Ulcerative Colitis (UC)
Conditions
Keywords
TD-1473, Janus kinase inhibitor, JAK inhibitor, Inflammatory Bowel Disease, IBD, Ulcerative colitis, UC, Gut selective
Brief summary
A Phase 2b/3 set of studies to evaluate the efficacy and safety of induction and maintenance therapy with TD-1473 in subjects with moderately-to-severely active ulcerative colitis with up to 60 weeks of treatment.
Detailed description
This protocol consists of 3 separate studies: an 8-week Phase 2b dose-finding induction study, an 8-week dose-confirming Phase 3 induction study, and a 44-week Phase 3 maintenance study. Subjects who respond to induction will enter the maintenance study; those who do not will receive TD-1473 during extended induction. The safety and efficacy data of the Phase 2b study will be analyzed to select the induction and maintenance dose regimens for the confirmatory Phase 3 studies. Participants who have disease relapse or complete the maintenance study may be eligible to enter a separate long-term safety study. Efficacy, pharmacokinetic, biomarkers, and safety will be evaluated in all 3 studies. 240 subjects are planned for the Phase 2b and the planned Primary Completion Date for this portion of the study is JULY 2021. 640 subjects are planned for the Phase 3 portion of the study.
Interventions
DRUGTD-1473 Dose A
See Arm description
DRUGTD-1473 Dose B
See Arm description
DRUGTD-1473 Dose C
See Arm description
DRUGPlacebo
See Arm description
Sponsors
Theravance Biopharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Integrated and Adaptive Design
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Is at least 18 years of age at screening * Has a history of UC for at least 3 months prior to screening * Has moderately-to-severely active UC, as defined by a Mayo endoscopic subscore of ≥2 points and an adapted Mayo score between 4 - 9 points inclusive * Is corticosteroid-dependent or has demonstrated inadequate response, or intolerance to conventional therapy (aminosalicylates, corticosteroids, immunomodulators) or biologics * Willing to use highly-effective methods of contraception during the study and for 7 days after the last dose * Additional inclusion criteria apply
Exclusion criteria
* Has symptoms suggestive of fulminant colitis, megacolon or intestinal perforation * Likely to require surgery for UC or other major surgeries * Has previously received / is currently receiving prohibited medications within specified timeframe * Is refractory to 3 biologics with ≥2 mechanisms of action * Has a current bacterial, parasitic, fungal, or viral infection * Has clinically significant abnormalities in laboratory evaluations * Has had any prior exposure to an approved Janus kinase (JAK) inhibitor or potential exposure to an investigational JAK inhibitor that was stopped due to intolerance or lack of efficacy * Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Mayo Score (tMS) at Week 8 | Baseline to Week 8 | Total Mayo Score (tMS) was calculated as the sum of four components: rectal bleeding (0-3), stool frequency (0-3), physician's global assessment (0-3) and Mayo endoscopic subscore (0-3). tMS was reported as a 0-12 point score with 12 reflecting the highest severity. |
| Phase 3 Maintenance: Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Maintenance Week (mWeek) 44 | mWeek 44 | Clinical remission by Adapted Mayo score was defined based on Adapted Mayo score components within specific ranges: stool frequency score of 0 or 1, a rectal bleeding subscore of 0 and a Mayo endoscopy subscore of 0 or 1. The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity. Participants with missing Week 44 values were imputed as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Week 8 | Week 8 | Clinical remission by Adapted Mayo score was defined based on Adapted Mayo score components within specific ranges: stool frequency score of 0 or 1, a rectal bleeding subscore of 0 and a Mayo endoscopy subscore of 0 or 1. The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity. |
| Phase 3 Maintenance: Number of Participants Who Demonstrated a Clinical Response by Adapted Mayo Score Components at mWeek 44 | Baseline to mWeek 44 | Clinical response was defined as a reduction from baseline in adapted Mayo score of ≥ 2 points and ≥ 30% relative to baseline. It also required ≥ 1 reduction in the rectal bleeding subscore or an absolute subscore ≤ 1. The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity. Participants with missing Week 44 values were imputed as non-responders. |
| Phase 3 Maintenance: Number of Participants Who Demonstrated Endoscopic Remission by Adapted Mayo Score Components at mWeek 44 | mWeek 44 | Endoscopic remission was defined as an endoscopic subscore ≤ 1. Endoscopic subscore was measured using scale of 0-3, where higher numbers reflected greater severity. |
| Phase 3 Maintenance: Number of Participants Who Demonstrated Symptomatic Remission by Adapted Mayo Score Components at mWeek 44 | mWeek 44 | Symptomatic remission was defined as a stool frequency score ≤ 1 and a rectal bleeding subscore of 0. Stool frequency score and rectal bleeding score were each measured using scale of 0-3, where higher numbers reflected greater severity. Participants with missing Week 44 values were imputed as non-responders. |
Countries
Australia, Bulgaria, Canada, France, Georgia, Germany, Greece, Hungary, Israel, Italy, Japan, Poland, Portugal, Romania, Serbia, Slovakia, South Africa, South Korea, Spain, Taiwan, Ukraine, United States
Participant flow
Recruitment details
A total of 239 participants were enrolled at sites in Europe, Asia/Pacific, the United States, Israel, Australia, and South Africa between 11 March 2019 and 20 October 2021.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive once-daily administrations of placebo for 8 weeks during the Induction Period.
Participants who achieved clinical response by adapted Mayo Score at Week 8 continued to receive blinded placebo in the Maintenance Period. Participants who did not achieve clinical response at Week 8 received 80 mg TD-1473 for 8 weeks in the Extended Induction Period.
Participants who achieved clinical response to a total of 8 weeks of TD-1473 induction therapy, either at Week 8 or Week 16, were re-randomized to received placebo; 20 mg, 80 mg, or 200 mg TD-1473 for 44 weeks in the Maintenance Period. Participants who did not achieve clinical response to a total of 8 weeks of TD-1473 induction therapy underwent study exit procedures. | 61 |
| TD-1473 20 mg Participants were randomized to receive once-daily administrations of 20 mg TD-1473 for 8 weeks during the Induction Period.
Participants who achieved clinical response by adapted Mayo Score at Week 8 continued to receive 20 mg TD-1473 in the Maintenance Period. Participants who did not achieve clinical response at Week 8 continued to receive 20 mg TD-1473 for 8 weeks in the Extended Induction Period.
Participants who achieved clinical response to a total of 16 weeks of TD-1473 induction therapy continued to receive 20 mg TD-1473 for 44 weeks in the Maintenance Period. Participants who did not achieve clinical response to a total of 16 weeks of TD-1473 induction therapy underwent study exit procedures. | 61 |
| TD-1473 80 mg Participants were randomized to receive once-daily administrations of 80 mg TD-1473 for 8 weeks during the Induction Period.
Participants who achieved clinical response by adapted Mayo Score at Week 8 continued to receive 80 mg TD-1473 in the Maintenance Period. Participants who did not achieve clinical response at Week 8 continued to receive 80 mg TD-1473 for 8 weeks in the Extended Induction Period.
Participants who achieved clinical response to a total of 16 weeks of TD-1473 induction therapy continued to receive 80 mg TD-1473 for 44 weeks in the Maintenance Period. Participants who did not achieve clinical response to a total of 16 weeks of TD-1473 induction therapy underwent study exit procedures. | 59 |
| TD-1473 200 mg Participants were randomized to receive once-daily administrations of 200 mg TD-1473 for 8 weeks during the Induction Period.
Participants who achieved clinical response by adapted Mayo Score at Week 8 continued to receive 200 mg TD-1473 in the Maintenance Period. Participants who did not achieve clinical response at Week 8 continued to receive 200 mg TD-1473 for 8 weeks in the Extended Induction Period.
Participants who achieved clinical response to a total of 16 weeks of TD-1473 induction therapy continued to receive 200 mg TD-1473 for 44 weeks in the Maintenance Period. Participants who did not achieve clinical response to a total of 16 weeks of TD-1473 induction therapy underwent study exit procedures. | 58 |
| Total | 239 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Extended Induction Period | Adverse Event | 1 | 1 | 0 | 1 |
| Extended Induction Period | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Extended Induction Period | Miscellaneous | 1 | 0 | 0 | 0 |
| Extended Induction Period | Physician Decision | 2 | 1 | 2 | 2 |
| Extended Induction Period | Protocol Violation | 0 | 0 | 0 | 1 |
| Extended Induction Period | Withdrawal by Subject | 8 | 1 | 7 | 3 |
| Induction Period | Adverse Event | 2 | 4 | 2 | 3 |
| Induction Period | Physician Decision | 1 | 1 | 3 | 0 |
| Induction Period | Protocol Violation | 0 | 0 | 0 | 1 |
| Induction Period | Withdrawal by Subject | 3 | 2 | 2 | 4 |
| Maintenance Period | Adverse Event | 1 | 2 | 0 | 0 |
| Maintenance Period | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Maintenance Period | Miscellaneous | 0 | 0 | 1 | 0 |
| Maintenance Period | Persistent Loss of Response During Maintenance | 3 | 1 | 2 | 0 |
| Maintenance Period | Protocol Violation | 0 | 1 | 0 | 0 |
| Maintenance Period | Study Terminated by Sponsor | 11 | 16 | 9 | 11 |
| Maintenance Period | Withdrawal by Subject | 1 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | TD-1473 200 mg | TD-1473 80 mg | TD-1473 20 mg | Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 41.51 years STANDARD_DEVIATION 14.905 | 44.38 years STANDARD_DEVIATION 14.122 | 42.02 years STANDARD_DEVIATION 15.317 | 38.87 years STANDARD_DEVIATION 14.576 | 40.92 years STANDARD_DEVIATION 15.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 1 Participants | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 224 Participants | 55 Participants | 56 Participants | 59 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 32 Participants | 6 Participants | 6 Participants | 11 Participants | 9 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 6 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 200 Participants | 51 Participants | 51 Participants | 50 Participants | 48 Participants |
| Sex: Female, Male Female | 93 Participants | 29 Participants | 20 Participants | 17 Participants | 27 Participants |
| Sex: Female, Male Male | 146 Participants | 29 Participants | 39 Participants | 44 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 61 | 0 / 61 | 0 / 59 | 0 / 42 | 0 / 58 | 0 / 29 | 0 / 31 | 0 / 25 | 0 / 22 |
| other Total, other adverse events | 7 / 61 | 11 / 61 | 9 / 59 | 4 / 42 | 14 / 58 | 6 / 29 | 14 / 31 | 5 / 25 | 1 / 22 |
| serious Total, serious adverse events | 4 / 61 | 4 / 61 | 2 / 59 | 3 / 42 | 4 / 58 | 1 / 29 | 2 / 31 | 2 / 25 | 1 / 22 |
Outcome results
Primary
Change From Baseline in Total Mayo Score (tMS) at Week 8
Total Mayo Score (tMS) was calculated as the sum of four components: rectal bleeding (0-3), stool frequency (0-3), physician's global assessment (0-3) and Mayo endoscopic subscore (0-3). tMS was reported as a 0-12 point score with 12 reflecting the highest severity.
Time frame: Baseline to Week 8
Population: Modified Intent-to-Treat (mITT) Analysis Set (Induction Period): Comprised all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Induction Period: Placebo | Change From Baseline in Total Mayo Score (tMS) at Week 8 | -1.75 score on a scale | Standard Error 0.341 |
| Induction Period: TD-1473 20 mg | Change From Baseline in Total Mayo Score (tMS) at Week 8 | -2.02 score on a scale | Standard Error 0.35 |
| Induction Period: TD-1473 80 mg | Change From Baseline in Total Mayo Score (tMS) at Week 8 | -2.12 score on a scale | Standard Error 0.351 |
| Induction Period: TD-1473 200 mg | Change From Baseline in Total Mayo Score (tMS) at Week 8 | -2.40 score on a scale | Standard Error 0.346 |
Comparison: Least square estimates, 95% CI, and p-values were obtained by fitting an ANCOVA model with terms for treatment, steroid use at baseline (yes, no) and prior biologic failure (yes, no), and baseline total Mayo score as covariate.p-value: 0.580995% CI: [-1.22, 0.69]ANCOVA
Comparison: Least square estimates, 95% CI, and p-values were obtained by fitting an ANCOVA model with terms for treatment, steroid use at baseline (yes, no) and prior biologic failure (yes, no), and baseline total Mayo score as covariate.p-value: 0.450195% CI: [-1.33, 0.59]ANCOVA
Comparison: Least square estimates, 95% CI, and p-values were obtained by fitting an ANCOVA model with terms for treatment, steroid use at baseline (yes, no) and prior biologic failure (yes, no), and baseline total Mayo score as covariate.p-value: 0.180995% CI: [-1.6, 0.3]ANCOVA
Primary
Phase 3 Maintenance: Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Maintenance Week (mWeek) 44
Clinical remission by Adapted Mayo score was defined based on Adapted Mayo score components within specific ranges: stool frequency score of 0 or 1, a rectal bleeding subscore of 0 and a Mayo endoscopy subscore of 0 or 1. The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity. Participants with missing Week 44 values were imputed as non-responders.
Time frame: mWeek 44
Population: mITT Analysis Set (Maintenance Period): All participants randomized into the Phase 3 Maintenance Study who were also treated. Only participants randomized at least 44 weeks prior to database lock were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction Period: Placebo | Phase 3 Maintenance: Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Maintenance Week (mWeek) 44 | 4 Participants |
| Induction Period: TD-1473 20 mg | Phase 3 Maintenance: Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Maintenance Week (mWeek) 44 | 3 Participants |
| Induction Period: TD-1473 80 mg | Phase 3 Maintenance: Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Maintenance Week (mWeek) 44 | 5 Participants |
| Induction Period: TD-1473 200 mg | Phase 3 Maintenance: Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Maintenance Week (mWeek) 44 | 3 Participants |
p-value: 0.3762Fisher Exact
p-value: 1Fisher Exact
p-value: 1Fisher Exact
Secondary
Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Week 8
Clinical remission by Adapted Mayo score was defined based on Adapted Mayo score components within specific ranges: stool frequency score of 0 or 1, a rectal bleeding subscore of 0 and a Mayo endoscopy subscore of 0 or 1. The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity.
Time frame: Week 8
Population: mITT Analysis Set (Induction Period): Comprised all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction Period: Placebo | Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Week 8 | 6 Participants |
| Induction Period: TD-1473 20 mg | Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Week 8 | 6 Participants |
| Induction Period: TD-1473 80 mg | Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Week 8 | 4 Participants |
| Induction Period: TD-1473 200 mg | Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Week 8 | 4 Participants |
p-value: 0.954295% CI: [-0.104, 0.11]Cochran-Mantel-Haenszel
p-value: 0.586395% CI: [-0.126, 0.071]Cochran-Mantel-Haenszel
p-value: 0.540895% CI: [-0.131, 0.069]Cochran-Mantel-Haenszel
Secondary
Phase 3 Maintenance: Number of Participants Who Demonstrated a Clinical Response by Adapted Mayo Score Components at mWeek 44
Clinical response was defined as a reduction from baseline in adapted Mayo score of ≥ 2 points and ≥ 30% relative to baseline. It also required ≥ 1 reduction in the rectal bleeding subscore or an absolute subscore ≤ 1. The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity. Participants with missing Week 44 values were imputed as non-responders.
Time frame: Baseline to mWeek 44
Population: mITT Analysis Set (Maintenance Period): All participants randomized into the Phase 3 Maintenance Study who were also treated. Only participants randomized at least 44 weeks prior to database lock were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction Period: Placebo | Phase 3 Maintenance: Number of Participants Who Demonstrated a Clinical Response by Adapted Mayo Score Components at mWeek 44 | 5 Participants |
| Induction Period: TD-1473 20 mg | Phase 3 Maintenance: Number of Participants Who Demonstrated a Clinical Response by Adapted Mayo Score Components at mWeek 44 | 5 Participants |
| Induction Period: TD-1473 80 mg | Phase 3 Maintenance: Number of Participants Who Demonstrated a Clinical Response by Adapted Mayo Score Components at mWeek 44 | 8 Participants |
| Induction Period: TD-1473 200 mg | Phase 3 Maintenance: Number of Participants Who Demonstrated a Clinical Response by Adapted Mayo Score Components at mWeek 44 | 6 Participants |
p-value: 0.6656Fisher Exact
p-value: 0.6424Fisher Exact
p-value: 0.6199Fisher Exact
Secondary
Phase 3 Maintenance: Number of Participants Who Demonstrated Endoscopic Remission by Adapted Mayo Score Components at mWeek 44
Endoscopic remission was defined as an endoscopic subscore ≤ 1. Endoscopic subscore was measured using scale of 0-3, where higher numbers reflected greater severity.
Time frame: mWeek 44
Population: mITT Analysis Set (Maintenance Period): All participants randomized into the Phase 3 Maintenance Study who were also treated. Only participants randomized at least 44 weeks prior to database lock were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction Period: Placebo | Phase 3 Maintenance: Number of Participants Who Demonstrated Endoscopic Remission by Adapted Mayo Score Components at mWeek 44 | 3 Participants |
| Induction Period: TD-1473 20 mg | Phase 3 Maintenance: Number of Participants Who Demonstrated Endoscopic Remission by Adapted Mayo Score Components at mWeek 44 | 1 Participants |
| Induction Period: TD-1473 80 mg | Phase 3 Maintenance: Number of Participants Who Demonstrated Endoscopic Remission by Adapted Mayo Score Components at mWeek 44 | 3 Participants |
| Induction Period: TD-1473 200 mg | Phase 3 Maintenance: Number of Participants Who Demonstrated Endoscopic Remission by Adapted Mayo Score Components at mWeek 44 | 2 Participants |
p-value: 1Fisher Exact
p-value: 0.2643Fisher Exact
p-value: 1Fisher Exact
Secondary
Phase 3 Maintenance: Number of Participants Who Demonstrated Symptomatic Remission by Adapted Mayo Score Components at mWeek 44
Symptomatic remission was defined as a stool frequency score ≤ 1 and a rectal bleeding subscore of 0. Stool frequency score and rectal bleeding score were each measured using scale of 0-3, where higher numbers reflected greater severity. Participants with missing Week 44 values were imputed as non-responders.
Time frame: mWeek 44
Population: mITT Analysis Set (Maintenance Period): All participants randomized into the Phase 3 Maintenance Study who were also treated. Only participants randomized at least 44 weeks prior to database lock were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Induction Period: Placebo | Phase 3 Maintenance: Number of Participants Who Demonstrated Symptomatic Remission by Adapted Mayo Score Components at mWeek 44 | 5 Participants |
| Induction Period: TD-1473 20 mg | Phase 3 Maintenance: Number of Participants Who Demonstrated Symptomatic Remission by Adapted Mayo Score Components at mWeek 44 | 7 Participants |
| Induction Period: TD-1473 80 mg | Phase 3 Maintenance: Number of Participants Who Demonstrated Symptomatic Remission by Adapted Mayo Score Components at mWeek 44 | 7 Participants |
| Induction Period: TD-1473 200 mg | Phase 3 Maintenance: Number of Participants Who Demonstrated Symptomatic Remission by Adapted Mayo Score Components at mWeek 44 | 5 Participants |
p-value: 1Fisher Exact
p-value: 1Fisher Exact
p-value: 1Fisher Exact