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Evaluation of the Efficacy and Safety Between Two Antiretroviral Regimens, in HIV-1-infected Treatment-naïve Subjects With Low CD4 Counts

Information source: Institut de Mdecine et d'Epidmiologie Applique - Fondation Internationale Lon M'Ba
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: HIV-1 Infection; Immunosuppression-related Infectious Disease

Intervention: DARUNAVIR (Drug); ATAZANAVIR (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Institut de Mdecine et d'Epidmiologie Applique - Fondation Internationale Lon M'Ba

Official(s) and/or principal investigator(s):
Laurence LS SLAMA, PhD, Principal Investigator, Affiliation: Hospital TENON
Roland RL LANDMAN, PhD, Principal Investigator, Affiliation: Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba

Overall contact:
Aïda AB BENALYCHERIF, Phone: +33.1.40.25.63.65, Email: aida.benalycherif@gmail.com

Summary

A phase IV, prospective, multicenter , randomized open label, 48 weeks study to evaluate the antiretroviral efficacy and safety of atazanavir/ritonavir or darunavir/ritonavir, each in combination with a fixed dose of tenofovir disoproxil fumarate- emtricitabine in HIV-1-infected treatment-nave subjects with CD4 counts below 200 µL.

Clinical Details

Official title: A Phase IV, Prospective, Multicenter , Randomized Open Label, 48 Weeks Study to Evaluate the Antiretroviral Efficacy and Safety of Atazanavir or Darunavir,Each in Combination With a Fixed Dose of Tenofovir Emtricitabine in HIV-1-infected Treatment-nave Subjects With CD4counts Below 200 L.

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Viral load of HIV-1 < 50 cp/ml

Secondary outcome:

• Proportion of subjets with virologic efficacy

• Proportion of subjects with confirmed virologic failure

Viral lod of HIV-1 on seminal fluid

Immunologic response

Differenciation and activation of lymphocytes

Pharmacokinetics evaluation of the drugs in plasma

Pharmacokinetic evaluation of the drugs in semen

• Evaluate the relationship of bilirubinemia with atazanavir

Fasting glucose, lipids and insulin

Clinic and biologic tolerance

Sexual behaviour

Adherence patient satisfaction

Detailed description: Principal objective To evaluate the virological efficacy and safety at week 48 of 2 regimens atazanavir/ritonavir (ATZ/r) 300/100 mg or darunavir/ritonavir (DRV/r) 800/100 mg, each in combination with a fixed-dose of tenofovir/emtracitabine in HIV-1 treatment-naïve subjects with CD4 counts below 200 µL. Secondary objectives

- Proportion of subjets with virologic efficacy at week 24

- Proportion of subjects with confirmed virologic failure at week 24 or later

- Proportion of patients with virologic mutations

- Evaluate the virologic effect in seminal fluid

- To evaluate immunological response over time up to week 48

- To assess plasma and seminal pharmacokinetics of the drugs in the treatment regimen at

week 4, 24, and 48

- Correlate the pharmacokinetic properties of the drugs with virologic outcome in

plasma and semen at week 4 and 48

- Correlate the free fraction (not bound to protein) of atazanavir and darunavir in

plasma and semen to virologic outcome

- Evaluate the relationship of bilirubinemia with atazanavir

- Change from baseline in fasting lipids, fasting glucose and insulin over time in the 2

arms

- Compare adherence patient satisfaction and sexual behaviour between the regimens

Methodology This is a 48 week, multicentre, prospective, open label, phase IV, randomized. non comparative, study. Inclusion criteria

- Male or female, aged > 18 years of age.

- HIV-1 infection determined by a positive ELISA and confirmed by Western blot

- Plasma HIV-RNA > 1 000 c/mL

- CD4+T cell count < =200 cells/mm3 at the time of screening, or < =250 cells/mm3 if the

CD4 count was <200 cells/mm3 12 weeks before screening.

- Women of childbearing potential must agree to use an effective method of barrier

contraception or have documented sterility.

- Subjects must have medical insurance throught the Securite Sociale

- Ability to understand and provide written informed consent.

Non-inclusion criteria

- Acute opportunistic infection within the past two weeks

- HIV-2 infection

- pregnant woman

- Any subject with drug resistance mutations at screening

- Any subject with a grade 3 or greater clinical or laboratory adverse event at screening

- Any subject who has received antiretoviral therapy except for prevention of mother to

child transmission and patients who has received post exposure prophylaxis for a a month or less

- calculated creatinine clearance < 60/mL as estimated by the Cockcroft- Gault equation

- Patients in the opinion of the investigator that are unlikley to be able to follow

study instructions

- Any subject unable to take antiretroviral medication for whatever reason

- Any subject taking a treatment or medication that is contraindicated when

co-administered with any arm or drug in the treatment. Treatment:

- Group 1 : ATV + TDF/FTC (or Abacavir/Lamivudine, [ABC/3TC], if TDF/FTc contre-indicated

- atazanavir/ritonavir 300/100mg/day and TDF/FTC 245 /200 mg by day, 3 pills once a day,

during 48 weeks during a meal

- Group 2 : DRV+ TDF/FTC (or ABC/3TC if TDF/FTc contre-indicated)

- darunavir/ritonavir 800/100mg/day and TDF/FTC 245 /200 mg by day, 4 pills once a day,

during 48 weeks during a meal Primary Endpoints :

- Proportion of patients with HIV-1 plasma viral load below 50 copies/mL at week 48 while

receiving their initial regimen

- Proportion of patients experiencing grade 2-4 adverse clinical and laboratory events

including hematology, chemistry, lipids (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides), glucose and insulin by week 48. Secondary endpoints:

- Proportion of patients with plasma HIV RNA below 50 cp/mL at week 24

- Proportion of patients with HIV RNA> 50 cp/mL at week 24 or later confirmed by a second

HIV RNA at least 14 days after the first test

- Development of resistance mutations in subjects who have virologic failure testing at

24 weeks or later tested by a genotypic resistance test

- Evaluate the virologic effect in seminal fluid at baseline, W4 and W48 by change in HIV

RNA concentrations in semen over time

- To evaluate immunological response over time up to week 48 in the 2 arms by CD4 cell

count ( W-4, W2,W4, W12, W36 and W48), differenciation and activation in T CD4 ( W2,W4, W12, W24 and W48); Change in lymphocyte subset reconsistution at week 48 compared to baseline. ; Change in immunolgic markers of inflammations at weeks 2, 4, 12, 24, 48

- To assess plasma and seminal pharmacokinetics of the drugs in the treatment regimen at

week 4, 24, and 48 through residual concentrations ( C min) of antiretroviral drugs at W4, W24, and W48

- Atazanavir and darunavir (plasma and seminal) drug concentrations and coorelation with

adverse clinical and laboratory events.

- Evaluate the relationship of bilirubinemia with atazanavir pharmacokinetics (Cmin)

- Evolution of lipid, glucose and insulin parameters from baseline to weeks 24 and 48

- Adherence to regimen, patient satisfaction and sexual behaviour between the regimens

at W2,W24 and W48 mesured by ( mettre ref)

- Evolution of anthropomorphic measurements from baseline to weeks 24, 48.

Substudies Brief description (2 lines maximum) and person in charge of the substudy

- Immunologic substudy ( Pr Brigitte Autran) : Change in immunolgic markers of

inflammations at weeks 2, 4, 12, 24, 48 and change in lymphocyte subset reconsistution at week 48 compared to baseline.

- Pharmacologic substudy ( Dr Gilles Peytavin) : To assess plasma and seminal

pharmacokinetics of the drugs in the treatment regimen at week 4, 24, and 48 through residual concentrations ( C min) of antiretroviral drugs at W4, W24, and W48

- Virologic substudy ( Dr Anne Geneviève Marcelin) : Evaluate the virologic effect in

seminal fluid at baseline, W4 and W48

- Behaviour substudy ( Dr France Lert) : Compare adherence patient satisfaction and

sexual behaviour between the regimens at W2,W24 and W48 Estimated enrolment: 120 subjects (60 per group) randomly assigned 1: 1

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria

- Male or female, aged > 18 years of age

- HIV-1 infection determined by a positive ELISA and confirmed by Western blot

- Plasma HIV-RNA > 1 000 c/mL

- CD4+T cell count < =200 cells/mm3 at the time of screening, or < =250 cells/mm3 if

the CD4 count was <200 cells/mm3 12 weeks before screening

- Women of childbearing potential must agree to use an effective method of barrier

contraception or have documented sterility

- Subjects must have medical insurance throught the Securite Sociale

- Ability to understand and provide written informed consent

Exclusion Criteria

- Acute opportunistic infection within the past two weeks

- HIV-2 infection

- Pregnant woman

- Any subject with drug resistance mutations at screening

- Any subject with a grade 3 or greater clinical or laboratory adverse event at

screening

- Any subject who has received antiretoviral therapy except for prevention of mother to

child transmission and patients who has received post exposure prophylaxis for a a month or less

- Calculated creatinine clearance < 60/mL as estimated by the Cockcroft- Gault equation

- Patients in the opinion of the investigator that are unlikley to be able to follow

study instructions

- Any subject unable to take antiretroviral medication for whatever reason

- Any subject taking a treatment or medication that is contraindicated when

co-administered with any arm or drug in the treatment

Locations and Contacts

Aïda AB BENALYCHERIF, Phone: +33.1.40.25.63.65, Email: aida.benalycherif@gmail.com

Centre Hospitalier D'Argenteuil, Argenteuil 95107, France; Recruiting
Juliette JG GERBE, Phone: +33.1.34.23.22.18, Email: juliette.gerbe@ch-argenteuil.fr
Virginie VM MASSE, PhD, Principal Investigator

Hopital Saint-Jacques, Besancon 25000, France; Recruiting
Véronique VB BOURDEAUX, PhD, Phone: +33.3.81.21.85.33, Email: c1bourdeaux@chu-besancon.fr
Bruno BH HOEN, PhD, Principal Investigator

Hopital Avicenne, Bobigny 93000, France; Recruiting
Gaëlle GO OBENGA, PhD, Phone: +33.1.48.95.54.21, Email: gaelle.obenga@avc.aphp.fr
Olivier OB BOUCHAUD, PhD, Principal Investigator

Hopital Jean Verdier, Bondy 93143, France; Recruiting
Mufide MK KAHRAMAN, Phone: +33.1.48.02.63.11, Email: mufide.kahraman@jvr.aphp.fr
Vincent VJ JEANTILS, PhD, Principal Investigator

Hopital Saint-Andre, Bordeaux 33075, France; Recruiting
Sabrina SC CALDATO, Phone: +33.5.56.79.57.33, Email: sabrina.caldato@chu-bordeaux.fr
Patrick PM MERCIE, PhD, Principal Investigator

Chu Cote de Nacre, Caen 14033, France; Recruiting
Philippe PF FERET, Phone: +33.2.31.06.50.87, Email: feret-p@chu-caen.fr
Renaud RV VERDON, PhD, Principal Investigator

Hopital Louis Mourier, Colombes 92700, France; Recruiting
Feng FZ ZENG, Phone: +33.1.47.60.61.84, Email: feng.zeng@lmr.aphp.fr
Emmanuel EM MORTIER, PhD, Principal Investigator

Hopital Le Bocage, Dijon 21034, France; Recruiting
Sandrine ST GOHIER, Phone: +33.3.80.29.36.31, Email: sandrine.gohier@chu-dijon.fr
Lionel LP PIROTH, PhD, Principal Investigator

Hopital Raymond Poincare, Garches 92380, France; Recruiting
Huguette HB BERTHE, Phone: +33.1.47.10.46.65, Email: huguette.berthe@rpc.aphp.fr
Pierre PT DE TRUCHIS, PhD, Principal Investigator

C.H.D de Vendee, La Roche Sur Yon 85925, France; Recruiting
Isabelle IS SUAUD, Phone: +33.2.51.37.49.66, Email: hjmpu@chd-vendee.fr
Philippe PP PERRE, PhD, Principal Investigator

Hopital Dupuytren, Limoges 87000, France; Recruiting
Claire CG GENET, PhD, Phone: +33.5.55.05.66.44, Email: claire.genet@unilim.fr
Claire CG GENET, PhD, Principal Investigator

Hopital Sainte-Marguerite, Marseille 13274, France; Recruiting
Alena AI IVANOVA, Phone: +33.4.91.74.61.63, Email: alena.ivanova@mail.ap-hm.fr
Isabelle IM POIZOT-MARTIN, PhD, Principal Investigator

Centre Hospitalier de Melun, Melun 77011, France; Recruiting
Ali AK KARA, PhD, Phone: +33.1.64.71.60.96, Email: ali.kara@ch-melun.fr
Ali AK KARA, PhD, Principal Investigator

Hopital L'Archet, Nice 06202, France; Recruiting
Marie-Ange MS SERINI, Phone: +33.4.92.03.90.22, Email: serini.ma@chu-nice.fr
Jacques JD DURANT, PhD, Principal Investigator

Hopital Bichat, Paris 75018, France; Recruiting
Zélie ZJ JULIA, Phone: +33.1.40.25.70.57, Email: zelie.julia@bch.aphp.fr
Véronique VJ JOLY, PhD, Principal Investigator

Hopital Cochin, Paris 75674, France; Recruiting
Marie-Pierre MP PIETRI, Phone: +33.1.58.41.21.34, Email: marie-pierre.pietri@cch.aphp.fr
Dominique DS SALMON, PhD, Principal Investigator

Hopital Europeen Georges Pompidou, Paris 75908, France; Recruiting
Erika EB BOURZAM, Phone: +33.1.56.09.33.03, Email: erika.bourzam@egp.aphp.fr
Laurence LW WEISS, PhD, Principal Investigator

Hopital Lariboisiere, Paris 75010, France; Recruiting
Maguy MP PARRINELLO, Phone: +33.1.49.95.63.43, Email: maguy.parrinello@lrb.aphp.fr
Jean-François JB BERGMANN, PhD, Principal Investigator

Hopital Necker, Paris 75015, France; Recruiting
Fatima FT TOUAM, Phone: +33.1.44.49.40.28, Email: fatima.touam@nck.aphp.fr
Claudine CD DUVIVIER, PhD, Principal Investigator

Hopital Pitie-Salpetriere, Paris 75013, France; Recruiting
Patricia PB BOURSE, Phone: +33.1.42.16.02.93, Email: patricia.bourse@psl.aphp.fr
Christine CK KATLAMA, PhD, Principal Investigator

Hopital Pitie-Salpetriere, Paris 75651, France; Recruiting
Catherine CL LUPIN, Phone: +33.1.42.16.10.95, Email: catherine.lupin@psl.aphp.fr
Anne AS SIMON, PhD, Principal Investigator

Hopital Saint Antoine, Paris 75012, France; Recruiting
Jean-Luc JL LAGNEAU, Phone: +33.1.49.28.24.86, Email: jean-luc.lagneau@sat.aphp.fr
Nadia NV VALIN, PhD, Principal Investigator

Hopital Tenon, Paris 75020, France; Recruiting
Laurence LS SLAMA, PhD, Phone: +33.1.56.01.74.36, Email: laurence.slama@tnn.aphp.fr
Nadège NV VELAZQUEZ, Phone: +33.1.56.01.74.36, Email: nadege.velazquez@tnn.aphp.fr
Laurence LS SLAMA, PhD, Principal Investigator

Hopital Saint-Jean Roussillon, Perpignan 66046, France; Recruiting
Martine MM MALET, Phone: +33.4.68.61.61.43, Email: recherche.clinique@ch-perpignan.fr
Hugues HA AUMAITRE, PhD, Principal Investigator

Hopital Rene Dubos, Pontoise 95303, France; Recruiting
Martine MD DESCHAUD, Phone: +33.1.30.75.47.24, Email: martine.deschaud@ch-pontoise.fr
Laurent LB BLUM, PhD, Principal Investigator

C.H.R.A, Pringy 74374, France; Recruiting
Gaëlle GC CLAVERE, Phone: +33.4.50.63.67.93, Email: gclavere@ch-annecy.fr
Jean-Pierre JB BRU, PhD, Principal Investigator

Hopital Civil, Strasbourg 67000, France; Recruiting
Patricia PF FISCHER, Phone: +33.3.69.55.05.01, Email: patricia.fischer@chru-strasbourg.fr
David DR REY, PhD, Principal Investigator

Hopital Gustave Dron, Tourcoing 59208, France; Recruiting
Sylvie SV VANDAMME, Email: svandamme@ch-tourcoing.fr
Yazdan YY YAZDANPANAH, PhD, Principal Investigator

Hopital Bretonneau, Tours 37044, France; Recruiting
Gaëlle GF FAJOLE, Phone: +33.2.47.47.37.14, Email: g.fajole@chu-tours.fr
Louis LB BERNARD, PhD, Principal Investigator

Hopital Zobda Quitman, Fort-de-france, Martinique 97261, France; Recruiting
André AC CABIE, PhD, Phone: +33.5.96.55.23.01, Email: andre.cabie@chu-fort-de-france.fr
André AC CABIE, PhD, Principal Investigator

Additional Information

Starting date: March 2011
Last updated: August 20, 2013

Page last updated: August 23, 2015

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