Evaluating a Combination of Immune-based Therapies to Achieve a Remission of HIV Infection

Study Overview
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Brief Summary
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A phase I/IIa, multinational, multicentric (IDIBAPS, IRSICAIXA, AARHUS, VUB, APHP), randomised, balanced by centre (to include participants from the 4 arms), open-label, controlled clinical trial. Each participant will be followed up a different time according to study arm: a minimum of 38 weeks in arm I, 31 weeks in arm II, 54 weeks in arm III and 26 weeks in the arm 4. The study duration will be 104 weeks from inclusion of the first participant. Participants will be randomised to one of the following 4 arms: Arm 1 (study): 14 participants will receive 3 vaccines of HIVARNA01.3 prime, 2 MVA-vectored vaccine boosts, 1 dose of 10-1074 antibodies and 3 doses of romidepsin Arm 2 (study): 14 participants will receive 5 vaccines of HIVARNA01.3, 1 dose of 10-1074 antibodies and 3 doses of romidepsin Arm 3 (study): 14 participants will receive 5 vaccines of personalized RNA vaccine (HIVACAR01), 1 dose of 10-1074 antibodies and 3 doses of romidepsin Arm 4 (control): 14 participants 1 dose of 10-1074 antibodies and 3 doses of romidepsin

Official Title
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A Phase I/IIa, Randomised Study to Evaluate the Safety and the Effectiveness of a Combination of Therapeutic Vaccine, Broadly Neutralising Antibody (10-1074), and the Latency Reversing Agent Romidepsin to Achieve a Remission of HIV Infection in Chronically HIV-infected Participants Under Stable Combined Antiretroviral Therapy.

Conditions
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HIV Infections

Intervention / Treatment
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* Other: HIVACAR
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between ≥ 18 to <60 years of age Voluntarily signed informed consent Male, or female with negative pregnancy test prior to enrolment Proven HIV-1 infection (with positive antibodies against HIV-1 and a detectable plasma HIV-1 RNA before cART) Must be on stable treatment with cART for at least 18 months (cART is defined as an antiretroviral regimen consisting of at least three registered antiretroviral agents; periods of mono/dual antiretroviral therapy if not first time therapy and confirmed viral suppression during these periods of mono/dual therapy are permitted) Nadir CD4+ cell counts must be above or equal to 350 cells/µl, 2-3 occasional determinations below 350 cells/μl are allowed. Current CD4+ cell count must be at least 450 cells/µl HIV-RNA must be below 50 copies/ mL for the last 12 months prior to inclusion, during at least two measurements (occasional so called 'blips' up to 500 copies/mL are permitted) If male or female of childbearing potential willing to take correct contraceptive measures: If heterosexually active female; using an effective method of contraception from 14 days prior to the first vaccination until at least 12 weeks after the last vaccination; all female volunteers must be willing to undergo urine or serum pregnancy tests at time points specified in the Schedule of Procedures. If heterosexually active male; willing to use an effective method of contraception or agree on the use of an effective method of contraception by his partner from the day of the first vaccination until 12 weeks after the last vaccination. If sexually active, willing to use a reliable method of reducing the risk of transmission to their sexual partners during treatment interruption (which could include pre-exposure prophylaxis [PrEP] for their sexual partners) Exclusion Criteria: Treatment with a non-cART regimen of antiretroviral agents prior to the start of any antiretroviral regimen History of a CDC class C event (see Appendix IV) Women of childbearing potential with a positive pregnancy test, or participants (male or female) who wish to plan a pregnancy during the trial period. 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 antiretroviral therapy failure and/or mutations conferring genotypic resistance to antiretroviral therapy Participants with severe cardiovascular diseases or long QT interval Active hepatitis C virus Hepatitis B infection Treatment with strong inhibitors or inducers of CYP3A4, except protease inhibitors for HIV treatment (see protocol section 5.7); if in treatment of protease inhibitors for HIV not willing to change inhibitor protease for an integrase inhibitor during the study. Any known allergy or intolerance to any of the study drugs or excipient Protein egg allergy Known past history of clinical Epstein-Barr Virus (EBV) infection or recurrent herpes zoster Hematologic abnormalities ≥Grade 1 Potassium or magnesium levels outside the upper limit of normal (ULN) and lower limit of normal (LLN) History of autoimmune disorders as multiple sclerosis. Any other condition which, in the opinion of the investigator, may interfere with the evaluation of the study objectives

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HIVACAR<br>Participants will receive 5 vaccines of personalized RNA vaccine (HIVACAR01), 2 dose of 10-1074 antibodies and 3 doses of romidepsin | Other: HIVACAR<br>* Participants will receive 5 vaccines of personalized RNA vaccine (HIVACAR01), 2 doses of 10-1074 antibodies and 3 doses of romidepsin<br>|
| Placebo Comparator: Placebo<br>Participants will receive 5 doses of placebo, 2 doses of 10-1074 antibodies and 3 doses of romidepsin | Other: placebo<br>* Participants will receive 5 vaccines of placebo of HIVACAR01, 2 doses of 10-1074 antibodies and 3 doses of romidepsin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3 or above severe local , systemic, clinical or laboratory adverse event t | Local adverse events may be pain, cutaneous reactions including induration and systemic emperature, chills, headache, nausea, vomiting, malaise, and myalgia. Clinical and laboratory must be confirmed at examination or on repeat testing respectively. Any adverse event attributable to the combination therapy leading to discontinuation of the study treatmen | 12 days (28 days after each inmuisation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who maintain an undetectable viral load | defined as a viral load below the threshold of 50 copies/ml | 12 weeks (after discontinuation of antiretroviral therapy) | 
| Percentage of participants with control of viral load below detectable level |  | 24 weeks (after discontinuation of antiretroviral therapy) | 
| Change from baseline in total proviral HIV-1 DNA per 10^6 CD4+ T cells. |  | up to 51 weeks | 
| Change from baseline in integrated proviral HIV-1 DNA per 10^6 CD4+ T cells. |  | up to 51 weeks | 
| Change from baseline in HIV-1 transcription. | According to CA US HIV-1 RNA measured in unfractionated CD4+ T cells | up to 39 weeks | 
| Change in plasma HIV-1 RNA from baseline |  | up to 39 weeks | 
| Breadth and magnitude of CD4+ HIV-specific T cell responses measured by IFN-gamma ELISPOT compared with baseline. |  | up to 27 weeks | 
| Breadth and magnitude of CD8+ HIV-specific T cell responses measured by IFN-gamma ELISPOT compared with baseline. |  | up to 27 weeks | 
| Breadth and magnitude of CD4+ HIV-specific T cell responses measured by Intra-cellular cytokine staining-ICS in the study arms as compared with baseline. |  | up to 27 weeks | 
| Breadth and magnitude of CD8+ HIV-specific T cell responses measured by Intra-cellular cytokine staining-ICS in the study arms as compared with baseline. |  | up to 27 weeks | 
| Change from baseline in CD8+ T-cell HIV suppressive capacity. |  | up to 51 weeks | 
| Change from baseline in T cell activation markers |  | up to 29 weeks | 
| Change from baseline in T cell activation markers |  | 3 weeeks | 
| Change from baseline in T cell activation markers |  | up to 24 weeks | 
| Change from baseline in T cell subset distribution |  | up to 29 weeks | 
| Change from baseline in T cell subset distribution |  | 14 weeks | 
| Change from baseline in T cell subset distribution |  | up to 27 weeks | 
| Change from baseline in PD-1 expression |  | up to 51 weeks | 
| Evaluate fecal microbiome |  | baseline and at week 14 | 
| Characterise viral escape from vaccine-induced immune T cell responses | Comparison of viral sequences pre-cART and rebounding after cART interruption | up to 51 weeks | 
| Analysis of changes in sensitivity to neutralisation by 10-1074 of rebounding viruses after cART interruption to identify neutralisation escape mutants. |  | up to 51 weeks | 
| To evaluate mRNA expression profiles in whole PBMC at baseline |  | at first romidepsin administration and 14 and 26 weeks after first romidepsin administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV