Crohn's Disease
Conditions
Keywords
TD-1473, Janus kinase inhibitor, JAK inhibitor, Inflammatory Bowel Disease, IBD, Crohn's Disease, Intestinal restriction
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 48 weeks of treatment.
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 Crohn's Disease. 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.
Interventions
DRUGPlacebo
Placebo will be taken daily by mouth (orally) for up to 12 weeks in the morning before eating.
DRUGTD-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.
Sponsors
Theravance Biopharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Crohn's Disease Activity Index (CDAI) Score | Baseline to Week 12 | The CDAI score was 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. Participants reported information regarding symptoms using a diary. The subscores of abdominal pain (0-3), general well-being (0-4), and number of very soft or liquid stools were then summed over the 7 days prior to each visit. Additionally, the remaining predictors were also noted and weighted to create the total CDAI score which ranged from 0-600 with a higher score indicating a worse outcome. Benchmarks for disease activity as measured by the CDAI were: \<150, clinical remission; 150 to 219, mildly active disease; 220-450, moderately active disease; and \>450, very severe disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Demonstrated a Clinical Response as Measured by CDAI | Week 12 | The CDAI score was 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. Participants reported information regarding symptoms using a diary. The subscores of abdominal pain (0-3), general well-being (0-4), and number of very soft or liquid stools were then summed over the 7 days prior to each visit. Additionally, the remaining predictors were also noted and weighted to create the total CDAI score which ranged from 0-600 with a higher score indicating a worse outcome. Benchmarks for disease activity as measured by the CDAI were: \<150, clinical remission; 150 to 219, mildly active disease; 220-450, moderately active disease; and \>450, very severe disease. Clinical response was defined as a reduction from baseline of ≥100 points or CDAI \<150 |
| Number of Participants Who Demonstrated CDAI Clinical Remission | Week 12 | The CDAI score was 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. Participants reported information regarding symptoms using a diary. The subscores of abdominal pain (0-3), general well-being (0-4), and number of very soft or liquid stools were then summed over the 7 days prior to each visit. Additionally, the remaining predictors were also noted and weighted to create the total CDAI score which ranged from 0-600 with a higher score indicating a worse outcome. Benchmarks for disease activity as measured by the CDAI were: \<150, clinical remission; 150 to 219, mildly active disease; 220-450, moderately active disease; and \>450, very severe disease. CDAI clinical remission was defined as a CDAI score less than 150 at Week 12. |
| Change From Baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD) at Week 12 | Baseline to Week 12 | The SES-CD incorporated 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 was scored in 5 segments (ileum, right colon, transverse colon, left colon, and rectum). The total score ranged from 0 to 56, with higher scores indicating a worse outcome. |
| Number of Participants With Endoscopic Response at Week 12 | Week 12 | Endoscopic Response was defined as a reduction of SES-CD score or Endoscopic Remission (defined as SES-CD ≤ 2) at Week 12. |
| Number of Participants With Stool Frequency and Abdominal Pain (SFAP) Clinical Remission | Week 12 | SFAP clinical remission was defined as an abdominal pain score ≤1 (on a scale of 0-3 with 0 representing 'no pain' and 3 representing 'severe pain'), stool frequency ≤2.8, and both not worse than baseline at Week 12. |
Countries
Australia, Austria, Bulgaria, Croatia, France, Georgia, Germany, Greece, Hungary, Israel, New Zealand, Poland, Portugal, Romania, Russia, Serbia, South Africa, South Korea, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 167 participants were randomized, of which 159 were eligible for analysis at sites in Australia, Asia/Pacific, Israel, Russia, the United States and South Africa between 19 November 2018 and 30 December 2021.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive once-daily oral administrations of placebo for 12 weeks during the Induction Period. Participants who completed the Induction Period received once-daily oral administrations of TD-1473 80 mg in the Active Treatment Extension period for up to 48 additional weeks. | 38 |
| TD-1473 80 mg Participants were randomized to receive once-daily oral administrations of TD-1473 80 mg for 12 weeks during the Induction Period. Participants who completed the Induction Period received once-daily oral administrations of TD-1473 80 mg in the Active Treatment Extension period for up to 48 additional weeks. | 58 |
| TD-1473 200 mg Participants were randomized to receive once-daily oral administrations of TD-1473 200 mg for 12 weeks during the Induction Period. Participants who completed the Induction Period received once-daily oral administrations of TD-1473 200 mg in the Active Treatment Extension period for up to 48 additional weeks. | 63 |
| Total | 159 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 9 | 14 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 |
| Overall Study | Miscellaneous | 0 | 0 | 1 |
| Overall Study | Physician Decision | 5 | 7 | 5 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Study Terminated by Sponsor | 11 | 17 | 21 |
| Overall Study | Withdrawal by Subject | 4 | 9 | 7 |
Baseline characteristics
| Characteristic | Placebo | TD-1473 80 mg | TD-1473 200 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 39.5 years STANDARD_DEVIATION 14.85 | 37.1 years STANDARD_DEVIATION 12.45 | 40.0 years STANDARD_DEVIATION 13.64 | 38.8 years STANDARD_DEVIATION 13.5 |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 36 Participants | 57 Participants | 60 Participants | 153 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Female | 18 Participants | 28 Participants | 31 Participants | 77 Participants |
| Sex: Female, Male Male | 20 Participants | 30 Participants | 32 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 38 | 0 / 58 | 0 / 33 | 0 / 63 |
| other Total, other adverse events | 11 / 38 | 23 / 58 | 7 / 33 | 22 / 63 |
| serious Total, serious adverse events | 3 / 38 | 9 / 58 | 3 / 33 | 10 / 63 |
Outcome results
Primary
Change From Baseline in Crohn's Disease Activity Index (CDAI) Score
The CDAI score was 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. Participants reported information regarding symptoms using a diary. The subscores of abdominal pain (0-3), general well-being (0-4), and number of very soft or liquid stools were then summed over the 7 days prior to each visit. Additionally, the remaining predictors were also noted and weighted to create the total CDAI score which ranged from 0-600 with a higher score indicating a worse outcome. Benchmarks for disease activity as measured by the CDAI were: \<150, clinical remission; 150 to 219, mildly active disease; 220-450, moderately active disease; and \>450, very severe disease.
Time frame: Baseline to Week 12
Population: Modified Intent-to-Treat Analysis Set: Comprised all randomized evaluable participants who received at least 1 dose of study drug, had at least one postbaseline CDAI score and had non-missing values at both baseline and postbaseline visit.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Crohn's Disease Activity Index (CDAI) Score | -104.86 score on a scale | Standard Error 15.496 |
| TD-1473 80 mg | Change From Baseline in Crohn's Disease Activity Index (CDAI) Score | -105.62 score on a scale | Standard Error 12.713 |
| TD-1473 200 mg | Change From Baseline in Crohn's Disease Activity Index (CDAI) Score | -117.99 score on a scale | Standard Error 12.423 |
p-value: 0.9795% CI: [-40.62, 39.11]Mixed Model Repeated Measures Analysis
p-value: 0.5195% CI: [-52.46, 26.19]Mixed Model Repeated Measures Analysis
Secondary
Change From Baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD) at Week 12
The SES-CD incorporated 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 was scored in 5 segments (ileum, right colon, transverse colon, left colon, and rectum). The total score ranged from 0 to 56, with higher scores indicating a worse outcome.
Time frame: Baseline to Week 12
Population: Modified Intent-to-Treat Analysis Set: Comprised all randomized evaluable participants who received at least 1 dose of study drug, had at least one postbaseline CDAI score and had non-missing values at both baseline and postbaseline visit.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD) at Week 12 | -1.9 score on a scale | Standard Error 1.27 |
| TD-1473 80 mg | Change From Baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD) at Week 12 | -0.2 score on a scale | Standard Error 0.96 |
| TD-1473 200 mg | Change From Baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD) at Week 12 | -1.9 score on a scale | Standard Error 0.95 |
p-value: 0.31695% CI: [-1.6, 4.8]ANCOVA
p-value: 0.98895% CI: [-3.2, 3.2]ANCOVA
Secondary
Number of Participants Who Demonstrated a Clinical Response as Measured by CDAI
The CDAI score was 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. Participants reported information regarding symptoms using a diary. The subscores of abdominal pain (0-3), general well-being (0-4), and number of very soft or liquid stools were then summed over the 7 days prior to each visit. Additionally, the remaining predictors were also noted and weighted to create the total CDAI score which ranged from 0-600 with a higher score indicating a worse outcome. Benchmarks for disease activity as measured by the CDAI were: \<150, clinical remission; 150 to 219, mildly active disease; 220-450, moderately active disease; and \>450, very severe disease. Clinical response was defined as a reduction from baseline of ≥100 points or CDAI \<150
Time frame: Week 12
Population: Modified Intent-to-Treat Analysis Set: Comprised all randomized evaluable participants who received at least 1 dose of study drug and had at least one postbaseline CDAI score.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Demonstrated a Clinical Response as Measured by CDAI | 19 Participants |
| TD-1473 80 mg | Number of Participants Who Demonstrated a Clinical Response as Measured by CDAI | 28 Participants |
| TD-1473 200 mg | Number of Participants Who Demonstrated a Clinical Response as Measured by CDAI | 34 Participants |
p-value: 0.510295% CI: [-0.277, 0.135]Cochran-Mantel-Haenszel Chi-square Test
p-value: 0.859195% CI: [-0.181, 0.218]Cochran-Mantel-Haenszel Chi-square Test
Secondary
Number of Participants Who Demonstrated CDAI Clinical Remission
The CDAI score was 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. Participants reported information regarding symptoms using a diary. The subscores of abdominal pain (0-3), general well-being (0-4), and number of very soft or liquid stools were then summed over the 7 days prior to each visit. Additionally, the remaining predictors were also noted and weighted to create the total CDAI score which ranged from 0-600 with a higher score indicating a worse outcome. Benchmarks for disease activity as measured by the CDAI were: \<150, clinical remission; 150 to 219, mildly active disease; 220-450, moderately active disease; and \>450, very severe disease. CDAI clinical remission was defined as a CDAI score less than 150 at Week 12.
Time frame: Week 12
Population: Modified Intent-to-Treat Analysis Set: Comprised all randomized evaluable participants who received at least 1 dose of study drug and had at least one postbaseline CDAI score.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Demonstrated CDAI Clinical Remission | 13 Participants |
| TD-1473 80 mg | Number of Participants Who Demonstrated CDAI Clinical Remission | 13 Participants |
| TD-1473 200 mg | Number of Participants Who Demonstrated CDAI Clinical Remission | 22 Participants |
p-value: 0.180595% CI: [-0.322, 0.061]Cochran-Mantel-Haenszel Chi-square Test
p-value: 0.921595% CI: [-0.204, 0.184]Cochran-Mantel-Haenszel Chi-square Test
Secondary
Number of Participants With Endoscopic Response at Week 12
Endoscopic Response was defined as a reduction of SES-CD score or Endoscopic Remission (defined as SES-CD ≤ 2) at Week 12.
Time frame: Week 12
Population: Modified Intent-to-Treat Analysis Set: Comprised all randomized evaluable participants who received at least 1 dose of study drug and had at least one postbaseline CDAI score.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Endoscopic Response at Week 12 | 6 Participants |
| TD-1473 80 mg | Number of Participants With Endoscopic Response at Week 12 | 5 Participants |
| TD-1473 200 mg | Number of Participants With Endoscopic Response at Week 12 | 15 Participants |
p-value: 0.182895% CI: [-0.27, 0.059]Cochran-Mantel-Haenszel Chi-square Test
p-value: 0.578595% CI: [-0.133, 0.244]Cochran-Mantel-Haenszel Chi-square Test
Secondary
Number of Participants With Stool Frequency and Abdominal Pain (SFAP) Clinical Remission
SFAP clinical remission was defined as an abdominal pain score ≤1 (on a scale of 0-3 with 0 representing 'no pain' and 3 representing 'severe pain'), stool frequency ≤2.8, and both not worse than baseline at Week 12.
Time frame: Week 12
Population: Modified Intent-to-Treat Analysis Set: Comprised all randomized evaluable participants who received at least 1 dose of study drug and had at least one postbaseline CDAI score.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Stool Frequency and Abdominal Pain (SFAP) Clinical Remission | 6 Participants |
| TD-1473 80 mg | Number of Participants With Stool Frequency and Abdominal Pain (SFAP) Clinical Remission | 6 Participants |
| TD-1473 200 mg | Number of Participants With Stool Frequency and Abdominal Pain (SFAP) Clinical Remission | 10 Participants |
p-value: 0.377695% CI: [-0.225, 0.095]Cochran-Mantel-Haenszel Chi-square Test
p-value: 0.606395% CI: [-0.189, 0.111]Cochran-Mantel-Haenszel Chi-square Test