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An HIV Vaccine Trial in Individuals Who Started ART During Primary or Chronic Infection (EHVAT01)

Primary Purpose

HIV-1-infection

Status

Terminated

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

GTU-MultiHIV B-clade vaccine + MVA HIV-B HIV vaccine

GTU-MultiHIV B-clade vaccine + MVA HIV-B HIV vaccine+ Vedolizumab

Vedolizumab 300 MG [Entyvio]

Placebo

About this trial

This is an interventional treatment trial for HIV-1-infection

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 24weeks 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 or 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 previous 12 weeks before 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, cardiovascular disease (angina, myocardial infarction, transient ischemic attack, stroke); participants with controlled blood pressure are eligible
Personal history of clinical autoimmune disease or reactive arthritis or family history of rheumatoid arthritis (parents or siblings)
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 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
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
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
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

Sites / Locations

CHUV
Chelsea & Westminster Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Arm Label

Injection only: Active:placebo (3:1)

Infusion only: Active:placebo (3:1)

Injection and Infusion: Active:placebo (3:1)

Placebo

Arm Description

GTU-MultiHIV B-clade + MVA HIV-B: GTU-MultiHIV B-clade - 2 mg of DNA in 1ml encoding a multi HIV antigen (synthetic fusion protein) administered intramuscularly into the non-dominant deltoid muscle at weeks 0 and 4 and MVA HIV-B 0.5ml(1 x108 pfu/ml) MVA encoding the full-length codon-optimized sequence of Gag administered intramuscularly into the non-dominant deltoid muscle at week 12.

Vedolizumab will be administered in the participant's dominant arm as an intravenous infusion over 30 mins.

GTU-MultiHIV B-clade + MVA HIV-B + Vedolizumab

Placebo1 for DNA: Sodium chloride for injection, 0.9% in 1ml administered intramuscularly into the non-dominant deltoid muscle at weeks 0 and 4. Placebo 2 for MVA: S08 buffer in 0.5ml administered intramuscularly into the non-dominant deltoid muscle at week 12. Placebo for mAb: Sodium Chloride (NaCl) for infusion, 0.9% in 250 ml infusion bags.

Outcomes

Primary Outcome Measures

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.

Safety: A clinical decision to discontinue the regimen for an adverse event that is considered related to product

Secondary Outcome Measures

Grade 3 and worse solicited clinical and laboratory adverse events

Any event leading to interruption in the vaccine schedule

Any event that results in resuming treatment during the ATI

Serious Adverse Events

Other clinical and laboratory adverse events

Time to VL suppression after restarting ART

Full Information

NCT ID

NCT02972450

First Posted

November 10, 2016

Last Updated

August 27, 2019

Sponsor

ANRS, Emerging Infectious Diseases

Collaborators

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 Malattie Infettive Lazaro Spallanzani, Universitätsklinikum Hamburg-Eppendorf, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Henri Mondor University Hospital, European Georges Pompidou Hospital, Saint-Louis Hospital, Paris, France

1. Study Identification

Unique Protocol Identification Number

NCT02972450

Brief Title

An HIV Vaccine Trial in Individuals Who Started ART During Primary or Chronic Infection

Acronym

EHVAT01

Official Title

A Phase I/II Randomised Therapeutic HIV Vaccine Trial in Individuals Who Started Antiretrovirals During Primary or Chronic Infection

Study Type

Interventional

2. Study Status

Record Verification Date

August 2019

Overall Recruitment Status

Terminated

Why Stopped

Due to the bankruptcy of FITBiotech, the provider of the GTU DNA vaccine.

Study Start Date

February 20, 2019 (Actual)

Primary Completion Date

July 11, 2019 (Actual)

Study Completion Date

July 11, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

ANRS, Emerging Infectious Diseases

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV-1-infection

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

1 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Injection only: Active:placebo (3:1)

Arm Type

Experimental

Arm Description

Arm Title

Infusion only: Active:placebo (3:1)

Arm Type

Experimental

Arm Description

Vedolizumab will be administered in the participant's dominant arm as an intravenous infusion over 30 mins.

Arm Title

Injection and Infusion: Active:placebo (3:1)

Arm Type

Experimental

Arm Description

GTU-MultiHIV B-clade + MVA HIV-B + Vedolizumab

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Biological

Intervention Name(s)

GTU-MultiHIV B-clade vaccine + MVA HIV-B HIV vaccine

Intervention Description

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.

Intervention Type

Biological

Intervention Name(s)

GTU-MultiHIV B-clade vaccine + MVA HIV-B HIV vaccine+ Vedolizumab

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Vedolizumab 300 MG [Entyvio]

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

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.

Primary Outcome Measure Information:

Title

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 Frame

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.

Title

Safety: A clinical decision to discontinue the regimen for an adverse event that is considered related to product

Time Frame

From randomisation

Secondary Outcome Measure Information:

Title

Grade 3 and worse solicited clinical and laboratory adverse events

Time Frame

From randomisation to study completion, about 60 weeks.

Title

Any event leading to interruption in the vaccine schedule

Time Frame

From randomisation to study completion, about 60 weeks.

Title

Any event that results in resuming treatment during the ATI

Time Frame

From randomisation to study completion, about 60 weeks.

Title

Serious Adverse Events

Time Frame

From randomisation to 30 days after the last protocol visit

Title

Other clinical and laboratory adverse events

Time Frame

From randomisation to study completion, about 60 weeks.

Title

Time to VL suppression after restarting ART

Time Frame

From randomisation to VL suppression after restarting ART

Other Pre-specified Outcome Measures:

Title

Secondary Immunological Outcomes

Description

Response rate, magnitude and polyfunctionality of vaccine induced CD4 and CD8 T-cell responses.

Time Frame

From randomisation

Title

Secondary Virological efficacy outcome measures

Description

Level of HIV total DNA and Cell Associated (CA) HIV RNA Quantification

Time Frame

From randomisation

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

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 24weeks 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 or 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 previous 12 weeks before 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, cardiovascular disease (angina, myocardial infarction, transient ischemic attack, stroke); participants with controlled blood pressure are eligible Personal history of clinical autoimmune disease or reactive arthritis or family history of rheumatoid arthritis (parents or siblings) 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 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 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 (see Appendix 4 for definitions). Hyperbilirubinaemia to be considered an exclusion criterion only when confirmed to be conjugated bilirubinaemia

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Yves Levy, MD

Organizational Affiliation

Institut National de la Santé Et de la Recherche Médicale, France

Official's Role

Study Director

Facility Information:

Facility Name

CHUV

City

Lausanne

ZIP/Postal Code

1011

Country

Switzerland

Facility Name

Chelsea & Westminster Hospital

City

London

ZIP/Postal Code

SW10 9NH

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

An HIV Vaccine Trial in Individuals Who Started ART During Primary or Chronic Infection

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