HIV-1-infection
Conditions
Brief summary
EVHA T01 is an international, phase I/II, multicentre, multi-stage, double-blind study that will evaluate at least three experimental arms compared to placebo control in HIV-1 infected participants to see if one or more has a clinically relevant impact on the control of viral replication.
Detailed description
The randomization ratio is 1:1:1:1 for vaccine: vedolizumab: combination: placebo in one of 3 schedules. The study contains a phase I component in order to evaluate the local and systemic reactogenicity following the first administration of products in the first 12 participants. The phase I will consist of a slow enrolment of the first 12 participants who will be randomised at a maximum rate of 1 per week for 4 weeks, then 2 per week for 4 weeks before increasing to 4 or more per week. The IDMC will review of cumulative adverse event data through to and including the first safety visit in the 12th participant and their recommendation will be sought with regard to expanding recruitment. The phase II component will assess the effectiveness and safety of the three experimental strategies upon viral control following analytic treatment interruption (ATI). The phase II component is divided into two stages, an interim efficacy stage and a final efficacy stage. There will be a pause in enrolment after 88 participants have been enrolled. A planned interim review by the IDMC at the end of the first stage will provide an opportunity to modify the design of subsequent stages or the recruitment strategy. Screening will take place during the 6 weeks prior to randomisation. Eligible participants will be enrolled at week 0 and randomised to vaccine, vedolizumab, the combination of vaccine and vedolizumab or matched placebos. Participants and study staff will be aware of the schedule the participant is randomised to, with a third allocated to injections, a third to infusions and a third to the combination of injections and infusions. Only staff authorised to prepare the products will know who is randomised to active product or placebo within each schedule in a ratio of 3:1 respectively. The vaccine regimen will start at week 0 and the vedolizumab regimen at week 2, each with matched placebo. Participants will continue on cART during the first 24 weeks covering the vaccination period and 5 of 6 vedolizumab/placebo infusions. Treatment will then be interrupted and resumed when the viral load is confirmed to have rebounded to ≥10,000 copies/ml, or the CD4 falls to ≤350 cells/mm3, or there is evidence of disease progression, or they have completed 24 weeks of treatment interruption.
Interventions
BIOLOGICALGTU-MultiHIV B-clade vaccine + MVA HIV-B HIV vaccine
The vaccine is a solution of HIV MVA vectors (see section 1.3.2) in S08 buffer (10mM Tris/hydrochloride (Tris/HCl), Saccharose 5% (w/v), 10mM Sodium Glutamate (Na Glu), 50mM Sodium Chloride (NaCl), water PPI, pH 8.0). 0.5ml of ANRS MVA HIV-B (1 x 108 pfu/ml) or placebo for MVA (S8 buffer) will be administered intramuscularly in the deltoid muscle of the non-dominant upper arm. Participants will be observed for one hour after the injection.
BIOLOGICALGTU-MultiHIV B-clade vaccine + MVA HIV-B HIV vaccine+ Vedolizumab
The vaccine is a solution of HIV MVA vectors (see section 1.3.2) in S08 buffer (10mM Tris/hydrochloride (Tris/HCl), Saccharose 5% (w/v), 10mM Sodium Glutamate (Na Glu), 50mM Sodium Chloride (NaCl), water PPI, pH 8.0). 0.5ml of ANRS MVA HIV-B (1 x 108 pfu/ml) or placebo for MVA (S8 buffer) will be administered intramuscularly in the deltoid muscle of the non-dominant upper arm. Participants will be observed for one hour after the injection. Vedolizumab is administered as an intravenous infusion over 30 mins in the dominant arm. After infusion, the line should be flushed with 30mls of normal saline.
DRUGVedolizumab 300 MG [Entyvio]
Vedolizumab is administered as an intravenous infusion over 30 mins in the dominant arm. After infusion, the line should be flushed with 30mls of normal saline.
OTHERPlacebo
Placebo for MVA it is a solution composed of S08 buffer (as for the MVA vaccine) that will be administered intramuscularly in the deltoid muscle of the non-dominant upper arm. Participants will be observed for one hour after the injection. Placebo for GTU-MultiHIV B-clade vaccine: Sodium Chloride (NaCl) for infusion, 0.9%. Placebo for Vedolizumab: Sodium Chloride (NaCl) for infusion, 0.9% in 250 ml infusion bags.
Sponsors
European Commission
Swiss Government
Medical Research Council
FIT Biotech Ltd.
Fred Hutchinson Cancer Center
University College, London
Centre Hospitalier Universitaire Vaudois
Imperial College London
Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani IRCCS
Universitätsklinikum Hamburg-Eppendorf
Institut d'Investigacions Biomèdiques August Pi i Sunyer
Henri Mondor University Hospital
European Georges Pompidou Hospital
Saint-Louis Hospital, Paris, France
ANRS, Emerging Infectious Diseases
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. HIV-1-infected 2. Aged 18 - 65 years old on the day of screening 3. Weight \>50kg 4. Willing and able to provide written informed consent 5. Nadir CD4 count \> 300 cells/mm3 6. CD4 count at screening \> 500 cells/mm3 7. Viral load \<50 copies/ml at screening 8. Started cART after 2009 and on cART for at least one year prior to screening 9. Willing to interrupt cART for up to 24weeks and change cART regimen if required 10. 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 PrEP for their sexual partners) 11. If heterosexually active and able to have children, willing to use a highly effective method of contraception with partner (combined oral contraceptive pill; injectable or implanted contraceptive; IUD/IUS; physiological or anatomical sterility (in self or partner) from 2 weeks before enrolment until 18 weeks after the last injection/infusion 12. If women of childbearing potential\*, willing to undergo urine pregnancy tests prior to administration of an injection or an infusion 13. Willing to avoid all other vaccines within 4 weeks of scheduled study injections 14. Willing and able to comply with visit schedule and provide blood samples 15. Being covered by medical insurance or in National Healthcare System * A woman will be considered of childbearing potential following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Exclusion criteria
1. Pregnant or lactating 2. HIV-2 infection (either isolated or associated with HIV-1) 3. VL \>200 copies/ml on 2 occasions in the 12 months prior to screening 4. Previous interruptions in cART 5. Previous virological failures defined by loss of virological suppression with the presence of resistant mutations 6. Haemoglobin (Hb \<12g/dL for males, \<11g/dL for females) 7. Concomitant or previous conditions that preclude injection of vaccines/infusion of monoclonal antibody and PML in the past 8. History of experimental vaccinations against HIV 9. Previous treatment with chemotherapy (except for chemotherapy injected into skin lesions for Kaposi's sarcoma) 10. Treatment with systemic corticoids or immuno-suppressive agents ongoing or in the previous 12 weeks before randomisation in the trial 11. Received natalizumab or rituximab ever in the past 12. Received a TNF blocker in the past 60 days 13. Administration of an inactivated vaccine within 30 days or a live vaccine within 60 days prior to randomisation 14. Presence of a skin condition or marking that precludes inspection of the injection/infusion site 15. History of cancer (except basal cellular skin carcinoma or Kaposi's sarcoma) 16. History of significant neurological disease, cardiovascular disease (angina, myocardial infarction, transient ischemic attack, stroke); participants with controlled blood pressure are eligible 17. Personal history of clinical autoimmune disease or reactive arthritis or family history of rheumatoid arthritis (parents or siblings) 18. Ongoing diseases including uncontrolled active severe infection, cardiac, pulmonary (excluding mild asthma), thyroid, renal or neurological (peripheral or central) diseases 19. Active or latent tuberculosis (unless prophylaxis in past as per local practice) - (participant must be screened for tuberculosis before starting infusions, according to routine practice) 20. Presence of pathogenic bacteria or parasites in faeces at screening 21. Participating in another biomedical research study within 30 days of randomisation. 22. Known hypersensitivity to any component of the vaccine formulations used in this trial including aminoglycosides and eggs or have severe or multiple allergies to drugs or pharmaceutical agents, or any hypersensitivity to the active substance or to any of the excipients of vedolizumab 23. Liver disease including hepatitis B (surface antigen positive) or hepatitis C (antigen or PCR positive) 24. A clinically significant abnormality on ECG 25. Hypernatraemia or hyperchloraemia 26. History of severe local or general reaction to vaccination defined as 1. local: extensive, indurated redness and swelling involving most of the arm, not resolving within 72 hours 2. general: fever \>= 39.5oC within 48 hours; anaphylaxis; bronchospasm; laryngeal oedema; collapse; convulsions or encephalopathy within 72 hours 27. Grade 2 or worse routine laboratory parameters (see Appendix 4 for definitions). Hyperbilirubinaemia to be considered an exclusion criterion only when confirmed to be conjugated bilirubinaemia
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety: A clinical decision to discontinue the regimen for an adverse event that is considered related to product | From randomisation |
| Efficacy: Time from treatment interruption to the earliest of reaching HIV RNA ≥ 10,000 copies/ml or resuming antiretroviral therapy for any reason over a period of 24 weeks. | Time from treatment interruption (scheduled for 12 weeks after completing the immunisation schedule) to the earliest of reaching HIV RNA ≥ 10,000 copies/ml or resuming antiretroviral therapy for any reason over a period of 24 weeks. |
Secondary
| Measure | Time frame |
|---|---|
| Any event leading to interruption in the vaccine schedule | From randomisation to study completion, about 60 weeks. |
| Any event that results in resuming treatment during the ATI | From randomisation to study completion, about 60 weeks. |
| Other clinical and laboratory adverse events | From randomisation to study completion, about 60 weeks. |
| Time to VL suppression after restarting ART | From randomisation to VL suppression after restarting ART |
| Serious Adverse Events | From randomisation to 30 days after the last protocol visit |
| Grade 3 and worse solicited clinical and laboratory adverse events | From randomisation to study completion, about 60 weeks. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Secondary Immunological Outcomes | From randomisation | Response rate, magnitude and polyfunctionality of vaccine induced CD4 and CD8 T-cell responses. |
| Secondary Virological efficacy outcome measures | From randomisation | Level of HIV total DNA and Cell Associated (CA) HIV RNA Quantification |
Countries
Switzerland, United Kingdom
Outcome results
None listed