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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Tuberculosis

Intervention / Treatment
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* Biological: M72/AS01E-4 Mycobacterium tuberculosis investigational vaccine
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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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 (this criterion can be waived if participant is unable to produce sufficient sputum). 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: Have reactive anti-HIV antibody at screening. Have been on antiretroviral therapy (ART) for at least 3 consecutive months at screening and agree to remain on ART throughout the trial. Have documented HIV Ribonucleic acid (RNA) <200 copies per milliliter (/mL) at screening. Have Cluster of differentiation (CD)4+ cell count ≥200 cells/microliter (μL) at screening. 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. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 44 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving M72/AS01E-4<br> | Biological: M72/AS01E-4 Mycobacterium tuberculosis investigational vaccine<br>* Participants will receive an intramuscular dose of M72 (recombinant fusion protein) reconstituted with AS01E-4 (an adjuvant system), on Day 1 and Day 29.<br>|
| Experimental: Participants receiving placebo<br> | Biological: Placebo<br>* Participants will receive an intramuscular dose of normal saline (0.9 percent [%] sodium chloride [NaCl]), on Day 1 and Day 29.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IGRA-Positive Cohort: Number of participants with laboratory-confirmed pulmonary tuberculosis (TB) | 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. | Up to Month 61 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IGRA-Negative Cohort: Number of participants with sustained QuantiFERON®-TB Gold Plus assay conversion |  | Up to Month 61 | 
| IGRA-Negative Cohort: Number of participants with laboratory-confirmed pulmonary TB |  | Up to Month 61 | 
| HIV Cohort: Number of participants with laboratory-confirmed pulmonary TB |  | Up to Month 61 | 
| IGRA-Positive Cohort: Number of participants with laboratory-confirmed pulmonary TB (Less stringent laboratory-confirmed pulmonary TB case definition) | 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. | Up to Month 61 | 
| All Cohorts: Number of participants with solicited Adverse events (AEs) |  | Up to 7 days | 
| All Cohorts: Number of participants with unsolicited AEs |  | Up to 28 days | 
| All Cohorts: Number of participants with serious adverse events (SAEs) |  | Up to Month 13 | 
| All Cohorts: Number of participants with potential immunemediated diseases (pIMDs) |  | Up to Month 13 | 
| All Cohorts: Number of participants with SAEs related to study participation |  | Up to Month 61 | 
| All cohorts: Number of participants with Geometric mean concentration (GMC) of M72-specific antibodies |  | 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 |  | At Day 1, Month 1, Month 2, Month 7, Month 13, Month 37, and Month 61 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mycobacterium tuberculosis, M72/AS01E-4 vaccine, Safety, Immunogenicity, Efficacy, Mtb, HIV, TB vaccine