iHIVARNA Clinical Trial in HIV Infected Individuals

Phase 2

Terminated

• Conditions: HIV Infections
• Interventions: Biological: Placebo; Biological: iHIVARNA-01; Biological: TriMix

• Registration Number: NCT02888756
• Lead Sponsor: Rob Gruters

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 Timeline

• Study First Submitted: 2016-08-23
• Study First Submitted QC: 2016-08-30
• Study First Posted: 2016-09-05
• Study Start: 2017-04-04
• Primary Completion: 2018-02-12
• Study Completion: 2018-02-12
• Results First Submitted: 2019-10-04
• Results First Submitted QC: 2019-11-20
• Status Verified: 2019-12
• Results First Posted: 2019-12-09
• Last Update Submitted: 2019-12-11
• Last Update Posted: 2019-12-23

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 33

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Water for injection 3 vaccinations, two weeks interval
iHIVARNA-01	iHIVARNA-01	Biological: 1200μg mRNA (900 μg HIV mRNA+300 μg TriMix mRNA) 3 vaccinations, two weeks interval
iHIVARNA-01	TriMix	Biological: 1200μg mRNA (900 μg HIV mRNA+300 μg TriMix mRNA) 3 vaccinations, two weeks interval
TriMix	TriMix	Biological: TriMix_300 μg TriMix mRNA 3 vaccinations, two weeks interval

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0	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	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

Secondary Outcome Measures

Name	Time	Method
Functional Cure	week 18	proportion of patients with viral load below detectable level of 50 copies/mL in plasma after ATI, week 18
Immunogenicity as Measured by Intracellular Cytokine Staining (ICS)	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).
Primary Immune Response Against Vaccine	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	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
Viral Immune Escape	week 18	viral immune escape: change in % mutated epitopes from pre-cART to post-ATI
Transcriptomics	week 6 and 18	host protein mRNA expression profiles in whole blood
Cell-associated RNA Viral Reservoir	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
Change in Plasma Viral Load	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
Time to Viral Rebound	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.
Proviral DNA Reservoir	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

Trial Locations

Locations (5)

Erasmus MC; 🇳🇱 Rotterdam, Netherlands

Institute for Tropical Medicine; 🇧🇪 Antwerp, Belgium

Hospital Universitari Germans Trias i Pujol; 🇪🇸 Badalona, Spain

UZ Brussel; 🇧🇪 Brussels, Belgium

Hospital Clinic; 🇪🇸 Barcelona, Spain