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 | 1,800 | 100 | 300 |
| Total Cohort | 2,600 | 23,400 | 300 | 900 |
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.
