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

Study Overview
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Brief Summary
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The main aim of the study is to assess if TAK-101 can reduce gluten related symptoms and immune activation in adult participants with celiac disease (CeD) on a gluten-free diet (GFD). Participants will receive TAK-101 and/or placebo through the vein on Day 1 and Day 8. All participants will receive active treatment at Week 24.

Detailed Description
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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 two cohorts planned. The first cohort has 1 dose level and the second cohort may include 1 or 2 dose levels, depending on safety, tolerability, and activity observed in the first cohort. Dosing in the second cohort will be based on data from the initial cohort. The study will enrol approximately 108 patients (18 per arm). In the first cohort, 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 on Day 1 and 1 on Day 8, followed by 1 infusion dose of 2 mg/kg TAK-101 at Week 24. Group B: 1 infusion dose of 2 mg/kg of TAK-101 on Day 1 followed by 1 infusion dose of placebo on Day 8, followed by 1 infusion dose of 2 mg/kg TAK-101 at Week 24. Group C: 2 infusion doses of 2 mg/kg of TAK-101, 1 on Day 1 and 1 on Day 8, followed by 1 infusion dose of 2 mg/kg TAK-101 at Week 24. After the review of Cohort 1 safety data, a decision will be made to either stop the study or continue the study by the sponsor safety management team (SMT), based on recommendations from independent data monitoring committee (IDMC). If it is deemed appropriate to enroll both the TAK-101 4 mg/kg and 1 mg/kg dose level, approximately 63 participants may be randomly assigned in 1:2:2:2 ratio in Cohort 2 to receive: Group D: Two infusion doses of placebo, 1 on Day 1 and 1 on Day 8, followed by 1 infusion dose of 2 mg/kg TAK-101 at Week 24. Group E: One infusion dose of 4 mg/kg TAK-101 on Day 1 followed by 1 infusion dose of placebo on Day 8, followed by 1 infusion dose of 4 mg/kg TAK-101 at Week 24. Group F: Two infusion doses of 4mg/kg, 1 on Day 1 and 1 on day 8, followed by 1 infusion dose of 4 mg/kg TAK-101 at Week 24. Group G: TAK-101 1 mg/kg: Two infusion doses of 1 mg/kg TAK-101, 1 on Day 1 and 1 on Day 8, followed by 1 infusion dose of 1 mg/kg TAK-101 at Week 24 (1 mg/kg may not be needed based on review of Cohort 1 data). In Cohort 2 if the 1 mg/kg treatment arm is not needed, Cohort 2 will consist of 45 participants in total, being randomized in a 1:2:2 ratio to 1 of the 3 treatment groups (Groups D, E, F) listed above. If it is decided not to open the second cohort at the 4 mg/kg dose level and if 1 mg/kg dose is recommended to be tested by the IDMC, approximately 45 participants will be randomly assigned in 1:2:2 ratio to receive: Group D: Two infusion doses of placebo, 1 on Day 1 and 1 on Day 8, followed by 1 infusion dose of 1 mg/kg TAK-101 at Week 24. Group E: One infusion dose of 1 mg/kg TAK-101 on Day 1 followed by 1 infusion dose of placebo on Day 8, followed by 1 infusion dose of 1 mg/kg TAK-101 at Week 24. Group F: Two infusion doses of 1 mg/kg, 1 on Day 1 and 1 on Day 8, followed by 1 infusion dose of 1 mg/kg TAK-101 at Week 24. This trial will be conducted in United States and Canada. The overall time to participate in this study is approximately 24 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.

Official Title
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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

Conditions
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Celiac Disease

Intervention / Treatment
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* Drug: Placebo
* Drug: TAK-101
* Dietary Supplement: Gluten


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy-confirmed CeD that is well-controlled, defined as mild or with no ongoing signs or symptoms felt to be related to active CeD and with immunoglobulin A (IgA) tissue transglutaminase (tTG) <2 × upper limit of normal (ULN) and IgG deamidated gliadin peptide (DGP) <3 × ULN. Note: Participants may be retested for IgA tTG and IgG DGP to meet eligibility criteria at the discretion of the investigator. Intermittent symptoms would not exclude participants from participation as long as symptoms are generally well controlled in the opinion of the investigator, and as long as symptoms are back to baseline for 2 weeks before the run-in gluten challenge. Must be attempting to maintain a gluten-free diet (GFD) for ≥6 months. Must be HLA-DQ2 and/or HLA-DQ8 positive during screening laboratory testing. Exclusion Criteria: Has received any investigational compound within 12 weeks (84 days) before signing of the informed consent or during the current study. Has received TAK-101 (TIMP-GLIA) in a previous clinical study or as a therapeutic agent. Has presence of inflammatory gastrointestinal disorders or autoimmune diseases, other than well-controlled autoimmune thyroid disease or well-controlled type 1 diabetes mellitus (defined as glycosylated hemoglobin <8% and no hospitalization in the last 12 months for hyper/hypoglycemia). Has known or suspected refractory CeD or ulcerative jejunitis. Has additional food allergies or intolerances that prevent participation in the food challenge. Is receiving ongoing systemic immunosuppressant, systemic (oral or IV) corticosteroid treatment, or has received treatment with systemic immunosuppressants or corticosteroids in the 12 weeks before run-in gluten challenge. Has known or suspected chronic liver disease or positive for hepatitis B or C. Has intolerable symptoms after the run-in gluten challenge and is unwilling to undergo subsequent posttreatment gluten challenges.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1, Group A: Placebo + Placebo + TAK-101 2 mg/kg<br>Following a single-day 3 gram (g) oral run-in gluten challenge, participants will receive TAK-101 placebo-matching 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 2 milligram per kilogram (mg/kg) will be given 23 weeks after the second dose at approximately Week 24. | Drug: Placebo<br>* TAK-101 placebo-matching intravenous infusion<br>Drug: TAK-101<br>* TAK 101 intravenous infusion<br>* Other names: TIMP-GLIA;Dietary Supplement: Gluten<br>* Powder form (vital wheat gluten)<br>|
| Experimental: Cohort 1, Group B: TAK-101 2 mg/kg + Placebo + TAK-101 2 mg/kg<br>Following a single-day 3 g oral run-in gluten challenge, participants will receive TAK-101 2 mg/kg, IV infusion once on Day 1 followed by TAK-101 placebo-matching 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 2 mg/kg will be given 23 weeks after the second dose at approximately Week 24. | Drug: Placebo<br>* TAK-101 placebo-matching intravenous infusion<br>Drug: TAK-101<br>* TAK 101 intravenous infusion<br>* Other names: TIMP-GLIA;Dietary Supplement: Gluten<br>* Powder form (vital wheat gluten)<br>|
| Experimental: Cohort 1, Group C: TAK-101 2 mg/kg + TAK-101 2 mg/kg + TAK-101 2 mg/kg<br>Following a single-day 3 g oral run-in gluten challenge, participants will receive TAK-101 2 mg/kg 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 2 mg/kg will be given 23 weeks after the second dose at approximately Week 24. | Drug: TAK-101<br>* TAK 101 intravenous infusion<br>* Other names: TIMP-GLIA;Dietary Supplement: Gluten<br>* Powder form (vital wheat gluten)<br>|
| Experimental: Cohort 2, Group D: Placebo + Placebo + TAK-101 2 mg/kg<br>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 2 mg/kg 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<br>* TAK-101 placebo-matching intravenous infusion<br>Drug: TAK-101<br>* TAK 101 intravenous infusion<br>* Other names: TIMP-GLIA;Dietary Supplement: Gluten<br>* Powder form (vital wheat gluten)<br>|
| Experimental: Cohort 2, Group E: TAK-101 4 mg/kg + Placebo + TAK-101 4 mg/kg<br>Following a single-day 3 g oral run-in gluten challenge, participants will receive TAK-101 4 mg/kg, IV infusion once on Day 1 followed by TAK-101 placebo-matching 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 4 mg/kg 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<br>* TAK-101 placebo-matching intravenous infusion<br>Drug: TAK-101<br>* TAK 101 intravenous infusion<br>* Other names: TIMP-GLIA;Dietary Supplement: Gluten<br>* Powder form (vital wheat gluten)<br>|
| Experimental: Cohort 2, Group F: TAK-101 4 mg/kg + TAK-101 4 mg/kg + TAK-101 4 mg/kg<br>Following a single-day 3 g oral run-in gluten challenge, participants will receive TAK-101 4 mg/kg 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 4 mg/kg 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<br>* TAK 101 intravenous infusion<br>* Other names: TIMP-GLIA;Dietary Supplement: Gluten<br>* Powder form (vital wheat gluten)<br>|
| Experimental: Cohort 2, Group G: TAK-101 1 mg/kg + TAK-101 1 mg/kg + TAK-101 1 mg/kg<br>Following a single-day 3 g oral run-in gluten challenge, participants will receive TAK-101 1 mg/kg 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 1 mg/kg will be given 23 weeks after the second dose at approximately Week 24 (1 mg/kg may not be needed based on review of Cohort 1 data). Cohort 2 would start based on the results of Cohort 1. | Drug: TAK-101<br>* TAK 101 intravenous infusion<br>* Other names: TIMP-GLIA;Dietary Supplement: Gluten<br>* Powder form (vital wheat gluten)<br>|
| Experimental: Cohort 2, Group D: Placebo + Placebo + TAK-101 1 mg/kg<br>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 1 mg/kg 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 the second cohort at the 4 mg/kg dose level i.e. if 4mg/kg Groups E and F are not opened. | Drug: Placebo<br>* TAK-101 placebo-matching intravenous infusion<br>Drug: TAK-101<br>* TAK 101 intravenous infusion<br>* Other names: TIMP-GLIA;Dietary Supplement: Gluten<br>* Powder form (vital wheat gluten)<br>|
| Experimental: Cohort 2, Group E: TAK-101 1 mg/kg + Placebo + TAK-101 1 mg/kg<br>Following a single-day 3 g oral run-in gluten challenge, participants will receive TAK-101 1 mg/kg, IV infusion once on Day 1 followed by TAK-101 placebo-matching 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 1 mg/kg 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 the second cohort at the 4 mg/kg dose level i.e. if 4mg/kg Groups E and F are not opened. | Drug: Placebo<br>* TAK-101 placebo-matching intravenous infusion<br>Drug: TAK-101<br>* TAK 101 intravenous infusion<br>* Other names: TIMP-GLIA;Dietary Supplement: Gluten<br>* Powder form (vital wheat gluten)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Interferon-gamma Spot Forming Units (IFN-γ SFUs) in Human Leukocyte Antigens Density Quotient (HLA-DQ2-positive) Participants Based on Results of a Gliadin-Specific Enzyme-Linked Immunospot (ELISpot) Assay | IFN-γ SFUs will be measured based on results of a gliadin-specific ELISpot assay using gluten-specific T cells which will be isolated from blood. | Baseline (Day 15, or Day 1 in the absence of Day 15) to Week 3 (Day 20) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing at Least One Adverse Event (AE), Infusion Related Reaction (IRR), and Cytokine Release Syndrome (CRS) | An 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 markedly abnormal physical examination finding, vital sign value, laboratory test value), symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug. IRR as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5 is defined as disorder characterized by adverse reaction to the infusion of pharmacological or biological substances. CRS as per NCI CTCAE Version 5 is defined as a disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath caused by the release of cytokines from the cells. | From the first IV dose up to 30 days after last IV dose (Up to Week 28) | 
| Change From Baseline in Nausea Severity as Measured by the Celiac Disease Symptom Diary (CDSD) 3-day Average Score | The CDSD version 2.1 is an 8-item, self-administered questionnaire that evaluates the celiac disease (CeD) symptoms using 5-point Likert-type scales, 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. The scores from the past 3 days with a 24-hour recall period will be averaged. For Weeks 8, 14, and 20, it is calculated as the average of the available daily scores recorded in the 3 days after the respective gluten challenge. The average score for Day 15 to 20 gluten challenge is the average of the daily scores from the initiation of gluten challenge to 3 days after the last gluten challenge. | Baseline and Day 1 post gluten challenge on Day 20 (Week 3) and Weeks 8, 14 and 20 | 
| Change From Baseline in CDSD 3-day Peak Nausea Severity Score | The CDSD version 2.1 is an 8-item, self-administered questionnaire that evaluates the CeD symptoms using 5-point Likert-type scales, 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. The scores from the past 3 days with a 24-hour recall period will be averaged. Peak score is the highest score in the 3 days following gluten challenge starting on the initiation of gluten challenge for challenges at Weeks 8, 14, and 20 and the highest score during and the 3 days following the Day 15-20 gluten challenge. | Baseline and Day 1 post gluten challenge on Day 20 (Week 3) and Weeks 8, 14 and 20 | 
| Change From Baseline Before Gluten Challenge to 4 hours Post-gluten Challenge in Plasma Interleukin-2 (IL-2) on Day 15 and Weeks 8, 14, and 20 | IL-2 levels in the plasma will be tested before and 4 hours after gluten challenge. IL-2 is acutely induced in participants with CeD and detected in the blood within 4 hours. | Baseline, Day 15, Weeks 8, 14, 20 | 
| Plasma Concentration of TAK-101 After Each Dose |  | Predose and postdose at Weeks 0, 1 and 24 | 
| Change From Baseline in Serum Concentration of Antidrug Antibody (ADAs) to TAK-101 | ADA includes deamidated gliadin peptide- immunoglobulin G (DGP- IgG). | Predose at Weeks 0 and 1 and before gluten challenge at Weeks 2, 8, 14, 20, and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy