Efficacy and Safety of TD-1473 in Crohn's Disease (DIONE)

• ClinicalTrials.gov Identifier: NCT03635112
• Recruitment Status: Recruiting
• First Posted: August 17, 2018
• Last Update Posted: September 23, 2019
• Sponsor: Theravance Biopharma
• Information provided by (Responsible Party): Theravance Biopharma

Study Description

Brief Summary:

A Phase 2 study to evaluate the efficacy, safety and tolerability of TD-1473 in subjects with moderately-to-severely active Crohn's Disease with up to 42 weeks of treatment.

Condition or disease	Intervention/treatment	Phase
Crohn's Disease	Drug: Placebo; Drug: TD-1473	Phase 2

Detailed Description:

A Phase 2 multi-center, randomized, double blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of 12 weeks of induction therapy with TD˗1473 in subjects with moderately-to-severely active CD. This study includes 3 phases: Screening, Induction, and Active Treatment Extension (ATE). The Induction phase of the study is a randomized, double blind, placebo controlled, parallel group study evaluating 2 oral dose levels of TD-1473 compared to placebo for 12 weeks in subjects with moderately to-severely active CD. Subjects who complete Induction will continue to receive TD-1473 in the ATE, for up to 48 additional weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 160 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Multi-Center, Randomized, Double-Blind, Placebo˗Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Induction Therapy With 2 Doses of TD-1473 in Subjects With Moderately-to-Severely Active Crohn's Disease
• Actual Study Start Date: November 19, 2018
• Estimated Primary Completion Date: February 2020
• Estimated Study Completion Date: September 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Active Treatment TD-1473 with Dose A; 1 oral Dose A daily of TD-1473 for 12 weeks in subjects with moderately to-severely active CD. Subjects who complete Induction will continue to receive TD-1473 at Dose A in the Active Treatment Arm for up to 48 additional weeks.	Drug: TD-1473; TD-1473, at Dose A or Dose B depending upon arm, will be taken daily by mouth (orally) for up to 12 weeks in the morning before eating. An additional 48 weeks either at Dose A or Dose B, depending on arm, may be administered if subjects finish the 12 week induction period.
Active Comparator: Active Treatment TD-1473 with Dose B; 1 oral Dose B daily of TD-1473 for 12 weeks in subjects with moderately to-severely active CD. Subjects who complete Induction will continue to receive TD-1473 at Dose B in the Active Treatment Arm for up to 48 additional weeks.	Drug: TD-1473; TD-1473, at Dose A or Dose B depending upon arm, will be taken daily by mouth (orally) for up to 12 weeks in the morning before eating. An additional 48 weeks either at Dose A or Dose B, depending on arm, may be administered if subjects finish the 12 week induction period.
Placebo Comparator: Placebo; 1 oral dose daily of placebo for 12 weeks in subjects with moderately to-severely active CD. Subjects who complete Induction will receive TD-1473 at Dose A in the Active Treatment Arm for up to 48 additional weeks.	Drug: Placebo; Placebo will be taken daily by mouth (orally) for up to 12 weeks in the morning before eating.; Drug: TD-1473; TD-1473, at Dose A or Dose B depending upon arm, will be taken daily by mouth (orally) for up to 12 weeks in the morning before eating. An additional 48 weeks either at Dose A or Dose B, depending on arm, may be administered if subjects finish the 12 week induction period.

Outcome Measures

Primary Outcome Measures :

1. Improvement in Crohn's Disease Activity Index (CDAI) score from Baseline to Week 12 (PRIMARY) [ Time Frame: 12 weeks ]

   To assess the effect of TD-1473 compared to placebo in improving Crohn's Disease Activity Index (CDAI) score at week 12 in subjects with moderately to severely active CD.

   The CDAI score is generated using regression coefficients for eight different predictors of disease activity: severity of abdominal pain, general well-being, very soft/liquid stool frequency, extra-intestinal symptoms, need for antidiarrheal drugs, presence of an abdominal mass, body weight and hematocrit. Patients will report information regarding symptoms using a diary.

Secondary Outcome Measures :

1. Clinical response measured by CDAI [ Time Frame: 12 weeks ]
   To assess the effects of TD-1473 given for 12 weeks compared to placebo. CDAI clinical response is determined by a CDAI score decreasing from baseline to Week 12 by a defined value or CDAI below a defined value by Week 12. Crohn's Disease Activity Index also known as CDAI is a research tool used to quantify the symptoms of patients with Crohn's disease.
2. CDAI clinical remission [ Time Frame: 12 weeks ]
   To assess the effects of TD-1473 given for 12 weeks compared to placebo. CDAI clinical remission is determined by a CDAI score being less than a defined value at Week 12. Crohn's Disease Activity Index also known as CDAI is a research tool used to quantify the symptoms of patients with Crohn's disease.
3. SES-CD (Simple Endoscopic Score for Crohn's Disease) change from baseline to Week 12 [ Time Frame: 12 weeks ]

   To assess the effects of TD-1473 given for 12 weeks compared to placebo. Simple Endoscopic Score for Crohn's Disease also known as SES-CD provides a quantitative assessment of Crohn's Disease across all 5 bowel segments and allow for comparison across populations and within an individual over time.

   The SES-CD incorporates 4 descriptors: the ulcer size, the proportion of surface covered by ulcer, the proportion of surface covered by other lesions, and the presence of stenosis. Each descriptor is graded from 0-3 and is scored in 5 segments (ileum, right colon, transverse colon, left colon, and rectum). The total score is calculated as the sum of all the items in each segment and can range from 0 to 60.

4. Endoscopic response [ Time Frame: 12 weeks ]

   To assess the effects of TD-1473 given for 12 weeks compared to placebo. Endoscopic Response is determined by a reduction of SES-CD (Simple Endoscopic Score for Crohn's Disease is also known as SES-CD) score or Endoscopic Remission at Week 12.

   Simple Endoscopic Score for Crohn's Disease also known as SES-CD provides a quantitative assessment of Crohn's Disease across all 5 bowel segments and allow for comparison across populations and within an individual over time.

   The SES-CD incorporates 4 descriptors: the ulcer size, the proportion of surface covered by ulcer, the proportion of surface covered by other lesions, and the presence of stenosis. Each descriptor is graded from 0-3 and is scored in 5 segments (ileum, right colon, transverse colon, left colon, and rectum). The total score is calculated as the sum of all the items in each segment and can range from 0 to 60.

5. Stool Frequency and Abdominal Pain (SFAP) clinical remission [ Time Frame: 12 weeks ]
   To assess the effects of TD-1473 given for 12 weeks compared to placebo. Stool Frequency and Abdominal Pain (SFAP) clinical remission is determined using a patient reported Abdominal Pain score [which uses a scale of 0 - 3 with 0 representing 'no pain' and 3 representing 'severe pain'] and patient reported Stool Frequency.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Is at least 18 years of age at screening
• Males and females with clinical evidence of Crohn's disease for at least 3 months duration at screening
• Moderately-to-severely active Crohn's Disease at baseline, as defined by a Crohn's Disease Activity Index (CDAI) score of 220-450 inclusive
• SES-CD score of ≥ 3 with ulceration (corresponding to a score of 1) in at least 1 of the 5 ileocolonic segments on the Ulcerated Surface subscore of the SES-CD]
• Is corticosteroid-dependent or has demonstrated inadequate response, or intolerance to conventional therapy (aminosalicylates, corticosteroids and immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate) or biologics (e.g., anti-TNF therapy, anti-IL-12/23 (anti-interleukin), anti-integrin).
• Additional inclusion criteria apply

Exclusion Criteria:

• Is currently receiving biologic (anti-TNF, anti-integrin, or anti-IL12/23) therapy
• Has a current bacterial, parasitic, fungal, or viral infection
• Has clinically significant abnormalities in laboratory evaluations
• Prior exposure or potential exposure to a JAK inhibitor that was stopped due to intolerance or lack of efficacy
• Subject has participated in another clinical trial of an investigational drug (or medical device) within 30 days prior to Screening or 5x the half-life of the investigational drug, whichever is longer, or is currently participating in another trial of an investigational drug (or medical device)
• Subject has failed ≥ 3 biologic agents of 3 different mechanisms of action (i.e., anti-TNF, anti-integrin, and anti-IL12/23)
• Additional exclusion criteria apply

Contacts and Locations

Contacts

Contact: Theravance Biopharma Call Center; 1-855-633-8479; medinfo@theravance.com

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Sponsors and Collaborators

Theravance Biopharma

Investigators

• Study Director: Medical Monitor; Theravance Biopharma

More Information

• Responsible Party: Theravance Biopharma
• ClinicalTrials.gov Identifier: NCT03635112 History of Changes
• Other Study ID Numbers: 0173; 2018-001272-37 ( EudraCT Number )
• First Posted: August 17, 2018
• Last Update Posted: September 23, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Theravance Biopharma, Inc. will not be sharing individual de-identified participant data or other relevant study documents.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Theravance Biopharma:

TD-1473; Janus kinase inhibitor; JAK inhibitor; Inflammatory Bowel Disease; IBD; Crohn's Disease; Intestinal restriction

Additional relevant MeSH terms:

Crohn Disease; Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases