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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV-1-infection
• Intervention / Treatment: Biological: Vaccine and vedolizumab (Entyvio); Biological: Placebo vaccine and vedolizumab infusion (Entyvio); Biological: Placebo vaccine and placebo infusion

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.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75004
    • Hotel Dieu
  • Creteil
    • Paris, Creteil, France, 94010
      • Service Immunologie clinique et maladies infectieuses, Hôpital Henri Mondor
• Switzerland
  • Vaud
    • Lausanne, Vaud, Switzerland, 1011
      • Centre d'Immunothérapie et Vaccinologie, CHUV
• United Kingdom
  • London, United Kingdom, SW10 9NH
    • St Stephens Centre, Chelsea & Westminster Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vaccine and Vedolizumab infusion; 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); 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.
Experimental: Placebo vaccine and Vedolizumab infusion; 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); 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.
Placebo Comparator: Placebo vaccine and placebo infusion; 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; 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety outcome measures: Grade 3 or worse solicited clinical and laboratory adverse events	Occurrence of grade 3 or worse solicited clinical and laboratory adverse events	From randomisation to study completion about 54 weeks
Safety outcome measures: Any adverse event leading to interruption in the vaccine/placebo or vedolizumab/placebo	Occurrence of any adverse event leading to interruption in the vaccine/placebo or vedolizumab/placebo	From randomisation to study completion about 54 weeks
Safety outcome measures: Any event that results in resuming treatment during the ATI	Occurrence of any event that results in resuming treatment during the ATI	Time form treatment interruption to resuming treatment, up to 24 weeks after ATI
Safety outcome measures: Serious Adverse Events	Occurrence of Serious Adverse Events	From randomisation until 30 days after the last protocol visit
Safety outcome measures: Other clinical and laboratory adverse events	Occurrence of other clinical and laboratory adverse events	From randomisation to study completion about 54 weeks
Safety outcome measures: Change in absolute CD4	Observation of change in absolute CD4 count	From randomisation to study completion about 54 weeks
Safety outcome measures: Time to VL suppression after restarting cART	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]
Exploratory Immunological outcome measures: Characterization of vaccine induced CD4 and CD8 T-cell produced cytokine profile	Observation of vaccine induced CD4 and CD8 T-cell produced cytokines by flow cytometry	From randomisation to study completion about 54 weeks

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases
• Collaborators: University College London Hospitals; Hospital Clinic of Barcelona; Imperial College London; Erasmus Medical Center; Medical Research Council; Centre Hospitalier Universitaire Vaudois; Saint-Louis Hospital, Paris, France; University of Liverpool; Universitätsklinikum Hamburg-Eppendorf; European Commission; Institut d'Investigacions Biomèdiques August Pi i Sunyer; Henri Mondor University Hospital; European Georges Pompidou Hospital; EuroVacc Foundation; Chelsea and Westminster Hospital, UK; Swiss Government; European AIDS Treatment Group (EATG); Istituto Nazionale Malattie Infettive Lazaro Spallanzani
• Investigators: Study Director: Yves Levy, MD, Institut National de la Santé Et de la Recherche Médicale, France

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2022
• Primary Completion (Actual): July 12, 2023
• Study Completion (Actual): July 12, 2023

Study Registration Dates

• First Submitted: September 30, 2019
• First Submitted That Met QC Criteria: October 7, 2019
• First Posted (Actual): October 9, 2019

Study Record Updates

• Last Update Posted (Actual): August 4, 2023
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Persistent Infection; Physiological Effects of Drugs; Immunologic Factors; Gastrointestinal Agents; Vaccines; Vedolizumab
• Other Study ID Numbers: EHVA T02/ANRS VRI07

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No