0 to Week 24 and Week 48
Secondary	HIV RNA viral load in semen	Sperm sub-study (120 patients)	Week 0, Week 24 and Week 48
Secondary	Residual plasmatic concentrations of the third antiretroviral agent	Measurement of the third antiretroviral agent plasmatic concentration (protease inhibitors or non-nucleoside reverse transcriptase inhibitors or integrase inhibitors)	Week 0, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84 and Week 96
Secondary	Residual plasmatic concentrations of tenofovir (TDF or TAF)	Measurement of tenofovir plasmatic concentration	Week 0, Week 4, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84 and Week 96
Secondary	Residual intracellular concentrations of the third antiretroviral agents	Immuno-viro-Pharmacological sub-study (120 patients) Measurement of the third antiretroviral agent intracellular concentration (protease inhibitors or non-nucleoside reverse transcriptase inhibitors or integrase inhibitors)	Week 0, Week 24 and Week 48
Secondary	Treatment adherence	Evaluation by a self-reported questionnaire	Week 0, Week 12, Week 24, Week 36, Week 48, Week 72,and Week 96
Secondary	Quality of life	Evaluation by a self-reported questionnaire	Week-4, Week 0, Week 48 and Week 96
Secondary	Patient satisfaction	Evaluation by a self-reported questionnaire	Week 0, Week 12, Week 48 and Week 96
Secondary	Pharmaco-economic aspects of the strategy	Assessment and comparison of cost essay between each arm.	Between Week 0 and Week 98
Secondary	Median time to virologic failure	Measure the delay between week 0 and the date of different virologic failure	Between week 0 and 98
Secondary	Frequency of grade 3 or more adverse events, adverse effects, drug-modifying adverse events, drug-related adverse events and serious adverse events (SAE)	according to the sponsor's grading scale	Between Week 0 and Week 98