Study to Assess Efficacy and Safety of M72/AS01E-4 Mycobacterium Tuberculosis (Mtb) Vaccine in Adolescents and Adults

• ClinicalTrials.gov Identifier: NCT06062238
• Recruitment Status: Recruiting
• First Posted: October 2, 2023
• Last Update Posted: May 15, 2024
• Sponsor: Bill & Melinda Gates Medical Research Institute
• Collaborators: Wellcome Trust; Bill and Melinda Gates Foundation
• Information provided by (Responsible Party): Bill & Melinda Gates Medical Research Institute

Tracking Information

• First Submitted Date: September 25, 2023
• First Posted Date: October 2, 2023
• Last Update Posted Date: May 15, 2024
• Actual Study Start Date: March 5, 2024
• Estimated Primary Completion Date: April 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 19, 2024)

IGRA-Positive Cohort: Number of participants with laboratory-confirmed pulmonary tuberculosis (TB) [ Time Frame: Up to Month 49 ]

Laboratory-confirmed pulmonary TB case is defined as a participant with suspected pulmonary TB presenting with one or more of the following signs or symptoms: unexplained cough, unintentional weight loss, hemoptysis, unexplained fever, night sweats, pleuritic chest pain; who has least 2 positive Mtb test results (positive Mtb culture and/or positive test result from Xpert Ultra or similar assay, excluding "trace positive"), from the same or from different sputum samples collected during the 3 suspected TB visits, preferably within a 7-day time frame, before initiation of TB treatment.

Original Primary Outcome Measures (submitted: September 25, 2023)

IGRA-Positive Cohort: Number of participants with laboratory-confirmed pulmonary tuberculosis (TB) [ Time Frame: Up to Month 61 ]

Laboratory-confirmed pulmonary TB case is defined as a participant with suspected pulmonary TB presenting with one or more of the following signs or symptoms: unexplained cough, unintentional weight loss, hemoptysis, unexplained fever, night sweats, pleuritic chest pain; who has at least 2 positive Mtb test results (positive Mtb culture and/or positive test result from Xpert Ultra or similar assay, excluding "trace positive"), for at least 1 of the 3 sputum samples collected at 3 different visits, preferably within a 7-day time frame, before initiation of TB treatment.

Current Secondary Outcome Measures (submitted: March 19, 2024)

• IGRA-Negative Cohort: Number of participants with sustained QuantiFERON®-TB Gold Plus assay conversion [ Time Frame: Up to Month 49 ]
• IGRA-Negative Cohort: Number of participants with laboratory-confirmed pulmonary TB [ Time Frame: Up to Month 49 ]
• HIV Cohort: Number of participants with laboratory-confirmed pulmonary TB [ Time Frame: Up to Month 49 ]
• IGRA-Positive Cohort: Number of participants with laboratory-confirmed pulmonary TB (Less stringent laboratory-confirmed pulmonary TB case definition) [ Time Frame: Up to Month 49 ]
  Laboratory-confirmed pulmonary TB case is defined as a participant with suspected pulmonary TB presenting with one or more of the following signs or symptoms: unexplained cough, unintentional weight loss, hemoptysis, unexplained fever, night sweats, pleuritic chest pain; who has at least 1 positive Mtb culture or at least 1 positive result from Xpert Ultra or similar assay (excluding "trace positive"), from the same or from different sputum samples collected during the 3 suspected TB visits, preferably within a 7-day time frame, before initiation of TB treatment. Compose
• All Cohorts: Number of participants with solicited adverse events (AEs) [ Time Frame: Up to 7 days ]
• All Cohorts: Number of participants with unsolicited AEs [ Time Frame: Up to 28 days ]
• All Cohorts: Number of participants with serious adverse events (SAEs) [ Time Frame: Up to Month 13 ]
• All Cohorts: Number of participants with potential immunemediated diseases (pIMDs) [ Time Frame: Up to Month 13 ]
• All Cohorts: Number of participants with SAEs related to trial participation [ Time Frame: Up to Month 49 ]
• All cohorts: Number of participants with geometric mean concentration (GMC) of M72-specific antibodies [ Time Frame: At Day 1, Month 1, Month 2, Month 7, Month 13, Month 37, and Month 49 ]
• All cohorts: Number of participants with seropositivity of M72-specific antibodies [ Time Frame: At Day 1, Month 1, Month 2, Month 7, Month 13, Month 37, and Month 49 ]

Original Secondary Outcome Measures (submitted: September 25, 2023)

• IGRA-Negative Cohort: Number of participants with sustained QuantiFERON®-TB Gold Plus assay conversion [ Time Frame: Up to Month 61 ]
• IGRA-Negative Cohort: Number of participants with laboratory-confirmed pulmonary TB [ Time Frame: Up to Month 61 ]
• HIV Cohort: Number of participants with laboratory-confirmed pulmonary TB [ Time Frame: Up to Month 61 ]
• IGRA-Positive Cohort: Number of participants with laboratory-confirmed pulmonary TB (Less stringent laboratory-confirmed pulmonary TB case definition) [ Time Frame: Up to Month 61 ]
  Laboratory-confirmed pulmonary TB case is defined as a participant with suspected pulmonary TB presenting with one or more of the following signs or symptoms: unexplained cough, unintentional weight loss, hemoptysis, unexplained fever, night sweats, pleuritic chest pain; who has at least 1 positive Mtb culture or at least 1 positive result from Xpert Ultra or similar assay (excluding "trace positive"), based on 3 sputum samples collected on 3 different visits, preferably within a 7-day time frame, before initiation of TB treatment.
• All Cohorts: Number of participants with solicited Adverse events (AEs) [ Time Frame: Up to 7 days ]
• All Cohorts: Number of participants with unsolicited AEs [ Time Frame: Up to 28 days ]
• All Cohorts: Number of participants with serious adverse events (SAEs) [ Time Frame: Up to Month 13 ]
• All Cohorts: Number of participants with potential immunemediated diseases (pIMDs) [ Time Frame: Up to Month 13 ]
• All Cohorts: Number of participants with SAEs related to study participation [ Time Frame: Up to Month 61 ]
• All cohorts: Number of participants with Geometric mean concentration (GMC) of M72-specific antibodies [ Time Frame: At Day 1, Month 1, Month 2, Month 7, Month 13, Month 37, and Month 61 ]
• All cohorts: Number of participants with seropositivity of M72-specific antibodies [ Time Frame: At Day 1, Month 1, Month 2, Month 7, Month 13, Month 37, and Month 61 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Assess Efficacy and Safety of M72/AS01E-4 Mycobacterium Tuberculosis (Mtb) Vaccine in Adolescents and Adults
• Official 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
• Brief Summary: The study is a 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 (IM) on a 0,1-month schedule to adolescents and adults. This trial will be conducted in 3 cohorts: Interferon gamma release assay (IGRA)-positive Cohort, IGRA-Negative Cohort and Human Immunodeficiency virus (HIV) Cohort.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Tuberculosis

Intervention

• Biological: M72/AS01E-4 Mycobacterium tuberculosis investigational vaccine
  Participants will receive an intramuscular dose of M72 (recombinant fusion protein) reconstituted with AS01E-4 (an adjuvant system), on Day 1 and Day 29.
• Biological: Placebo
  Participants will receive an intramuscular dose of normal saline (0.9 percent [%] sodium chloride [NaCl]), on Day 1 and Day 29.

Study Arms

• Experimental: Participants receiving M72/AS01E-4
  Intervention: Biological: M72/AS01E-4 Mycobacterium tuberculosis investigational vaccine
• Experimental: Participants receiving placebo
  Intervention: Biological: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 19, 2024): 20000
• Original Estimated Enrollment (submitted: September 25, 2023): 26000
• Estimated Study Completion Date: April 2028
• Estimated Primary Completion Date: April 2028 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

• Capable of giving informed consent or informed assent (as appropriate). For participants below the age of consent, the participant's parent, or legally authorized representative (LAR) will be required to sign a statement of informed consent, in addition to the minor's signed statement of assent.
• In the opinion of the investigator, can and will comply with the requirements of the protocol (e.g., completion of diary cards as applicable, and return for follow-up visits).
• Agree to actively stay in contact with the trial site for the duration of the trial for the participants own safety.
• Agree to provide updated contact information as necessary, and have no current plans to relocate from the trial area for the duration of the trial.
• Healthy, or with preexisting stable disease, as established by medical history and physical examination and as determined by the investigator.
• Negative sputum Xpert Ultra or similar assay result at screening.
• Both males and females are included. Females are included with restrictions. Females must either be of non-childbearing potential, defined as pre-menarche, have a history of either current tubal ligation, hysterectomy, or ovariectomy, or post-menopause, or, if she is of childbearing potential, she has practiced abstinence from penile-vaginal intercourse or adequate contraception for 28 days prior to vaccination, has a negative pregnancy test on the day of screening and the day of first vaccination, and agrees to continue abstinence or adequate contraception until 2 months after the second dose of trial intervention.
• HIV-negative test result at screening (IGRA-Positive Cohort and IGRA-Negative Cohort only).

• HIV Cohort only: Participants with documented HIV infection who fulfill all of the following criteria:

  1. Have reactive anti-HIV antibody at screening.
  2. Have been on antiretroviral therapy (ART) for at least 3 consecutive months at screening and agree to remain on ART throughout the trial.
  3. Have documented HIV Ribonucleic acid (RNA) <200 copies per milliliter (/mL) at screening.
  4. Have Cluster of differentiation (CD)4+ cell count ≥200 cells/microliter (μL) at screening.
  5. Have had Tuberculosis preventive therapy (TPT) in the past and are not receiving TPT at the time of screening, according to the judgment of the investigators.
  6. Have an IGRA-positive or negative result at screening.

Exclusion criteria:

• Current TB, or history of TB or treatment for TB disease.
• Clinical suspicion of pulmonary TB at screening, defined as a participant presenting with one or more of the following signs or symptoms: unexplained cough, unexplained fever, night sweats, unintentional weight loss, hemoptysis, pleuritic chest pain.
• Any current medical, psychiatric, occupational, or substance abuse problems that, in the opinion of the investigator, will make it unlikely that the participant will comply with the protocol, or that will interfere with the assessments or the safety of the participant.
• Any confirmed or suspected immunosuppressive or immunodeficient condition resulting from disease (e.g., invasive, or malignant cancers), other than HIV infection in the HIV Cohort.
• Known bleeding disorder that is considered a contraindication to intramuscular injection or phlebotomy.
• Any cytotoxic drugs or administration of medications known to have a major impact on the immune system, as determined by the investigator, within 90 days prior to Day 1. These include immune globulin, blood, or blood products, potent immunosuppressants and immunomodulators, and systemic corticosteroids (exceeding 20 mg/day prednisone equivalent). Inhaled, topical, and intra-articular corticosteroids are allowed.
• Planned receipt of blood, or blood products during the trial period.
• Receipt or planned receipt of any vaccine in the period starting 28 days before, and ending 28 days after, each dose of the trial vaccine.
• History of previous administration of an experimental Mtb vaccine including M72/AS01E in a previous trial.
• History of allergy or hypersensitivity to the trial intervention, excipients, or related Substances.
• An indeterminate IGRA test result at screening
• Female participants with any one of the following conditions: currently pregnant or lactating; having positive serum pregnancy test during the screening window, positive urine pregnancy test on Day 1, planning a pregnancy within 2 months after completion of the vaccination series.
• Only in the HIV Cohort: Safety laboratory values at screening that are of concern, based on investigator's judgment. Note that preexisting stable chronic disease will not necessarily lead to exclusion, especially if laboratory values are graded as mild.
• Participation in an interventional clinical trial in which the participant has been or will be exposed to an investigational product (pharmaceutical product or device), within 28 days prior to signing consent or assent, or during the trial period.
• Individuals who are acting as personnel for this trial, or who have immediate family members (brother, sister, child, parent, or the spouse/partner) who are acting as personnel for this trial.
• Child in Care, defined as a child who is under the care (control or protection) of an agency, organization, institution or entity by the courts, the government body, acting in accordance with powers conferred in them by law or regulations. The definition of a child in care can include a child who is cared for by foster parents or living in a care home or institution, provided that the arrangements fall within the definition above. The definition of a child in care does not include a child who is adopted or has an appointed LAR.
• Participants who had a Tuberculin Skin Test (TST) within 6 months prior to Day 1.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 15 Years to 44 Years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Gates MRI; +1 857 702 2108; clinical.trials@gatesmri.org

Contact: Gates MRI (Toll Free Number); +1 866 789 5767

• Listed Location Countries: Indonesia, Kenya, Malawi, Mozambique, South Africa, Vietnam, Zambia

Administrative Information

• NCT Number: NCT06062238
• Other Study ID Numbers: Gates MRI-TBV02-301
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

• Current Responsible Party: Bill & Melinda Gates Medical Research Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Bill & Melinda Gates Medical Research Institute
• Original Study Sponsor: Same as current

Collaborators

• Wellcome Trust
• Bill and Melinda Gates Foundation

Investigators

• Study Director: Gates MRI; Bill & Melinda Gates Medical Research Institute

• PRS Account: Bill & Melinda Gates Medical Research Institute
• Verification Date: April 2024