Protocol No: ECCT/24/06/01 Date of Protocol: 08-01-2024

Study Title:

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.

Study Objectives:
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

Secondary Efficacy Objectives:

  • To evaluate the VE of M72/AS01E-4 in the prevention of Mtb infection among the IGRA-Negative Cohort in the PP analysis set
  • 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
  • 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
  • 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

Secondary Safety Objective:

  • To evaluate the safety and reactogenicity following administration of M72/AS01E-4 vaccine or placebo

Secondary Immunogenicity Objective:

  • To assess the humoral immunogenicity of M72/AS01E-4 vaccination

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
Laymans Summary:

Tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (Mtb); it typically affects the lungs but can also affect other sites. TB is spread from person to person via the respiratory route and is manifested by the presence of Mtb in sputum. TB is the second leading infectious killer after COVID-19 (above HIV/AIDS). It is present in all countries and age groups, but the larger number of new cases occur in countries of the South-East Asian Region and African Region.

Bacille Calmette-Guérin, known as BCG, is the only licensed TB vaccine to date; however, the impact of BCG on the transmission of Mtb in adults is limited, since it offers minimal or no protection against pulmonary TB in adults. TB treatment is lengthy, and compliance is often incomplete, resulting in an increasing incidence of multi-drug resistant (MDR)-TB and extensively drug resistant (XDR)-TB.

Given the substantial morbidity and mortality associated with TB, the challenges associated with TB treatment, and the limited options for prevention, a vaccine is urgently needed, both to protect against disease, including the progression from latent Mtb infection to active TB, and to accelerate the end of the TB epidemic.

 

 

Abstract of Study:

Modeling suggests that the most effective contribution to TB control in high burden countries would be a vaccine that prevents pulmonary TB in adolescents and adults [WHO2021]. In very high incidence geographies, the incidence rate of TB is highest in older adolescents and young adults (e.g., 15 to 44 years of age). In addition, pulmonary TB is the predominant form of TB in this age group (with the primary mode of TB transmission being via aerosol), and young adults are more likely to transmit to more contacts because they are active and mix extensively [Knight2014].

The primary objective of this Phase 3 efficacy trial is to evaluate VE in the prevention of laboratory-confirmed pulmonary TB in IGRA-positive participants who do not have HIV. The rationale for focusing on IGRA-positive participants is based on Phase 3 trial simulations that evaluated the feasibility of demonstrating VE in an “all-comer” population (i.e., regardless of IGRA status) of young adults (15 to 44 years of age) in very high burden settings with an IGRA-positive prevalence of 67%. Based on these simulations, it appears feasible to demonstrate vaccine efficacy against tuberculosis disease (VE[D]) in an IGRA-positive, HIV-negative population, with a sample size of 9,000 participants per arm, within 4 years from start of enrollment, whereas a trial in an all-comer population would have to be much larger, and the larger population would still be inadequate to demonstrate VE(D) in IGRA-negative participants.

Trial simulation assumptions included an annual IGRA conversion rate of 3% per person-year, and an incidence of active pulmonary TB of 0.4% per person-year. These simulations suggested that even with a 67% IGRA-positive prevalence at enrollment, more than 90% of laboratory-confirmed cases of TB would be observed in IGRA-positive participants, and less than 10% in IGRA-negative participants; such a trial would not be powered to demonstrate VE(D) in IGRA-negative participants as a subset.

A confirmatory trial in IGRA-negative participants is not considered feasible (in a reasonable amount of time and with a reasonable population size), given the low rate of laboratory-confirmed cases expected in baseline IGRA-negative participants. Given the inability to demonstrate VE(D) in IGRA-negative participants as a subset in an ‘all-comer’ trial, this Phase 3 trial aims to demonstrate VE(D) in IGRA-positive participants only, and to generate descriptive safety, immunogenicity, and VE(D) data in a HIV-negative, IGRA-negative Cohort  (N=1,000) and in a cohort of PLHIV (N=1,000) of either positive or negative IGRA status.

GlaxoSmithKline Biologicals, SA (GSK) developed M72/AS01E-4, an investigational TB vaccine, to protect against the development of TB in Mtb-infected adolescents and adults. The GSK Phase 2b trial (TB-018) evaluated vaccine safety and efficacy in approximately 3500 IGRA-positive adults (1:1, M72/AS01E-4 and placebo) [Van Der Meeren2018; Tait2019]. Most participants in the TB-018 trial had previously received the BCG vaccine as neonates. The observed VE against active pulmonary TB in the Phase 2b trial was 49.7% (95% CI: 2.1% to 74.2%) at 36 months and no safety signals that would prevent further development were observed [Tait2019].

In 2020, the Bill & Melinda Gates Medical Research Institute (Gates MRI) licensed the M72/AS01E-4 investigational TB vaccine for continued development.