Safety, Dosage, and Microbiome Engraftment Study of MGT-006 for Ulcerative Colitis (ROOT Study) (ROOT)

Participants receive no antibiotic pretreatment. MGT-006 is administered orally at four capsules per dose, three times daily before meals, for 56 days. Participants are observed for four weeks after completion of MGT-006 treatment.

MGT-006 is an investigational enteric-coated oral capsule filled with lyophilized human fecal material containing viable gut microbiota. In Phase 1b, four capsules are taken three times daily before meals for 56 days (12 capsules per day). Dose reduction, interruption, discontinuation, and re-escalation may occur according to protocol-defined safety rules. Phase 2a doses, dosing frequency, and treatment duration will be determined based on Phase 1b findings and specified in an amended protocol.

Participants receive oral vancomycin hydrochloride at a total daily dose of 500 mg (as vancomycin), divided into four daily administrations, for five days. MGT-006 is then administered orally at four capsules per dose, three times daily before meals, for 56 days, followed by four weeks of observation. MGT-006 starts within two days after completion of vancomycin pretreatment.

MGT-006 is an investigational enteric-coated oral capsule filled with lyophilized human fecal material containing viable gut microbiota. In Phase 1b, four capsules are taken three times daily before meals for 56 days (12 capsules per day). Dose reduction, interruption, discontinuation, and re-escalation may occur according to protocol-defined safety rules. Phase 2a doses, dosing frequency, and treatment duration will be determined based on Phase 1b findings and specified in an amended protocol.

Vancomycin hydrochloride is administered orally as pretreatment at a total daily dose of 500 mg (as vancomycin), divided into four daily administrations, for five days before MGT-006. In Phase 1b, it is administered only to participants randomized to the vancomycin pretreatment arm. Its use in Phase 2a depends on the pretreatment approach selected from Phase 1b.

Subjects allocated to the AFM group will receive pretreatment antibiotics for 5 days after final registration. Amoxicillin hydrate 1500 mg/day (as amoxicillin), fosfomycin calcium hydrate 3000 mg/day (as fosfomycin), and metronidazole 750 mg/day will be orally administered three times a day for 5 days.

MGT-006 is an investigational enteric-coated oral capsule filled with lyophilized human fecal material containing viable gut microbiota. In Phase 1b, four capsules are taken three times daily before meals for 56 days (12 capsules per day). Dose reduction, interruption, discontinuation, and re-escalation may occur according to protocol-defined safety rules. Phase 2a doses, dosing frequency, and treatment duration will be determined based on Phase 1b findings and specified in an amended protocol.

Subjects allocated to the AFM group will receive pretreatment antibiotics for 5 days after final registration. Amoxicillin hydrate 1500 mg/day (as amoxicillin), fosfomycin calcium hydrate 3000 mg/day (as fosfomycin), and metronidazole 750 mg/day will be orally administered three times a day for 5 days. Its use in Phase 2a depends on the pretreatment approach selected from Phase 1b.

The dosage/administration and duration of treatment are subject to change depending on the Phase 1b progress.

MGT-006 is an investigational enteric-coated oral capsule filled with lyophilized human fecal material containing viable gut microbiota. In Phase 1b, four capsules are taken three times daily before meals for 56 days (12 capsules per day). Dose reduction, interruption, discontinuation, and re-escalation may occur according to protocol-defined safety rules. Phase 2a doses, dosing frequency, and treatment duration will be determined based on Phase 1b findings and specified in an amended protocol.

Vancomycin hydrochloride is administered orally as pretreatment at a total daily dose of 500 mg (as vancomycin), divided into four daily administrations, for five days before MGT-006. In Phase 1b, it is administered only to participants randomized to the vancomycin pretreatment arm. Its use in Phase 2a depends on the pretreatment approach selected from Phase 1b.

Subjects allocated to the AFM group will receive pretreatment antibiotics for 5 days after final registration. Amoxicillin hydrate 1500 mg/day (as amoxicillin), fosfomycin calcium hydrate 3000 mg/day (as fosfomycin), and metronidazole 750 mg/day will be orally administered three times a day for 5 days. Its use in Phase 2a depends on the pretreatment approach selected from Phase 1b.

The dosage/administration and duration of treatment are subject to change depending on the Phase 1b progress.

MGT-006 is an investigational enteric-coated oral capsule filled with lyophilized human fecal material containing viable gut microbiota. In Phase 1b, four capsules are taken three times daily before meals for 56 days (12 capsules per day). Dose reduction, interruption, discontinuation, and re-escalation may occur according to protocol-defined safety rules. Phase 2a doses, dosing frequency, and treatment duration will be determined based on Phase 1b findings and specified in an amended protocol.

Vancomycin hydrochloride is administered orally as pretreatment at a total daily dose of 500 mg (as vancomycin), divided into four daily administrations, for five days before MGT-006. In Phase 1b, it is administered only to participants randomized to the vancomycin pretreatment arm. Its use in Phase 2a depends on the pretreatment approach selected from Phase 1b.

Subjects allocated to the AFM group will receive pretreatment antibiotics for 5 days after final registration. Amoxicillin hydrate 1500 mg/day (as amoxicillin), fosfomycin calcium hydrate 3000 mg/day (as fosfomycin), and metronidazole 750 mg/day will be orally administered three times a day for 5 days. Its use in Phase 2a depends on the pretreatment approach selected from Phase 1b.

The dosage/administration and duration of treatment are subject to change depending on the Phase 1b progress.

MGT-006 is an investigational enteric-coated oral capsule filled with lyophilized human fecal material containing viable gut microbiota. In Phase 1b, four capsules are taken three times daily before meals for 56 days (12 capsules per day). Dose reduction, interruption, discontinuation, and re-escalation may occur according to protocol-defined safety rules. Phase 2a doses, dosing frequency, and treatment duration will be determined based on Phase 1b findings and specified in an amended protocol.

Vancomycin hydrochloride is administered orally as pretreatment at a total daily dose of 500 mg (as vancomycin), divided into four daily administrations, for five days before MGT-006. In Phase 1b, it is administered only to participants randomized to the vancomycin pretreatment arm. Its use in Phase 2a depends on the pretreatment approach selected from Phase 1b.

Subjects allocated to the AFM group will receive pretreatment antibiotics for 5 days after final registration. Amoxicillin hydrate 1500 mg/day (as amoxicillin), fosfomycin calcium hydrate 3000 mg/day (as fosfomycin), and metronidazole 750 mg/day will be orally administered three times a day for 5 days. Its use in Phase 2a depends on the pretreatment approach selected from Phase 1b.

The number and percentage of subjects experiencing the AEs will be calculated for each group and overall. If a subject experiences multiple AEs, the subject will be counted only once per category. Similar summaries will be provided for adverse events related to the study drugs or procedures. These related adverse events will be summarized together in a single table by the source of relationship (i.e., MGT-006, pretreatment antibiotics, and study procedures).

Engraftment is defined at the strain (clonal) level. Specifically, a strain detected in the MGT-006 product lot is considered engrafted when it is detected in the participant after dosing. Detection sensitivity depends on the genetic distance between the product-derived strain and a baseline endogenous strain of the same species retained by the participant, as measured by the number of SNVs in species-specific marker genes.

1. Clinical remission rate is the percentage of subjects who achieved all of the following scores based on the MMS:

   • Stool frequency subscore of ≤1 and no greater than baseline
   • Rectal bleeding subscore of 0 points
   • Endoscopic subscore of ≤1 point

2. Clinical response rate is the percentage of subjects who achieved all of the following scores based on the MMS:

   • MMS decreased by ≥2 points and ≥30% from baseline
   • Rectal bleeding subscore decreased ≥1 point from baseline or became ≤1 point.

3. Endoscopic improvement rate is the percentage of subjects whose endoscopic subscore is ≤1 point.

For efficacy parameters in this clinical study, the MMS will be used.

<Endoscopic Subscore> At the time of confirmation of subject enrollment criteria (Visit 1), the investigator (sub-investigator) will evaluate the endoscopic subscore.

The endoscopic subscore as an efficacy endpoint (Visit 1, Visit 7) will be evaluated by the Central Evaluation Committee.

<UCEIS> The Central Imaging Evaluation Committee will evaluate three items: vascular pattern, bleeding, and erosions and ulcers.

The following will be used for evaluation in this study:

• UCEIS endoscopic remission rate: Score of 0 at 8 weeks after the start of MGT-006 administration
• UCEIS endoscopic improvement rate: Score decreased by 2 or more from baseline at 8 weeks after the start of MGT-006 administration

Partial Mayo score: Total score of 3 subscores excluding endoscopic subscore among the Mayo scores (0 to 12) Summary statistics will be calculated for the measured values and changes from baseline in the Partial Mayo Score at each evaluation time point.

Change from baseline is calculated per participant as the value at each post-dose timepoint minus the value at baseline, for the following indices: species richness, Shannon index, Bray-Curtis dissimilarity to donor, and Jaccard similarity to donor.

A dietary survey of subjects will be conducted by questionnaire according to "Appendix 4 Survey Items for Dietary Survey."

A patient acceptability assessment of MGT-006 will be conducted by questionnaire according to "Appendix 5 Patient Acceptability Assessment of MGT-006 as a Patient-Reported Outcome (PRO)."

Subjects will record administration of study medications in a medication diary, including:

• Pretreatment antibiotics (if assigned, e.g., vancomycin)
• Investigational product (MGT-006) The diary will capture, at minimum, the date of administration and any missed doses.

For the FAS, PPS and SAS, the medication adherence rate for the entire pretreatment antibiotics administration period will be calculated. For the AFM group, the adherence rate will be calculated and summarized for each drug (amoxicillin, fosfomycin, and metronidazole) separately.