Long-Term Study Of CP-690,550 In Subjects With Ulcerative Colitis

A MULTI-CENTER, OPEN-LABEL STUDY OF CP-690,550 IN SUBJECTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01470612

Acronym

OCTAVE

Enrollment

944

Registered

2011-11-11

Start date

2012-10-01

Completion date

2020-08-06

Last updated

2021-09-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Ulcerative Colitis

Keywords

Ulcerative colitis, open-label, long term treatment

Brief summary

This study is an open label, long-term extension study for subjects with moderate to severe ulcerative colitis designed to evaluate long term therapy of CP-690,550.

Interventions

DRUGCP-690,550

5 mg tablets, BID, for at least 12 months

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Subjects who completed induction studies A3921094 or A3921095 and were classified as not meeting clinical response criteria; OR * Subjects who completed maintenance study A3921096 or who discontinued treatment early in Study A3921096 due to treatment failure.

Exclusion criteria

* Subjects who had a major protocol violation in Study A3921094, A3921095 or A3921096. * Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, or clinical findings suggestive of Crohn's disease. * Subjects who have had surgery for ulcerative colitis or in the opinion of the investigator, are likely to require surgery for ulcerative colitis during the study period.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Baseline up to 28 days after last dose of study drug (up to 81 months for Tofacitinib 5 mg BID group and up to 85 months for Tofacitinib 10 mg BID group)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 81 months for Tofacitinib 5 mg BID group and up to 85 months for Tofacitinib 10 mg BID group that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and all non-serious AEs.
Number of Participants With Serious Infections as Treatment Emergent Adverse Events (TEAEs)	Baseline up to 28 days after last dose of study drug (up to 81 months for Tofacitinib 5 mg BID group and up to 85 months for Tofacitinib 10 mg BID group)	Serious infections were treated infections that required parenteral antimicrobial therapy or hospitalization for treatment or; met other criteria that required the infection to be classified as a serious adverse event (SAE). SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 81 months for Tofacitinib 5 mg BID group and up to 85 months for Tofacitinib 10 mg BID group that were absent before treatment or that worsened relative to pretreatment state.
Number of Participants With Laboratory Test Abnormalities	Baseline up to 28 days after last dose of study drug (up to 81 months for Tofacitinib 5 mg BID group and up to 85 months for Tofacitinib 10 mg BID group)	Laboratory abnormalities: Hemoglobin, hematocrit, RBC: \<0.8\* LLN; reticulocytes (absolute \[Abs\], %): \<0.5\* LLN, \>1.5\* ULN; MCV, MCH: \<0.9\* LLN, \>1.1\* ULN; platelets:\<0.5\* LLN, \>1.75\* ULN; WBC:\<0.6\* LLN,\>1.5\* ULN; lymphocytes (Abs, %), total neutrophils (Abs,%):\<0.8\* LLN, \>1.2\* ULN; Basophils (Abs,%),eosinophils(Abs, %),monocytes(Abs, %):\>1.2\* ULN; total bilirubin,direct bilirubin,indirect bilirubin:\>1.5\* ULN; AST,ALT,gamma GT, LDH,ALP: \>3.0\* ULN; total protein,albumin: \<0.8\* LLN,\>1.2\* ULN: BUN,creatinine: \>1.3\* ULN;uric acid:\>1.2\* ULN; cholesterol,triglycerides: \>1.3\* ULN; cholesterol (HDL: \<0.8\* LLN; LDL: \>1.2\* ULN); sodium: \<0.95\* LLN, \>1.05\* ULN; potassium, chloride, calcium, bicarbonate: \<0.9\* LLN, \>1.1\* ULN; glucose: \<0.6\* LLN; creatine kinase \>2.0\* ULN; urine specific gravity: \<1.003; urine pH: \<4.5; urine (glucose,protein,blood,nitrite,leukocyte,esterase): \>=1; Urine (RBC,WBC): \>=20; urine epithelial cells:\>=6; urine (casts,granular casts,hyaline casts): \>1; urine bacteria:\>20.
Number of Participants With Vital Sign Abnormalities	Baseline up to 28 days after last dose of study drug (up to 81 months for Tofacitinib 5 mg BID group and up to 85 months for Tofacitinib 10 mg BID group)	Vital sign abnormalities included greater than or equal to (\>=) 30 millimeter of mercury \[mmHg\] increase in systolic blood pressure (BP), \>=30 mmHg decrease in systolic BP, Systolic BP (less than \[\<\] 90 mmHg), \>=20 mmHg increase in diastolic BP, \>=20 mmHg decrease in diastolic BP, diastolic BP (\<50 mmHg), pulse rate (\<40 beats per minute \[BPM\]), pulse rate (greater than \[\>\] 120 BPM).
Number of Participants With Clinically Significant Changes in Physical Examinations From Baseline	Baseline up to 28 days after last dose of study drug (up to 81 months for Tofacitinib 5 mg BID group and up to 85 months for Tofacitinib 10 mg BID group)	Physical examinations included weight, general appearance, head, ears, eyes, nose, mouth, throat, thyroid, skin (presence of rash), lungs (auscultation), heart (auscultation for presence of murmurs, gallops, rubs, peripheral edema), abdominal (palpation and auscultation), perianal, musculoskeletal, extremities, neurologic (mental status, gait, reflexes, motor and sensory function, coordination) and lymph nodes. Clinically significant changes were judged by the investigator.
Number of Participants With Electrocardiogram (ECG) Abnormalities	Baseline up to 28 days after last dose of study drug (up to 81 months for Tofacitinib 5 mg BID group and up to 85 months for Tofacitinib 10 mg BID group)	ECG abnormalities criteria: maximum PR interval (\>=300 millisecond); maximum QRS complex (\>=200 millisecond); and maximum QT interval (\>=500 millisecond).
Incidence Rates for Adjudicated Cardiovascular, Malignancy, Opportunistic Infections and Thromboembolic Safety Events	Baseline up to 28 days after last dose of study drug (up to 81 months for Tofacitinib 5 mg BID group and up to 85 months for Tofacitinib 10 mg BID group)	Incidence rates for adjudicated cardiovascular (major adverse cardiovascular event \[MACE\]), malignancy (non-melanoma skin cancer \[NMSC\], malignancies excluding NMSC, opportunistic infections (OIs) (both herpes zoster and non herpes zoster OIs) and thromboembolic (venous thromboembolism) safety events were analyzed. This outcome measure was measured in participants with events per 100 participants-years (pt with events/100 pts-yrs).

Secondary

Measure	Time frame	Description
Number of Participants Who Achieved Mucosal Healing at Months 2, 12, 24 and 36: Non-responder Imputation- Last Observation Carried Forward (NRI-LOCF)	Months 2, 12, 24 and 36	Mucosal healing in participants was defined as mayo endoscopic sub score of 0 or 1. The mayo endoscopic sub score consisted of the findings of flexible sigmoidoscopy, graded from 0 to 3 with higher sub scores indicating higher disease severity.
Number of Participants in Remission at Months 2, 12, 24 and 36: Observed Cases	Months 2, 12, 24 and 36	Remission in participants was defined as a total Mayo score of less than or equals to (\<=) 2, with no individual sub score exceeding 1 point and a rectal bleeding sub score of 0. Mayo score was an instrument designed to measure disease activity of ulcerative colitis (UC). It consisted of 4 sub scores: stool frequency, rectal bleeding, findings of flexible sigmoidoscopy and physician global assessment (PGA), each sub score graded from 0 to 3 with higher scores indicated higher disease severity. These sub scores were summed up to give a total Mayo score range of 0 to 12, where higher score indicated more severe disease.
Number of Participants With Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score >=170 at Months 2, 6, 12, 18, 24, 30, 36, 48, 60, 72 and 84: Non-responder Imputation- Last Observation Carried Forward (NRI-LOCF)	Months 2, 6, 12, 18, 24, 30, 36, 48, 60, 72 and 84	IBDQ was a psychometrically validated patient reported outcome (PRO) instrument for measuring the disease-specific quality of life in participants with inflammatory bowel disease (IBD), including ulcerative colitis consisted of 32 items scored from 1 (worst response) to 7 (best response). For each domain, higher score indicates better quality of life (QOL). Total IBDQ score was the sum of each item score, and ranged from 32 to 224 with a higher score indicated better QOL.
Number of Participants in Remission at Months 2, 12, 24 and 36: Non-responder Imputation- Last Observation Carried Forward (NRI-LOCF)	Months 2, 12, 24 and 36	Remission in participants was defined as a total Mayo score of \<=2, with no individual sub score exceeding 1 point and a rectal bleeding sub score of 0. Mayo score was an instrument designed to measure disease activity of UC. It consisted of 4 sub scores: stool frequency, rectal bleeding, findings of flexible sigmoidoscopy and PGA, each sub score graded from 0 to 3 with higher scores indicated higher disease severity. These sub scores were summed up to give a total Mayo score range of 0 to 12, where higher score indicated more severe disease.
Number of Participants in Clinical Remission at Months 2, 12, 24 and 36: Observed Cases	Months 2, 12, 24 and 36	Clinical remission in participants was defined as a total Mayo score of \<=2 with no individual sub score exceeding 1 point. Mayo score was an instrument designed to measure disease activity of UC. It consisted of 4 sub scores: stool frequency, rectal bleeding, findings of flexible sigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicated higher disease severity. These sub scores were summed up to give a total Mayo score range of 0 to 12, where higher score indicated more severe disease.
Number of Participants in Clinical Remission at Months 2, 12, 24 and 36: Non-responder Imputation- Last Observation Carried Forward (NRI-LOCF)	Months 2, 12, 24 and 36	Clinical remission in participants was defined as a total Mayo score of \<=2 with no individual sub score exceeding 1 point. Mayo score was an instrument designed to measure disease activity of UC. It consisted of 4 sub scores: stool frequency, rectal bleeding, findings of flexible sigmoidoscopy and PGA, each graded from 0 to 3 with higher scores indicated higher disease severity. These sub scores were summed up to give a total Mayo score range of 0 to 12, where higher score indicated more severe disease.
Number of Participants in Partial Mayo Score (PMS) Remission at Months 1, 4, 6, 9, 15, 18, 21, 27, 30, 33, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81 and 84: Observed Cases	Months 1, 4, 6, 9, 15, 18, 21, 27, 30, 33, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81 and 84	PMS was an instrument designed to measure disease activity of UC without endoscopy. It consisted of 3 sub scores: stool frequency, rectal bleeding and PGA, each sub score graded from 0 to 3 with higher scores indicated higher disease severity. These sub scores were summed up to give a total score range of 0 to 9, where higher score indicated more severe disease. PMS remission was defined as a partial Mayo score \<=2 with no individual sub score \>1.
Number of Participants in Partial Mayo Score (PMS) Remission at Months 1, 4, 6, 9, 15, 18, 21, 27, 30, 33, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81 and 84: Non-responder Imputation- Last Observation Carried Forward (NRI-LOCF)	Months 1, 4, 6, 9, 15, 18, 21, 27, 30, 33, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81 and 84	PMS was an instrument designed to measure disease activity of UC without endoscopy. It consisted of 3 sub scores: stool frequency, rectal bleeding and PGA, each sub score graded from 0 to 3 with higher scores indicated higher disease severity. These sub scores were summed up to give a total PMS score range of 0 to 9, where higher score indicated more severe disease. PMS remission was defined as a partial Mayo score \<=2 with no individual sub score \>1.
Number of Participants Who Achieved Mucosal Healing at Months 2, 12, 24 and 36: Observed Cases	Months 2, 12, 24 and 36	Mucosal healing in participants was defined as Mayo endoscopic sub score of 0 or 1. The Mayo endoscopic sub score consisted of the findings of flexible sigmoidoscopy, graded from 0 to 3 with higher sub scores indicated higher disease severity.

Countries

Australia, Austria, Belgium, Brazil, Canada, Colombia, Croatia, Czechia, Denmark, Estonia, France, Germany, Hungary, Israel, Italy, Japan, Latvia, Netherlands, New Zealand, Poland, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Taiwan, Ukraine, United Kingdom, United States

Participant flow

Recruitment details

Participants enrolled in this Study A3921139: 1) who had completed or had early withdrawal due to treatment failure in Study A3921096 (NCT01458574) 2) or who were non-responders after completing induction studies A3921094 (NCT01465763) or A3921095 (NCT01458951). Eligible participants assigned to either Tofacitinib 5 mg BID or 10 mg BID depending if participant was in remission at baseline of A3921139. Remission=total Mayo score \<=2 with no individual sub score \>1, rectal bleeding sub score =0.

Pre-assignment details

Treatment failure for Study A3921096 was an increase in Mayo score of \>=3 points from baseline value, with an increase in rectal bleeding sub score by \>=1 point, and an increase of endoscopic sub score of \>=1 point after a minimum of 8 weeks treatment. If endoscopic sub score and baseline endoscopic sub score was 3 (maximum value), then an increase by \>=1 point was not needed for treatment failure. But all other components of the treatment failure criteria were needed to be met.

Participants by arm

Arm	Count
Tofacitinib 5 mg BID Participants who completed Study A3921096 and were in remission at Week 52 of Study A3921096, received Tofacitinib 5 milligram (mg) tablets twice daily (BID) for maximum of 80 months in this Study A3921139.	175
Tofacitinib 10 mg BID Participants who had completed Study A3921096 and not in remission, or who had early withdrawal due to treatment failure from Study A3921096, or who were non responders after completing A3921094 or A3921095 received Tofacitinib 10 mg tablets twice daily for maximum of 84 months in this Study A3921139.	769
Total	944

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	20	80
Overall Study	Death	0	1
Overall Study	Did not meet entrance criteria	0	1
Overall Study	Lack of Efficacy	20	326
Overall Study	Lost to Follow-up	2	5
Overall Study	Other	14	156
Overall Study	Pregnancy	2	10
Overall Study	Protocol Violation	2	7
Overall Study	Withdrawal by Subject	24	79

Baseline characteristics

Characteristic	Tofacitinib 5 mg BID	Tofacitinib 10 mg BID	Total
Age, Continuous	44.5 years STANDARD_DEVIATION 14.6	40.5 years STANDARD_DEVIATION 13.5	41.2 years STANDARD_DEVIATION 13.8
Race/Ethnicity, Customized Asian	25 Participants	97 Participants	122 Participants
Race/Ethnicity, Customized Black	0 Participants	9 Participants	9 Participants
Race/Ethnicity, Customized Other	9 Participants	24 Participants	33 Participants
Race/Ethnicity, Customized Unspecified	5 Participants	24 Participants	29 Participants
Race/Ethnicity, Customized White	136 Participants	615 Participants	751 Participants
Sex: Female, Male Female	79 Participants	310 Participants	389 Participants
Sex: Female, Male Male	96 Participants	459 Participants	555 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 175	6 / 769
other Total, other adverse events	134 / 175	550 / 769
serious Total, serious adverse events	39 / 175	147 / 769

Outcome results

Primary

Incidence Rates for Adjudicated Cardiovascular, Malignancy, Opportunistic Infections and Thromboembolic Safety Events

Incidence rates for adjudicated cardiovascular (major adverse cardiovascular event \[MACE\]), malignancy (non-melanoma skin cancer \[NMSC\], malignancies excluding NMSC, opportunistic infections (OIs) (both herpes zoster and non herpes zoster OIs) and thromboembolic (venous thromboembolism) safety events were analyzed. This outcome measure was measured in participants with events per 100 participants-years (pt with events/100 pts-yrs).