Clinical trial NCT04066881: A Combination Efficacy Study in Africa of Two DNA-MVA-Env Protein or DNA-Env Protein HIV-1 Vaccine Regimens With PrEP
Official title: A Phase IIb Three-arm, Two-stage HIV Prophylactic Vaccine Trial With a Second Randomisation to Compare TAF/FTC to TDF/FTC as Pre-exposure Prophylaxis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: HIV
Vaccine
Pre-exposure prophylaxis
Africa
Lead sponsor: MRC/UVRI and LSHTM Uganda Research Unit
Sponsor class: OTHER
Collaborators: name: Imperial College London
name: University College, London
name: International AIDS Vaccine Initiative
name: EuroVacc Foundation
name: Medical Research Council, South Africa
name: National Institute for Medical Research, Tanzania
name: Muhimbili University of Health and Allied Sciences
name: Instituto Nacional de Saúde, Mozambique
name: Ludwig-Maximilians - University of Munich
name: King's College London
name: Centre Hospitalier Universitaire Vaudois
name: Karolinska Institutet
name: CONRAD
name: Gilead Sciences
First posted: 2019-08-26
Enrollment: 1512
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Group A: DNA-HIV-PT123/AIDSVAX B/E®/TDF/FTC (Truvada) once daily (wks 0-26) Group B: DNA-HIV-PT123 and CN54gp140+MPLA-L (wks 0,4), then MVA-CMDR and CN54gp140+MPLA-L/ TDF/FTC(Truvada) once daily (wks 0-26) Group C: Saline placebo (wks 0,4,24,48)/ TDF/FTC (Truvada) once daily (wks 0-26) Group D: DNA-HIV-PT123/AIDSVAX B/E®/ TAF/FTC (Descovy) once daily (wks 0-26) Group E: DNA-HIV-PT123 and CN54gp140+MPLA-L (wks 0,4), then MVA-CMDR and CN54gp140+MPLA-L/ TAF/FTC (Descovy) once daily (wks 0-26) Group F: Saline placebo (wks 0,4,24,48)/ TAF/FTC (Descovy) once daily (wks 0-26)

Group G: Saline placebo (wks 0,4,24,48)/ TAF/FTC (Descovy) once daily (wks 0-26)
Primary purpose: PREVENTION

Brief summary: This international, multi-centre, double-blind vaccine study is a three-arm prospective 1:1:1 randomisation comparing each of two experimental combination vaccine regimens i.e. DNA/AIDSVAX (weeks 0,4,24,48) and DNA/CN54gp140 (weeks 0,4) + MVA/CN54gp140 (weeks 24,48) with placebo control. There will be a concurrent open-label 1:1 randomisation to compare daily TAF/FTC (week 0-26) to daily TDF/FTC (weeks 0-26) as pre-exposure prophylaxis.

The study aims to randomise up to 1668 eligible adults (18-40 years) through collaborating clinical research centres in 4 countries (Mozambique; South Africa; Tanzania; and Uganda). Each participant will be followed for a minimum of 74 weeks after enrolment.

The trial is designed to detect a reduction in HIV incidence that has public health relevance sufficient to justify implementation of the combination vaccine regimen. In light of the high level of effectiveness demonstrated in the PrEP trials (up to 86% reduction in HIV), this trial is powered to detect a protective vaccine efficacy of 70% at the final analysis.

The PrEP component will determine whether the effectiveness of TAF/FTC is unacceptably lower than the effectiveness of TDF/FTC.

Detailed description: This international, multi-centre, double-blind vaccine study will be a three-arm prospective 1:1:1 randomisation comparing each of two experimental combination vaccine regimens with placebo control.

Pre-screening for risk and HIV status will take place as part of a Registration Cohort which will precede and continue in parallel to the PrEPVacc trial enrolments. This will give HIV negative volunteers time to learn about the PrEPVacc trial and facilitate timely enrolment.

Clinical screening for the vaccine trial will take place during the 8 weeks prior to randomisation from local communities in Mozambique, South Africa, Tanzania and Uganda where the clinical research centres are located. Eligible participants who are HIV-uninfected adults aged 18-40 years at high risk of HIV infection will be enrolled at week 0 and randomised to one of three vaccine arms:

1. Vaccine group A: DNA-HIV-PT123 and AIDSVAX® B/E (weeks 0,4,24,48)
2. Vaccine group B: DNA-HIV-PT123 and CN54gp140 in MPLA-L (wks 0,4), then MVA-CMDR and CN54gp140 in MPLA-L (wks 24,48)
3. Vaccine group C: Saline Placebo (wks 0,4,24,48)

There will be a concurrent open-label 1:1 randomisation to one of two PrEP regimens:

1. Control PrEP: Daily TDF/FTC (week 0-26)
2. Experimental PrEP: Daily TAF/FTC (week 0-26)

Participants will be randomised at each clinical centre through web randomisation after entering the quantifiable eligibility criteria. Randomisation will be stratified by centre and by gender for vaccines and for PrEP. Clinic staff and participants will be blind to allocation of active or placebo vaccines, but the pharmacist preparing the vaccines will know. As the volume of gp140 in MPLA-L is 0.4ml and given at the same timepoints as products with a volume of 1ml, clinic staff will be able to identify participants allocated to the CN54gp140 in MPLA-L or matched placebo.

Clinic staff and participants will know which PrEP agent each participant is allocated to. Participants will continue to receive study PrEP through to week 26 after which access to PrEP will revert to local supply of generic drug.

The target accrual is around 1668 HIV uninfected adults, but this is an endpoint driven multi-arm, multi-stage (MAMS) trial design, and therefore the target may be adjusted following a recommendation from the IDMC. In addition, participants who do not complete the third immunisation will be replaced whilst this is feasible. Participants will be followed up for a minimum of 74 weeks after enrolment.

The primary efficacy outcome measure for the vaccine analysis is HIV acquisition by a participant who completed three immunisations and was HIV negative at week 26.

The primary efficacy outcome for the PrEP analysis is HIV acquisition at or before week 26 by a participant who was HIV negative at enrolment.

The primary safety outcome for both analyses is a clinical decision to discontinue the vaccine or PrEP regimen for an adverse event that is considered related to product.

This trial is designed to detect a reduction in HIV incidence that has public health relevance sufficient to justify implementation of the combination vaccine regimen. In light of the high level of effectiveness demonstrated in the PrEP trials (up to 86% reduction in HIV), this trial is powered to detect a protective vaccine efficacy of 70% at the final analysis.

The PrEP component of the trial aims to show the effectiveness of TAF/FTC is not unacceptably lower than the effectiveness of TDF/FTC, assessed from the observed lower confidence limit for the Averted Infections Ratio (AIR).

The Independent Data Monitoring Committee will review an interim analysis of vaccine efficacy in order to determine whether each active vaccine arm has demonstrated sufficient efficacy to warrant further investigation. This analysis will only consider new infections arising after the week 26 visit and only those in individuals who have completed the first three immunisations. The analysis will take place after approximately 7 of these infections have occurred in the placebo group. The investigators will not be informed of the timing of the interim analysis, unless there is a recommendation to modify the protocol.

The PrEP analysis will consider new infections up to the week 26 visit in individuals who were HIV negative at enrolment.

To enhance understanding of the trial results within their broader context, indepth interviews and group discussions with trial participants, as well as structured debriefs with study staff, will be conducted throughout the trial (week 0-74). These activities will examine risk and adherenvce behaviours, along with knowledge, attitudes and perceptions of participants, study staff and wider community.

Eligibility criteria: Inclusion criteria

1. HIV uninfected adults aged between 18 and 40 years old on the day of screening
2. Willing and able to provide informed consent prior to participation
3. Willing and able to comply with the visit schedule and provide blood, urine and other samples at the required time points
4. Home address accessible for visiting and intending to remain within the recruitment area for at least 82 weeks from screening
5. Likely to be at risk from exposure to HIV during follow up
6. Willing to undergo HIV testing, receive HIV test results and risk reduction counselling which includes promotion of PrEP and condoms
7. If female, of child-bearing age and not sterilised, willing to use a highly effective method of contraception from screening until 18 weeks after the last injection
8. If male and not sterilised, willing to avoid impregnating female partners from screening until 18 weeks after the last injection

Exclusion criteria

1. HIV infection or indeterminate HIV result at screening or enrolment
2. Hepatitis B surface antigen positive
3. If female, currently pregnant (evidence from positive serum or urine pregnancy test), or lactating
4. Participating in another biomedical research study or in receipt of a live vaccine within 30 days prior to randomisation
5. Participation in a previous HIV vaccine or HIV immunotherapy trial
6. Receiving blood products or immunoglobulins within 12 weeks of screening
7. Known hypersensitivity to any component of the vaccine formulations used in this trial or history of severe or multiple allergies to vaccines, drugs or pharmaceutical agents
8. Presence of a systemic disease at the time of randomisation or history of chronic illness that in the opinion of the investigator may compromise the participant's safety, preclude vaccination or compromise an immune response to vaccine
9. Abnormalities in routine laboratory parameters (Hb, creatinine, AST/ALT, alkaline phosphatase, total Bilirubin and glucose) of Grade 2 and above using the DAIDS toxicity table, version 2.1 July 2017 or estimated glomerular filtration rate less than 50ml/min

Primary outcomes:
measure: Incident HIV infection
timeFrame: after week 26
measure: Incident HIV infection
timeFrame: week 0-26
measure: A clinical decision to discontinue the vaccine regimen for an adverse event that is considered related to product
timeFrame: week 0-48
measure: A clinical decision to discontinue PrEP regimen for an adverse event that is considered related to product
timeFrame: week 0-26
Secondary outcomes:
measure: Grade 3 and worse solicited clinical and laboratory adverse events
timeFrame: week 0-74
measure: Discontinuation or interruption of vaccine regimen
timeFrame: week 0-74
measure: Discontinuation or interruption of PrEP
timeFrame: week 0-26
measure: Grade 3 and worse solicited clinical and laboratory adverse events
timeFrame: within 7 days of receiving vaccine injection
measure: Serious adverse events
timeFrame: week 0-74
measure: Other clinical and laboratory adverse events
timeFrame: week 0-74
measure: Binding antibodies
timeFrame: week 0-74
measure: Resistance mutations to tenofovir and emtricitabine
timeFrame: week 0-74
measure: Number of PrEP pills missed
timeFrame: week 0-26
measure: Tenofovir level in urine
timeFrame: week 0-26
measure: Tenofovir level in red blood cells
timeFrame: week 0-26
measure: Number of PrEP Pills dispensed
timeFrame: week 0-26
Other outcomes:
Locations:
city: Entebbe
country: Uganda
facility: MRC/UVRI and LSHTM Uganda Research Unit
Study officials:
affiliation: MRC/UVRI and LSHTM Uganda Resae
name: Pontiano Kaleebu, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: MRC CTU at UCL
name: Sheena McCormack, MSc
role: STUDY_CHAIR
affiliation: Imperial College London
name: Jonathan Weber, PhD
role: STUDY_DIRECTOR
References:
citation: Chimukuche RS, Kawuma R, Mahapa N, Mkhwanazi S, Singh N, Siva S, Ruzagira E, Seeley J; PrEPVacc Study Group. Examining oral pre-exposure prophylaxis (PrEP) literacy among participants in an HIV vaccine trial preparedness cohort study. BMC Health Serv Res. 2022 Nov 10;22(1):1336. doi: 10.1186/s12913-022-08730-8.