Back to resultsA Phase I, Open Label Dose Escalation Study to Evaluate Safety of iHIVARNA-01 in Chronically HIV-infected Patients Under Stable Combined Antiretroviral Therapy
Primary Purpose
HIV-infection
Status
Completed
Phase
Phase 1
Locations
Spain
Study Type
Interventional
Intervention
TriMix_100
TriMix_300
600μg mRNA (300 μg HIV mRNA+300 μg TriMix mRNA)
900μg mRNA (600 μg HIV mRNA+300 μg TriMix mRNA)
1200μg mRNA (900 μg HIV mRNA+300 μg TriMix mRNA)
Sponsored by
About this trial
This is an interventional treatment trial for HIV-infection
Eligibility Criteria
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
Sites / Locations
- Hospital Clínic de Bacelona
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Other
Other
Experimental
Experimental
Experimental
Arm Label
100 μg TriMix mRNA (TriMix_100)
300 μg TriMix mRNA (TriMix_300)
600μg mRNA (300 μg HIV mRNA+300 μg TriMix mRNA)
900μg mRNA (600 μg HIV mRNA+300 μg TriMix mRNA)
1200μg mRNA(900 μg HIV mRNA+300 μg TriMix mRNA)
Arm Description
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).
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).
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).
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).
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).
Outcomes
Primary Outcome Measures
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
Secondary Outcome Measures
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.
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)
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
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02413645
Brief Title
A Phase I, Open Label Dose Escalation Study to Evaluate Safety of iHIVARNA-01 in Chronically HIV-infected Patients Under Stable Combined Antiretroviral Therapy
Official Title
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 Type
Interventional
2. Study Status
Record Verification Date
October 2017
Overall Recruitment Status
Completed
Study Start Date
June 2015 (Actual)
Primary Completion Date
June 2016 (Actual)
Study Completion Date
October 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Judit Pich Martínez
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV-infection
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
21 (Actual)
8. Arms, Groups, and Interventions
Arm Title
100 μg TriMix mRNA (TriMix_100)
Arm Type
Other
Arm Description
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).
Arm Title
300 μg TriMix mRNA (TriMix_300)
Arm Type
Other
Arm Description
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).
Arm Title
600μg mRNA (300 μg HIV mRNA+300 μg TriMix mRNA)
Arm Type
Experimental
Arm Description
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).
Arm Title
900μg mRNA (600 μg HIV mRNA+300 μg TriMix mRNA)
Arm Type
Experimental
Arm Description
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).
Arm Title
1200μg mRNA(900 μg HIV mRNA+300 μg TriMix mRNA)
Arm Type
Experimental
Arm Description
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).
Intervention Type
Biological
Intervention Name(s)
TriMix_100
Intervention Description
100 μg of TriMix in
Intervention Type
Biological
Intervention Name(s)
TriMix_300
Intervention Description
300 μg of TriMix in
Intervention Type
Biological
Intervention Name(s)
600μg mRNA (300 μg HIV mRNA+300 μg TriMix mRNA)
Other Intervention Name(s)
iHIVARNA-01.1
Intervention Description
600 μg of mRNA (300 μg TriMix + 300 μg HIVACAT)
Intervention Type
Biological
Intervention Name(s)
900μg mRNA (600 μg HIV mRNA+300 μg TriMix mRNA)
Other Intervention Name(s)
iHIVARNA-01.2
Intervention Description
900 μg of mRNA (300 μg TriMix + 600 μg HIVACAT)
Intervention Type
Biological
Intervention Name(s)
1200μg mRNA (900 μg HIV mRNA+300 μg TriMix mRNA)
Other Intervention Name(s)
iHIVARNA-01.3
Intervention Description
1200 μg of mRNA (300 μg TriMix + 900 μg HIVACAT)
Primary Outcome Measure Information:
Title
Dose limiting toxicity (DLT)
Description
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
Time Frame
week 8
Secondary Outcome Measure Information:
Title
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.
Description
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.
Time Frame
week 24
Title
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
Description
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)
Time Frame
week 24
Title
Cell-associated HIV-1 RNA (CA-RNA) quantification at week 0, 4, 6, 8 and 24
Description
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
Time Frame
week 24
Title
Genome wide transcriptome and microRNA analysis at weeks 0 and 6
Description
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
Time Frame
week 6
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Felipe García
Organizational Affiliation
Hospital Clinic of Barcelona
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Clínic de Bacelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
12. IPD Sharing Statement
Citations:
PubMed Identifier
30289805
Citation
Leal L, Guardo AC, Moron-Lopez S, Salgado M, Mothe B, Heirman C, Pannus P, Vanham G, van den Ham HJ, Gruters R, Andeweg A, Van Meirvenne S, Pich J, Arnaiz JA, Gatell JM, Brander C, Thielemans K, Martinez-Picado J, Plana M, Garcia F; iHIVARNA consortium. Phase I clinical trial of an intranodally administered mRNA-based therapeutic vaccine against HIV-1 infection. AIDS. 2018 Nov 13;32(17):2533-2545. doi: 10.1097/QAD.0000000000002026. Erratum In: AIDS. 2019 Oct 1;33(12):1957.
Results Reference
derived
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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
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