Safety and Immunogenicity Study of DNA.HTI, MVA.HTI and ChAdOx1.HTI in HIV-1-positive Patients (AELIX-002)
Study Details
Study Description
Brief Summary
The AELIX-002 study aims to evaluate the safety and the immunogenicity of an heterologous prime-boost regimen with DNA.HTI, MVA.HTI and ChAdOx1.HTI in early diagnosed and treated HIV-1 positive individuals, males and females,18-60 years of age.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
AELIX Therapeutics has developed a novel immunogen, which was designed to be used as a a therapeutic HIV vaccine that could help HIV infected individuals to control viral replication in the absence of antiretroviral treatment. HIVACAT T cell immunogen (HTI) is a novel T cell immunogen covering the most vulnerable regions of HIV. The encoding DNA sequence that has been inserted in various vaccine vectors, including viral and non-viral vectors. Administration of the HTI immunogen is implemented through a heterologous prime-boost approach. The aim of the sequential administration of the therapeutic vaccines is to achieve a so-called "functional cure," in which HIV-infected participants can control viral replication in the absence of ART.
The AELIX-002 Phase I study will evaluate the safety and immunogenicity of an heterologous regime with DNA.HTI, MVA.HTI and ChAdOx1.HTI in HIV-1 positive participants on suppressive antiretroviral treatment who started Combination Antiretroviral Therapy (cART) within the first 6 months of confirmed HIV-1 acquisition. In Phase A, participants were randomized to receive active vaccine or placebo in a double blinded fashion. There was a sentinel group of three participants; two received active vaccine and one received placebo (0.9% normal saline). During the sentinel phase of the study only one participant was enrolled per day. Two weeks later and in the absence of any related SAE or ≥ Grade 3 adverse event lasting >72h after vaccination in any of the 3 sentinel participants, six individuals in the remaining cohort were enrolled (in blocks of 3 patients per day) and the final six participants one week later, also in blocks of 3 participants per day. On each vaccination day, 2 participants received active IMP and 1 received placebo (2:1).
After the first 15 participants (3 sentinel and 12 non-sentinel) have reached week 22 visit and a favourable report from the Safety Monitoring Committee has been released, transition to Phase B was performed to include 30 participants (Group 3). Participants were recruited sequentially and without following blocks of pre-defined number of vaccines and placebos per immunization day.
At week 32, all participants were invited to participate in an extension sub-study (Roll-over Phase) to assess long-term safety, tolerability and immunogenicity of DNA.HTI and MVA.HTI administrations until start of Phase C. There were no interventions during this extension Roll over Phase.
After a favourable SMC report, transition to Phase C occurred. During Roll-over Phase participants in Phase A/B were offered to participate in Phase C. Participants who received active treatment (DDDMM) in Phase A/B will continue to receive active treatment (CCM) in Phase C, while participants who received placebo in Phase A/B will continue to receive placebo (PPP). Treatment allocation remained blind. Eight weeks after the third MVA.HTI/placebo administration, all participants will undergo an Analytical Treatment Interruption (ATI) of up to 24 weeks of duration. At visit Phase C week 56 (end-of-ATI visit), or before according to pre-specified criteria, cART will be resumed, and participants will be followed during a safety period of 12 weeks.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: DDDMM + CCM DNA.HTI 0.5mL at weeks 0, 4 and 8 + MVA.HTI 0.5mL at weeks 12 and 20. At least 24 weeks since second MVA.HTI administration (week 20), administration of ChAdOx1.HTI 0.5mL at weeks 0 and 12 + MVA.HTI 0.5mL at week 24. |
Biological: DNA.HTI 0.5mL at weeks 0, 4 and 8 + MVA.HTI 0.5mL at weeks 12 and 20 (DDDMM)
Vaccine DNA.HTI 0.5mL at weeks 0, 4 and 8 + Vaccine MVA.HTI 0.5mL at weeks 12 and 20 (DDDMM).
Other Names:
Biological: At least 24 weeks since DDDMM, ChAdOx1.HTI 0.5mL at weeks 0 and 12 + MVA.HTI 0.5mL at week 24 (CCM)
At least 24 weeks since second MVA.HTI administration (week 20), administration of ChAdOx1.HTI 0.5mL at weeks 0 and 12 + MVA.HTI 0.5mL at week 24.
Other Names:
|
| Placebo Comparator: Placebo 0.9% sterile normal saline solution at weeks 0, 4, 8, 12 and 20. At least 24 weeks since fifth placebo administration, administration of 0.9% sterile normal saline solution at weeks 0, 12 and 24. |
Drug: Placebo
0.9% sterile normal saline solution at weeks 0, 4, 8, 12 and 20. At least 24 weeks since the fifth Placebo administration, 0.9% sterile normal saline solution at weeks 0, 12 and 24
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Proportion of participants that develop Grade 3 or 4 local reactions [From first DNA.HTI/Placebo administration to week 32 and from first ChAdOx1.HTI/Placebo administration to week 32]
Grade 3 or 4 local reactions as assessed by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events
- Proportion of participants that develop Grade 3 or 4 systemic reactions [From first DNA.HTI/Placebo administration to week 32 and from first ChAdOx1.HTI/Placebo administration to week 32]
Grade 3 or 4 systemic reactions as assessed by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events
Secondary Outcome Measures
- Proportion of participants that develop T cell responses to HTI-encoded regions [From first DNA.HTI/Placebo administration to week 32 and from first ChAdOx1.HTI/Placebo administration to week 32]
Proportion of patients that develop T cell responses to HTI-encoded regions as determined by IFN-γ ELISPOT assay in vaccine and placebo recipients
- Breadth of total vaccine induced HIV-specific responses [From first DNA.HTI/Placebo administration to week 32 and from first ChAdOx1.HTI/Placebo administration to week 32]
Breadth of total vaccine induced HIV-specific responses measured IFN-γ ELISPOT in vaccine and placebo recipients
- Magnitude of total vaccine induced HIV-specific responses [From first DNA.HTI/Placebo administration to week 32 and from first ChAdOx1.HTI/Placebo administration to week 32]
Magnitude of total vaccine induced HIV-specific responses measured IFN-γ ELISPOT in vaccine and placebo recipients
- Percentage of participants with viral remission, defined as plasma viral load (pVL) <50 copies/mL 12 and 24 weeks after start of Analytical Treatment Interruption (ATI) [From ATI start (visit Phase C week 32) to weeks 12 and 24 after ATI start (visits Phase C week 44 and week 56).]
Percentage of participants with viral remission, defined as plasma viral load (pVL) <50 copies/mL 12 and 24 weeks after start of ATI
- Percentage of participants with pVL <2,000 copies/mL at 12 and 24 weeks after start of ATI [From ATI start (visit Phase C week 32) to weeks 12 and 24 after ATI start (visits Phase C week 44 and week 56).]
Percentage of participants with pVL <2,000 copies/mL at 12 and 24 weeks after start of ATI
- Time to viral detection, defined as the time from ATI start (visit Phase C week 32) to first occurrence of detectable pVL (>50 copies/mL) [From ATI start (visit Phase C week 32) to first occurrence of detectable pVL (>50 copies/mL) up to week 56]
Time to viral detection, defined as the time from ATI start (visit Phase C week 32) to first occurrence of detectable pVL (>50 copies/mL).
- Time to viral rebound, defined as the time from ATI start (visit Phase C week 32) to first occurrence of pVL >10,000 copies/mL. [From ATI start (visit Phase C week 32) to first occurrence of pVL >10,000 copies/mL up to week 56]
Time to viral rebound, defined as the time from ATI start (visit Phase C week 32) to first occurrence of pVL >10,000 copies/mL.
- Percentage of participants who remain off cART at 12 and 24 weeks after ATI (visits Phase C week 44 and week 56). [From ATI start (visit Phase C week 32) to weeks 12 and 24 after ATI start (visits Phase C week 44 and week 56).]
Percentage of participants who remain off cART at 12 and 24 weeks after ATI (visits Phase C week 44 and week 56).
- Time off cART, defined as time to cART resumption since ATI start (visit Phase C week 32). [From ATI start (visit Phase C week 32) to cART resumption through study completion, up to week 68]
Time off cART, defined as time to cART resumption since ATI start (visit Phase C week 32).
- Proportion of participants who develop symptoms compatible with acute retroviral syndrome (ARS) during ATI. [From ATI start (visit Phase C week 32) to cART resumption up to week 56]
Proportion of participants who develop symptoms compatible with acute retroviral syndrome (ARS) during ATI.
- Proportion of participants who develop new mutations not present in the pre-cART genotype conferring clinically-significant resistance to antiretroviral drugs (out of the individuals not reaching viral re-suppression 12 weeks after cART resumption). [From ATI start (visit Phase C week 32) to cART resumption up to week 56]
Proportion of participants who develop new mutations not present in the pre-cART genotype conferring clinically-significant resistance to antiretroviral drugs (out of the individuals not reaching viral re-suppression 12 weeks after cART resumption).
- Proportion of participants who suppress pVL to <50 copies/mL 12 weeks after cART resumption. [12 weeks after cART resumption.]
Proportion of participants who suppress pVL to <50 copies/mL 12 weeks after cART resumption.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Confirmed HIV-1 infection
-
On combined antiretroviral treatment (defined as ≥ 3 antiretroviral drugs) initiated within 6 months of estimated time of HIV-1 acquisition.
-
Willing and able to be adherent to their cART regimen for the duration of the study.
-
Optimal virological suppression for at least 1 year defined as maintained pVL below the limit of detection (based on current available assays, 20, 40 or 50 copies/ml) allowing for isolated blips.
-
Being on the same cART regimen for at least 4 weeks at screening visit.
-
Nadir CD4 count ≥ 200 cells per mm3. Isolated lower counts at the moment of acute HIV-1 infection will be allowed only if appropriate immune recovery was followed after cART initiation (as is criteria 7).
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Stable CD4 counts ≥ 400 cells per mm^3 for the last 6 months at screening visit.
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Availability of stored biological sample (including PBMC and plasma) before any cART initiation.
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Aged at least 18 years on the day of screening and no greater than 60 years on the day of the first vaccination.
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Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study.
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In the opinion of the principal investigator or designee, the patient has understood the information provided and capable of giving written informed consent.
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If heterosexually active female; using an effective method of contraception (hormonal contraception, intra-uterine device (IUD), or anatomical sterility in self or partner) 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 pregnancy tests at time points specified in the Schedule of Procedures.
-
If heterosexually active male; willing to use an effective method of contraception (anatomical sterility in self) or agree on the use of an effective method of contraception by his partner (hormonal contraception, intra-uterine device (IUD), or anatomical sterility) from the day of the first vaccination until 12 weeks after the last vaccination.
-
Willing to accept blood draws and collect stool at time points specified in the Schedule of Procedures.
-
Willing to forgo donating blood during the study.
Exclusion Criteria:
-
Pregnancy or lactating.
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Presence of resistance drug mutations in a pre-cART genotype.
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Reported periods of suboptimal adherence to cART.
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History of past antiretroviral treatment interruptions longer than 2 weeks.
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Participation in another clinical trial within 12 weeks of study entry (at screening visit).
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Any AIDS-defining disease or progression of HIV-related disease.
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History of autoimmune disease.
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History or clinical manifestations of any physical or psychiatric disorder which could impair the subject's ability to complete the study.
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Receipt of approved vaccines within 2 weeks of study entry and along the duration of the trial.
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History of anaphylaxis or severe adverse reaction to vaccines.
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Previous immunisation with any experimental immunogens.
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Receipt of blood products within 6 months of study entry.
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Treatment for cancer or lymphoproliferative disease within 1 year of study entry.
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Any other current or prior therapy which, in the opinion of the investigators, would make the individual unsuitable for the study or influence the results of the study.
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Current or recent use (within last 3 months) of interferon or systemic corticosteroids or other immunosuppressive agents (use on inhaled steroids for asthma or topic steroids for localized skin conditions are permitted).
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Any laboratory abnormalities including:
Haematology
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Haemoglobin < 10.0 g/dl
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Absolute Neutrophil Count (ANC) ≤ 1,000 /mm3
-
Absolute Lymphocyte Count (ALC) ≤ 600 /mm3
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Platelets ≤100,000 /mm3, ≥ 550,000 /mm3
Biochemistry
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Creatinine > 1.3 x ULN
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Aspartate aminotransferase (AST) > 2.5 x ULN
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Alanine aminotransferase (ALT) > 2.5 x ULN
Microbiology
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Positive for hepatitis B surface antigen,
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Positive for hepatitis C antibody, unless confirmed clearance of HCV infection (spontaneous or following treatment)
-
Positive serology indicating active syphilis requiring treatment
- Complete refusal to cART interruption
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol | Badalona | Barcelona | Spain | 08916 |
Sponsors and Collaborators
- Aelix Therapeutics
Investigators
- Principal Investigator: Beatriz Mothe, MD, PhD, IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- AELIX-002