A Phase 3, randomized, double-blind, placebo-controlled, multicenter, clinical trial to assess the prophylactic efficacy, safety, and immunogenicity of the investigational M72/AS01E-4 Mycobacterium tuberculosis (Mtb) vaccine when administered intramuscularly on a 0,1-month schedule to adolescents and adults
Sponsor: Bill & Melinda Gates Medical Research Institute (Gates MRI)
Purpose and Rationale: In the previously completed Phase 2b trial, the investigational M72/AS01E-4 Mtb vaccine conferred approximately 50% protection at 36 months (49.7%: 95% confidence interval [CI]: 2.1–74.2) against developing laboratory-confirmed pulmonary tuberculosis disease (TB) when administered to adults who were interferon gamma release assay (IGRA)-positive, and human immunodeficiency virus (HIV)-negative.
This Phase 3 trial is designed to confirm the previously observed efficacy in IGRA-positive, HIV-negative people, as well as to generate safety and immunogenicity data in IGRA-positive and negative adolescents and adults, including people living with HIV (PLHIV).
Overall Design:
- Disclosure Statement: This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, clinical trial to assess the prophylactic efficacy, safety, and immunogenicity of the investigational M72/AS01E-4 Mtb vaccine when administered intramuscularly on a 0,1- month schedule to adolescents and adults (15 to 44 years of age).
- Trial Intervention: The trial will include 2 groups (M72/AS01E-4 group and placebo group). Participants will receive 2 doses of either M72/AS01E-4 or placebo based on randomization, administered intramuscularly (IM) in the deltoid muscle, preferably in the nondominant arm, given approximately one month apart.
- M72/AS01E-4: A 0.5 mL dose of M72/AS01E-4 contains 10μg M72, reconstituted with AS01E- 4, a GlaxoSmithKline (GSK) proprietary adjuvant system containing 25 μg MPL (3-O- desacyl-4-monophosphoryl lipid A, produced by GSK), and 25 μg QS-21 (Quillaja saponaria Molina, fraction 21).
- Placebo: A 0.5 mL dose contains 0.5 mL normal saline (0.9% NaCl).Blinding: Data will be collected in an observer-blind manner. The observer-blind methodology is a way to maintain a double-blind study when the treatments differ in appearance. To achieve this, the vaccine and placebo will be prepared by an unblinded pharmacist, who will not participate in data collection, evaluation, review, or the entry of any trial endpoint (i.e., reactogenicity, safety, and efficacy). The pharmacist will mask the syringe prior to sending it to the blinded trial intervention administrator, who will administer the investigational product. The laboratories responsible for sample testing will be blinded to the trial intervention assignment. Codes will be used to link the participant to their samples (without any link to the intervention received).
Number of participants: Approximately 26,000
Trial Cohorts (for enrollment and analyses):
| Cohorts | Approximate number of participants per cohort | Approximate number of participants in Immunogenicity Sub-Cohort | ||
|---|---|---|---|---|
| 15-17 years | 18-44 years | 15-17 years | 18-44 years | |
| IGRA-Positive Cohort | 2,000 | 18,000 | 100 | 300 |
| IGRA-Negative Cohort | 400 | 3,600 | 100 | 300 |
| HIV Cohort | 200 | 18,000 | 100 | 300 |
| Total Cohort | 2,600 | 23,400 | 300 | 900 |
IGRA-Positive Cohort: Approximately 20,000 participants who are IGRA-positive and HIV-negative at screening
IGRA-Negative Cohort: Approximately 4,000 participants who are IGRA-negative and HIV-negative at screening
HIV Cohort: Approximately 2,000 virally-suppressed, antiretroviral-treated participants with well-controlled HIV who fulfill the following criteria at screening:
- have reactive anti-HIV antibody
- are on antiretroviral therapy (ART) for at least 3 consecutive months
- have documented HIV RNA <200 copies/mL
- have CD4+ cell counts ≥200 cells/μL
- had TB preventive therapy (TPT) in the past and are not currently receiving TPT, based on investigator assessment are IGRA-positive or negative.
Participants in the HIV Cohort will be enrolled from selected sites that, at a minimum, are confirmed to have an acceptable transit time (1) from sample collection to a sample processing facility, and (2) from the processing facility to the central laboratory where HIV- related laboratory specimens are tested.
Total Cohort: Approximately 26,000 (20,000 in IGRA-Positive Cohort, 4,000 in IGRA- Negative Cohort and 2,000 in HIV Cohort)
Sub-Cohorts include:
Immunogenicity Sub-Cohort: Approximately 1,200: 400 in IGRA-Positive Cohort, 400 in IGRA-Negative Cohort and 400 in HIV Cohort. Participants in the Immunogenicity Sub-Cohort will be enrolled from selected sites that, at a minimum, are confirmed to have access to a peripheral blood mononuclear cell (PBMC) processing facility that meets Sponsor’s quality requirements, and to have an acceptable transit time from sample collection to a PBMC processing facility.
Correlates of Protection (CoP) and Correlates of Risk (CoR) Sub-Cohort: Approximately 10,000 participants in IGRA-Positive Cohort. Participants in this Sub-Cohort will be enrolled only from South Africa.
Randomization: Participants in each of the cohorts (IGRA-positive, IGRA-negative, and HIV) will be randomized 1:1 to receive M72/AS01E-4 or placebo, stratified by site, age group, and sex. The participants in the HIV Cohort will also be stratified by IGRA status.
| Primary Objective | Primary Endpoint |
|---|---|
| Primary Efficacy Objective: To evaluate the vaccine efficacy (VE) of M72/AS01E-4 in the prevention of laboratory-confirmed pulmonary TB among IGRA- positive participants without HIV infection (IGRA-Positive Cohort) in the per-protocol (PP) analysis set |
Primary Efficacy Endpoint: Laboratory-confirmed pulmonary TB over a period starting 1 month post Dose 2 and lasting up to End of Trial (EoT) where a laboratory-confirmed pulmonary TB case is defined as a participant with:
who has
|
| Secondary Objectives | Secondary Endpoints |
| Secondary Efficacy Objectives | Secondary Efficacy Endpoints |
| To evaluate the VE of M72/AS01E-4 in the prevention of Mtb infection among the IGRA-Negative Cohort in the PP analysis set |
Sustained QuantiFERON®-TB Gold Plus assay (or similar) conversion (i.e., initial conversion and IGRA-positive test result at next attended scheduled visit) over a period starting 1 month post dose 2 and lasting up to EoT |
| To evaluate the VE of M72/AS01E-4 in the prevention of laboratory- confirmed pulmonary TB among the IGRA-Negative Cohort in the PP analysis set |
Laboratory-confirmed pulmonary TB over a period starting 1 month post Dose 2 and lasting up to EoT, where a laboratory- confirmed pulmonary TB case follows the same definition as the primary endpoint |
| To evaluate the VE of M72/AS01E-4 in the prevention of laboratory- confirmed pulmonary TB among the HIV Cohort in the PP analysis set |
Laboratory-confirmed pulmonary TB over a period starting 1 month post Dose 2 and lasting up to EoT, where a laboratory- confirmed pulmonary TB case follows the same definition as the primary endpoint |
| To evaluate the VE of M72/AS01E-4 in the prevention of less stringently defined laboratory-confirmed pulmonary TB among the IGRA- Positive Cohort in the PP analysis set |
Laboratory-confirmed pulmonary TB over a period starting 1 month post Dose 2 and lasting up to EoT, where a laboratory- confirmed pulmonary TB case is defined less stringently as a participant with:
|
| Secondary Safety Objective | Secondary Safety Endpoints |
| To evaluate the safety and reactogenicity following administration of M72/AS01E-4 vaccine or placebo |
|
| Secondary Immunogenicity Objective | Secondary Immunogenicity Endpoint |
| To assess the humoral immunogenicity of M72/AS01E-4 vaccination | Geometric mean concentration (GMC) and seropositivity of M72-specific antibodies at Day 1, Month 1, Month 2, Month 7, Month 13, Month 37, and Month 61 (or EoT) among each of the IGRA-Positive Cohort, IGRA-Negative Cohort, and HIV Cohorts in the per-protocol for immunogenicity (PPI) analyses set |
j Any medical conditions that may lead to exclusion from any PP/PPI analysis set will be recorded through the EoT Visit (refer to Section 8.11.1 and Section 8.11.2).
k Selected medications (refer to Section 6.4) will be recorded through the EoT Visit.
l Blood samples for M72 specific immunogenicity responses (humoral and cellular immunogenicity) will be collected from participants in the Immunogenicity Sub-Cohort.
m Correlates of Protection (CoP) and Correlates of Risk (CoR): blood samples will be collected from participants in the CoP/CoR Sub-Cohort for the identification of CoP and CoR, including PBMC, plasma, and RNA for transcriptomics, as feasible. If a participant in this Sub-Cohort requires a suspected TB visit, the blood sample for transcriptomics will be taken on the first of the 3 visits.
| Exploratory Objectives |
|---|
| To further explore the VE of M72/AS01E-4 in the prevention of laboratory-confirmed pulmonary TB as defined for the primary endpoint, among the IGRA-Positive Cohort in the mITT analysis set |
| To explore the effect of potential covariates on the VE of M72/AS01E-4 in the prevention of laboratory-confirmed pulmonary TB as defined for the primary endpoint, among the IGRA-Positive Cohort in the PP analysis set |
| To explore the VE of M72/AS01E-4 in the prevention of laboratory-confirmed pulmonary TB, where sputum was collected up to 28 days after treatment initiation among IGRA-positive, IGRA-negative, and HIV Cohorts, respectively, in the mITT analysis set. |
| To explore the VE of M72/AS01E-4 in the prevention of clinical TB (including extrapulmonary TB) defined as a participant for whom a clinician has diagnosed TB, and has initiated TB treatment, in the absence of laboratory-confirmed pulmonary TB, among IGRA-positive, IGRA-negative, and HIV Cohorts, respectively, in the mITT analysis set. |
| To explore the VE of M72/AS01E-4 in the prevention of subclinical TB, defined as a participant with a positive result from Xpert Ultra or similar assay (excluding “trace positive”) from a single sputum sample at the EoT visit, in the absence of signs or symptoms of pulmonary TB, among IGRA-positive, IGRA-negative, and HIV Cohorts, respectively, in the mITT analysis set. |
| To assess the cellular immunogenicity of M72/AS01E-4 vaccination using M72-specific CD4+ and CD8+ T-cell responses measured by co-expression of 2 or more cytokines using intracellular cytokine staining (ICS) |
| To further explore the cellular immunogenicity of M72/AS01E-4 vaccination using M72-specific CD4+ and CD8+ T-cell responses measured by co-expression of multiple functional markers by ICS |
| To confirm candidate CoP and CoR if identified in the M72 Immune Correlates Program and to explore new candidate CoP and CoR |
| To explore characteristics of Mtb isolates, including drug susceptibility profiles and genetic diversity |
