Study To Evaluate The Efficacy And Safety Of Oral PF-06651600 And PF-06700841 In Subjects With Moderate To Severe Crohn's Disease
- Conditions
- Crohn's Disease
- Interventions
- Registration Number
- NCT03395184
- Lead Sponsor
- Pfizer
- Brief Summary
The objectives of this study are to evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06651600 (200 mg for 8 weeks followed by 50 mg for 4 weeks) dosed once daily and PF-06700841 (60 mg for 12 weeks) dosed once daily during an induction period of 12 weeks, followed by an open label extension period at doses of 50 mg and 30 mg of PF 06651600 and PF 06700841, respectively, for 52 weeks.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 244
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Male and/or female subjects 18 years to 75 years of age
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Documented diagnosis of ileal, ileocolonic, or colonic CD with a minimum disease duration of 3 months, as determined by endoscopic and histopathology assessment.
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Endoscopic confirmation of active disease with total SES CD total score of at least 7. For isolated ileal disease, SES CD total score should be at least 4.
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An average daily liquid/soft stool frequency (SF) greater than or equal to 2.5 or daily abdominal pain (AP) greater than or equal to 2.0.
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Must have inadequate response to, loss of response to, or intolerance to at least one conventional therapy for CD:
•Steroids; Immunosuppressants (azathioprine [AZA], 6 MP, or methotrexate [MTX]); Anti TNF inhibitors (infliximab, adalimumab,certolizumab); Anti integrin inhibitors (eg, vedolizumab); Anti IL 12/23 inhibitor (ustekinumab).
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Subjects currently receiving the following treatment for CD are eligible providing they have been on stable doses as described below:
- Oral corticosteroids (prednisone or equivalent up to 25 mg/day; budesonide up to 9 mg/day). Stable dose for at least 2 weeks prior to baseline. If oral corticosteroids have been recently discontinued, they must have been stopped at least 2 weeks prior to baseline. Decreases in steroid use due to AEs are allowed.
- Oral 5 ASA or sulfasalazine are allowed providing that the dose is stable for at least 4 weeks prior to baseline.
- Crohn's disease related antibiotics are allowed providing that the dose is stable for at least 4 weeks prior to baseline. If antibiotics are stopped prior to baseline, they must be discontinued at least 4 days prior to baseline.
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Diagnosis of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis, diverticular disease, ulcerative colitis (UC), or clinical findings suggestive of UC.
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Presence of active (draining) fistulae or intra abdominal or perineal abscesses.
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Strictures with obstructive symptoms.
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Short bowel syndrome.
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History of bowel perforation requiring surgical intervention within the past 12 months.
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Previous bowel surgery resulting in an existing stoma. Subjects who have a j pouch are excluded, as a j pouch can result in a stoma.
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History of bowel surgery within 6 months prior to baseline.
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Subjects displaying clinical signs of fulminant colitis or toxic megacolon.
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Subjects with primary sclerosing cholangitis.
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Subjects with evidence of colonic adenomas, dysplasia or neoplasia.
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Abnormal findings on the chest x ray film such as presence of tuberculosis (TB), general infections, heart failure, or malignancy.
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Any history of either untreated or inadequately treated latent or active TB infection, current treatment for active or latent TB infection or evidence of currently active TB by chest x ray, residing with or frequent close contact with individual(s) with active TB.
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Subjects receiving the following therapies within the time period described below or expected to receive any of these therapies during the study period:
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>9 mg/day of oral budesonide or >25 mg/day of prednisone or equivalent oral systemic corticosteroid dose within 2 weeks prior to baseline.
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IV, IM (parenteral), or topical (rectal) treatment of 5 ASA or corticosteroid enemas/suppositories within 2 weeks prior to baseline.
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Azathioprine, 6 mercaptopurine, or methotrexate within 2 weeks prior to baseline.
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Anti TNF inhibitors (or biosimilars thereof) as described below:
- Infliximab within 8 weeks prior to baseline;
- Adalimumab within 8 weeks prior to baseline;
- Certolizumab within 8 weeks prior to baseline;
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Anti integrin inhibitors (eg, vedolizumab) within 8 weeks prior to baseline.
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Ustekinumab within 8 weeks prior to baseline.
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Interferon therapy within 8 weeks prior to baseline.
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Subjects with prior treatment with lymphocyte depleting agents/therapies within 1 year prior to baseline (eg, CamPath[alemtuzumab], alkylating agents [eg, cyclophosphamide or chlorambucil], total lymphoid irradiation, etc).
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Subjects who have received rituximab or other selective B lymphocyte depleting agents within 1 year prior to baseline.
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Subjects previously receiving leukocyte apheresis, including selective lymphocyte, monocyte, or granulocyte apheresis, or plasma exchange within 6 months prior to baseline.
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Other marketed immunosuppressants or biologics with immunomodulatory properties within 3 months prior to baseline.
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Subjects who have received other JAK inhibitors within 3 months prior to baseline.
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Subjects who have not responded to or have been intolerant of other JAK inhibitors.
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Other investigational procedures(s) or product(s), such as immunosuppressants used in transplantation (eg, mycophenolate mofetil, cyclosporine, rapamycin, or tacrolimus) or live (attenuated) vaccine within 30 days prior to baseline.
- Subjects with history of thrombotic event(s), including deep venous thrombosis (DVT), and known inherited conditions that predispose to hypercoagulability.
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Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description PF-06700841 or placebo Placebo PF-06700841 - PF-06700841 or placebo PF-06700841 - PF-06651600 or placebo PF-06651600 Placebo - PF-06651600 or placebo PF-06651600 -
- Primary Outcome Measures
Name Time Method Percentage of Participants Achieving Greater Than or Equal to (>=) 50 Percent (%) Reduction in Simple Endoscopic Score for Crohn's Disease (SES CD50) at Week 12: Induction Period Week 12 SES CD50 was defined as 50% improvement from baseline in SES-CD. Baseline was defined as last measurement prior to first dosing on Day 1. Following bowel segments were used for calculating SES-CD scores: Ileum, right colon(C), transverse C, left C and rectum. Each segment assessed for four domains: presence of ulcers, ulcerated surface, affected surface and presence of narrowing, each scored on a scale of 0 to 3, higher scores indicated more severe condition. Presence of ulcers score: 0=none, 1=small ulcer: (0.1-0.5 centimeter\[cm\]), 2=Large ulcer(0.5-2 cm), 3=very large ulcer(\>2 cm); ulcerated surface score: 0=none, 1=\<10%, 2=10-30% and 3=\>30%; affected surface score: 0=unaffected segment, 1=\<50%, 2=50-75% and 3=\>75%; presence of narrowing score: 0=none,1=single, can be passed, 2=multiple, can be passed and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments and ranged from 0 to 60, higher score indicating more severe disease.
Number of Participants With Laboratory Test Abnormalities During OLE Period From start of study intervention in OLE period up to 4 weeks after last dose of study intervention (up to 56 weeks) Pre-specified criteria for lab abnormalities included- hematology: hemoglobin(Hb), erythrocytes (ery),hematocrit:\<0.8\*lower limit of normal(LLN);reticulocytes: \<0.5\*LLN, \>1.5\*upper limit of normal(ULN); ery mean corpuscular(EMC) volume: \<0.9\*ULN, \>1.11\*ULN;EMC Hb: \<0.9\*LLN; platelets:\>1.75\*ULN; leukocytes(10\^9/L): \<0.6\*LLN,\>1.5\*ULN;lymphocyte,neutrophil(10\^9/L):\<0.8\*LLN,\>1.2\*ULN;basophil,eosinophil,monocyte(10\^9/L):\>1.2\*ULN;activated partial thromboplastin time (sec): \>1.1\*ULN. Chemistry: bilirubin(mg/dL),aspartate aminotransferase(AT),alanine AT(units per litre)\>3.0\*ULN; protein, albumin(g/dL):\<0.8\*LLN; creatinine, triglycerides (mg/dL):\>1.3\*ULN; urate(mg/dL):\>1.2\*ULN, potassium (mEq/L):\<0.9\*LLN; calcium (mg/dL): \<0.9\*LLN,\>1.1\*ULN. Urinalysis: pH\>8;urine,glucose,protein(mg/dl); ketones, nitrite, urine Hb(scalar):\>=1. Number of participants with any lab abnormality meeting pre-specified criteria are reported.
Number of Participants According to Categorization of Vital Signs During OLE Period From start of study intervention in OLE period up to 4 weeks after last dose of study intervention (up to 56 weeks) Vital signs including blood pressure (diastolic blood pressure \[DBP\], systolic blood pressure \[SBP\], and pulse rate \[PR\]) were measured in a supine position using automated devices. DBP included value \< 50 (millimeter of mercury \[mmHg\]), change \>=20 (mmHg) increase and change \>=20 (mmHg) decrease; SBP: value \< 90 (mmHg), change \>= 30 (mmHg) increase and change \>= 30 (mmHg) decrease; PR: value \> 120 (beats per minute \[bpm\]).
Number of Participants With Abnormal Clinically Significant Electrocardiogram Findings During OLE Period From start of study intervention in OLE period up to 4 weeks after last dose of study intervention (up to 56 weeks) Single twelve lead ECGs were obtained using an automated ECG machine after participant had rested quietly for at least 10 minutes in a supine position. QTc prolongations were defined as a QTc \>=480 milli second (msec) or an absolute change in QTc greater than (\>) 60 msec. Clinically significant ECG findings were determined by the investigator.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) During OLE Period From start of study intervention in OLE period up to 4 weeks after last dose of study intervention (up to 56 weeks) An adverse event (AE) was any untoward medical occurrence in a study participant administered a study intervention; the event need not necessarily have a causal relationship with the treatment or usage. An AE was considered TEAE to a given treatment if the event started during the effective duration of treatment regardless of whether a similar event of equal or greater severity existed in the baseline period.
Number of Participants With Treatment Emergent Serious Adverse Events (TESAE) During OLE Period From start of study intervention in OLE period up to 4 weeks after last dose of study intervention (up to 56 weeks) A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions) or resulted in congenital anomaly/birth defect or was considered an important medical event. An SAE was considered as TESAE if the event started during the effective duration of treatment regardless of whether a similar event of equal or greater severity existed in the baseline period.
Number of Participants With Discontinuations Due to Adverse Events During OLE Period From start of study intervention in OLE period up to 4 weeks after last dose of study intervention (up to 56 weeks) An AE was any untoward medical occurrence in a study participant administered a study intervention; the event need not necessarily have a causal relationship with the treatment or usage. Discontinuations from study due to TEAEs were defined as participants with an AE record indicating the AE caused permanent discontinuation from the study but action taken with study treatment was not drug withdrawn. Permanent discontinuations from any study intervention due to TEAEs were defined as participants with an AE record indicating that action taken with study treatment was drug withdrawn. In this outcome measure number of participants with discontinuation from study due to AEs and permanent discontinuation from study intervention due to AEs are reported.
- Secondary Outcome Measures
Name Time Method Number of Participants With Laboratory Test Abnormalities During Induction Period From start of study intervention on Day 1 up to Week 12 Pre-specified criteria for lab abnormalities included- hematology: hemoglobin, erythrocytes, hematocrit:\<0.8\*LLN; reticulocytes: \<0.5\*LLN, \>1.5\*ULN; EMC volume: \<0.9\*ULN, \>1.11\*ULN;EMC Hb: \<0.9\*LLN; platelets:\>1.75\*ULN; leukocytes(10\^9/L): \<0.6\*LLN, \>1.5\*ULN; lymphocyte, neutrophil(10\^9/L):\<0.8\*LLN, \>1.2\*ULN; basophil, eosinophil, monocyte(10\^9/L):\>1.2\*ULN; activated partial thromboplastin time (sec): \>1.1\*ULN. Chemistry: bilirubin(mg/dL),aspartate aminotransferase(AT),alanine AT(units per litre)\>3.0\*ULN; protein, albumin(g/dL):\<0.8\*LLN; creatinine, triglycerides (mg/dL):\>1.3\*ULN; urate(mg/dL):\>1.2\*ULN, potassium (mEq/L):\<0.9\*LLN; calcium (mg/dL): \<0.9\*LLN,\>1.1\*ULN. Urinalysis: pH\>8; urine, glucose, protein(mg/dl); ketones, nitrite, urine Hb(scalar):\>=1. Number of participants with any lab abnormality meeting pre-specified criteria are reported.
Number of Participants According to Categorization of Vital Signs During Induction Period From start of study intervention on Day 1 up to Week 12 Vital signs including blood pressure (diastolic blood pressure \[DBP\], systolic blood pressure \[SBP\], and pulse rate \[PR\]) were measured in a supine position using automated devices. DBP included value \< 50 (mmHg), change \>=20 (mmHg) increase and change \>=20 (mmHg) decrease; SBP: value \< 90 (mmHg), change \>= 30 (mmHg) increase and PR: value \> 120 (bpm).
Number of Participants With Abnormal Clinically Significant Electrocardiogram Findings During Induction Period From start of study intervention on Day 1 up to Week 12 Single twelve lead ECGs were obtained using an automated ECG machine after participant had rested quietly for at least 10 minutes in a supine position. QTc prolongations were defined as a QTc greater than or equal to (\>=)480 milli second (msec) or an absolute change in QTc greater than (\>)60 msec. Clinically significant ECG findings were determined by the investigator.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) During Induction Period From start of study intervention on Day 1 up to Week 12 An AE was any untoward medical occurrence in a study participant administered a study intervention; the event need not necessarily have a causal relationship with the treatment or usage. An AE was considered TEAE to a given treatment if the event started during the effective duration of treatment regardless of whether a similar event of equal or greater severity existed in the baseline period.
Number of Participants With Treatment Emergent Serious Adverse Events (TESAE) During Induction Period From start of study intervention on Day 1 up to Week 12 A SAE was any untoward medical occurrence at any dose that: resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions) or resulted in congenital anomaly/birth defect or was considered an important medical event. An SAE was considered as TESAE if the event started during the effective duration of treatment regardless of whether a similar event of equal or greater severity existed in the baseline period.
Number of Participants Discontinuation Due to Adverse Events During Induction Period From start of study intervention on Day 1 up to Week 12 An AE was any untoward medical occurrence in a study participant administered a study intervention; the event need not necessarily have a causal relationship with the treatment or usage. Discontinuations from study due to TEAEs were defined as participants with an AE record indicating the AE caused permanent discontinuation from the study but action taken with study treatment was not drug withdrawn. Permanent discontinuations from any study intervention due to TEAEs were defined as participants with an AE record indicating that action taken with study treatment was drug withdrawn. In this outcome measure number of participants with discontinuation from study due to AEs and permanent discontinuation from study intervention due to AEs are reported.
Number of Participants With Serious Infections During Induction Period From start of study intervention on Day 1 up to Week 12 Participants were monitored for development of any infection (viral, bacterial and fungal). Serious infections were treated infections that required parenteral antimicrobial therapy and were present with positive pre-treatment culture and required hospitalization for treatment/met other criteria that required the infection to be classified as SAE. An SAE was any untoward medical occurrence at any dose that: resulted in death; is life-threatening; requires inpatient hospitalization/prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity/results in congenital anomaly/birth defect. Treated infections were infections that required antimicrobial therapy by any route of administration/required any surgical intervention (e.g., incision and drainage).
Percentage of Participants Who Achieved Clinically Meaningful Endoscopic Improvement (CMEI) (Reduction of >=3 Points From Baseline in SES-CD Score) at Week 12: Induction Period Week 12 CMEI was defined as reduction of \>=3 points from baseline in SES-CD score as assessed by centrally read SES-CD score. Baseline: last measurement prior to first dosing on Day1. Following bowel segments were used for calculating SES-CD scores: Ileum, right C, transverse C, left C and rectum. Each segment assessed for 4 domains: presence of ulcers, ulcerated surface, affected surface and presence of narrowing, each scored on scale of 0-3, higher scores indicated more severe condition. Presence of ulcers score: 0=none,1=small ulcer: (0.1-0.5cm),2=Large ulcer(0.5-2cm),3=very large ulcer(\>2cm); ulcerated surface score: 0=none,1=\<10%,2=10-30% and 3=\>30%; affected surface score: 0=unaffected segment, 1=\<50%, 2=50-75% and 3=\>75%; presence of narrowing score: 0=none,1=single, can be passed, 2=multiple, can be passed and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments and ranged from 0 to 60, higher score indicating more severe disease.
Mean Change From Baseline in SES-CD Score at Week 12: Induction Period Baseline and Week 12 Mean change from baseline in SES-CD score at Week 12 analyzed using analysis of covariance(ANCOVA)model with treatment,baseline disease activity/extent as factors, baseline SES CD score as covariate. Baseline=last measurement prior to first dosing on Day 1. Following bowel segments used for calculating SES-CD scores: Ileum,right C,transverse C,left C,rectum. Each segment assessed for four domains:presence of ulcers, ulcerated surface, affected surface,presence of narrowing, each score on a scale of 0-3,higher scores=more severe condition. Presence of ulcers score:0=none,1=small ulcer:(0.1-0.5cm),2=large ulcer(0.5-2cm),3=very large ulcer(\>2 cm);ulcerated surface score:0=none,1=\<10%,2=10-30%,3=\>30%;affected surface score:0=unaffected segment,1=\<50%, 2=50-75%,3=\>75%;presence of narrowing score:0=none,1=single,can be passed,2=multiple can be passed,3=cannot be passed. Total SES CD score=sum of each domain score for all 5 bowel segments,range from 0 to 60,higher score =more severe disease.
Percentage of Participants Achieving >=25% Reduction in SES-CD From Baseline (SES-CD 25) at Week 12: Induction Period Week 12 SES CD25 was defined as \>=25% improvement from baseline in SES CD. Baseline was defined as the last measurement prior to first dosing on Day 1. Following bowel segments were used for calculating SES-CD scores: Ileum, right C, transverse C, left C and rectum. Each segment assessed for four domains: presence of ulcers, ulcerated surface, affected surface and presence of narrowing, each scored on a scale of 0 to 3, higher scores indicated more severe condition. Presence of ulcers score: 0=none, 1=small ulcer: (0.1-0.5 centimeter\[cm\]), 2=Large ulcer(0.5-2 cm), 3=very large ulcer(\>2 cm); ulcerated surface score: 0=none, 1=\<10%, 2=10-30% and 3=\>30%; affected surface score: 0=unaffected segment, 1=\<50%, 2=50-75% and 3=\>75%; presence of narrowing score: 0=none,1=single, can be passed, 2=multiple, can be passed and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments and ranged from 0 to 60, higher score indicating more severe disease.
Percentage of Participants Achieving Endoscopic Remission (SES-CD Score of <= 2) at Week 12: Induction Period Week 12 Endoscopic remission was defined as SES-CD score of \<= 2. Following bowel segments were used for calculating SES-CD scores: Ileum, right colon(C), transverse C, left C and rectum. Each segment assessed for four domains: presence of ulcers, ulcerated surface, affected surface and presence of narrowing, each scored on a scale of 0 to 3, higher scores indicated more severe condition. Presence of ulcers score: 0=none, 1=small ulcer: (0.1-0.5 centimeter\[cm\]), 2=Large ulcer(0.5-2 cm), 3=very large ulcer(\>2 cm); ulcerated surface score: 0=none, 1=\<10%, 2=10-30% and 3=\>30%; affected surface score: 0=unaffected segment, 1=\<50%, 2=50-75% and 3=\>75%; presence of narrowing score: 0=none,1=single, can be passed, 2=multiple, can be passed and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments and ranged from 0 to 60, higher score indicating more severe disease.
Percentage of Participants Achieving CMEI at Week 64 Among Participants Who Achieved CMEI Response at Week 12 (Baseline of OLE Period): OLE Period Week 64 (Week 52 of OLE period) CMEI was defined as reduction of \>=3 points from baseline as assessed by centrally read SES CD score. Baseline: last measurement prior to first dosing on Day 1 of Week 12. Following bowel segments were used for calculating SES-CD scores: Ileum, right C, transverse C, left C and rectum. Each segment assessed for four domains: presence of ulcers, ulcerated surface, affected surface and presence of narrowing, each scored on scale of 0-3, higher scores indicated more severe condition. Presence of ulcers score: 0=none,1=small ulcer: (0.1-0.5 cm),2=Large ulcer(0.5-2 cm),3=very large ulcer(\>2 cm); ulcerated surface score: 0=none,1=\<10%, 2=10-30% and 3=\>30%; affected surface score: 0=unaffected segment, 1=\<50%, 2=50-75% and 3=\>75%; presence of narrowing score: 0=none,1=single, can be passed, 2=multiple, can be passed and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments and ranged from 0-60, higher score indicating more severe disease.
Percentage of Participants Achieving SES CD 25 and SES CD 50 at Week 64 Among Participants Who Achieved SES CD 25 and SES CD 50 at Week 12 (Baseline of OLE Period): OLE Period Week 64 (Week 52 of OLE period) SES CD50 and SES CD25: 50% and 25% improvement from baseline, respectively. Baseline: last measurement prior to first dosing on Day 1 of Week 12. Following bowel segments were used for calculating SES-CD scores: Ileum, right C, transverse C, left C and rectum. Each segment assessed for four domains: presence of ulcers, ulcerated surface, affected surface and presence of narrowing, each scored on a scale of 0 to 3, higher scores indicated more severe condition. Presence of ulcers score: 0=none, 1=small ulcer: (0.1-0.5 cm), 2=Large ulcer(0.5-2 cm), 3=very large ulcer(\>2 cm); ulcerated surface score: 0=none, 1=\<10%, 2=10-30% and 3=\>30%; affected surface score: 0=unaffected segment, 1=\<50%, 2=50-75% and 3=\>75%; presence of narrowing score: 0=none,1=single, can be passed, 2=multiple, can be passed and 3=cannot be passed. Total SES CD score was determined by sum of each domain score for all 5 bowel segments and ranged from 0 to 60, higher score indicating more severe disease.
Percentage of Participants Achieving Mucosal Healing at Week 12: Induction Period Week 12 Mucosal healing was defined as complete absence of ulcers.
Trial Locations
- Locations (186)
Regional Municipal Non-profit Enterprise "Chernivtsi Regional Clinical Hospital", Surgery Department
🇺🇦Chernivtsi, Ukraine
Dothan Surgery Center
🇺🇸Dothan, Alabama, United States
Gut P.C., dba Digestive Health Specialists of the Southeast
🇺🇸Dothan, Alabama, United States
Brighton Surgical Center
🇺🇸Beverly Hills, California, United States
Entertainment Medical Group
🇺🇸Los Angeles, California, United States
Gastrointestinal Biosciences Clinical Trials, LLC
🇺🇸Los Angeles, California, United States
Stanford Medicine Outpatient Center - Digestive Health Center
🇺🇸Redwood City, California, United States
Front Range Endoscopy Center
🇺🇸Colorado Springs, Colorado, United States
Peak Gastroenterology Associates
🇺🇸Colorado Springs, Colorado, United States
Gastro Florida
🇺🇸Clearwater, Florida, United States
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