Efficacy, Safety and Tolerability of PF-06687234 as Add-on Therapy to Infliximab in Active UC Subjects Not in Remission.

Study Overview
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Brief Summary
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The purpose of this study is to determine if PF-06687234 is effective and safe as add-on therapy to infliximab in subjects with active ulcerative colitis who are not in remission.

Detailed Description
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This is a Phase 2a, double-blind, placebo-controlled, parallel group study in subjects with active ulcerative colitis and a non-remission (partial) response to infliximab. All enrolled subjects must have been on infliximab for a minimum of 14 weeks with last dose 8 weeks prior to the date of randomization. Subjects will be randomly assigned to 1 of 2 treatment arms (PF-06687234 or placebo) administered subcutaneously every week for a total of 12 doses. Blood, stool and tissue samples will be collected at various time points throughout the study to evaluate efficacy, safety, tolerability, pharmacokinetics and immunogenicity. Duration of participation for subjects will be approximately 6 months.

Official Title
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A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY AND PHARMACOKINETICS OF PF-06687234 AS ADD-ON THERAPY TO INFLIXIMAB IN ACTIVE ULCERATIVE COLITIS SUBJECTS WHO ARE NOT IN REMISSION (BUILD UC)

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: PF-06687234
* Drug: Placebo


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 and weight > 40 kg at the time of informed consent. A diagnosis of active UC (histologic) for 4 months. Subjects with active UC as defined by (via screening endoscopy) a total Mayo Score of 4 or more but 9 or less and an endoscopic subscore of 2.or more. UC extending at least 15 cm proximal to the anal verge at the time of the screening endoscopy. Must be on a stable dose 5-10 mg/kg of Remicade, Inflectra, or Remsima for a minimum of 14 weeks with no anticipation of need for change in infliximab treatment regimen throughout the study Male subjects able to father children and female subjects of childbearing potential and at risk for pregnancy must agree to use two methods of contraception (at least one of which is considered as highly effective) throughout the study and until the Week 16 visit Exclusion Criteria: Subjects with a diagnosis or documented history of total colectomy and/or pouchitis, indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis, and diverticular disease associated with colitis, or clinical findings suggestive of Crohn's disease. Subjects need for surgery or with major elective surgery scheduled during the study. Subjects with extensive colitis for at least 8 years who have not had a colonoscopy with surveillance biopsies within 2 years prior to baseline. Subjects with history of or at screening endoscopy, biopsy documented colonic dysplasia or neoplasia. Subjects who require infliximab dosing interval other than every 6 weeks or every 8 weeks. Subjects displaying clinical signs of fulminant colitis or toxic megacolon, with primary sclerosing cholangitis, known colonic stricture, history of colonic, small bowel obstruction or resection, with history of or current colonic or small bowel stoma. Cyclic neutropenia, thrombocytopenia, lymphopenia, leukopenia or history of chronic anemia. Presence of active enteric infection. Known history of human immunodeficiency virus (HIV) based on documented history with positive serological test, or positive HIV serologic test. Presence of transplanted organ. Anticipated need for any live vaccine. Class III or Class IV heart failure. Acute coronary syndrome and any history of cerebrovascular disease. Subjects with current, or a history of QT prolongation. Subjects receiving the following therapies within the designated time period: >9 mg/day of oral budesonide or >20 mg/day of prednisone or equivalent within 2 weeks prior to baseline. IV, IM or topical (rectal) treatment of 5-ASA or corticosteroid enemas within 2 weeks prior to baseline. Anti integrin inhibitors within 14 weeks prior to baseline. Any use of natalizumab. Interferon therapy within 8 weeks prior to baseline. Prior treatment with lymphocyte depleting therapies and alkylating agents. Received selective B lymphocyte depleting agents within 1 year prior to baseline. Receiving leukocyte apheresis, granulocyte apheresis, or plasma exchange within 6 months of baseline. JAK inhibitors within 3 months prior to baseline. Any investigational procedures(s) or product(s)30 days prior to baseline. History of sensitivity to heparin or heparin induced thrombocytopenia Known history of hypersensitivity, intolerance, or allergic reaction to PF-06687234 or any constituent of the IP.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06687234<br>PF-06687234 subcutaneous (SC) weekly (QW) x 12 doses | Drug: PF-06687234<br>* SC QW<br>* Other names: Investigational product;|
| Placebo Comparator: Placebo<br>PF-06687234 matched Placebo SC QW x 12 doses | Drug: Placebo<br>* SC QW<br>* Other names: PF-06687234 matched placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in Modified Clinical Remission at Week 12 (Traditional Endoscopic Subscore <=1, Observed Cases) | The Mayo score consists of 4 subscores (Endoscopic, stool frequency, rectal bleeding and Physician's global assessment [PGA]), each graded 0 to 3 with the higher score indicating more severe disease activity. Modified clinical remission is defined as a modified total Mayo Score (total Mayo score excluding the PGA subscore) <=2, no individual subscore >1, traditional endoscopic subscore <=1 (where mild friability was scored as of 1; moderate or severe friability was scored as 2) and rectal bleeding subscore=0. Participants with missing values were handled by observed case approach (the missing data were used as is). The percentage of participants achieving modified clinical remission was calculated based on the number of participants with observed data. | Week 12 | 
| Percentage of Participants in Modified Clinical Remission at Week 12 (Traditional Mayo Endoscopic Subscore <=1, Treatment Failure Approach) | The Mayo score consists of 4 subscores (Endoscopic, stool frequency, rectal bleeding and Physician's global assessment [PGA]), each graded 0 to 3 with the higher score indicating more severe disease activity. Modified clinical remission is defined as a modified total Mayo Score (total Mayo score excluding the PGA subscore) <=2, no individual subscore >1, traditional endoscopic subscore <=1 (where mild friability was scored as of 1; moderate or severe friability was scored as 2) and rectal bleeding subscore=0. Participants with missing values were handled by treatment failure approach (participants who had missing value for any reasons were considered as treatment failures). | Week 12 | 
| Percentage of Participants in Modified Clinical Remission at Week 12 (Modified Mayo Endoscopy Subscore = 0 or 1, Observed Cases) | The Mayo score consists of 4 subscores (Endoscopic, stool frequency, rectal bleeding and Physician's global assessment), each graded 0 to 3 with the higher score indicating more severe disease activity. Modified clinical remission is defined as a modified total Mayo Score (total Mayo score excluding the PGA subscore) with endoscopic subscore = 0 or 1 (where any friability was scored as a mayo endoscopic subscore of 2), stool frequency subscore = 0 or 1, and rectal bleeding subscore = 0. Participants with missing values were handled by observed case approach (the missing data were used as is). The percentage of participants achieving modified clinical remission was calculated based on the number of participants with observed data. | Week 12 | 
| Percentage of Participants in Modified Clinical Remission at Week 12 (Modified Mayo Endoscopy Subscore = 0 or 1, Treatment Failure Approach) | The Mayo score consists of 4 subscores (Endoscopic, stool frequency, rectal bleeding and Physician's global assessment [PGA]), each graded 0 to 3 with the higher score indicating more severe disease activity. Modified clinical remission is defined as a modified total Mayo Score (total Mayo score excluding the PGA subscore) with endoscopic subscore = 0 or 1 (where any friability was scored as a mayo endoscopic subscore of 2), stool frequency subscore = 0 or 1, and rectal bleeding subscore = 0. Participants with missing values were handled by treatment failure approach (participants who had missing value for any reasons were considered as treatment failures). | Week 12 | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs; All Causalities) | Treatment-emergent AEs are those with initial onset or that worsen in severity after the first dose of the study medication. All AEs in the table below were treatment-emergent AEs. An serious adverse event (SAE) is any untoward medical occurrence at any dose that: results in death; is life threatening (immediate risk of death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); results in congenital anomaly/birth defect; or that is considered to be an important medical event that may jeopardize the participant or may require intervention to prevent one of the other AE outcomes. Severe AEs were defined as AEs that interfered significantly with participant's usual function. Both SAEs and severe AEs were according to the investigator's assessment. | Baseline (Day 1) through and including a minimum of 28 calendar days after the last administration of the investigational products (22 weeks in total) | 
| Number of Participants With Treatment-Emergent AEs (Treatment Related) | Treatment-emergent AEs are those with initial onset or that worsen in severity after the first dose of the study medication. All AEs in the table below were treatment-emergent AEs. An SAE is any untoward medical occurrence at any dose that: results in death; is life threatening (immediate risk of death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); results in congenital anomaly/birth defect; or that is considered to be an important medical event that may jeopardize the participant or may require intervention to prevent one of the other AE outcomes. Severe AEs were defined as AEs that interfered significantly with participant's usual function. Both SAEs and severe AEs were according to the investigator's assessment. Treatment-related AEs were also determined by the investigator. | Baseline (Day 1) through and including a minimum of 28 calendar days after the last administration of the investigational products (22 weeks in total) | 
| Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | The laboratory tests as defined in the protocol, including hematology, chemistry, urinalysis and other, were performed. Baseline was defined as the last measurement prior to first dosing (Day 1). | From baseline through Week 16 | 
| Number of Participants With Categorical Vital Signs | Single sitting blood pressure (BP), pulse rate, and temperature were measured. At Day 1 and Week 1, BP and pulse were collected approximately 30 minutes prior to dosing, approximately 30 minutes post dosing and approximately 1 hour post dosing. For participants with no safety issues (eg, severe injection site reactions, severe elevations BP and/or pulse), BP and pulse were collected approximately 30 minutes prior to dosing and approximately 30 minutes post dosing from Weeks 2-16. Vital signs were analyzed as per pre-specified categories. | From baseline through Week 16 | 
| Number of Participants With Categorical Electrocardiogram (ECG) Data | Twelve (12) lead ECGs were collected. All scheduled ECGs were performed after the participants had rested quietly for at least 10 minutes in a supine position. When the timing of these measurements coincided with a blood collection, the ECG was obtained prior to the nominal time of the blood collection, blood pressure, and pulse rate. ECG data were analyzed as per pre-specified categories. PR=pulse rate; QTc=QT interval corrected for heart rate; QTcF=QTc corrected using Fridericia's formula. | From baseline through Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Endoscopic Improvement at Week 12 ( Observed Cases) | Endoscopic improvement is defined as a decrease of >=1 point in a modified endoscopic subscore (any friability is scored as 2) or an absolute endoscopy score of <=1 without friability. Participants with missing values were handled by observed case approach (the missing data were used as is). The percentage of participants achieving endoscopic improvement was calculated based on the number of participants with observed data. | Week 12 | 
| Percentage of Participants With Endoscopic Improvement at Week 12 ( Treatment Failure Approach) | Endoscopic improvement is defined as a decrease of >=1 point in a modified endoscopic subscore (any friability is scored as 2) or an absolute endoscopy score of <=1 without friability. Participants with missing values were handled by treatment failure approach (participants who had missing value for any reasons were considered as treatment failures). | Week 12 | 
| Percentage of Participants Achieving Geboes Index Remission at Week 12 (Observed Cases) | Geboes index is a structured six-grade classification system ordered as follows: 0, structural changes (sub-grade: 0-0.3); 1, chronic inflammatory infiltrate (sub-grade: 1-1.3); 2, lamina propria neutrophils and eosinophils (sub-grade: 2A-2B.3); 3, neutrophils in epithelium (sub-grade: 3-3.3); 4, crypt destruction (sub-grade: 4-4.3); and 5, erosion and ulceration (sub-grade: 5-5.4). The final index ranges from 0 to 5.4, with low score associated with no inflammation or less inflammation and high score associated with severe inflammation or ulceration. Geboes index remission was defined as Geboes index < 3 and Grade 3 < 3.1 at week 12. Participants with missing values were handled by observed case approach (the missing data were used as is). The percentage of participants achieving Geboes index remission was calculated based on the number of participants with observed data. | Week 12 | 
| Change From Baseline in Robart's Histology Index at Week 12 (Observed Cases) | Robart's histology index is based on the Geboes scores, and the final score is obtained by the summation of four main items (chronic inflammatory infiltrate level, lamina propria neutrophils, neutrophils in the epithelium, and erosion or ulceration), which are classified from 0 (no inflammation) to 3 (severe inflammation or ulceration), yielding a final score that ranges between 0 (no inflammation) and 33 (severe inflammation or ulceration). Participants with missing values were handled by observed case approach (the missing data were used as is). | Week 12 | 
| Percentage of Participants With a Clinical Response at Week 12 (Observed Cases) | The Mayo score consists of 4 subscores (Endoscopic, stool frequency, rectal bleeding and Physician's global assessment [PGA]), each graded 0 to 3 with the higher score indicating more severe disease activity. Clinical response is defined with a decrease from baseline of at least 3 points in total Mayo score with at least 30% change, accompanied by at least one-point decrease or absolute score of 0 or 1 in rectal bleeding subscore. Participants with missing values were handled by observed case approach (the missing data were used as is). | Week 12 | 
| Percentage of Participants With a Clinical Response at Week 12 (Treatment Failure Approach) | The Mayo score consists of 4 subscores (Endoscopic, stool frequency, rectal bleeding and Physician's global assessment [PGA]), each graded 0 to 3 with the higher score indicating more severe disease activity. Clinical response is defined with a decrease from baseline of at least 3 points in total Mayo score with at least 30% change, accompanied by at least one-point decrease or absolute score of 0 or 1 in rectal bleeding subscore. Participants with missing values were handled by treatment failure approach (participants who had missing value for any reasons were considered as treatment failures). | Week 12 | 
| Percentage of Participants With Change From Baseline in Derived Partial Mayo Score of <=2 With no Individual Subscore >1 at Weeks 2, 4, 8 and 12 (Observed Cases) | The Mayo score is determined by the summation of 4 subscores (Endoscopic, stool frequency, rectal bleeding and Physician's global assessment [PGA]), each graded 0 (normal) to 3 (worst). Derived partial mayo score is defined as total Mayo score excluding the endoscopic subscore (stool frequency, rectal bleeding and PGA only), ranging from 0 (normal) to 9 (the most severe). The percentages of participants with change from baseline in derived partial Mayo score of <=2 with no individual subscore >1 at Weeks 2, 4, 8 and 12 were calculated for this endpoint. Participants with missing values were handled by observed case approach (the missing data were used as is). Generalized Linear Mixed Model (GLMM) was used with fixed effects of treatment, visit and treatment by visit interaction. | Baseline, Weeks 2, 4, 8 and 12 | 
| Serum Concentrations of PF-06687234 20 mg | Samples for serum PF-06687234 concentration were collected approximately 30 minutes prior to dosing. Concentration values below the lower limit of quantification were excluded when calculating the geometric mean (geometric coefficient of variation). | Prior to dosing on Day 1 and at Weeks 1, 3, 7, 11, 12 (168 hours post dose) and 16 | 
| Percentage of Participants With the Development of Human Anti-Fusion Antibodies (HAFAs) and Neutralizing Antibodies (NAbs) Against PF-06687234 | Plasma samples were analyzed for anti PF-06687234, anti PF-06687234 IL-10 neutralizing antibody (AB) and anti PF-06687234 single chain variable fragment (scFv) neutralizing AB. Samples inadvertently analyzed were excluded. | At screening, Day 1, Weeks 3, 7, 11, 12 and 16 (prior to dosing) |