A Phase I, Open Label Dose Escalation Study to Evaluate Safety of iHIVARNA-01 in Chronically HIV-infected Patients Under Stable Combined Antiretroviral Therapy

Study Overview
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Brief Summary
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The mai 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

Official Title
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A Phase I, Open Label Dose Escalation Study to Evaluate Safety of iHIVARNA-01 in Chronically HIV-infected Patients Under Stable Combined Antiretroviral Therapy

Conditions
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HIV-infection

Intervention / Treatment
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* 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)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 100 μg TriMix mRNA (TriMix_100)<br>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). | Biological: TriMix_100<br>* 100 μg of TriMix in<br>|
| Other: 300 μg TriMix mRNA (TriMix_300)<br>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). | Biological: TriMix_300<br>* 300 μg of TriMix in<br>|
| Experimental: 600μg mRNA (300 μg HIV mRNA+300 μg TriMix mRNA)<br>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). | Biological: 600μg mRNA (300 μg HIV mRNA+300 μg TriMix mRNA)<br>* 600 μg of mRNA (300 μg TriMix + 300 μg HIVACAT)<br>* Other names: iHIVARNA-01.1;|
| Experimental: 900μg mRNA (600 μg HIV mRNA+300 μg TriMix mRNA)<br>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). | Biological: 900μg mRNA (600 μg HIV mRNA+300 μg TriMix mRNA)<br>* 900 μg of mRNA (300 μg TriMix + 600 μg HIVACAT)<br>* Other names: iHIVARNA-01.2;|
| Experimental: 1200μg mRNA(900 μg HIV mRNA+300 μg TriMix mRNA)<br>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). | Biological: 1200μg mRNA (900 μg HIV mRNA+300 μg TriMix mRNA)<br>* 1200 μg of mRNA (300 μg TriMix + 900 μg HIVACAT)<br>* Other names: iHIVARNA-01.3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) | 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 | week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity (number of spot-forming cells (SFC) per million of IFN-gamma producing PBMC directed against HIV-1 sequences) as measured by ELISPOT at baseline and weeks 4, 6, 8 and 24. | ELISPOT assays will be performed to measure the numbers of IFN-gamma producing PBMC directed against HIV-1 sequences. Results were expressed as the number of spot-forming cells (SFC) per million of PBMC after substracting the background. | week 24 | 
| Effect of vaccination on plasma viral load (pVL) (ultrasensitive assay) using the Single copy assay (SCA) at screening and weeks 2, 4, 6, 8 and 24 | Effect of vaccination on plasma viral load (pVL) (ultrasensitive assay) at screening and weeks 2, 4, 6, 8 and 24. Low-level HIV-1 viral loads will be measured using the Single copy assay (SCA). The limit of detection of the SCA will be standardized to the highest limit for any individual (0.7 copies/ml) | week 24 | 
| Cell-associated HIV-1 RNA (CA-RNA) quantification at week 0, 4, 6, 8 and 24 | Intracellular HIV RNA species at week 0, 4, 6, 8 and 24. Cell-associated HIV-1 RNA (CA-RNA) will be isolated from cryopreserved PBMCs. CA-RNA will be quantified using a real-time PCR approach with primers/probes targeting conserved regions of the HIV long terminal repeat (LTR)/gag | week 24 | 
| Genome wide transcriptome and microRNA analysis at weeks 0 and 6 | Transcriptome analysis at weeks 0 and 6 Genome wide transcriptome and microRNA analysis on the same PBMC samples will be performed. Plasma samples will be analyzed for protein expression patterns using multiplex ELISA (Luminex technology). All data will be integrated into the multidimensional database VASP a web based -omics data analysis and storage pipeline developed by Erasmus University Rotterdam to ensure data consistency and ease of analysis to all partners. Advanced bioinformatics and statistical analysis will be used to reveal the impact of vaccination on the virus-host interaction in chronic HIV infection | week 6 |