Protocol No: ECCT/24/12/02 Date of Protocol: 14-08-2024

Study Title:
IAVI C113: A Phase 2b, double-blind, randomized, placebo-controlled study to evaluate the efficacy, safety and immunogenicity of a candidate tuberculosis (TB) vaccine, MTBVAC, against TB disease in interferon gamma release assay positive adolescents and adults aged 14-45 years, living in a TB endemic region.
Study Objectives:
  • Primary Objective: Efficacy: To evaluate the protective efficacy of one dose of MTBVAC against bacteriologically confirmed pulmonary TB disease, not associated with HIV infection, diagnosed by more than one diagnostic test with sputum obtained before initiation of TB treatment, as compared to placebo.
    • Primary Endpoint: Efficacy: Incident cases of definite pulmonary TB disease in participants with clinical suspicion of pulmonary TB disease, with M.tb identified by at least two positive diagnostic tests (microbiological culture, Xpert MTB/RIF Ultra, or both) from sputum specimens taken before initiation of TB treatment and confirmed HIV-negative at the time of TB diagnosis, over a period starting 28 days following vaccination and lasting up to 36 months post vaccination. 
  • Secondary Objectives:
    • Efficacy:
  1. To evaluate the protective efficacy of one dose of MTBVAC against bacteriologically confirmed pulmonary TB disease, not associated with HIV infection, diagnosed with sputum obtained before initiation of TB treatment, as compared to placebo.
  2. To evaluate the protective efficacy of one dose of MTBVAC against definite Xpert MTB/RIF Ultra positive pulmonary TB disease not associated with HIV infection, diagnosed with sputum obtained before initiation of TB treatment, as compared to placebo.
  3. To evaluate the protective efficacy of one dose of MTBVAC against clinical TB, as compared to placebo.
  • Safety: To assess the safety and reactogenicity of one dose of MTBVAC.

Cellular Immunogenicity: To assess the immunogenicity of one dose of MTBVAC via assessment of cell-mediated immune (CMI) responses in a subset of the enrolled participants.

Secondary Endpoints:

Efficacy:

  1. Incident cases of definite pulmonary TB disease in participants with clinical suspicion of pulmonary TB disease, with M.tb identified by microbiological culture and/or Xpert MTB/RIF Ultra from sputum specimens taken before initiation of TB treatment and confirmed HIV negative at the time of TB diagnosis, over a period starting 28 days following vaccination and lasting up to 36 months post vaccination.
  2. Incident cases of definite pulmonary TB disease in participants with clinical suspicion of pulmonary TB disease, with M.tb identified by Xpert MTB/RIF Ultra from sputum specimens taken before initiation of TB treatment and confirmed HIV-negative at the time of TB diagnosis, over a period starting 28 days following vaccination and lasting up to 36 months post last vaccination.
  3. Incident cases of clinical TB disease diagnosed by a clinician who has decided to treat the patient with TB treatment, over a period starting 28 days following vaccination and lasting up to 36 months post last vaccination.

Safety:

  1. The proportion of participants with SAEs until Month 6 following vaccination.
  2. The proportion of participants with vaccine related SAEs during the entire study period.
  3. The proportion of participants with solicited injection site reactions and solicited systemic AEs in the safety sub-cohort for 14 days following vaccination (day of vaccination and 14 subsequent days).
  4. The proportion of participants with unsolicited AEs for 28 days following vaccination (day of vaccination and 28 subsequent days).
  5. The proportion of participants with unsolicited injection site reactions during the 84 days following vaccination (day of vaccination and 84 subsequent days).
  6. Proportion of participants with grade 3 or higher injection site reactions during the 84 days following vaccination (day of vaccination and 84 subsequent days).
  7. Proportion of participants with grade 2 or higher haematological and chemistry laboratory AEs, in the safety sub- cohort.
  8. The proportion of participants with AESIs until month 6 following vaccination

Cellular Immunogenicity:

  1. Evaluation of CMI responses with respect to components of the study vaccine, in the immunogenicity sub-cohort at Day 1 (prior to vaccination), Day 29, Month 12, Month 24 and Month 36 (if applicable).

Exploratory Objectives:

Subclinical TB: To evaluate the impact of MTBVAC on the incidence of subclinical TB developing in this cohort.

Humoral Immunogenicity: To assess the immunogenicity of one dose of MTBVAC via assessment of humoral immune responses in a subset of the enrolled participants. (Immunogenicity sub-cohort only.)

Correlates of Immune Protection: To evaluate potential biological markers correlated to the risk for TB and to evaluate immune correlates of protection from TB in participants vaccinated with MTBVAC.

 

Exploratory Endpoints:

Subclinical TB: Bacteriologically confirmed M.tb infection in sputum samples obtained on Day 1 (prior to vaccination), Month 12, Month 24, and at end of study from trial participants without signs or symptoms of active pulmonary TB, and who consented to have their sputum collected for long term storage, for analysis after end of study.

Humoral Immunogenicity: Evaluation of humoral immune responses with respect to components of the study vaccine, in the immunogenicity sub-cohort at Day 1 (prior to vaccination), Day 29, Month 12, Month 24 and Month 36 (if applicable).

Correlates of Immune Protection: Blood samples collected from participants who consent for long term storage, on Day 1 (prior to vaccination), Day 3, Day 8, Day 29, Month 12, and at time of TB diagnosis.

 

Laymans Summary:

Tuberculosis (TB) is a major cause of death worldwide. Because TB is very harmful and there are difficulties in treating and preventing it, there is a strong need for a vaccine to protect people from getting sick with TB and to help stop the spread of the disease. MTBVAC is a weakened form of human tuberculosis bacteria. It has the same genes as the bacteria but with two genes removed to stop it from causing TB disease. A company called BIOFABRI, S.L.U. in Spain made and tested MTBVAC as a freeze-dried vaccine according to strict guidelines to comply with Good Manufacturing Practices (GMP).

This study aims to check how effective this vaccine is in preventing TB disease in the lungs in adolescents and adults living in areas where TB is common and who test positive M.tb infection TB and who are HIV negative. The study will also do further checks on whether it is safe to use the vaccine in humans and how their immune system will respond to the vaccine.

In this study, neither the participants nor the researchers will know who is receiving the actual treatment or an inactive treatment (placebo). It will include 4,300 healthy adults and adolescents who have tested positive for M.tb infection  with a specific immune response blood test known as Interferon-Gamma Release Assay (IGRA). People from various locations in South and Eastern Africa will be invited to take part, and those who meet the requirements will be randomly assigned to receive either a single dose of the vaccine called MTBVAC or a placebo on the first day of the study. Before getting the vaccine, participants will undergo tests up to 30 days in advance, and they will be monitored for a minimum of 24 months and a maximum of 36 months after receiving the vaccine.

MTBVAC has been found to be safe and effective in preventing pulmonary tuberculosis in both adult and newborn animals. It has been shown to be as safe as BCG but more effective in generating an immune response. This research supports the need for human trials to further evaluate its potential in preventing tuberculosis in areas where the disease is common. The study aims to provide initial evidence of MTBVAC's effectiveness in protecting against pulmonary tuberculosis among adolescent and adult humans.

 

Abstract of Study:

Worldwide, tuberculosis (TB) is one of the leading causes of death from a single infectious agent. Given the substantial morbidity and mortality associated with TB, challenges associated with TB treatment and limited options for prevention, a vaccine is urgently needed, to protect against the disease, including the progression from lMycobacterium Tuberculosis (M.tb) infection to active TB, and to accelerate the end of the TB epidemic.

MTBVAC is a live rationally attenuated derivative of a human M.tb isolate. It contains all the genes present in M.tb strains and two independent stable deletions in the virulence genes phoP and fadD26. The Spanish vaccine manufacturer BIOFABRI, S.L.U. has produced and characterized the live MTBVAC as a freeze-dried preparation in compliance with Good Manufacturing Practices following the European Pharmacopoeia monograph and the WHO Recommendations to Assure the Quality, Safety and Efficacy of BCG Vaccines.

MTBVAC has shown adequate attenuation and safety profile comparable to BCG, with superior immunogenicity and efficacy against pulmonary forms of TB in adult and newborn animal models supporting evaluation in human clinical trials. The study will serve as a “proof-of-concept" investigation, intended to obtain, for the first time, evidence of MTBVAC efficacy in preventing pulmonary TB disease in adolescents and adults living in TB endemic areas. Demonstration of safety and efficacy in this study will provide the basis for progression to a phase 3 licensure/registration study thus closing the gap towards new vaccine arsenals against tuberculosis disease among adolescents and adults.

The primary goal of this phase 2b study is to assess the efficacy of MTBVAC in preventing pulmonary TB disease in Interferon-Gamma Release Assay (IGRA) positive, Human Immunodeficiency Virus (HIV)-negative adolescents and adults living in areas endemic for TB. The study also will assess MTBVAC safety and immunogenicity.

The study is a double-blind, randomized, placebo-controlled, safety and efficacy study in 4,300 healthy adults with a positive IGRA test result. Participants will be enrolled by multiple Clinical Research Centres (CRCs) globally, and those meeting the enrolment criteria will be randomized in a 1:1 ratio to receive a single dose of MTBVAC or placebo administered intradermally on Study Day 1.

Participants will then be followed up for efficacy for a minimum of 24 months and a maximum of 36 months following vaccination via regular visits and contacts to screen for possible TB. The primary endpoint is  incident cases of definite pulmonary TB disease in participants with clinical suspicion of pulmonary TB disease, with M.tb identified by at least two positive diagnostic tests (microbiological culture, Xpert MTB/RIF Ultra, or both) from sputum specimens taken before initiation of TB treatment and confirmed HIV-negative at the time of TB diagnosis, over a period starting 28 days following vaccination and lasting up to 36 months post vaccination.

KEMRI Centre for Respiratory Diseases Research (CRDR) aims to enroll at least 287 participants. Victoria Biomedical Research Institute (VIBRI) plans to enroll up to 287 participants at the Clinical Research Centres (CRCs) located at Kisumu County Referral Hospital in Kisumu County and Rachuonyo County Hospital in Homabay County. Enrollment for the study is competitive and the site can enroll more.