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

1. Background
Registration Number	INA-WPHZ4SM
Date of registry approval	29-10-2024
Registration Date	21-10-2024
Secondary identifiers	Yes
Name of issuing authority (for example protocol number, other registries, etc)	Gates MRI-TBV02-301
Secondary identifier number	Gates MRI-TBV02-301
Scientific 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
Public (popular 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

2. Sponsor and Funding
Primary Sponsor	Bill & Melinda Gates Medical Research Institute
Source(s) of monetary or material support	Bill & Melinda Gates Foundation and Wellcome
Other partners	IQVIA RDS Indonesia

3. Contact details
Principal Investigator
Principal investigator	National Principal Investigator: Prof. Dr. dr. Erlina Burhan, M.Sc, Sp.P(K); Principal Investigator site RC3ID UNPAD: Prof. Rovina Ruslami, dr., Sp.PD, PhD; Principal Investigator site FKUI: Prof. Dr. dr. Sri Rezeki Hadinegoro, Sp.A(K); Principal Investigator site RSUP Persahabatan: Dr. dr. Fathiyah Isbaniah, M.Pd.Ked., Sp.P(K); Principal Investigator site RSUI: dr. Rania Imaniar, Sp.P(K); Principal Investigator site RSIJ Cempaka Putih: dr. Cut Yulia, Sp.P
City	Bandung, Jakarta, & Depok
Country	Indonesia
Principal investigator's affiliation	Prof. Dr. dr. Erlina Burhan, M.Sc, Sp.P(K): RSUP Persahabatan; Prof. Rovina Ruslami, dr., Sp.PD, PhD: RC3ID Universitas Padjadjaran; Prof. Dr. dr. Sri Rezeki Hadinegoro, Sp.A(K): Fakultas Kedokteran Universitas Indonesia; Dr. dr. Fathiyah Isbaniah, M.Pd.Ked., Sp.P(K): RSUP Persahabatan; dr. Rania Imaniar, Sp.P(K): RS Universitas Indonesia; dr. Cut Yulia, Sp.P: RS Islam Cempaka Putih, Jakarta.
Principal Investigator's email address	Prof. Dr. dr. Erlina Burhan, M.Sc, Sp.P(K): erlina_burhan@yahoo.com; Prof. Rovina Ruslami, dr., Sp.PD, PhD: n.ruslami@gmail.com; Prof. Dr. dr. Sri Rezeki Hadinegoro, Sp.A(K): shadinegoro46@gmail.com; Dr. dr. Fathiyah Isbaniah, M.Pd.Ked., Sp.P(K): fathiyah21@gmail.com; dr. Rania Imaniar, Sp.P(K): raniaimaniar@ymail.com; dr. Cut Yulia, Sp.P: cutyuliaindah@gmail.com
Public Queries
Contact person name for public queries	Gates MRI
Address for public queries	One Kendall Square, Building 600, Suite 6-301
City	Cambridge, MA
Country	Unites States of America
ZIP	02139
Affiliation for public queries	Gates MRI
Email address for public queries	clinical.trials@gatesmri.org
Phone number for public queries	+18577022108; +18667895767
Scientific Queries
Name of Contact for scientific queries	Gates MRI
Address for scientific queries	Gates MRI
City	Cambridge, MA
Country	Unites States of America
ZIP	02139
Affiliation of scientific queries contact	Gates MRI
Email address for scientific queries	clinical.trials@gatesmri.org

4. IRB & Regulatory
Ethical Approval number	Site RC3ID UNPAD: Initial: No. 1343/UN6.KEP/EC/2023, Amendment: No. 23/UN6.KEP/EC/2024; Site FKUI: Initial: KET-1775/UN2.F1/ETIK/PPM.00.02/2023, Amendment: ND-284/UN2.F1/ETIK/PPM.00.02/2024; Site RSUP Persahabatan: Initial: 141/KEPK-RSUPP/10/2023, Amendment: 141.1.A/KEPK-RSUPP/04/2024; Site RSUI: Initial: S-075/KETLIT/RSUI/X/2023, Amendment: ND-020/KETLIT/RSUI/IV/2024; Site RSIJ Cempaka Putih: Initial: 010/EC/KEP/09/2023, Amendment: 013/EC/KEP/04/2024
Name of Ethics committee	Site RC3ID UNPAD: Komite Etik Penelitian Universitas Padjadjaran; Site FKUI: Komite Etik Penelitian Kesehetan RSUPN Dr. Cipto Mangunkusumo/Fakultas Kedokteran Universitas Inodnesia; Site RSUP Persahabatan: Komite Etik Penelitian Kesehatan RSUP Persahabatan; Site RSUI: Komite Etik Penelitian Rumah Sakit Universitas Indonesia; Site RSIJ Cempaka Putih: Komite Etik Penelitian Rumah Sakit Islam Jakarta Cempaka Putih
Date of Ethic approval	18-10-2023
Contact details of Ethic Committee (phone, email, and office)	Komite Etik Penelitian Universitas Padjadjaran: Telp. & Fax. 022-2038697 email: kep@unpad.ac.id, website: kep.unpad.ac.id; Komite Etik Penelitian Kesehetan RSUPN Dr. Cipto Mangunkusumo – Fakultas Kedokteran Universitas Inodnesia: Telp: 021-3157008; website: https://komite-etik.fk.ui.ac.id/p/index.php/p; Komite Etik Penelitian Kesehatan RSUP Persahabatan: Telp: 021-4891708; info@rsuppersahabatan.co.id; Komite Etik Penelitian Rumah Sakit Universitas Indonesia: kep@rs.ui.ac.id; keprsui23@gmail.com; Komite Etik Penelitian Rumah Sakit Islam Jakarta Cempaka Putih: etikpenelitian.rsijcp@gmail.com
Number of Persetujuan Pelaksanaan Uji Klinik (PPUK)/Persetujuan Protokol Uji BE (PPUB)	Site RC3ID UNPAD: T-RG.01.06.32.05.24.99, dated 06 May 2024; Site FKUI: T-RG.01.06.32.05.24.112, dated 21 May 2024; Site RSUP Persahabatan: RG.01.06.32.321.4.2024.3959, dated 19 April 2024; Site RSUI: T-RG.01.06.32.04.24.91, dated 26 April 2024; Site RSIJ

5. Status
Countries of recruitment	South Africa, Kenya, Zambia, Mozambique, Malawi, Indonesia, Vietnam
Study sites in Indonesia	Site RC3ID Universitas Padjadjaran; Site Fakultas Kedokteran Universitas Indonesia; Site RSUP Persahabatan; Site RSUI; Site RSIJ Cempaka Putih
Recruitment status	Recruit
Date of first enrollment	13-09-2024
Targeted Sample size	02500 -
Number of enrolled participants	8 subjects as of 17 September 2024
Date of study completion (last participant, last visit)

6. Study Design & Purpose
Primary health condition(s) or problem(s) studied (e.g., depression, breast cancer,medication error)	Laboratory confirmed pulmonary tuberculosis
Purpose of the study	Prevention
Study type	Interventional
Interventional Study category	Clinical trial
Study phase	Phase 3
Method of allocation	Randomized allocation
Description of the allocation concealment mechanism and sequence generation	Participants in the IGRA-positive, IGRA-negative, and HIV cohorts will be randomized 1:1 to receive M72/AS01E-4 or placebo, stratified by site, age group (15 to 17 years and 18 to 44 years) and sex. The participants in the HIV Cohort will also be stratified by IGRA status at screening. Participants will be randomized to one of 2 interventions (M72/AS01E-4 or placebo) based on a randomly-generated sequence of participant identification (identifier) numbers (randomization schedule) using a validated Interactive Voice/Web Response System (IVRS/IWRS). The randomization schedule will be prepared by a statistician who will not be involved in the analysis of the trial in order to maintain the blind of the trial team.
Masking	Double-blind
Study intervention (study arm)	Intervention Name: (2 injections during the study): Vaccine: Mycobacterium tuberculosis M72/AS01E-4 vaccine, Placebo control: Normal saline, solution placebo; Unit-Dose Strength: Vaccine: 10 μg, Placebo control: Normal saline solution (0.9% NaCl); Dosage Volume: Vaccine: 0.5 mL per injection (per dose), Placebo control: 0.5 mL per injection; Giving Route: Vaccine and Placebo control: IM Injection.
Control intervention (control arm)	Placebo control: Normal saline, solution placebo; Unit-Dose Strength: Normal saline solution (0.9% NaCl); Dosage Volume: 0.5 mL per injection; Giving Route: IM Injection
Intervention assignment	Parallel

7. Eligibility Criteria
Gender inclusion criteria	Not specified
Minimum age	15
Maximum age	44
Inclusion criteria	Participant must be 15 to 44 years of age (inclusive), at the time of signing the consent or assent; 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. Preexisting stable disease is defined as not requiring significant change in therapy or hospitalization for worsening disease during the 28 days before enrollment; 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: have reactive anti-HIV antibody at screening, have been on ART for at least 3 consecutive months at screening and agree to remain on ART throughout the trial, have documented HIV RNA
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 (Section 13); 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.

8. Study Outcome
Primary Outcome
Name of primary outcome	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
Metric/method of measurement	Laboratory-confirmed pulmonary TB over a period starting 1 month post Dose 2 and lasting up to End of Trial (EoT) where a laboratory-confirmed pulmonary TB case is defined as a participant with: Suspected pulmonary TB as defined as a participant 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”), 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.
Timepoint(s) of measurement	Up to month 49
Secondary outcome 1
Name of secondary outcome 1 (SO1)	IGRA-Negative Cohort: Number of participants with sustained QuantiFERON®-TB Gold Plus assay conversion
Metric/method of measurement (SO1)	NA
Timepoint(s) of measurement (SO1)	Up to Month 49
Secondary outcome 2
Name of secondary outcome 2 (SO2)	IGRA-Negative Cohort: Number of participants with laboratory-confirmed pulmonary TB
Metric/method of measurement (SO2)	NA
Timepoint(s) of measurement (SO2)	Up to Month 49
Secondary outcome 3
Name of secondary outcome 3 (SO3)	HIV Cohort: Number of participants with laboratory-confirmed pulmonary TB
Metric/method of measurement (SO3)	NA
Timepoint(s) of measurement (SO3)	Up to Month 49
Secondary outcome 4
Name of secondary outcome 4 (SO4)	IGRA-Positive Cohort: Number of participants with laboratory-confirmed pulmonary TB (Less stringent laboratory-confirmed pulmonary TB case definition)
Metric/method of measurement (SO4)	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
Timepoint(s) of measurement (SO4)	Up to Month 49
Secondary outcome 5
Name of secondary outcome 5 (SO5)	a. All Cohorts: Number of participants with solicited adverse events (AEs) b. All Cohorts: Number of participants with unsolicited AEs c. All Cohorts: Number of participants with serious adverse events (SAEs) d. All Cohorts: Number of participants with potential immunemediated diseases (pIMDs) e. All Cohorts: Number of participants with SAEs related to trial participation f. All cohorts: Number of participants with geometric mean concentration (GMC) of M72-specific antibodies g. All cohorts: Number of participants with seropositivity of M72-specific antibodies
Metric/method of measurement (SO5)	NA
Timepoint(s) of measurement (SO5)	a. Up to 7 days b. Up to 28 days c. Up to Month 13 d. Up to Month 13 e. Up to Month 49 f. At Day 1, Month 1, Month 2, Month 7, Month 13, Month 37, and Month 49 g. At Day 1, Month 1, Month 2, Month 7, Month 13, Month 37, and Month 49

9. Study Results
Brief summary of study results
Date of results summaries
Participant flow
Baseline characteristic	NA
Adverse events
Outcome measures

10. Publication
URL hyperlink(s) related to results and publications
IPD sharing statement (Statement regarding the intended sharing of deidentified individual clinical trial participant-level data (IPD))	No
Plan for IPD sharing (what IPD will be shared, when, by what mechanism, with whom, and for what types of analyses)
Other important informations	NA