Study To Evaluate The Efficacy And Safety Of Oral PF-06651600 And PF-06700841 In Subjects With Moderate To Severe Crohn's Disease

Study Overview
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Brief Summary
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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.

Official Title
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A PHASE 2A, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ORAL PF-06651600 AND PF-06700841 AS INDUCTION AND OPEN LABEL EXTENSION TREATMENT IN SUBJECTS WITH MODERATE TO SEVERE CROHN'S DISEASE

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: PF-06651600 Placebo
* Drug: PF-06651600
* Drug: Placebo PF-06700841
* Drug: PF-06700841


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and/or female subjects 18 years to 75 years of age Documented diagnosis of ileal, ileocolonic, or colonic CD with a minimum disease duration of 3 months, as determined by endoscopic and histopathology assessment. 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. 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. 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). 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. Exclusion Criteria: Diagnosis of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis, diverticular disease, ulcerative colitis (UC), or clinical findings suggestive of UC. Presence of active (draining) fistulae or intra abdominal or perineal abscesses. Strictures with obstructive symptoms. Short bowel syndrome. History of bowel perforation requiring surgical intervention within the past 12 months. 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. History of bowel surgery within 6 months prior to baseline. Subjects displaying clinical signs of fulminant colitis or toxic megacolon. Subjects with primary sclerosing cholangitis. Subjects with evidence of colonic adenomas, dysplasia or neoplasia. Abnormal findings on the chest x ray film such as presence of tuberculosis (TB), general infections, heart failure, or malignancy. 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. Subjects receiving the following therapies within the time period described below or expected to receive any of these therapies during the study period: >9 mg/day of oral budesonide or >25 mg/day of prednisone or equivalent oral systemic corticosteroid dose within 2 weeks prior to baseline. IV, IM (parenteral), or topical (rectal) treatment of 5 ASA or corticosteroid enemas/suppositories within 2 weeks prior to baseline. Azathioprine, 6 mercaptopurine, or methotrexate within 2 weeks prior to baseline. 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; Anti integrin inhibitors (eg, vedolizumab) within 8 weeks prior to baseline. Ustekinumab within 8 weeks prior to baseline. Interferon therapy within 8 weeks prior to baseline. 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). Subjects who have received rituximab or other selective B lymphocyte depleting agents within 1 year prior to baseline. Subjects previously receiving leukocyte apheresis, including selective lymphocyte, monocyte, or granulocyte apheresis, or plasma exchange within 6 months prior to baseline. Other marketed immunosuppressants or biologics with immunomodulatory properties within 3 months prior to baseline. Subjects who have received other JAK inhibitors within 3 months prior to baseline. Subjects who have not responded to or have been intolerant of other JAK inhibitors. 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. 14) Subjects with history of thrombotic event(s), including deep venous thrombosis (DVT), and known inherited conditions that predispose to hypercoagulability.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06700841 or placebo<br> | Drug: Placebo PF-06700841<br>* 12 weeks, followed by PF-06700841, 30 mg QD for 52 weeks<br>Drug: PF-06700841<br>* 60 mg QD for 12 weeks followed by 30 mg QD for up to 52 weeks<br>|
| Experimental: PF-06651600 or placebo<br> | Drug: PF-06651600 Placebo<br>* 12 weeks, followed by PF-06651600, 50 mg once daily (QD) for 52 weeks<br>Drug: PF-06651600<br>* 200 mg QD for 8 weeks, followed by 50 mg QD up to 56 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving SES CD 50 (>50% reduction in SES CD from baseline) at Week 12. |  | 12 weeks | 
| Number of subjects with adverse events |  | Baseline of extension period (Week 12) to week 68 | 
| Number of subjects with serious adverse events |  | Baseline of extension period (Week 12) to week 68 | 
| Number of subjects with electrocardiogram findings of potential clinical importance |  | Baseline of extension period (Week 12) to week 68 | 
| Number of subjects with laboratory tests findings of potential clinical importance |  | Baseline of extension period (Week 12) to week 68 | 
| Number of subjects withdrawal due to adverse events |  | Baseline of extension period (Week 12) to week 68 | 
| Number of subjects with vital signs findings of potential clinical importance |  | Baseline of extension period (Week 12) to week 68 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with potentially clinically important serious infections findings |  | 64 weeks | 
| Mean change from baseline in SES-CD score at Week 12. |  | Baseline, week 12 | 
| Proportion of subjects achieving SES-CD 25 at Week 12. | Number of subjects achieving SES-CD 25 at Week 12. | Baseline, week 12 | 
| Proportion of subjects achieving endoscopic remission (SES-CD less than or equal to 2) at Week 12. | Number of subjects achieving endoscopic remission (SES-CD less than or equal to 2) at Week 12. | Week 12 | 
| Proportion of subjects achieving mucosal healing at Week 12. | Number of subjects achieving mucosal healing at Week 12. | Week 12 | 
| Number of subjects with adverse events | Number of participants with reported adverse events | Baseline of induction period to week 12 | 
| Number of subjects with serious adverse events | Number of participants with reported serious adverse events | Baseline of induction period to week 12 | 
| Number of subjects with electrocardiogram findings of potential clinical importance. | Number of participants with potentially clinically important electrocardiogram findings. | Baseline of induction period to week 12 | 
| Number of subjects withdrawal due to adverse events | Number of subjects withdrawal due to adverse events. | Baseline of induction period to week 12 | 
| Number of subjects with vital signs findings of potential clinical importance. | Number of participants with potentially clinically important vital signs findings. | Baseline of induction period to week 12 | 
| Number of subjects with laboratory tests findings of potential clinical importance. | Number of participants with potentially clinically important laboratory findings. | Baseline of induction period to week 12 | 
| Proportion of subjects achieving SES CD 25 and SES CD 50 at Week 64 among subjects who achieved SES CD 25 and SES CD 50 at week 12 respectively. | Number of subjects achieving SES-CD 25 and SES-CD 50 at Week 64 among subjects who achieved SES CD 25 and SES CD 50 at week 12 | week 64 | 
| Proportion of subjects achieving clinically meaningful endoscopic improvement (CMEI response) at week 64 among subjects who achieved CMEI response at Week 12. | Number of subject achieving clinically meaningful endoscopic improvement (CMEI response) at week 64 among subjects who achieved CMEI response at week 12. | week 64 | 
| Proportion of subjects achieving clinically meaningful endoscopic improvement (reduction of > or equal 3 points from baseline in SES CD score) at Week 12. |  | Week 12 |