HIV-1-infection
Conditions
Brief summary
EHVA T02 is an international, phase II, double-blind study to evaluate two experimental arms each compared to placebo control in HIV-1 positive participants to see if either has a clinically relevant impact on viral replication.
Detailed description
Screening will take place during the 6 weeks prior to randomisation. Eligible participants will be enrolled at week 0 and randomised to MVA HIV-B vaccine followed by vedolizumab, vedolizumab + placebo vaccine, or placebo vaccine + placebo infusions. Participants will be randomised at each centre through web-based randomisation after entering the eligibility criteria. There will be two strata: one for those who started treatment during primary infection, and one for those who started treatment during chronic infection. 69 eligible individuals from collaborating European Countries will be enrolled, aiming for approximately half who started cART in primary infection and half who started in chronic infection. Participants continue from the screening visit (up to 6 weeks before enrolment) to the last visit, a maximum of 60 weeks (around 14 months), although follow-up will continue through to the time when virus is fully suppressed. Treatment will be interrupted at week 18 and resumed when the viral load is confirmed to have rebounded to ≥100,000 copies/ml, or the CD4 falls to ≤350 cells/mm3, confirmed, or there is evidence of disease progression, or they have completed 24 weeks of treatment interruption.
Interventions
BIOLOGICALVaccine and vedolizumab (Entyvio)
Vaccine and vedolizumab infusion (Entyvio): 0.5ml of MVA HIV-B (1 x 108 pfu/ml) will be administered intramuscularly in the deltoid muscle of the non-dominant upper arm at weeks 0 and 8. Participants will be observed after the injection. Vedolizumab (300mg) is administered as an intravenous infusion (255 ml) over 30 mins in the dominant arm at weeks 10,12,16,20,24,28 and 32. After infusion, the line should be flushed with 30ml of normal saline. Participants will be observed throughout and after the infusion.
BIOLOGICALPlacebo vaccine and vedolizumab infusion (Entyvio)
Placebo Vaccine: The placebo for MVA HIV-B to be used is a solution composed of S08 buffer (as for the MVA vaccine) that will be intramuscularly in the deltoid muscle of the non-dominant upper arm at weeks 0 and 8. Participants will be observed after the injection. Vedolizumab infusion (Entyvio): Vedolizumab (300mg) is administered as an intravenous infusion (255 ml) over 30 mins in the dominant arm at weeks 10,12,16,20,24,28 and 32. After infusion, the line should be flushed with 30ml of normal saline. Participants will be observed throughout and after the infusion.
BIOLOGICALPlacebo vaccine and placebo infusion
Placebo Vaccine: The placebo for MVA HIV-B to be used is a solution composed of S08 buffer (as for the MVA vaccine) that will be intramuscularly in the deltoid muscle of the non-dominant upper arm at weeks 0 and 8. Participants will be observed after the injection. Placebo infusion (Entyvio): 255ml Sodium Chloride (NaCl) 0.9% bag administered as an intravenous infusion over 30 mins in the dominant arm at weeks 10,12,16,20,24,28 and 32. Participants will be observed throughout and after the infusion.
Sponsors
EuroVacc Foundation
European AIDS Treatment Group (EATG)
Medical Research Council
University College London Hospitals
University of Liverpool
Erasmus Medical Center
Henri Mondor University Hospital
European Georges Pompidou Hospital
Saint-Louis Hospital, Paris, France
Centre Hospitalier Universitaire Vaudois
Chelsea and Westminster Hospital, UK
Universitätsklinikum Hamburg-Eppendorf
Hospital Clinic of Barcelona
Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani IRCCS
Imperial College London
Institut d'Investigacions Biomèdiques August Pi i Sunyer
European Commission
Swiss Government
ANRS, Emerging Infectious Diseases
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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 24 weeks 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 and 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 12 weeks prior to 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 or cardiovascular disease (angina, myocardial infarction, transient ischemic attack, stroke); participants with controlled blood pressure are eligible 17. History of clinical autoimmune disease 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 formulation used in this trial including 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. Hyperbilirubinaemia to be considered an exclusion criterion only when confirmed to be conjugated bilirubinaemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area under the HIV RNA curve | Time from treatment interruption (scheduled for 18 weeks after entering the trial) to 24 weeks post-treatment interruption | Area under the HIV RNA curve from treatment interruption (scheduled for 18 weeks after entering the trial) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Virological outcome measures | For participants commencing treatment interruption only, critical time points weeks 19 through to to week 42. | Time from treatment interruption (scheduled for 18 weeks after entering the trial) to the earliest of reaching HIV RNA ≥ 100 000 copies/ml (confirmed on a separate sample) or resuming antiretroviral therapy for any reason over a period of 24 weeks. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety outcome measures: Any adverse event leading to interruption in the vaccine/placebo or vedolizumab/placebo | From randomisation to study completion about 54 weeks | Occurrence of any adverse event leading to interruption in the vaccine/placebo or vedolizumab/placebo |
| Safety outcome measures: Any event that results in resuming treatment during the ATI | Time form treatment interruption to resuming treatment, up to 24 weeks after ATI | Occurrence of any event that results in resuming treatment during the ATI |
| Safety outcome measures: Serious Adverse Events | From randomisation until 30 days after the last protocol visit | Occurrence of Serious Adverse Events |
| Safety outcome measures: Time to VL suppression after restarting cART | From randomisation to VL suppression (= VL is undetectable (<50copies/ml)) after restarting cART until the participant returns to an undetectable viral load, about 54 weeks] | Time to VL suppression after restarting cART |
| Safety outcome measures: Change in absolute CD4 | From randomisation to study completion about 54 weeks | Observation of change in absolute CD4 count |
| Exploratory Immunological outcome measures: Characterization of vaccine induced CD4 and CD8 T-cell produced cytokine profile | From randomisation to study completion about 54 weeks | Observation of vaccine induced CD4 and CD8 T-cell produced cytokines by flow cytometry |
| Safety outcome measures: Other clinical and laboratory adverse events | From randomisation to study completion about 54 weeks | Occurrence of other clinical and laboratory adverse events |
| Safety outcome measures: Grade 3 or worse solicited clinical and laboratory adverse events | From randomisation to study completion about 54 weeks | Occurrence of grade 3 or worse solicited clinical and laboratory adverse events |
Countries
France, Switzerland, United Kingdom
Outcome results
None listed