A HIV Vaccine Trial in Individuals Who Started Antiretrovirals During Primary or Chronic Infection (EHVA T02)

Study Overview
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Brief Summary
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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
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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.

Official Title
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EHVA T02 (European HIV Vaccine Alliance Therapeutic Trial 02)/ANRS VRI07: A Phase II Randomised, Placebo-controlled Trial of Vedolizumab With or Without Therapeutic HIV MVA Vaccine in Individuals Who Started Antiretrovirals During Primary or Chronic Infection

Conditions
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HIV-1-infection

Intervention / Treatment
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* Biological: Vaccine and vedolizumab (Entyvio)
* Biological: Placebo vaccine and vedolizumab infusion (Entyvio)
* Biological: Placebo vaccine and placebo infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1-infected Aged 18 - 65 years old on the day of screening Weight >50kg Willing and able to provide written informed consent Nadir CD4 count > 300 cells/mm3 CD4 count at screening > 500 cells/mm3 Viral load <50 copies/ml at screening. Started cART after 2009 and on cART for at least one year prior to screening Willing to interrupt cART for up to 24 weeks and change cART regimen if required 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) 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 If women of childbearing potential*, willing to undergo urine pregnancy tests prior to administration of an injection and an infusion Willing to avoid all other vaccines within 4 weeks of scheduled study injections Willing and able to comply with visit schedule and provide blood samples 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: Pregnant or lactating HIV-2 infection (either isolated or associated with HIV-1) VL >200 copies/ml on 2 occasions in the 12 months prior to screening Previous interruptions in cART Previous virological failures defined by loss of virological suppression with the presence of resistant mutations Haemoglobin (Hb <12g/dL for males, <11g/dL for females) Concomitant or previous conditions that preclude injection of vaccines/infusion of monoclonal antibody and PML in the past History of experimental vaccinations against HIV Previous treatment with chemotherapy (except for chemotherapy injected into skin lesions for Kaposi's sarcoma) Treatment with systemic corticoids or immuno-suppressive agents ongoing or in the 12 weeks prior to randomisation in the trial Received natalizumab or rituximab ever in the past Received a TNF blocker in the past 60 days Administration of an inactivated vaccine within 30 days or a live vaccine within 60 days prior to randomisation Presence of a skin condition or marking that precludes inspection of the injection/infusion site History of cancer (except basal cellular skin carcinoma or Kaposi's sarcoma) History of significant neurological disease or cardiovascular disease (angina, myocardial infarction, transient ischemic attack, stroke); participants with controlled blood pressure are eligible History of clinical autoimmune disease Ongoing diseases including uncontrolled active severe infection, cardiac, pulmonary (excluding mild asthma), thyroid, renal or neurological (peripheral or central) diseases 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) Presence of pathogenic bacteria or parasites in faeces at screening Participating in another biomedical research study within 30 days of randomisation 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. Liver disease including hepatitis B (surface antigen positive) or hepatitis C (antigen or PCR positive) A clinically significant abnormality on ECG Hypernatraemia or hyperchloraemia History of severe local or general reaction to vaccination defined as local: extensive, indurated redness and swelling involving most of the arm, not resolving within 72 hours general: fever >= 39.5oC within 48 hours; anaphylaxis; bronchospasm; laryngeal oedema; collapse; convulsions or encephalopathy within 72 hours Grade 2 or worse routine laboratory parameters. Hyperbilirubinaemia to be considered an exclusion criterion only when confirmed to be conjugated bilirubinaemia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaccine and Vedolizumab infusion<br>Vaccine: The vaccine is MVA HIV-B which is a solution of HIV MVA vectors 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). Vedolizumab infusion (Entyvio): Vedolizumab (300mg) is administered as an intravenous infusion (255 ml). | Biological: Vaccine and vedolizumab (Entyvio)<br>* 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.<br>|
| Experimental: Placebo vaccine and Vedolizumab infusion<br>Placebo vaccine: The placebo for MVA HIV-B to be used in this trial is a solution composed of S08 buffer (as for the MVA vaccine). Vedolizumab infusion (Entyvio): Vedolizumab (300mg) is administered as an intravenous infusion (255 ml) | Biological: Placebo vaccine and vedolizumab infusion (Entyvio)<br>* 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.<br>|
| Placebo Comparator: Placebo vaccine and placebo infusion<br>Placebo vaccine: The placebo for MVA HIV-B to be used in this trial is a solution composed of S08 buffer (as for the MVA vaccine). Placebo infusion: Sodium Chloride (NaCl) 0.9% administered as an intravenous infusion (255ml) | Biological: Placebo vaccine and placebo infusion<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the HIV RNA curve | Area under the HIV RNA curve from treatment interruption (scheduled for 18 weeks after entering the trial) | Time from treatment interruption (scheduled for 18 weeks after entering the trial) to 24 weeks post-treatment interruption | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological outcome measures | 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. | For participants commencing treatment interruption only, critical time points weeks 19 through to to week 42. | 
| Virological outcome measures | Level of HIV total RNA | From randomisation to study completion about 54 weeks | 
| Virological outcome measures | Cell Associated (CA) HIV RNA Quantification | From randomisation to study completion about 54 weeks | 
| Virological outcome measures | First local maximum (peak) level of HIV total RNA during treatment interruption | Time from treatment interruption, only in participants commencing treatment interruption, up to 24 weeks after ATI | 
| Virological outcome measures | Rate of increase of HIV total RNA between the last measure below the lower detection and the first local maximum | Time from treatment interruption, only in participants commencing treatment interruption, up to 24 weeks after ATI | 
| Virological outcome measures | Setpoint (two stable measures following a transient increase of HIV RNA) | Time from treatment interruption, only in participants commencing treatment interruption, up to 24 weeks after ATI |