Ulcerative Colitis
Conditions
Keywords
tofacitinib, CP-690, 550, Moderate to severe ulcerative colitis, phase 3 clinical trial, Mayo score
Brief summary
This study is designed to evaluate the efficacy and safety of tofacitinib (CP-690,550) in patients with moderate to severe ulcerative colitis who have failed or be intolerant to one of following treatments for ulcerative colitis: oral steroids, azathiopurine/6-mercaptopurine, or anti-TNF-alpha therapy.
Interventions
DRUGtofacitinib
10 mg oral BID
DRUGPlacebo
Plabebo oral BID
Sponsors
Pfizer
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
* Subject must be at least 18 years of age. * Males and females with a documented diagnosis of UC at least 4 months prior to entry into the study. * Subjects with moderately to severely active UC based on Mayo score criteria. * Subjects must have failed or be intolerant of at least one of the following treatments for UC: * Corticosteroids (oral or intravenous). * Azathioprine or 6 mercaptopurine (6 MP). * Anti TNF-alpha therapy.
Exclusion criteria
* Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, or clinical findings suggestive of Crohn's disease. * Subjects with disease limited to distal 15 cm. * Subjects without previous treatment for UC (ie, treatment naïve). * Subjects displaying clinical signs of fulminant colitis or toxic megacolon.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Remission at Week 8 | Week 8 | Remission in participants was defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a rectal bleeding subscore of 0. Mayo score is an instrument designed to measure disease activity of ulcerative colitis (UC). It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and physician global assessment (PGA), each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher scores indicating more severe disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Clinical Response at Week 8 | Week 8 | Clinical response in participants was defined by a decrease from baseline in Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher scores indicating more severe disease. |
| Percentage of Participants With Endoscopic Remission at Week 8 | Week 8 | Endoscopic remission in participants was defined by Mayo endoscopic subscore of 0. The Mayo endoscopic subscore consisted of the findings of centrally read flexible proctosigmoidoscopy, graded from 0 to 3 with higher scores indicating more severe disease. |
| Percentage of Participants With Clinical Remission at Week 8 | Week 8 | Clinical remission in participants was defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher scores indicating more severe disease. |
| Percentage of Participants With Symptomatic Remission at Week 8 | Week 8 | Symptomatic remission in participants was defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, and 0 subscore for both rectal bleeding and stool frequency. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher scores indicating more severe disease. |
| Percentage of Participants Achieving Mucosal Healing at Week 8 | Week 8 | Mucosal healing in participants was defined by Mayo endoscopic subscore of 0 or 1. The Mayo endoscopic subscore consisted of the findings of centrally read flexible proctosigmoidoscopy, graded from 0 to 3 with higher scores indicating more severe disease. |
| Partial Mayo Scores | Baseline, Weeks 2, 4, 8 | A Partial Mayo Score (mayo score without endoscopy) graded from 0 (normal or inactive disease) to 9 (severe disease) and calculated as the sum of 3 subscores (stool frequency, rectal bleeding and PGA) with each grading from 0 to 3 with higher scores indicating more severe disease. |
| Change From Baseline in Partial Mayo Scores at Weeks 2, 4 and 8 | Baseline, Weeks 2, 4, 8 | Change in partial mayo scores at weeks 2, 4, 8 relative to baseline were reported. A Partial Mayo Score (mayo score without endoscopy) graded from 0 (normal or inactive disease) to 9 (severe disease) and calculated as the sum of 3 subscores (stool frequency, rectal bleeding and PGA) with each grading from 0 to 3 with higher scores indicating more severe disease. |
| Change From Baseline in Total Mayo Scores at Week 8 | Baseline, Week 8 | Change in total Mayo scores at Week 8 relative to Baseline was reported. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher scores indicating more severe disease. |
| Percentage of Participants With Deep Remission at Week 8 | Week 8 | Deep remission in participants was defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and 0 subscore for both rectal bleeding and endoscopic subscores. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher scores indicating more severe disease. |
Countries
Australia, Austria, Belgium, Canada, Colombia, Croatia, Czechia, Denmark, Estonia, France, Germany, Hungary, Israel, Italy, Japan, Latvia, Netherlands, New Zealand, Poland, Romania, Russia, Serbia, Slovakia, South Africa, Spain, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
Participants were randomized to tofacitinib 10 milligram (mg) or placebo twice a day (BID)(4:1 ratio) after protocol amendment 3, which removed tofacitinib 15 mg BID. Due to low participant numbers, tofacitinib 15 mg BID was excluded from efficacy analyses, but was included in participant flow, baseline characteristics and adverse events analyses.
Participants by arm
| Arm | Count |
|---|---|
| Tofacitinib 10 mg BID Participants received tofacitinib 10 mg, tablets, orally, BID for 9 weeks of double blind treatment period. | 476 |
| Tofacitinib 15 mg BID Participants received tofacitinib 15 mg, tablets, orally, BID for 9 weeks of double blind treatment period. | 16 |
| Placebo BID Participants received tofacitinib-matched placebo tablets, orally, BID for 9 weeks of double blind treatment period. | 122 |
| Total | 614 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 0 | 1 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Insufficient Clinical Response | 11 | 0 | 1 |
| Overall Study | Other | 2 | 0 | 0 |
| Overall Study | Protocol Violation | 4 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 0 | 1 |
Baseline characteristics
| Characteristic | Tofacitinib 10 mg BID | Tofacitinib 15 mg BID | Placebo BID | Total |
|---|---|---|---|---|
| Age, Customized 18 to 44 Years | 295 participants | 11 participants | 72 participants | 378 participants |
| Age, Customized 45 to 64 Years | 145 participants | 4 participants | 39 participants | 188 participants |
| Age, Customized Greater Than or Equal to (>=) 65 Years | 36 participants | 1 participants | 11 participants | 48 participants |
| Sex: Female, Male Female | 199 Participants | 7 Participants | 45 Participants | 251 Participants |
| Sex: Female, Male Male | 277 Participants | 9 Participants | 77 Participants | 363 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 148 / 476 | 12 / 16 | 38 / 122 |
| serious Total, serious adverse events | 16 / 476 | 0 / 16 | 5 / 122 |
Outcome results
Primary
Percentage of Participants With Remission at Week 8
Remission in participants was defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a rectal bleeding subscore of 0. Mayo score is an instrument designed to measure disease activity of ulcerative colitis (UC). It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and physician global assessment (PGA), each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher scores indicating more severe disease.
Time frame: Week 8
Population: Full analysis set (FAS) included all participants randomly assigned to either tofacitinib 10 mg BID or placebo BID.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tofacitinib 10 mg BID | Percentage of Participants With Remission at Week 8 | 18.5 percentage of participants |
| Placebo BID | Percentage of Participants With Remission at Week 8 | 8.2 percentage of participants |
Comparison: P-value based on Cochran-Mantel-Haenszel (CMH) chi-square test stratified by prior treatment with anti-tumor necrosis factor (TNF), steroid use at baseline and geographic region. Difference and its 95% CI based on normal approximation for the difference in binomial proportions. Missing data were imputed using Non-responder imputation (NRI).p-value: 0.00795% CI: [4.3, 16.3]CMH Chi-square test
Secondary
Change From Baseline in Partial Mayo Scores at Weeks 2, 4 and 8
Change in partial mayo scores at weeks 2, 4, 8 relative to baseline were reported. A Partial Mayo Score (mayo score without endoscopy) graded from 0 (normal or inactive disease) to 9 (severe disease) and calculated as the sum of 3 subscores (stool frequency, rectal bleeding and PGA) with each grading from 0 to 3 with higher scores indicating more severe disease.
Time frame: Baseline, Weeks 2, 4, 8
Population: FAS included all participants randomly assigned to either tofacitinib 10 mg BID or placebo BID. Here, 'n' signifies those participants who were evaluable at specified time point for each arm, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tofacitinib 10 mg BID | Change From Baseline in Partial Mayo Scores at Weeks 2, 4 and 8 | Change at Week 2: (n= 464, 121) | -2.1 units on a scale | Standard Error 0.1 |
| Tofacitinib 10 mg BID | Change From Baseline in Partial Mayo Scores at Weeks 2, 4 and 8 | Change at week 4: (n= 460, 117) | -2.8 units on a scale | Standard Error 0.1 |
| Tofacitinib 10 mg BID | Change From Baseline in Partial Mayo Scores at Weeks 2, 4 and 8 | Change at week 8: (n= 448, 118) | -3.1 units on a scale | Standard Error 0.1 |
| Placebo BID | Change From Baseline in Partial Mayo Scores at Weeks 2, 4 and 8 | Change at Week 2: (n= 464, 121) | -1.2 units on a scale | Standard Error 0.2 |
| Placebo BID | Change From Baseline in Partial Mayo Scores at Weeks 2, 4 and 8 | Change at week 4: (n= 460, 117) | -1.6 units on a scale | Standard Error 0.2 |
| Placebo BID | Change From Baseline in Partial Mayo Scores at Weeks 2, 4 and 8 | Change at week 8: (n= 448, 118) | -1.6 units on a scale | Standard Error 0.2 |
Comparison: At Week 2: The change from baseline was analyzed using mixed effect model with treatment group, prior treatment with antiTNF, steroid use at baseline, geographic region, visit and visit by treatment group all as fixed effects, and participants as a random effect.p-value: <0.000195% CI: [-1.3, -0.5]Mixed-Effects Model
Comparison: At Week 4: The change from baseline was analyzed using mixed effect model with treatment group, prior treatment with antiTNF, steroid use at baseline, geographic region, visit and visit by treatment group all as fixed effects, and participants as a random effect.p-value: <0.000195% CI: [-1.5, -0.7]Mixed-Effects Model
Comparison: At Week 8: The change from baseline was analyzed using mixed effect model with treatment group, prior treatment with antiTNF, steroid use at baseline, geographic region, visit and visit by treatment group all as fixed effects, and participants as a random effect.p-value: <0.000195% CI: [-1.9, -1.1]Mixed-Effects Model
Secondary
Change From Baseline in Total Mayo Scores at Week 8
Change in total Mayo scores at Week 8 relative to Baseline was reported. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher scores indicating more severe disease.
Time frame: Baseline, Week 8
Population: FAS included all participants randomly assigned to either tofacitinib 10 mg BID or placebo BID. Here, 'n' signifies those participants who were evaluable at specified time point for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tofacitinib 10 mg BID | Change From Baseline in Total Mayo Scores at Week 8 | Baseline (n= 472, 121) | 9.0 units on a scale | Standard Deviation 1.4 |
| Tofacitinib 10 mg BID | Change From Baseline in Total Mayo Scores at Week 8 | Change at Week 8 (n= 443, 117) | -3.8 units on a scale | Standard Deviation 2.8 |
| Placebo BID | Change From Baseline in Total Mayo Scores at Week 8 | Baseline (n= 472, 121) | 9.1 units on a scale | Standard Deviation 1.4 |
| Placebo BID | Change From Baseline in Total Mayo Scores at Week 8 | Change at Week 8 (n= 443, 117) | -1.9 units on a scale | Standard Deviation 2.5 |
Comparison: The change from Baseline at Week 8 was analyzed using an analysis of covariance (ANCOVA) model with treatment group, prior treatment with anti-TNF, steroid use at baseline and geographic region as factors and baseline as a covariate based on the observed-case data.p-value: <0.000195% CI: [-2.5, -1.4]ANCOVA
Secondary
Partial Mayo Scores
A Partial Mayo Score (mayo score without endoscopy) graded from 0 (normal or inactive disease) to 9 (severe disease) and calculated as the sum of 3 subscores (stool frequency, rectal bleeding and PGA) with each grading from 0 to 3 with higher scores indicating more severe disease.
Time frame: Baseline, Weeks 2, 4, 8
Population: FAS included all participants randomly assigned to either tofacitinib 10 mg BID or placebo BID. Here, 'n' signifies those participants who were evaluable at specified time point for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tofacitinib 10 mg BID | Partial Mayo Scores | Baseline: (n= 475, 121) | 6.3 units on a scale | Standard Deviation 1.2 |
| Tofacitinib 10 mg BID | Partial Mayo Scores | At Week 2: (n= 465, 122) | 4.2 units on a scale | Standard Deviation 2.2 |
| Tofacitinib 10 mg BID | Partial Mayo Scores | At Week 4: (n= 461, 118) | 3.5 units on a scale | Standard Deviation 2.3 |
| Tofacitinib 10 mg BID | Partial Mayo Scores | At week 8: (n= 449, 119) | 3.2 units on a scale | Standard Deviation 2.4 |
| Placebo BID | Partial Mayo Scores | At week 8: (n= 449, 119) | 4.8 units on a scale | Standard Deviation 2.5 |
| Placebo BID | Partial Mayo Scores | Baseline: (n= 475, 121) | 6.5 units on a scale | Standard Deviation 1.2 |
| Placebo BID | Partial Mayo Scores | At Week 4: (n= 461, 118) | 4.8 units on a scale | Standard Deviation 2.4 |
| Placebo BID | Partial Mayo Scores | At Week 2: (n= 465, 122) | 5.2 units on a scale | Standard Deviation 2.1 |
Secondary
Percentage of Participants Achieving Clinical Response at Week 8
Clinical response in participants was defined by a decrease from baseline in Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher scores indicating more severe disease.
Time frame: Week 8
Population: FAS included all participants randomly assigned to either tofacitinib 10 mg BID or placebo BID.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tofacitinib 10 mg BID | Percentage of Participants Achieving Clinical Response at Week 8 | 59.9 percentage of participants |
| Placebo BID | Percentage of Participants Achieving Clinical Response at Week 8 | 32.8 percentage of participants |
Comparison: P-value based on CMH chi-square test stratified by prior treatment with anti-TNF, steroid use at baseline and geographic region. Difference and its 95% CI based on normal approximation for the difference in binomial proportions. Missing data were imputed using NRI.p-value: <0.000195% CI: [17.7, 36.5]CMH Chi-square test
Secondary
Percentage of Participants Achieving Mucosal Healing at Week 8
Mucosal healing in participants was defined by Mayo endoscopic subscore of 0 or 1. The Mayo endoscopic subscore consisted of the findings of centrally read flexible proctosigmoidoscopy, graded from 0 to 3 with higher scores indicating more severe disease.
Time frame: Week 8
Population: FAS included all participants randomly assigned to either tofacitinib 10 mg BID or placebo BID.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tofacitinib 10 mg BID | Percentage of Participants Achieving Mucosal Healing at Week 8 | 31.3 percentage of participants |
| Placebo BID | Percentage of Participants Achieving Mucosal Healing at Week 8 | 15.6 percentage of participants |
Comparison: P-value based on CMH chi-square test stratified by prior treatment with anti-TNF, steroid use at baseline and geographic region. Difference and its 95% CI based on normal approximation for the difference in binomial proportions. Missing data were imputed using NRI.p-value: 0.000595% CI: [8.1, 23.4]CMH Chi-square test
Secondary
Percentage of Participants With Clinical Remission at Week 8
Clinical remission in participants was defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher scores indicating more severe disease.
Time frame: Week 8
Population: FAS included all participants randomly assigned to either tofacitinib 10 mg BID or placebo BID.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tofacitinib 10 mg BID | Percentage of Participants With Clinical Remission at Week 8 | 18.5 percentage of participants |
| Placebo BID | Percentage of Participants With Clinical Remission at Week 8 | 8.2 percentage of participants |
Comparison: P-value based on CMH chi-square test stratified by prior treatment with anti-TNF, steroid use at baseline and geographic region. Difference and its 95% CI based on normal approximation for the difference in binomial proportions. Missing data were imputed using NRI.p-value: 0.00795% CI: [4.3, 16.3]CMH Chi-square test
Secondary
Percentage of Participants With Deep Remission at Week 8
Deep remission in participants was defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and 0 subscore for both rectal bleeding and endoscopic subscores. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher scores indicating more severe disease.
Time frame: Week 8
Population: FAS included all participants randomly assigned to either tofacitinib 10 mg BID or placebo BID.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tofacitinib 10 mg BID | Percentage of Participants With Deep Remission at Week 8 | 6.5 percentage of participants |
| Placebo BID | Percentage of Participants With Deep Remission at Week 8 | 0 percentage of participants |
Comparison: P-value based on CMH chi-square test stratified by prior treatment with anti-TNF, steroid use at baseline and geographic region. Difference and its 95% CI based on normal approximation for the difference in binomial proportions. Missing data were imputed using NRI.p-value: 0.004395% CI: [4.3, 8.7]CMH Chi-square test
Secondary
Percentage of Participants With Endoscopic Remission at Week 8
Endoscopic remission in participants was defined by Mayo endoscopic subscore of 0. The Mayo endoscopic subscore consisted of the findings of centrally read flexible proctosigmoidoscopy, graded from 0 to 3 with higher scores indicating more severe disease.
Time frame: Week 8
Population: FAS included all participants randomly assigned to either tofacitinib 10 mg BID or placebo BID.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tofacitinib 10 mg BID | Percentage of Participants With Endoscopic Remission at Week 8 | 6.7 percentage of participants |
| Placebo BID | Percentage of Participants With Endoscopic Remission at Week 8 | 1.6 percentage of participants |
Comparison: P-value based on CMH chi-square test stratified by prior treatment with anti-TNF, steroid use at baseline and geographic region. Difference and its 95% CI based on normal approximation for the difference in binomial proportions. Missing data were imputed using NRI.p-value: 0.034595% CI: [1.9, 8.3]CMH Chi-square test
Secondary
Percentage of Participants With Symptomatic Remission at Week 8
Symptomatic remission in participants was defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, and 0 subscore for both rectal bleeding and stool frequency. Mayo score is an instrument designed to measure disease activity of UC. It consisted of 4 subscores: stool frequency, rectal bleeding, findings of centrally read flexible proctosigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicating more severe disease. These scores were summed up to give a total score range of 0 to 12; where higher scores indicating more severe disease.
Time frame: Week 8
Population: FAS included all participants randomly assigned to either tofacitinib 10 mg BID or placebo BID.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tofacitinib 10 mg BID | Percentage of Participants With Symptomatic Remission at Week 8 | 11.8 percentage of participants |
| Placebo BID | Percentage of Participants With Symptomatic Remission at Week 8 | 5.7 percentage of participants |
Comparison: P-value based on CMH chi-square test stratified by prior treatment with anti-TNF, steroid use at baseline and geographic region. Difference and its 95% CI based on normal approximation for the difference in binomial proportions. Missing data were imputed using NRI.p-value: 0.060195% CI: [1, 11.1]CMH Chi-square test