TAK-018 for Prevention of the Recurrence of Postoperative Crohn's Disease (CD)

• ClinicalTrials.gov Identifier: NCT03943446
• Recruitment Status: Recruiting
• First Posted: May 9, 2019
• Last Update Posted: January 15, 2021
• Sponsor: Millennium Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Takeda ( Millennium Pharmaceuticals, Inc. )

Tracking Information

• First Submitted Date: May 7, 2019
• First Posted Date: May 9, 2019
• Last Update Posted Date: January 15, 2021
• Actual Study Start Date: August 4, 2020
• Estimated Primary Completion Date: April 15, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 18, 2020)

Percentage of Participants With Endoscopic Recurrence of CD as Assessed by Rutgeerts Grading Scale at Week 26 [ Time Frame: Week 26 ]

Endoscopic recurrence is defined as a Rutgeerts' score greater than or equal to (>=) i2. The Rutgeerts scoring is a 5-point scale used to assess endoscopic recurrence at the ileocolonic anastomosis and preanastomotic ileum. The scale ranges from i0 to i4; where i0 equal to (=) no lesions, i1= less than or equal to (<=) 5 aphthous ulcers, i2= greater than (>) 5 aphthous ulcers with normal mucosa between lesions or lesions are confined to the anastomosis, i3= diffuse aphthous ileitis with diffusely inflamed mucosa and i4= diffuse inflammation with larger ulcers, nodules, and/or narrowing.

Original Primary Outcome Measures (submitted: May 7, 2019)

Percentage of Participants who Experience Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From first dose of study drug up to Week 30 ]

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 (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is defined as an untoward medical occurrence, significant hazard, contraindication, side effect or precaution that at any dose: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

Current Secondary Outcome Measures (submitted: February 18, 2020)

• Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 [ Time Frame: Weeks 3, 6, 12, 18, 26 and 30 ]
  Stool samples will be collected for analysis of fecal calprotectin, a biomarker of intestinal inflammatory activity.
• Ctrough: Observed Plasma Trough Concentrations of TAK-018 [ Time Frame: Week 3 pre-dose and at multiple time points (up to 12 hours) post-dose ]

Original Secondary Outcome Measures (submitted: May 7, 2019)

• Percentage of Participants with Severe Endoscopic Recurrence as Assessed by Rutgeerts Scoring Scale at Weeks 12 and 26 [ Time Frame: Weeks 12 and 26 ]
  Severe endoscopic recurrence is defined as a Rutgeerts' score ≥i3 (diffuse aphthous ileitis with diffusely inflamed mucosa). The Rutgeerts scoring is a 5-point scale used to assess endoscopic recurrence at the ileocolonic anastomosis and preanastomotic ileum. The scale ranges from 0-4; where 0= no lesions, 1= ≤5 aphthous ulcers, 2= >5 aphthous ulcers with normal mucosa between lesions or lesions are confined to the anastomosis, 3= diffuse aphthous ileitis with diffusely inflamed mucosa and 4= diffuse inflammation with larger ulcers, nodules, and/or narrowing.
• Percentage of Participants with Endoscopic Remission as Assessed by Rutgeerts Scoring Scale at Weeks 12 and 26 [ Time Frame: Weeks 12 and 26 ]
  Endoscopic remission is defined as a Rutgeerts' score ≤i1 (≤5 aphthous ulcers). The Rutgeerts scoring is a 5-point scale used to assess endoscopic recurrence at the ileocolonic anastomosis and preanastomotic ileum. The scale ranges from 0-4; where 0= no lesions, 1= ≤5 aphthous ulcers, 2= >5 aphthous ulcers with normal mucosa between lesions or lesions are confined to the anastomosis, 3= diffuse aphthous ileitis with diffusely inflamed mucosa and 4= diffuse inflammation with larger ulcers, nodules, and/or narrowing.
• Percentage of Participants With Endoscopic Recurrence as Assessed by Rutgeerts Scoring Scale at Weeks 12 and 26 [ Time Frame: Weeks 12 and 26 ]
  Endoscopic recurrence is defined as a Rutgeerts' score ≥i2 (>5 aphthous ulcers with normal mucosa between lesions or lesions are confined to the anastomosis). The Rutgeerts scoring is a 5-point scale used to assess endoscopic recurrence at the ileocolonic anastomosis and preanastomotic ileum. The scale ranges from 0-4; where 0= no lesions, 1= ≤5 aphthous ulcers, 2= >5 aphthous ulcers with normal mucosa between lesions or lesions are confined to the anastomosis, 3= diffuse aphthous ileitis with diffusely inflamed mucosa and 4= diffuse inflammation with larger ulcers, nodules, and/or narrowing.
• Percentage of Participants With Elevated Fecal Calprotectin at Weeks 3, 6, 12, 18 and 26 [ Time Frame: Weeks 3, 6, 12, 18 and 26 ]
  Stool samples will be collected for analysis of fecal calprotectin, a biomarker of intestinal inflammatory activity.
• Ctrough: Observed Plasma Trough Concentrations of TAK-018 [ Time Frame: Week 3: Predose and at multiple timepoints (Up to 12 hours) postdose ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: TAK-018 for Prevention of the Recurrence of Postoperative Crohn's Disease (CD)
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase 2a Study to Evaluate the Safety, Tolerability, and Early Proof of Concept of TAK-018 for the Prevention of Postoperative Crohn's Disease Recurrence
• Brief Summary: The purpose of this study is to evaluate the efficacy of TAK-018 in reducing endoscopic recurrence of intestinal inflammation in postoperative participants with CD after a planned laparoscopic ileocecal resection with primary anastomosis.

Detailed Description

The drug being tested in this study is called TAK-018. TAK-018 is used for the prevention of postoperative CD recurrence. This study will evaluate the efficacy of TAK-018 in reducing endoscopic recurrence of intestinal inflammation in postoperative participants with CD after planned laparoscopic ileocecal resection with primary anastomosis.

The study will enroll approximately 96 participants. Participants will be randomly assigned (by chance, like flipping a coin) in 1:1:1 ratio to one of the three treatment groups-which will remain undisclosed to the participants and study doctor during the study (unless there is an urgent medical need):

• TAK-018 0.30 g Low dose
• TAK-018 1.5 g High dose
• Placebo

All participants will be asked to take the tablets twice daily immediately after a meal (that is, breakfast and dinner) with water, approximately 8 to 12 hours apart.

Participants will have flexibility to either to opt for home health care (HHC) solutions at Screening, Week 3, Week 6, Week 12, Week 18 and Week 30 or travel to the clinic for all scheduled visits per protocol as permitted by local regulations. This flexible approach is designed in response to health care delivery challenges presented by the coronavirus disease (COVID-19) pandemic and to provide additional flexibility during the course of the trial.

This multi-center trial will be conducted in the United States, United Kingdom, France, Austria and Germany. The overall time to participate in this study is approximately 34 weeks. Participants will make final visit to the clinic or can opt for HHC visit at Week 30 (30 days after the Week 26 endoscopy) for safety follow-up.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention
• Condition: Crohn Disease

Intervention

• Drug: TAK-018
  TAK-018 immediate-release tablets.
  Other Name: EB8018
• Drug: TAK-018 Placebo
  TAK-018 placebo-matching tablets.

Study Arms

• Experimental: TAK-018 0.30 g Low Dose
  TAK-018 3*0.10 gram (g), tablets, orally, twice daily (BID) for up to 26 weeks.
  Intervention: Drug: TAK-018
• Experimental: TAK-018 1.5 g High Dose
  TAK-018 3*0.50 g, tablets, orally, BID for up to 26 weeks.
  Intervention: Drug: TAK-018
• Placebo Comparator: Placebo
  TAK-018 placebo-matching 3*0 g tablets, orally, BID for up to 26 weeks.
  Intervention: Drug: TAK-018 Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 18, 2020): 96
• Original Estimated Enrollment (submitted: May 7, 2019): 75
• Estimated Study Completion Date: May 16, 2022
• Estimated Primary Completion Date: April 15, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Must have a documented diagnosis of CD confirmed by endoscopic biopsy before resection or by tissue obtained at resection.
2. Planned to undergo a laparoscopic ileocecal resection with primary anastomosis within 72 hours before randomization Day 1. Confirmation that no active disease has been left behind after resection will be based on surgeon's documentation in the operative report.
3. With postoperative discontinuation of all concomitant medications specifically related to the treatment of CD. This includes anti-tumor necrosis factor-alpha (TNF-α) and anti-integrin therapy, anti- interleukin (IL) 12/23, thiopurines and other immunomodulators, steroids, 5-minosalicylates, and prophylactic use of antibiotics for the prevention of postoperative recurrence such as metronidazole.
4. Has resumed oral intake and is capable of swallowing tablets after surgery.

Exclusion Criteria:

1. Has active perianal CD.
2. Has had >3 previous surgical procedures for CD.
3. Has macroscopically active CD that was not resected at the time of surgery as documented in the surgeon's operative report.
4. With small bowel resection that exceeds 100 centimeter (cm) or a participant who is considered at risk of short bowel syndrome by the surgeon or investigator.
5. Has active or latent tuberculosis, regardless of treatment history, as evidenced by any of the following: history of tuberculosis, OR positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests, OR a tuberculin skin test reaction >=10 millimeter (mm) (>=5 mm in participants receiving the equivalent of >15 milligram per day (mg/day) prednisone).
6. Has chronic hepatitis B (hepatitis B surface antigen positive, or positive for both hepatitis B surface antibody and hepatitis B core antibody but negative for hepatitis B surface antigen) or hepatitis C infection (evident by viral replication by polymerase chain reaction) within 30 days of randomization.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Takeda Study Registration Call Center; +1-877-825-3327; medinfoUS@takeda.com

• Listed Location Countries: Austria, France, Germany, United Kingdom, United States
• Removed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT03943446
• Other Study ID Numbers: TAK-018-2001; 2019-000886-19 ( EudraCT Number ); U1111-1225-5064 ( Registry Identifier: WHO ); NR266345 ( Registry Identifier: IRAS ); NL71098.018.19 ( Registry Identifier: CCMO )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://vivli.org/ourmember/takeda/

• Responsible Party: Takeda ( Millennium Pharmaceuticals, Inc. )
• Study Sponsor: Millennium Pharmaceuticals, Inc.
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Takeda

• PRS Account: Takeda
• Verification Date: January 2021