Dose-Ranging Study of the Efficacy and Safety of TAK-101 for Prevention of Gluten-Specific T Cell Activation in Participants With Celiac Disease on a Gluten-Free Diet

The drug being tested in this study is called TAK-101. TAK-101 is being tested to treat people who have celiac disease. The study has 2 cohorts planned. Cohort 1 has 1 dose level and the Cohort 2 may include 1 or 2 additional dose levels, depending on safety, tolerability, and activity observed in Cohort 1. Dosing in the Cohort 2 will be based on data from Cohort 1.

The study will enroll approximately 90 patients. In Cohort 1, approximately 45 participants will be randomly assigned in 1:2:2 ratio in one of the three arm groups which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need). Eligible participants in Cohort 1 will receive:

• Group A: 2 infusion doses of placebo, 1 infusion dose on Day 1 and 1 infusion dose on Day 8, followed by 1 infusion dose of 25 micrograms per kilogram (µg/kg) Gluten Epitopes (GE) TAK-101 at Week 24.
• Group B: 1 infusion dose of 25 µg/kg GE TAK-101 on Day 1 followed by 1 infusion dose of placebo on Day 8, followed by 1 infusion dose of 25 µg/kg GE TAK-101 at Week 24.
• Group C: 2 infusion doses of 25 µg/kg GE TAK-101, 1 infusion dose on Day 1 and 1 infusion dose on Day 8, followed by 1 infusion dose of 25 µg/kg GE TAK-101 at Week 24.

If it is deemed appropriate to enroll both the TAK-101 50 µg/kg GE and the 12.5 µg/kg GE dose levels in Cohort 2, approximately 45 participants may be randomly assigned in 1:2:2 ratio in Cohort 2 to receive:

• Group A: Two infusion doses of placebo, 1 infusion dose on Day 1 and 1 infusion dose on Day 8, followed by 1 infusion dose of 25 µg/kg GE TAK-101 at Week 24.
• Group D: Two infusion doses of 50 µg/kg GE TAK-101, 1 infusion dose on Day 1 and 1 infusion dose on Day 8, followed by 1 infusion dose of 50 µg/kg GE TAK-101 at Week 24.
• Group F: Two infusion doses of 12.5 µg/kg GE TAK-101, 1 infusion dose on Day 1 and 1 infusion dose on Day 8, followed by 1 infusion dose of 12.5 µg/kg GE TAK-101 at Week 24.

If it is decided not to open the second cohort at the 50 µg/kg GE dose level and if 12.5 µg/kg GE dose is recommended to be tested by the independent data monitoring committee (IDMC), approximately 27 participants will be randomly assigned in 1:2 ratio to receive:

• Group E: Two infusion doses of placebo, 1 infusion dose on Day 1 and 1 infusion dose on Day 8, followed by 1 infusion dose of 12.5 µg/kg GE TAK-101 at Week 24.
• Group F: Two infusion doses of 12.5 µg/kg GE TAK-101, 1 infusion dose on Day 1 and 1 infusion dose on Day 8, followed by 1 infusion dose of 12.5 µg/kg TAK-101 at Week 24.

This trial will be conducted globally. The overall time to participate in this study is approximately 34 weeks. Participants will make multiple visits to the clinic, and will be contacted by telephone OR plus a final visit after receiving their last dose of study drug for a follow-up assessment.

Following a single-day 3 gram (g) oral run-in gluten challenge, participants will receive TAK-101 matching placebo intravenous (IV) infusion dose, once each on Days 1 and 8, followed by 12 g/day gluten for 3 days followed by 6 g/day gluten for 3 days starting at Week 2. Participants will then undergo single-day 3 g gluten challenges at Weeks 8, 14, and 20. A third IV infusion dose of TAK-101 25 microgram per kilogram (µg/kg) GE will be given 23 weeks after the second dose at approximately Week 24.

Drug: Placebo · Drug: TAK-101 · Dietary Supplement: Gluten

Following a single-day 3 g oral run-in gluten challenge, participants will receive TAK-101 25 µg/kg, IV infusion once on Day 1 followed by TAK-101 matching placebo IV infusion, once on Day 8, followed by 12 g/day gluten for 3 days followed by 6 g/day gluten for 3 days starting at Week 2. Participants will then undergo single-day 3 g gluten challenges at Weeks 8, 14, and 20. A third IV infusion dose of TAK-101 25 µg/kg GE will be given 23 weeks after the second dose at approximately Week 24.

Drug: Placebo · Drug: TAK-101 · Dietary Supplement: Gluten

Following a single-day 3 g oral run-in gluten challenge, participants will receive TAK-101 25 µg/kg GE IV infusion, once each on Days 1 and 8, followed by 12 g/day gluten for 3 days followed by 6 g/day gluten for 3 days starting at Week 2. Participants will then undergo single-day 3 g gluten challenges at Weeks 8, 14, and 20. A third IV infusion dose of TAK-101 25 µg/kg GE will be given 23 weeks after the second dose at approximately Week 24.

Drug: TAK-101 · Dietary Supplement: Gluten

Following a single-day 3 g oral run-in gluten challenge, participants will receive TAK-101 matching placebo IV infusion, once each on Days 1 and 8, followed by 12 g/day gluten for 3 days followed by 6 g/day gluten for 3 days starting at Week 2. Participants will then undergo single-day 3 g gluten challenges at Weeks 8, 14, and 20. A third IV infusion dose of TAK-101 25 µg/kg GE will be given 23 weeks after the second dose at approximately Week 24. Cohort 2 would start based on the results of Cohort 1.

Drug: Placebo · Drug: TAK-101 · Dietary Supplement: Gluten

Following a single-day 3 g oral run-in gluten challenge, participants will receive TAK-101 50 µg/kg GE IV infusion, once each on Days 1 and 8, followed by 12 g/day gluten for 3 days followed by 6 g/day gluten for 3 days starting at Week 2. Participants will then undergo single-day 3 g gluten challenges at Weeks 8, 14, and 20. A third IV infusion dose of TAK-101 50 µg/kg GE will be given 23 weeks after the second dose at approximately Week 24. Cohort 2 would start based on the results of Cohort 1.

Drug: TAK-101 · Dietary Supplement: Gluten

Following a single-day 3 g oral run-in gluten challenge, participants will receive TAK-101 placebo-matching IV infusion, once each on Days 1 and 8, followed by 12 g/day gluten for 3 days followed by 6 g/day gluten for 3 days starting at Week 2. Participants will then undergo single-day 3 g gluten challenges at Weeks 8, 14, and 20. A third IV infusion dose of TAK-101 12.5 µg/kg GE will be given 23 weeks after the second dose at approximately Week 24. Cohort 2 would start based on the results of Cohort 1. This group would be opened only if it is decided not to open Cohort 2 at the 50 µg/kg GE dose level.

Drug: Placebo · Drug: TAK-101 · Dietary Supplement: Gluten

Following a single-day 3 g oral run-in gluten challenge, participants will receive TAK-101 12.5 µg/kg GE IV infusion, once each on Days 1 and 8, followed by 12 g/day gluten for 3 days followed by 6 g/day gluten for 3 days starting at Week 2. Participants will then undergo single-day 3 g gluten challenges at Weeks 8, 14, and 20. A third IV infusion dose of TAK-101 12.5 µg/kg GE will be given 23 weeks after the second dose at approximately Week 24. Cohort 2 would start based on the results of Cohort 1.

Drug: TAK-101 · Dietary Supplement: Gluten

TAK-101 matching placebo intravenous infusion

TAK 101 intravenous infusion

Powder form (vital wheat gluten)

Plazo: Baseline (Day 15), Week 3 (Day 20)

IFN-γ SFUs were measured based on results of a gliadin-specific ELISpot assay using peripheral blood mononuclear cells (PBMCs). Gliadin-specific cluster of differentiation 4 (CD4) T cells were a small percentage of the PBMCs and responded to gliadin peptide stimulation in vitro by producing the IFN-γ cytokine. Baseline was defined as Day 15.

Plazo: Up to Week 28

An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory value), symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug. A TEAE was defined as an AE that started, or severity worsened, or intensity increased after receiving the first study drug administration and up to within 30 days of last dose of study drug. An AESI (serious or nonserious) is one of scientific and medical concern specific to the compound or program, for which ongoing monitoring and rapid communication by the investigator to the sponsor may be appropriate. AESIs are reported based on the Standardized MedDRA Queries (SMQs) and based on case report forms (CRFs).

Plazo: Run-in (Visit 2 at Week -4), Weeks 8, 14, and 20

CDSD version 2.1 is a 8-item (severity of diarrhea, abdominal pain, bloating, nausea, and tiredness, frequency of bowel movement and vomiting, and a count of loosest stool forms), self-administered questionnaire that evaluates CeD symptoms using 5-point Likert-type scales (\[0\] none, \[1\] mild, \[2\] moderate, \[3\] severe, and \[4\] very severe), where lower score indicating no symptoms and higher score indicating severe symptoms for all items except for frequency questions relating to stool counts, diarrhea, and vomiting frequency. Scores from past 3 days with a 24-hour recall period were averaged. For Run-in, Weeks 8, 14, and 20, each score was calculated as average of available daily scores recorded in 3 days prior and after the respective gluten challenge. Results are reported as least squares (LS) mean change from run-in at Weeks 8, 14 and 20, determined using a linear mixed-effect model for repeated measures (MMRM) analysis. A negative change from run-in indicates improvement.

Plazo: Run-in (Visit 2 at Week -4), Weeks 8, 14, and 20

CDSD version 2.1 is an 8-item (severity of diarrhea, abdominal pain, bloating, nausea, and tiredness, frequency of bowel movement and vomiting, and a count of loosest stool forms), self-administered questionnaire that evaluates CeD symptoms using 5-point Likert-type scales (\[0\] none, \[1\] mild, \[2\] moderate, \[3\] severe, and \[4\] very severe), where lower score indicating no symptoms and higher score indicating severe symptoms for all items except for frequency questions relating to stool counts, diarrhea, and vomiting frequency. Scores from past 3 days with a 24-hour recall period were averaged. For Run-in, Weeks 8, 14, and 20, each score was calculated as average of the available daily scores recorded in the 3 days prior and after the respective gluten challenge. Results are reported as LS mean change from run-in at Weeks 8, 14 and 20, determined using a linear MMRM analysis. A negative change from run-in indicates improvement.

Plazo: Run-in (Visit 2 at Week -4), Weeks 8, 14, and 20

CDSD GI symptom severity score is an average of the daily GI symptom severity scores during the week. The daily GI symptom severity score is the average of the severity score for diarrhea, abdominal pain, bloating and nausea, ranging from 0 to 4. Symptom severity is evaluated using 5-point Likert-type scales (none, mild, moderate, severe, and very severe). Higher scores indicate more severe symptoms. Results are reported as LS mean change from run-in at Weeks 8, 14 and 20, determined using a linear MMRM analysis. A negative change from run-in indicates improvement.

Plazo: Run-in (Visit 2 at Week -4), Week 2 (Day 15), and Weeks 8, 14, and 20

The pre-gluten to 4 hours post-gluten challenge log transformed fold change in plasma IL-2 from Run-in (Visit 2) to Day 15, and Weeks 8, 14, and 20 were compared. Results are reported as LS mean change from run-in at Day 15, Weeks 8, 14 and 20, determined using a linear MMRM analysis.

Plazo: Run-in (Visit 2 at Week -4), Week 2 (Day 15), and Weeks 8, 14, and 20

The pre-gluten to 4 hours post-gluten challenge log-transformed fold change in plasma IL-2 at each of the time points is reported.

Plazo: At end of infusion of Weeks 0, 1 and 24

Free gliadin concentration in the plasma was measured and reported.

Plazo: Predose at Weeks 1 and 24; and before gluten challenge at Weeks 2, 14, and 20

ADA includes deamidated gliadin peptide- immunoglobulin G (DGP- IgG). Serum Concentration of ADAs was measured in Enzyme-Linked ImmunoAssay Units per milliliter denoted as EliA U/mL.

A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Dose-Ranging Study to Evaluate the Efficacy and Safety of TAK-101 for the Prevention of Gluten-Specific T Cell Activation in Subjects With Celiac Disease on a Gluten-Free Diet