Crohn Disease
Conditions
Keywords
Drug Therapy
Brief summary
The main aim is to see if TAK-018 reduces the recurrence of intestinal inflammation after abdominal resection surgery in adults with Crohn's disease. Participants will take either TAK-018 or placebo tablets by mouth, 2 times each day for up to 26 weeks after surgery. The placebo looks like TAK-018 but will not have any medicine in it. Participants will have 6 study visits while receiving treatment. Visits 1 and 6 will be conducted at the study clinic. The others can be in the clinic or at the participant's home. Follow-up will occur 4 weeks after final treatment.
Detailed description
The drug being tested in this study is called TAK-018 (Sibofimloc). 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. Assessments after surgery and endoscopy at Week 26 will be conducted at the clinic. All other study visits may be conducted by telehealth and home health care (HHC). 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.
Interventions
DRUGTAK-018
TAK-018 immediate-release tablets.
DRUGTAK-018 Placebo
TAK-018 placebo-matching tablets.
Sponsors
Takeda Development Center Americas, Inc.
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 within 72 hours 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Endoscopic Recurrence of CD as Assessed by Rutgeerts Grading Scale at Week 26 | At Week 26 | Endoscopic recurrence (ER) is defined as a Rutgeerts' score ≥ i2. The Rutgeerts scoring is a 5-point scale used to assess endoscopic recurrence at the ileocolonic anastomosis and preanastomotic ileum. The total score ranges from i0 to i4; where i0 = no lesions, i1= ≤ 5 aphthous ulcers, i2= \> 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. Higher score indicates worsening. Percentages are rounded off to the nearest single decimal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Weeks 3, 6, 12, 18, 26 and 30 | Stool samples were collected for analysis of fecal calprotectin, a biomarker of intestinal inflammatory activity. Percentages are rounded off to the nearest single decimal. |
| Ctrough: Observed Plasma Trough Concentrations of TAK-018 | Pre-dose and at multiple time points (up to 12 hours) post-dose at Week 3 | — |
Countries
Austria, France, Germany, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 18 investigative sites in the United States, Australia, Germany, France and United Kingdom from 4 August 2020 to 25 August 2022.
Pre-assignment details
Participants with Crohn's disease (CD) who had undergone a planned laparoscopic ileocecal resection received TAK-018 for prevention of the recurrence of postoperative CD. The participants were randomized in 1:1:1 ratio to three treatment groups i.e. TAK-018 low dose, TAK-018 high dose, or placebo for a 26-week treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo TAK-018 placebo-matching tablets, orally, twice daily (BID) for up to 27.7 weeks. | 12 |
| TAK-018 0.30 g Low Dose TAK-018 0.30 g, tablets, orally, BID for up to 31.7 weeks. | 11 |
| TAK-018 1.5 g High Dose TAK-018 1.5 g, tablets, orally, BID for up to 26.1 weeks. | 11 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Reason not Specified | 5 | 1 | 3 |
| Overall Study | Study Terminated by Sponsor | 1 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | TAK-018 1.5 g High Dose | TAK-018 0.30 g Low Dose |
|---|---|---|---|---|
| Age, Continuous | 42.97 years STANDARD_DEVIATION 13.133 | 39.97 years STANDARD_DEVIATION 13.457 | 39.25 years STANDARD_DEVIATION 11.297 | 37.42 years STANDARD_DEVIATION 16.179 |
| Body Mass Index (BMI) | 24.57 kilogram per meters squared (kg/m^2) STANDARD_DEVIATION 4.617 | 24.85 kilogram per meters squared (kg/m^2) STANDARD_DEVIATION 5.214 | 26.09 kilogram per meters squared (kg/m^2) STANDARD_DEVIATION 6.175 | 23.92 kilogram per meters squared (kg/m^2) STANDARD_DEVIATION 5.037 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 26 Participants | 10 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 1 Participants | 3 Participants |
| Height | 171.87 centimeters (cm) STANDARD_DEVIATION 7.709 | 170.83 centimeters (cm) STANDARD_DEVIATION 8.019 | 172.57 centimeters (cm) STANDARD_DEVIATION 8.594 | 167.95 centimeters (cm) STANDARD_DEVIATION 7.692 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 7 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 10 Participants | 27 Participants | 10 Participants | 7 Participants |
| Region of Enrollment Austria | 4 Participants | 8 Participants | 2 Participants | 2 Participants |
| Region of Enrollment France | 3 Participants | 9 Participants | 1 Participants | 5 Participants |
| Region of Enrollment Germany | 1 Participants | 6 Participants | 4 Participants | 1 Participants |
| Region of Enrollment United Kingdom | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment United States | 4 Participants | 10 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Female | 5 Participants | 17 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Male | 7 Participants | 17 Participants | 8 Participants | 2 Participants |
| Weight | 72.44 kilograms (kg) STANDARD_DEVIATION 13.514 | 72.66 kilograms (kg) STANDARD_DEVIATION 16.394 | 77.95 kilograms (kg) STANDARD_DEVIATION 19.971 | 67.61 kilograms (kg) STANDARD_DEVIATION 15.111 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 11 / 12 | 6 / 11 | 9 / 11 |
| serious Total, serious adverse events | 1 / 12 | 4 / 11 | 2 / 11 |
Outcome results
Primary
Percentage of Participants With Endoscopic Recurrence of CD as Assessed by Rutgeerts Grading Scale at Week 26
Endoscopic recurrence (ER) is defined as a Rutgeerts' score ≥ i2. The Rutgeerts scoring is a 5-point scale used to assess endoscopic recurrence at the ileocolonic anastomosis and preanastomotic ileum. The total score ranges from i0 to i4; where i0 = no lesions, i1= ≤ 5 aphthous ulcers, i2= \> 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. Higher score indicates worsening. Percentages are rounded off to the nearest single decimal.
Time frame: At Week 26
Population: FAS included all participants to whom study treatment had been assigned by randomization and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Endoscopic Recurrence of CD as Assessed by Rutgeerts Grading Scale at Week 26 | 91.7 percentage of participants |
| TAK-018 0.30 g Low Dose | Percentage of Participants With Endoscopic Recurrence of CD as Assessed by Rutgeerts Grading Scale at Week 26 | 81.8 percentage of participants |
| TAK-018 1.5 g High Dose | Percentage of Participants With Endoscopic Recurrence of CD as Assessed by Rutgeerts Grading Scale at Week 26 | 90.9 percentage of participants |
p-value: =0.5995% CI: [-0.44, 0.23]Fisher Exact
p-value: =195% CI: [-0.34, 0.31]Fisher Exact
Secondary
Ctrough: Observed Plasma Trough Concentrations of TAK-018
Time frame: Pre-dose and at multiple time points (up to 12 hours) post-dose at Week 3
Population: Pharmacokinetic (PK) analysis set included participants from the safety analysis set with at least 1 reported PK concentration. Overall number of participants analyzed is the number of participants available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Ctrough: Observed Plasma Trough Concentrations of TAK-018 | 13.8 milligrams per Litre (mg/L) | Standard Deviation 9.39 |
| TAK-018 0.30 g Low Dose | Ctrough: Observed Plasma Trough Concentrations of TAK-018 | 36.2 milligrams per Litre (mg/L) | Standard Deviation 21.7 |
Secondary
Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30
Stool samples were collected for analysis of fecal calprotectin, a biomarker of intestinal inflammatory activity. Percentages are rounded off to the nearest single decimal.
Time frame: At Weeks 3, 6, 12, 18, 26 and 30
Population: FAS included all participants to whom study treatment had been assigned by randomization and received at least 1 dose of study drug. Overall number of participants analyzed is the number of participants available for analyses. Number analyzed indicates number of participants available for analysis at the given timepoints.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 3 | 55.6 percentage of participants |
| Placebo | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 12 | 44.4 percentage of participants |
| Placebo | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 18 | 75.0 percentage of participants |
| Placebo | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 26 | 71.4 percentage of participants |
| Placebo | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 30 | 40.0 percentage of participants |
| Placebo | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 6 | 27.3 percentage of participants |
| TAK-018 0.30 g Low Dose | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 6 | 50.0 percentage of participants |
| TAK-018 0.30 g Low Dose | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 3 | 75.0 percentage of participants |
| TAK-018 0.30 g Low Dose | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 26 | 75.0 percentage of participants |
| TAK-018 0.30 g Low Dose | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 30 | 66.7 percentage of participants |
| TAK-018 0.30 g Low Dose | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 12 | 37.5 percentage of participants |
| TAK-018 0.30 g Low Dose | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 18 | 50.0 percentage of participants |
| TAK-018 1.5 g High Dose | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 12 | 33.3 percentage of participants |
| TAK-018 1.5 g High Dose | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 18 | 60.0 percentage of participants |
| TAK-018 1.5 g High Dose | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 6 | 83.3 percentage of participants |
| TAK-018 1.5 g High Dose | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 26 | 50.0 percentage of participants |
| TAK-018 1.5 g High Dose | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 3 | 42.9 percentage of participants |
| TAK-018 1.5 g High Dose | Percentage of Participants With Fecal Calprotectin (FCP) >135 Microgram Per Gram (mcg/g) at Weeks 3, 6, 12, 18, 26 and 30 | At Week 30 | 25.0 percentage of participants |