Phase I, Open Label Dose Escalation Study to Evaluate Safety of iHIVARNA-01 in Chronically HIV-infected Patients

Phase 1

Completed

Conditions: HIV-infection

Interventions: Biological: TriMix_100
Biological: TriMix_300
Biological: 600μg mRNA (300 μg HIV mRNA+300 μg TriMix mRNA)
Biological: 900μg mRNA (600 μg HIV mRNA+300 μg TriMix mRNA)
Biological: 1200μg mRNA (900 μg HIV mRNA+300 μg TriMix mRNA)

Registration Number: NCT02413645

Lead Sponsor: Judit Pich Martínez

Brief Summary: The main purpose of the study is to evaluate the safety and to establish the recommended dose of iHIVARNA-01 as a new therapeutic vaccine against HIV

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

Inclusion Criteria

Patient is ≥ 18 years of age
Voluntarily signed informed consent
Patient is male, or female with negative pregnancy test prior to enrolment
Patient has a proven HIV-1 infection (with positive antibodies against HIV-1 and a detectable plasma HIV-1 RNA before cART)
Patient must be on stable treatment with cART for at least 6 months (cART is defined as an antiretroviral regimen consisting of at least three registered antiretroviral agents)
Nadir CD4+ cell counts must be above or equal to 350 cells/μl (1 or 2 occasional determinations below 350 will be allowed)
Current CD4+ cell count must be at least 450 cells/μl
HIV-RNA must be below 50 copies/ mL for the last 6 months prior to inclusion, during at least two measurements (occasional so called 'blips' up to 50 copies/mL are permitted)

Exclusion Criteria

Treatment with a non-cART regimen of antiretroviral agents prior to the start of cART;
History of a CDC class C event (see Appendix V);
Patient is female and has a positive pregnancy test or the wish of pregnancy:
Active opportunistic infection, or any active infection or malignancy within 30 days prior to screening visit;
Therapy with immunomodulatory agents, including cytokines (e.g. IL2) and gamma globulin, or cytostatic chemotherapy within 90 days prior to screening visit;
Use of anti-coagulant medication;
Use of any investigational drug during the 90 days prior to study entry;
Previous failure to antiretroviral and/or mutations conferring genotypic resistance to antiretroviral therapy EudraCT No. 2014-004591-32 33 Protocol version 1.1, dated 10 February 2015
Any other condition which, in the opinion of the investigator, may interfere with the evaluation of the study objectives.
Active hepatitis C virus or hepatitis B virus co-infection
Non-subtype B HIV infection

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
100 μg TriMix mRNA (TriMix_100)	TriMix_100	Cohort 1 (control group) 3 patients will receive 100 μg of mRNA (i.e. 100 μg TriMix mRNA).If two or more of the three patients have a dose limiting toxicity (DLT), DSMB should be consulted and study will be terminated. If one or no patients have a dose limiting toxicity, three patients will be enrolled at the next dose level. Each patient will receive 3 immunizations (at weeks 0, 2 and 4).
300 μg TriMix mRNA (TriMix_300)	TriMix_300	Cohort 2 (control group) 3 patients will receive 300 μg of mRNA (i.e. 100 μg TriMix mRNA).If two or more of the three patients have a DLT, DSMB should be consulted and study will be terminated. If one or no patients have a dose limiting toxicity, three patients will be enrolled at the next dose level. Each patient will receive 3 immunizations (at weeks 0, 2 and 4).
600μg mRNA (300 μg HIV mRNA+300 μg TriMix mRNA)	600μg mRNA (300 μg HIV mRNA+300 μg TriMix mRNA)	Cohort 3 (experimental group) 3 patients will receive 600 μg of mRNA (300 μg HIV mRNA + 300 μg TriMix mRNA). If two or more of the three patients have a DLT, DSMB should be consulted and study will be terminated. If one or no patients have a dose limiting toxicity, three patients will be enrolled at the next dose level. Each patient will receive 3 immunizations (at weeks 0, 2 and 4).
900μg mRNA (600 μg HIV mRNA+300 μg TriMix mRNA)	900μg mRNA (600 μg HIV mRNA+300 μg TriMix mRNA)	Cohort 4 (experimental group) 3 patients will receive 900 μg of mRNA (i.e. 600 μg HIV mRNA and 300 μg TriMix mRNA). If two or more of the three first patients have a DLT, then additional three patients will be enrolled at the previous level dose (dose will be reduced to 600 μg of mRNA per vaccination). If one or no patients have a DLT, additional three patients will be enrolled at 900 μg dose level. If two or more of the six patients receiving 900 μg of mRNA have a DLT, then additional 3 patients will be enrolled at the previous level dose (dose will be reduced to 600 μg of mRNA per vaccination). If one or no patients of the six patients have a DLT, six patients will be enrolled at the next dose level. Each patient will receive 3 immunizations (at weeks 0, 2 and 4).
1200μg mRNA(900 μg HIV mRNA+300 μg TriMix mRNA)	1200μg mRNA (900 μg HIV mRNA+300 μg TriMix mRNA)	Cohort 5 (experimental group) 6 patients will receive 1200 μg of mRNA (i.e. 900 μg HIV mRNA + 300 μg TriMix mRNA) in case one or no patients of the six patients at the previous dose level have a DLT. Each patient will receive 3 immunizations (at weeks 0, 2 and 4).

Primary Outcome Measures

Name	Time	Method
Dose Limiting Toxicity (DLT)	week 24	Safety as measured by dose limiting toxicity (DLT), defined as: * 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

Secondary Outcome Measures

Name	Time	Method
Secondary Endpoint: Immunogenicty - Changes in the Magnitude of Total HIV-1-specific Immune Response Against IN Peptide Pools as Measured by ELISPOT at Baseline and Weeks 4, 6, 8 and 24 Measured by ELISPOT at Baseline and Weeks 4, 6, 8 and 24.	weeks 4, 6, 8 and 24	Changes in the magnitude of total HIV-1-specific immune response against IN peptide pools as measured by ELISPOT at baseline and weeks 4, 6, 8 and 24 Results were considered positive if the number of SFC/106 cells in stimulated wells was two-fold higher than that in unstimulated control wells, and if there were at least 50 SFC/106 cells after background subtraction.
Secondary Endpoint: Immunogenicty - Changes in the Magnitude of Total HIV-1-specific Immune Response Against OUT Peptide Pools as Measured by ELISPOT at Abseline and Weeks 4, 6, 8 and 24 Measured by ELISPOT at Baseline and Weeks 4, 6, 8 and 24.	weeks 4, 6, 8 and 24	Changes in the magnitude of total HIV-1-specific immune response against OUT peptide pools as measured by ELISPOT at abseline and weeks 4, 6, 8 and 24. Results were considered positive if the number of SFC/106 cells in stimulated wells was two-fold higher than that in unstimulated control wells, and if there were at least 50 SFC/106 cells after background subtraction.
Secondary End Point: Effect on Reservoir	weeks 4, 6, 8 and 24	Changes from baseline in the intracelullar viral RNA copy number per million cells during and after the immunzation at week 4, 6, 8 and 24