A Study of TAK-062 in Treatment of Active Celiac Disease in Participants Attempting a Gluten-Free Diet

Study Overview
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Brief Summary
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The main aim is to see how TAK-062 works to reduce celiac-related symptoms and improve small intestinal damage due to gluten exposure, in participants with celiac disease (CeD) attempting to maintain a gluten-free diet (GFD) in treated participants versus placebo controls.

Detailed Description
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The drug being tested in this study is called TAK-062. TAK-062 is designed to break down gluten in the stomach and is being tested to treat people who have active CeD, attempting to maintain a GFD. The study will enroll approximately 357 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups in Cohort 1: Cohort 1 (Age 18 and older): TAK-062 Placebo + SIGE Gluten-Bar Cohort 1 (Age 18 and older): TAK-062 Dose 1 + SIGE Gluten-Bar After the interim analysis (IA), Cohort 1 data will be reviewed by an external independent data monitoring committee (DMC), and based on the Sponsor's decision, adolescent participants will be enrolled in Cohort 2. Adult participants, 18 years and older will be enrolled into Cohort 2 once Cohort 1 has completed enrolment. Adult participants will be randomly assigned to one of the five study drug and SIGE treatment groups (Groups a-e), and approximately 21 adolescent participants will be enrolled and randomly assigned to Groups d, e, and f (adolescents only). Adolescents in Cohort 2 will receive only gluten-free SIGE bars. Cohort 2 (Age 18 and older): TAK-062 Placebo + SIGE Gluten-Bar Cohort 2 (Age 18 and older): TAK-062 Dose 2 + SIGE Gluten-Bar Cohort 2 (Age 18 and older): TAK-062 Dose 3 + SIGE Gluten-Bar Cohort 2 (Age 12 and older): TAK-062 Placebo + Gluten-free SIGE Bar Cohort 2 (Age 12 and older): TAK-062 Dose 1 + Gluten-free SIGE Bar Cohort 2 (Age 12-17): TAK-062 Dose 2 + Gluten-free SIGE Bar This multi-center trial will be conducted in the United States (US), Canada, United Kingdom and the European Union. The overall time to participate in this study is approximately 36 weeks.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Efficacy and Safety of TAK-062 for the Treatment of Active Celiac Disease in Subjects Attempting a Gluten-Free Diet

Conditions
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Celiac Disease

Intervention / Treatment
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* Drug: TAK-062
* Dietary Supplement: Simulated Inadvertent Gluten Exposure (SIGE) Gluten-Bar
* Drug: TAK-062 Placebo
* Dietary Supplement: Simulated Inadvertent Gluten Exposure (SIGE) Gluten-free Bar


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has an adequate comprehension of a gluten-free diet (GFD) assessed by the site investigator after review of responses to a knowledge test. The final determination of a participant's adequate comprehension of a GFD is at the discretion of the investigator. Has at least 1 CeD-related GI symptom of moderate or greater severity, as measured by the CDSD, on at least 3 days out of any consecutive 7-day period during the screening period (Week -8 visit until Week -4 visit), felt by the investigator to be related to gluten exposure. The CeD-related symptom(s) may vary day by day as long as the severity of at least 1 symptom is moderate or greater. The participants must meet symptom criteria to undergo esophagogastroduodenoscopy (EGD)/video capsule endoscopy (VCE). Has been attempting to maintain a GFD for at least 12 months as self-reported by the participant. Has small intestinal villous atrophy on duodenal biopsy defined as Vh:Cd <2.5 at Week -4. The participant is human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8 positive. The participant is in a good general state of health according to clinical history and physical examination, in the opinion of the investigator. Have a body mass index (BMI) between 16 and 45 kilogram per meter square (kg/m^2), inclusive. Note: Individuals with BMI of 40 to 45 should be discussed with the medical monitor and confirmed to be appropriate for endoscopy according to local site guidelines. The participant is willing and able to continue any current dietary and/or medical regimens (including gastric acid suppression) in effect at the first visit (Visit 1). There should be no changes to diet, medications (prescription or over-the-counter) or supplements during study participation. Exclusion Criteria: Has the presence of other inflammatory GI disorders or systemic autoimmune diseases that either have the potential to cause persistent GI symptoms similar to CeD or are not well controlled without the use of excluded medication. Examples of conditions that are exclusionary include inflammatory bowel disease, eosinophilic esophagitis, gastroenteritis or colitis, microscopic colitis diagnosed at screening or requiring treatment in the 6 months before screening. Examples of conditions that may be permissible after discussion with the medical monitor include systemic autoimmune disease such as scleroderma, psoriatic or rheumatoid arthritis, or lupus that is stable and without GI involvement; well controlled autoimmune thyroid disease; well-controlled type 1 diabetes; or proton pump inhibitor (PPI) responsive eosinophilic esophagitis in symptomatic and histologically confirmed remission. Has ongoing systemic immunosuppressant, systemic corticosteroid treatment excluding medication given for the endoscopies, or treatment with systemic immunosuppressants or systemic corticosteroids in the 12 weeks before Screening. • The participant is receiving immunosuppressive doses of corticosteroids: 3 mg per day or more of budesonide for more than 3 consecutive days within 3 months before Screening, more than 20 mg of prednisone given daily or on alternative days for 2 weeks or more within 90 days before the first dose, any dose of oral or intravenous (IV) corticosteroids within 30 days of the first dose, or high-dose inhaled corticosteroids (>960 micrograms per day [μg/day] of beclomethasone dipropionate or equivalent), or other systemic immunosuppressive agents. Has ongoing use of over-the-counter digestive enzymes or digestive supplements, other than lactase, including those for gluten digestion. Probiotics are allowable if they were started before Screening and not discontinued or changed in dose or type during the study. Has completed the CDSD on ≤75% of the evaluable days during the run-in period until randomization. Has active microscopic colitis requiring treatment in the 6 months before Screening. • Microscopic colitis detected at screening if sigmoidoscopy is performed would exclude the participant. Has known or suspected type 2 refractory CeD or ulcerative jejunitis. Has ongoing chronic use (defined as >7 days continuous use) of a nonsteroidal anti-inflammatory drug aside from <100 mg aspirin, daily, for prophylactic use. Has ongoing use, or use in the 3 months before screening, of medications known to cause villous abnormalities (e.g., mycophenolate mofetil, angiotensin receptor blockers, colchicine). Has used treatments for GI symptoms including antiemetics, antidiarrheals, antispasmodics, medical marijuana, (use of medical marijuana indicated for non-GI conditions is not exclusionary) within 2 weeks of Screening and during the run-in period. Participants on stable dose (i.e., more than 4 weeks) of an osmotic, bulking-forming or emollient (surface active agent) laxative are eligible, provided symptoms are considered not related to CeD in the opinion of the investigator. Has a known or suspected severe enteric infection (viral, bacterial, or parasitic) within 6 months before randomization. Severe enteric infection is defined as requiring emergency room visit or hospitalization or treatment with antibiotics or anti-infectives due to infection. Non enteric viral infections, either resolved or well-controlled are not exclusionary. Has a contraindication to endoscopy with duodenal biopsy. --Contraindication to VCE (strictures, anastomoses, etc) is not an exclusion if the participant is able to complete the other aspects of the study. Has additional food allergies (tapioca syrup, oats, almonds, rice crisp, chocolate, almond, butter, wheat gluten, cocoa butter, oat flour, glycerin, sunflower lecithin, salt, and natural flavors) to nongluten ingredients in the SIGE bar study food or significant symptoms upon ingestion of the gluten-free SIGE bar during screening. Has a history of intolerance, hypersensitivity, or idiosyncratic reaction to an aminoglycoside. Has a known human immunodeficiency virus (HIV) infection or positive tests for hepatitis B or C. The participant has a known clinically significant chronically active hepatopathy of any origin, including cirrhosis, and participants with persistent positive hepatitis B virus surface antigen and quantitative hepatitis B virus polymerase chain reaction (PCR), or positive serology for hepatitis C virus (HCV) and quantitative HCV PCR within 6 months before the screening visit. Is positive for severe acute respiratory syndrome coronavirus 2 at the time of screening and exhibits symptoms that, in the opinion of the investigator, may interfere with study compliance, completion, or accurate assessment of study outcomes or safety. Has a known hypersensitivity reaction and/or allergy, including anaphylaxis, to wheat and/or gluten. Has known history of hypersensitivity, idiosyncratic reaction, or intolerance to any ingredients or excipients in TAK-062 and/or placebo. The participant has a current diagnosis of active malignancy or is receiving treatment for active malignancy (hormone therapy alone is not exclusionary). Participants with fully resected Stage 0 (carcinoma in situ) or Stage 1 tumor without signs of recurrence may participate. All other individuals with malignancies diagnosed in the 5 years prior to screening are excluded. Region-specific Exclusion Criteria: 18. Participant enrolling in a study in France is not affiliated to a social security scheme or a beneficiary of such a scheme. 19. Participant enrolling in a study in France is deprived of their liberty by a judicial or administrative decision.

Ages Eligible for Study
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Minimum Age: 12 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Cohort 1: TAK-062 Placebo + SIGE Gluten-Bar<br>TAK-062 placebo-matching 4 tablets, orally, taken within pre-determined time before the start of a meal and SIGE gluten bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. | Dietary Supplement: Simulated Inadvertent Gluten Exposure (SIGE) Gluten-Bar<br>* SIGE gluten bars.<br>Drug: TAK-062 Placebo<br>* TAK-062 placebo-matching tablets.<br>|
| Experimental: Cohort 1: TAK-062 Dose 1 + SIGE Gluten-Bar<br>TAK-062 Dose 1, 4 tablets, orally, taken within pre-determined time before the start of a meal and SIGE gluten bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. | Drug: TAK-062<br>* TAK-062 tablets.<br>Dietary Supplement: Simulated Inadvertent Gluten Exposure (SIGE) Gluten-Bar<br>* SIGE gluten bars.<br>|
| Placebo Comparator: Cohort 2: TAK-062 Placebo + SIGE Gluten-Bar<br>TAK-062 placebo-matching 4 tablets, orally, taken within pre-determined time before the start of a meal and SIGE gluten bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. | Dietary Supplement: Simulated Inadvertent Gluten Exposure (SIGE) Gluten-Bar<br>* SIGE gluten bars.<br>Drug: TAK-062 Placebo<br>* TAK-062 placebo-matching tablets.<br>|
| Experimental: Cohort 2: TAK-062 Dose 2 + SIGE Gluten-Bar<br>TAK-062 Dose 2, 4 tablets, orally, taken within pre-determined time before the start of a meal and SIGE gluten bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. | Drug: TAK-062<br>* TAK-062 tablets.<br>Dietary Supplement: Simulated Inadvertent Gluten Exposure (SIGE) Gluten-Bar<br>* SIGE gluten bars.<br>|
| Experimental: Cohort 2: TAK-062 Dose 3 + SIGE Gluten-Bar<br>TAK-062 Dose 3, 4 tablets, orally, taken within pre-determined time before the start of a meal and SIGE gluten bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. | Drug: TAK-062<br>* TAK-062 tablets.<br>Dietary Supplement: Simulated Inadvertent Gluten Exposure (SIGE) Gluten-Bar<br>* SIGE gluten bars.<br>|
| Placebo Comparator: Cohort 2: TAK-062 Placebo + Gluten-free SIGE Bar<br>TAK-062 placebo-matching 4 tablets, orally, taken within pre-determined time before the start of a meal and gluten-free SIGE bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. | Drug: TAK-062 Placebo<br>* TAK-062 placebo-matching tablets.<br>Dietary Supplement: Simulated Inadvertent Gluten Exposure (SIGE) Gluten-free Bar<br>* SIGE gluten-free bars.<br>|
| Experimental: Cohort 2: TAK-062 Dose 1 + Gluten-free SIGE Bar<br>TAK-062 Dose 1, 4 tablets, orally, taken within pre-determined time before the start of a meal and gluten-free SIGE bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. | Drug: TAK-062<br>* TAK-062 tablets.<br>Dietary Supplement: Simulated Inadvertent Gluten Exposure (SIGE) Gluten-free Bar<br>* SIGE gluten-free bars.<br>|
| Experimental: Cohort 2: TAK-062 Dose 2 + Gluten-free SIGE Bar<br>TAK-062 4 tablets, orally, taken within pre-determined time before the start of a meal and gluten-free SIGE bar, orally, with a meal, at protocol defined timepoints, for up to 24 weeks. | Drug: TAK-062<br>* TAK-062 tablets.<br>Dietary Supplement: Simulated Inadvertent Gluten Exposure (SIGE) Gluten-free Bar<br>* SIGE gluten-free bars.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Weekly Celiac Disease Symptom Diary (CDSD) Gastrointestinal (GI) Symptom Severity Score from Baseline to Week 12 | 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 severe symptoms. | Baseline (Week -1) to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Villous Height to Crypt Depth Ratio (Vh:Cd) from Baseline to Week 24 | The Vh:Cd ratio represents mucosal architectural changes and a lower Vh:Cd ratio indicates more severe intestinal injury characterized by a flattening of the mucosa. | Baseline (Week -4, Run-in Period) to Week 24 | 
| Percentage of Participants Experiencing at Least One Treatment-Emergent Adverse Event (TEAE), Serious Adverse Events (SAEs) and Treatment-Related TEAEs | Adverse event (AE)= 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. AE can therefore be any unfavorable and unintended sign (e.g., clinically significant abnormal laboratory value, electrocardiogram[ECG] value, or vital sign measurement), symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug. TEAE=new onset or worsening AEs after the first dose of study treatment regardless of relationship to study drug. SAE= any untoward medical occurrence at any dose that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is an important medical event. TEAEs considered related to the study drug as assessed by the Investigator will be reported. | Up to Week 28 | 
| Percentage of Participants with Positive Antidrug Antibodies (ADA) in Serum for TAK-062 | A positive ADA participant is defined as a participant who has at least 1 positive ADA result during the study and is further categorized as: Transiently positive- defined as participants with confirmed positive ADA in at least 1 sample and no consecutive samples; Persistently positive- defined as participants with confirmed positive ADA in 2 or more consecutive positive ADA samples. | Up to Week 28 | 

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