Therapeutic Intensification Plus Immunomodulation in HIV-infected Patients (ERAMUNE-01)

This study has been completed.
Sponsor:
Collaborators:
Cytheris SA
Merck Sharp & Dohme Corp.
Pfizer
Information provided by (Responsible Party):
Objectif Recherche Vaccins SIDA
ClinicalTrials.gov Identifier:
NCT01019551
First received: November 23, 2009
Last updated: June 12, 2013
Last verified: June 2013
  Purpose

Viral eradication in selected HIV-infected patients is possible with intensive antiretroviral therapy plus immunomodulation


Condition Intervention Phase
HIV-1 Infection
Drug: ART Intensification
Biological: Immunomodulation
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: International, Multicenter, Randomized, Non-comparative Controlled Study of Therapeutic Intensification Plus Immunomodulation in HIV-infected Patients With Long-term Viral Suppression

Resource links provided by NLM:


Further study details as provided by Objectif Recherche Vaccins SIDA:

Primary Outcome Measures:
  • Decrease from baseline in HIV proviral DNA in the PBMCs at week 56 of at least 0.5 log, as expressed as numbers of HIV DNA copies per million PBMCs [ Time Frame: End of study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Percentage of patients with undetectable HIV DNA (< 1 copy/million PBMCs) after 56 weeks [ Time Frame: End of study ] [ Designated as safety issue: No ]
  • Change from baseline in HIV proviral DNA in any of the sub-compartments explored (gut lymphoid tissue), as expressed as numbers of HIV DNA copies per million mononuclear cells [ Time Frame: From Day 0 to Week 56 ] [ Designated as safety issue: No ]
  • Change from baseline in HIV proviral DNA in the CD4 T cell subsets, as expressed as numbers of HIV DNA copies per million CD4 T cells [ Time Frame: From Day 0 to Week 56 ] [ Designated as safety issue: No ]
  • Changes from baseline in HIV plasma viral load (number of copies of HIV RNA per millilitre), measured by quantitative ultrasensitive PCR [ Time Frame: From Day 0 to Week 56 ] [ Designated as safety issue: No ]
  • Proportion of patients without inducible HIV RNA, DNA and/or p24 [ Time Frame: End of study ] [ Designated as safety issue: No ]
  • Changes from baseline in CD4 lymphocyte count [ Time Frame: From Day 0 to Week 56 ] [ Designated as safety issue: No ]
  • Changes in the activation and differentiation markers of the CD4 and CD8 peripheral blood T cells [ Time Frame: End of study ] [ Designated as safety issue: No ]
  • Development of a mathematical model exploring the dynamics of the HIV-DNA decay [ Time Frame: From Day 0 to Week 56 ] [ Designated as safety issue: No ]
  • Development of a mathematical model exploring the dynamics of T cells activation (CD38) [ Time Frame: From Day 0 to Week 56 ] [ Designated as safety issue: No ]
  • Genetic determinants influencing HIV-1-specific immune response and HIV control [ Time Frame: End of study ] [ Designated as safety issue: No ]
  • Antiretroviral drugs pharmacokinetics in the blood and rectal mucosa [ Time Frame: From Day 0 to Week 56 ] [ Designated as safety issue: No ]
  • Safety and tolerability of the intensified treatment regimen and immunomodulatory therapy [ Time Frame: From Day 0 to Week 56 ] [ Designated as safety issue: Yes ]

Enrollment: 29
Study Start Date: September 2010
Study Completion Date: February 2013
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ARM A : ART intensification alone
Raltegravir PO 400 mg BID Maraviroc PO 150, 300 or 600 mg BID depending on the concomitant ART regimen
Drug: ART Intensification
Current ART regimen plus raltegravir and maraviroc Raltegravir : 400 mg PO BID for 56 weeks Maraviroc : 150, 300 or 600 mg PO BID depending on concomitant ART treatment, for 56 weeks
Experimental: ARM B : ART intensification + Immunomodulation
Raltegravir PO 400 mg BID during 56 weeks Maraviroc PO 150, 300 or 600 mg BID depending on the concomitant ART regimen during 56 weeks 3 weekly injections of r-hIL-7 (CYT107) at a 20 micrograms/kg dose starting at Week 8
Drug: ART Intensification
Current ART regimen plus raltegravir and maraviroc Raltegravir : 400 mg PO BID for 56 weeks Maraviroc : 150, 300 or 600 mg PO BID depending on concomitant ART treatment, for 56 weeks
Biological: Immunomodulation
Starting at Week 8, 1 cycle of 3 injections (1 per week) of recombinant human Interleukin-7 (r-hIL-7 / CYT107) at a 20 µg/kg dose.

Detailed Description:

The overall strategy of the ERAMUNE 01 Trial is to treat selected patients with an optimal synergistic antiretroviral regimen plus one or more immunomodulating agents. Among immunomodulating treatments the candidates include therapies from two functional classes: 1) agents that target actively replicating cells and 2) agents activating latently infected cells31.

The novelty of this approach is three-fold: first, the use of highly potent antiretroviral therapy combining drugs with different HIV enzymes targets or receptors and different penetrations in cells, with the aim to suppress virus to truly undetectable levels as measured by the most sophisticated viral quantification techniques; secondly, the addition of an immunomodulatory therapy that specifically targets viral reservoirs to this intensification strategy; and lastly, the rigorous selection of patients having already a low HIV reservoir as measured by peripheral blood HIV DNA content. To our knowledge, this type of strategy has not been implemented. We believe this strategy is feasible.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV-1 infection, documented by any licensed ELISA test kit and confirmed by Western Blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test
  • 18 ≤ Age ≤ 70 years
  • At least 3 years of suppressive ART without any interruption (less than one month cumulative),
  • ART treatment unchanged in the 3 months prior to screening
  • One HIV plasma viral load (RNA) documented at least 3 years prior to entry, and at least 2 HIV plasma viral loads (RNA) documented per year thereafter
  • HIV plasma viral load (RNA) ≤ 500 copies/ml at least 3 years prior to entry and HIV plasma viral load ≤ 500 copies/ml for ≥ 90% of the measures thereafter
  • HIV plasma viral load (RNA) below the limit of detection for all values within the past year. Note: the assay used must have a lower limit of detection of 75 copies/ml or less
  • CD4+ count ≥ 350 cells/mm3 within 60 days of entry
  • 10 ≤ Proviral DNA ≤ 1000 copies/106 PBMCs within 60 days of entry
  • Documented laboratory values: Haemoglobin ≥ 10 g/dl, Platelets ≥ 100,000 per microliter, Hepatic transaminases ≤ 2.5 x ULN, Creatinine clearance ≥ 50 ml/min by the Cockcroft-Gault equation
  • All subjects must agree not to participate in the conception process (e.g. active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the subject/partner must use at least two reliable forms of contraceptives (condoms, with or without spermicidal agent, a diaphragm or cervical cap with spermicide, an IUD, or hormone-based contraception), while receiving study treatment and for 6 weeks after stopping study treatment
  • Ability and willingness to provide informed consent.

Exclusion Criteria:

  • Sexually active men and women who will not practice at least one form of barrier birth control (male partner using condoms, female partner using condoms, other barrier contraception, etc)
  • Pregnancy as documented by a urine pregnancy test, or lactating women
  • Hepatitis B antigen (HBsAg) positive
  • Hepatitis C virus (HCV-Ab) positive or HCV RNA detectable
  • Previous use of an integrase inhibitor (ie raltegravir) or a CCR5 inhibitor (ie maraviroc, vicriviroc). Use of raltegravir for non-treatment failure indications such as intensification and toxicity switches is allowed, provided that 1) virologic suppression was maintained before, during and after raltegravir treatment and 2) the patient has not received raltegravir treatment in the 6 months prior to study entry.
  • Previous immunologic therapeutic intervention (e.g. IL-2, IL-7) within the past year
  • Participation in another clinical drug or device trial where the last dose of drug was within the past 30 days or an investigational medical device is currently implanted
  • Diagnosis of cancer within the last 5 years (except basal cell cutaneous cancers and cutaneous KS not requiring systemic therapy)
  • Co-morbid condition with an expected survival less than 12 months
  • History of hypersensitivity to vaccination
  • History of autoimmune disease, such as systemic lupus erythematosis (SLE) or Hashimoto's thyroiditis
  • Active drug or alcohol use or dependence that, in the opinion of the center investigator, would interfere with adherence to study requirements.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01019551

Locations
France
Groupe Hospitalier Pitié-Salpêtrière
Paris, France, 75013
Italy
San Raffaele Scientific Institute
Milan, Italy, 20127
Spain
Fundacio Irsicaixa
Badalona, Spain, 08916
University Hospital Clinic of Barcelona
Barcelona, Spain, 08036
United Kingdom
Royal Free Hospital
London, United Kingdom, NW3 2QG
Sponsors and Collaborators
Objectif Recherche Vaccins SIDA
Cytheris SA
Merck Sharp & Dohme Corp.
Pfizer
Investigators
Principal Investigator: Christine KATLAMA, MD Groupe Hospitalier Pitié-Salpêtrière
Study Chair: Steven DEEKS, MD University of California, San Francisco
Study Director: François LECARDONNEL, MSc ORVACS
  More Information

Publications:
Responsible Party: Objectif Recherche Vaccins SIDA
ClinicalTrials.gov Identifier: NCT01019551     History of Changes
Other Study ID Numbers: ORVACS 010
Study First Received: November 23, 2009
Last Updated: June 12, 2013
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Italy: The Italian Medicines Agency
Spain: Spanish Agency of Medicines
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Objectif Recherche Vaccins SIDA:
Controlled viremia
Viral reservoirs
Virus eradication
Therapeutic intensification
Immunointervention

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases

ClinicalTrials.gov processed this record on April 16, 2014