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iHIVARNA Clinical Trial in HIV Infected Individuals (iHIVARNA-01)

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ClinicalTrials.gov Identifier: NCT02888756
Recruitment Status : Terminated (Interim analysis did not show sufficient immunogenicity of IMP compared to placebo)
First Posted : September 5, 2016
Results First Posted : December 9, 2019
Last Update Posted : December 23, 2019
Sponsor:
Collaborators:
Institut d'Investigacions Biomèdiques August Pi i Sunyer
IrsiCaixa
Institute of Tropical Medicine, Belgium
Vrije Universiteit Brussel
Synapse bv
Asphalion
eTheRNA immunotherapies
CR2O
Hospital Clinic of Barcelona
Germans Trias i Pujol Hospital
Universitair Ziekenhuis Brussel
Information provided by (Responsible Party):
Rob Gruters, Erasmus Medical Center

Tracking Information
First Submitted Date  ICMJE August 23, 2016
First Posted Date  ICMJE September 5, 2016
Results First Submitted Date  ICMJE October 4, 2019
Results First Posted Date  ICMJE December 9, 2019
Last Update Posted Date December 23, 2019
Actual Study Start Date  ICMJE April 4, 2017
Actual Primary Completion Date February 12, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 20, 2019)
  • Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 [ Time Frame: week 6 ]
    • Grade 3 or above local adverse event (pain, cutaneous reactions including induration).
    • Grade 3 or above systemic adverse event (temperature, chills, headache, nausea, vomiting, malaise, and myalgia).
    • Grade 3 or above other clinical or laboratory adverse event confirmed at examination or on repeat testing respectively.
    Any event attributable to vaccination leading to discontinuation of the immunisation regimen.
  • Immunogenicity as Measured by Elispot [ Time Frame: week 6 and week 18 ]
    Change from baseline immunogenicity as measured by ELISPOT at week 6 and 18, i.e. two weeks and 14 weeks after the last immunization compared to both control groups
Original Primary Outcome Measures  ICMJE
 (submitted: August 30, 2016)
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: week 6 ]
    • Grade 3 or above local adverse event (pain, cutaneous reactions including induration).
    • Grade 3 or above systemic adverse event (temperature, chills, headache, nausea, vomiting, malaise, and myalgia).
    • Grade 3 or above other clinical or laboratory adverse event confirmed at examination or on repeat testing respectively.
    Any event attributable to vaccination leading to discontinuation of the immunisation regimen.
  • Immunogenicity [ Time Frame: week 6 ]
    Change from baseline immunogenicity as measured by ELISPOT up to week 6, i.e. two weeks after the last immunization compared to both control groups
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 11, 2019)
  • Immunogenicity as Measured by Intracellular Cytokine Staining (ICS) [ Time Frame: week 10, 18 and 30 ]
    HIV-specific CD4+ and CD8+ T cell responses after immunization by the number of poly-functional T cells as determined by intracellular cytokine staining, (ICS).
  • Time to Viral Rebound [ Time Frame: week 6-18 ]
    time until viral rebound (defined as two consecutive measurements of plasma viral load > 1000 copies/mL separated by at least 15 days) after discontinuation at week 6.
  • Change in Plasma Viral Load [ Time Frame: week 6-18 ]
    difference in log10 copies/ml plasma viral load in vivo after analytical treatment interruption (ATI, week 6-restart ART), compared to placebo WFI
  • Functional Cure [ Time Frame: week 18 ]
    proportion of patients with viral load below detectable level of 50 copies/mL in plasma after ATI, week 18
  • Primary Immune Response Against Vaccine [ Time Frame: from baseline to week 6 ]
    Change in frequency of at least 0.7log10 HIV-specific T-cell responses between baseline and week 6
  • CD8 T Cell Mediated Viral Suppression [ Time Frame: week 4 ]
    The capacity of CD8 T cells to suppress virus production in HIV infected autologous CD4 T cells, after vaccination. For this purpose PBMC are isolated and separated in CD8 and CD4 T cells. CD4 cells are infected with HIV. Thereafter CD4 cells are co-cultured with pre-stimulated CD8 cells and the capacity to suppress virus production at different effector to target (E:T) ratios is measured, by the change of p24 Gag production. Pannus et al AIDS 2019, PMID: 30702513
  • Proviral DNA Reservoir [ Time Frame: day 0-90 (week 4, week 4 + 1 day and week 5 and week 6) and day 90-130 (week 18) and day >130 (week 30) ]
    effect on reservoir as measured by changes in the proviral DNA copy numbers per million cells during and after immunization
  • Viral Immune Escape [ Time Frame: week 18 ]
    viral immune escape: change in % mutated epitopes from pre-cART to post-ATI
  • Transcriptomics [ Time Frame: week 6 and 18 ]
    host protein mRNA expression profiles in whole blood
  • Cell-associated RNA Viral Reservoir [ Time Frame: day 0-30 (week 4, week 4 + 1 day and week 5) and day 30-80 (week 6), 80-150 days (week 18) and >150 days (week 30) ]
    effect on reservoir as measured by changes in the intracellular viral RNA copy numbers per million cells during and after immunization
Original Secondary Outcome Measures  ICMJE
 (submitted: August 30, 2016)
  • Immunogenicity [ Time Frame: week 10, 18 and 30 ]
    o magnitude and the kinetics of the HIV-specific CD4+ and CD8+ T cell responses after immunization (ELISPOT) as defined by the increase in the number of spot forming units and if positive the number of poly-functional T cells as determined by intracellular cytokine staining, (ICS).
  • Time to viral rebound [ Time Frame: week 6-18 ]
    time until viral rebound (defined as two consecutive measurements of plasma viral load > 1000 copies/mL separated by at least 15 days) after discontinuation at week 6.
  • Plasma viral load [ Time Frame: week 18 and 30 ]
    plasma viral load in vivo after ATI, week 18 and 30
  • Functional cure [ Time Frame: week 18 and 30 ]
    proportion of patients with viral load below detectable level of 50 copies/mL in plasma after ATI, week 18 and 30
  • Primary immune response against vaccine [ Time Frame: week 6 ]
    Change in frequency of at least 0.7log10 HIV-specific T-cell responses between baseline and week 6
  • CD8 T cell mediated viral suppression [ Time Frame: week 4 ]
    the in vivo vaccine-induced capacity of ex-vivo CD8 T cells to suppress HIV growth in autologous CD4 T cells
  • Viral reservoir [ Time Frame: week 4 and 6 ]
    effect on reservoir as measured by changes in the proviral DNA copy numbers per million cells and the intracellular viral RNA copy numbers per million cells during and after immunization
  • Viral Immune escape [ Time Frame: week 18 ]
    viral immune escape: change in % mutated epitopes from pre-cART to post-ATI
  • Transcriptomics [ Time Frame: week 6 and 18 ]
    host protein mRNA expression profiles in whole blood
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE iHIVARNA Clinical Trial in HIV Infected Individuals
Official Title  ICMJE A Phase IIa Randomized, Placebo Controlled, Double Blinded Study to Evaluate the Safety and Immunogenicity of iHIVARNA-01 in Chronically HIV-infected Patients Under Stable Combined Antiretroviral Therapy
Brief Summary iHIVARNA-01 is a novel therapeutic vaccine for the treatment of HIV-1-infected patients based on in vivo modification of DCs. It consists of HIVACAT-TriMix: mRNA encoding a mixture of APC activation molecules (CD40L, a constitutively active variant of TLR4 and CD70) and the HIV target antigens contained in HIVACAT to be administered through the intranodal route. iHIVARNA-01 aims to achieve the 'functional cure' of HIV infection, i.e. controlling viral replication in the absence of anti-retroviral therapy.
Detailed Description

Objective: To evaluate the safety and immunogenicity of iHIVARNA-01 as a new therapeutic vaccine in HIV infected patients.

Study design and duration: Phase IIa, multicentre double-blind placebo controlled intervention study. Each patient will be followed for 30 weeks. The study duration will be 38 weeks from inclusion of the first patient.

Sites: Erasmus MC, Rotterdam The Netherlands (sponsor), Hospital Clínic de Barcelona and Institut de Recerca de la Sida - Caixa, Barcelona, Spain, Instituut voor Tropische Geneeskunde Antwerp, Belgium and Vrije Universiteit Brussel/UZ Brussel, Belgium

Study population: Chronically HIV-1- infected patients under stable cART with plasma viral load (pVL) ≤ 50 copies/ml and stable CD4+ T-cell counts ≥ 450/μl, aged 18 years or above.

Sample size: after recruitment and screening, 70 patients will be included and randomized to one of the study-arms.

Intervention: One group (n=40) receives the HIVACAT-TriMix (300 microgram TriMix + 900 microgram HIVACAT) vaccine intranodally on three occasions with a two-week interval. One control group (n=15) receives TriMix only (300 microgram TriMix) and one group (n=15) receives saline intranodally on three occasions with a two-week interval. Two weeks after the last vaccination cART treatment will be interrupted. If plasma virus is detectable, cART will be re-initiated twelve weeks after treatment interruption. cART can always be re-initiated for medical reasons, as judged by the clinical investigator.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE HIV Infections
Intervention  ICMJE
  • Biological: iHIVARNA-01
    Therapeutic vaccination, followed by treatment interruption
    Other Names:
    • HIVACAT
    • TriMix
  • Biological: TriMix
    Therapeutic vaccination, followed by treatment interruption
  • Biological: Placebo
    Therapeutic vaccination, followed by treatment interruption
Study Arms  ICMJE
  • Experimental: iHIVARNA-01
    Biological: 1200μg mRNA (900 μg HIV mRNA+300 μg TriMix mRNA) 3 vaccinations, two weeks interval
    Interventions:
    • Biological: iHIVARNA-01
    • Biological: TriMix
  • Active Comparator: TriMix
    Biological: TriMix_300 μg TriMix mRNA 3 vaccinations, two weeks interval
    Intervention: Biological: TriMix
  • Placebo Comparator: Placebo
    Water for injection 3 vaccinations, two weeks interval
    Intervention: Biological: Placebo
Publications * de Jong W, Aerts J, Allard S, Brander C, Buyze J, Florence E, van Gorp E, Vanham G, Leal L, Mothe B, Thielemans K, Plana M, Garcia F, Gruters R; iHIVARNA consortium. iHIVARNA phase IIa, a randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of iHIVARNA-01 in chronically HIV-infected patients under stable combined antiretroviral therapy. Trials. 2019 Jun 17;20(1):361. doi: 10.1186/s13063-019-3409-1. Erratum in: Trials. 2019 Dec 13;20(1):721.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: November 16, 2017)
33
Original Estimated Enrollment  ICMJE
 (submitted: August 30, 2016)
70
Actual Study Completion Date  ICMJE February 12, 2018
Actual Primary Completion Date February 12, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. ≥ 18 years of age;
  2. Voluntarily signed informed consent;
  3. Proven HIV-1 infection (with documented antibodies against HIV-1 and a detectable plasma HIV-1 RNA before initiation of therapy);
  4. On stable treatment with cART regimen (antiretroviral therapy consisting of at least three registered antiretroviral agents) for at least 3 years;
  5. Nadir CD4+ ≥ 350 cells/μl (up to 2 occasional determinations ≤ 350 cells/μl are allowed);
  6. Current CD4+ cell count ≥ 450 cells/μl;
  7. HIV-RNA below 50 copies/mL in the last 6 months prior to randomization, during at least two measurements (occasional so called 'blips' ≤ 500 copies/mL are permitted);
  8. If sexually active, willing to use a reliable method of reducing the risk of transmission to their sexual partners during treatment interruption (including PrEP).

    1. For heterosexually active female, using an effective method of contraception with partner (combined oral contraceptive pill; injectable or implanted contraceptive; IUD/IUS; consistent record with condoms; physiological or anatomical sterility (in self or partner) from 14 days prior to the first vaccination until 4 months after the last vaccination.

For heterosexually active male, using an effective method of contraception with their partner from the first day of vaccination until 4 months after the last vaccination. -

Exclusion Criteria:

  1. Treatment with non-cART regimen prior to cART regimen;
  2. Previous failure to antiretroviral and/or mutations conferring genotypic resistance to antiretroviral therapy;
  3. Non-subtype B HIV infection;
  4. Active Hepatitis B virus and/or Hepatitis C virus co-infection;
  5. History of a CDC class C event (see appendix A);
  6. Pregnant female (screened with a positive pregnancy test), lactating or intending to become pregnant during the study;
  7. Active malignancy ≤ 30 days (extended period on the clinical assessment of the investigator) prior to screening;
  8. Active infection with fever (38°C or above) ≤ 10 days of screening and/or first vaccination;
  9. Therapy with immunomodulatory agents (e.g. systemic corticosteroids), including cytokines (e.g. IL-2), immunoglobulins and/or cytostatic chemotherapy ≤ 90 days prior to screening. This does not include seasonal influenza, hepatitis B and/or other travel related vaccines;
  10. Congenital, acquired or induced coagulation disorders, such as thrombocytopenia (thrombocytes < 150x109/L) and/or current use of anti-coagulant medication (e.g. coumarins, inhibitors of Xa); Usage of NSAIDs (including acetylsalicylic acid) is allowed, however it is advised to interrupt therapy 10 days ahead of vaccination;
  11. Usage of any investigational drug ≤ 90 days prior to study entry;
  12. An employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, or is a family member of an employee or the investigator Any other condition, which, in the opinion of the investigator, may interfere with the evaluation of the study objectives
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Netherlands,   Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02888756
Other Study ID Numbers  ICMJE iHIVARNA phase II
2016-002724-83 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Rob Gruters, Erasmus Medical Center
Study Sponsor  ICMJE Rob Gruters
Collaborators  ICMJE
  • Institut d'Investigacions Biomèdiques August Pi i Sunyer
  • IrsiCaixa
  • Institute of Tropical Medicine, Belgium
  • Vrije Universiteit Brussel
  • Synapse bv
  • Asphalion
  • eTheRNA immunotherapies
  • CR2O
  • Hospital Clinic of Barcelona
  • Germans Trias i Pujol Hospital
  • Universitair Ziekenhuis Brussel
Investigators  ICMJE
Principal Investigator: Rob A Gruters, PhD Erasmus Medical Center
PRS Account Erasmus Medical Center
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP