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Safety, Efficacy, and Tolerability Study of PF-06480605 in Subjects With Moderate to Severe Ulcerative Colitis.

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ClinicalTrials.gov Identifier: NCT02840721
Recruitment Status : Completed
First Posted : July 21, 2016
Results First Posted : June 19, 2019
Last Update Posted : June 19, 2019
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE June 27, 2016
First Posted Date  ICMJE July 21, 2016
Results First Submitted Date  ICMJE May 29, 2019
Results First Posted Date  ICMJE June 19, 2019
Last Update Posted Date June 19, 2019
Actual Study Start Date  ICMJE October 26, 2016
Actual Primary Completion Date May 31, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 29, 2019)
  • Number of Participants With Treatment-Emergent Adverse Events, Serious Adverse Events, and Who Withdrew Due to Adverse Events [ Time Frame: Day 1 up to final onsite visit (Week 26) ]
    An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. A serious AE (SAE) was any untoward medical occurrence at any dose that (1) resulted in death; (2) was life-threatening (immediate risk of death); (3) required inpatient hospitalization or prolongation of existing hospitalization; (4) resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); (5) resulted in congenital anomaly/birth defect. A treatment-emergent AE (TEAE) was defined as an event that emerged during treatment having been absent pre-treatment, or worsened relative to the pre-treatment state. Causality to study treatment was determined by the investigator.
  • Number of Participants With Laboratory Abnormalities [ Time Frame: Day 1 up to final onsite visit (Week 26) ]
    The following parameters were evaluated: hematology (hemoglobin, hematocrit, erythrocytes, erythrocyte mean corpuscular volume, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes, activated partial thromboplastin time, and prothrombin time), clinical chemistry (bilirubin, direct bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, protein, albumin, blood urea nitrogen, creatinine, urate, sodium, potassium, chloride, calcium, glucose, and creatine kinase), and urinalysis (urine glucose, ketones, urine protein, urine hemoglobin, nitrite, leukocyte esterase, urine erythrocytes, urine leukocytes, hyaline casts, and bacteria).
  • Number of Participants With Vital Signs Data Meeting Pre-specified Criteria [ Time Frame: Baseline up to final onsite visit (Week 26) ]
    Vital signs evaluation included sitting diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse rate. Sitting blood pressure was measured with the participant's arm supported at the level of the heart, and recorded to the nearest millimeters of mercury (mm Hg). The same size BP cuff which had been properly sized and calibrated was used to measure BP each time. Number of participants with vital signs data meeting pre-specified criteria is presented.
  • Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria [ Time Frame: Baseline up to final onsite visit (Week 26) ]
    All scheduled 12-lead ECGs were performed after the participant had rested quietly for at least 10 minutes in a supine position. Number of participants with ECG data meeting pre-specified criteria is presented.
  • Percentage of Participants Achieving Endoscopic Improvement at Week 14, Based on Uniformly Minimum-Variance Unbiased Estimator (UMVUE) - Per Protocol Analysis Set [ Time Frame: Week 14 ]
    Endoscopic improvement at Week 14 was defined as Mayo endoscopic sub-score of 0 or 1, and without friability. The Mayo scoring system was used to assess ulcerative colitis activity, and it ranges from 0 to 12, calculated as sum of 4 sub-scores, with higher scores indicating more severe disease. The 4 sub-scores are stool frequency (0=normal number of stools; 1=1 to 2 stools more than normal; 2=3 to 4 stools more than normal; 3= 5 or more stools more than normal); rectal bleeding (0=no blood seen; 1=streaks of blood with stools less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes); findings on endoscopy (0=normal or inactive disease; 1=mild disease [erythema, decreased vascular pattern, mild friability]; 2=moderate disease [marked erythema, lack of vascular pattern, friability, erosions]; 3=severe disease [spontaneous bleeding, ulceration]); and physician's global assessment (0=normal; 1=mild disease; 2=moderate disease; 3=severe disease).
Original Primary Outcome Measures  ICMJE
 (submitted: July 18, 2016)
  • Incidence of intolerability treatment-related AEs [ Time Frame: Baseline Week 0 through Week 26 ]
  • Incidence, severity, and causal relationship of treatment emergent AEs (TEAEs), withdrawals due to AEs, and SAEs [ Time Frame: Baseline Week 0 through Week 26 ]
  • Incidence and magnitude of abnormal laboratory findings [ Time Frame: Baseline Week 0, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 26 ]
  • Abnormal and clinically relevant changes in vital signs, blood pressure (BP) and electrocardiogram (ECG) parameters [ Time Frame: Baseline Week 0, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 26 ]
  • Evaluate efficacy of PF-06480605 in induction of endoscopic improvement [ Time Frame: Week 14 ]
    Assessed by Mayo endoscopic subscore
Change History Complete list of historical versions of study NCT02840721 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 29, 2019)
  • Percentage of Participants Achieving Remission at Week 14 - Full Analysis Set [ Time Frame: Week 14 ]
    Remission: total Mayo score <=2 with no individual subscore >1. Mayo scoring system was used to assess ulcerative colitis activity (range: 0 to 12, calculated as sum of 4 subscores, higher scores indicating more severe disease). The 4 subscores are stool frequency (0=normal number of stools; 1=1 to 2 stools more than normal; 2= 3 to 4 stools more than normal; 3= 5 or more stools more than normal); rectal bleeding (0=no blood seen; 1=streaks of blood with stools less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes); findings on modified endoscopy (0=normal or inactive disease; 1=mild disease [erythema, decreased vascular pattern, no friability]; 2=moderate disease [marked erythema, lack of vascular pattern, friability, erosions]; 3=severe disease [spontaneous bleeding, ulceration]); and physician's global assessment (0=normal; 1=mild disease; 2=moderate disease; 3=severe disease).
  • Percentage of Participants Achieving Remission at Week 14 - Per Protocol Analysis Set [ Time Frame: Week 14 ]
    Remission: total Mayo score <=2 with no individual subscore >1. Mayo scoring system was used to assess ulcerative colitis activity (range: 0 to 12, calculated as sum of 4 subscores, higher scores indicating more severe disease). The 4 subscores are stool frequency (0=normal number of stools; 1=1 to 2 stools more than normal; 2= 3 to 4 stools more than normal; 3= 5 or more stools more than normal); rectal bleeding (0=no blood seen; 1=streaks of blood with stools less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes); findings on modified endoscopy (0=normal or inactive disease; 1=mild disease [erythema, decreased vascular pattern, no friability]; 2=moderate disease [marked erythema, lack of vascular pattern, friability, erosions]; 3=severe disease [spontaneous bleeding, ulceration]); and physician's global assessment (0=normal; 1=mild disease; 2=moderate disease; 3=severe disease).
  • Percentage of Participants Achieving Endoscopic Remission at Week 14 - Full Analysis Set [ Time Frame: Week 14 ]
    Endoscopic remission at Week 14 was defined as Mayo endoscopic sub-score of 0. The Mayo scoring system was used to assess ulcerative colitis activity, and it ranges from 0 to 12, calculated as sum of 4 sub-scores, with higher scores indicating more severe disease. The 4 sub-scores are stool frequency (0=normal number of stools; 1=1 to 2 stools more than normal; 2= 3 to 4 stools more than normal; 3= 5 or more stools more than normal); rectal bleeding (0=no blood seen; 1=streaks of blood with stools less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes); findings on endoscopy (0=normal or inactive disease; 1=mild disease [erythema, decreased vascular pattern, mild friability]; 2=moderate disease [marked erythema, lack of vascular pattern, friability, erosions]; 3=severe disease [spontaneous bleeding, ulceration]); and physician's global assessment (0=normal; 1=mild disease; 2=moderate disease; 3=severe disease).
  • Maximum Serum Concentration (Cmax) of PF-06480605 [ Time Frame: 30 minutes pre-dose and 1 hour post-dose on Day 85 ]
    Maximum serum concentration (Cmax) of PF-06480605 was observed directly from data.
  • Average Serum Concentration (Cav) of PF-06480605 [ Time Frame: 30 minutes pre-dose and 1 hour post-dose on Day 85 ]
    Average serum concentration (Cav) of PF-06480605 was calculated as AUCtau/tau, where tau was the dosing interval (tau=14 days), and AUCtau was the area under the concentration-time profile from time 0 to time tau.
  • Lowest Serum Concentration (Cmin) of PF-06480605 [ Time Frame: 30 minutes pre-dose and 1 hour post-dose on Day 85 ]
    Lowest serum concentration (Cmin) of PF-06480605 was observed directly from data.
  • Area Under the Concentration-time Profile From Time Zero to Time Tau (AUCtau) of PF-06480605 [ Time Frame: 30 minutes pre-dose and 1 hour post-dose on Day 85 ]
    AUCtau of PF-06480605 was calculated using linear/log trapezoidal method; tau was the dosing interval (=14 days).
  • Percentage of Participants Who Developed Anti-drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) [ Time Frame: Day 1 up to final onsite visit (Week 26) ]
    Serum samples were analyzed using a new ADA assay with acid pre-treatment followed by a more drug-tolerant cell-based NAb assay. For ADA assay with acid pre-treatment, the sample was deemed positive if log titer >=1.30; for cell-based NAb assay, the sample was deemed positive if log titer >=0.699.
  • Change From Baseline in Fecal Calprotectin [ Time Frame: Baseline, Weeks 2, 8, 12 and 26 ]
    Fecal calprotectin has been used to detect intestinal inflammation (colitis or enteritis) and can serve as a biomarker for inflammatory bowel diseases. Elevated fecal calprotectin levels indicate migration of neutrophils into the intestinal mucosa, which occurs during intestinal inflammation.
  • Change From Baseline in High Sensitivity C-reactive Protein (HsCRP) [ Time Frame: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, and 26 ]
    HsCRP is used mainly as a marker of inflammation.
  • Change From Baseline in Serum Total Soluable Tumor Necrosis Factor-like Ligand 1A (sTL1A) [ Time Frame: Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, and 26 ]
    TL1A is a member of the tumor necrosis factor (TNF) family of cytokines. The investigational product of this study PF-06480605 is a fully human neutralizing antibody against TL1A.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 18, 2016)
  • Evaluate efficacy of PF-06480605 in induction of remission [ Time Frame: Week 14 ]
    Defined as total Mayo score less than or equal to 2 with no individual subscore greater than 1
  • Change From Baseline in Fecal Calprotectin [ Time Frame: Baseline Week 0, Weeks 2, 8, 12, 26 ]
  • Change From Baseline in High Sensitivity C-reactive Protein (HsCRP) [ Time Frame: Baseline Week 0, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 26 ]
  • Change from baseline in total serum soluble TL1A (sTL1A) [ Time Frame: Baseline Week 0, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 26 ]
  • Evaluate Peak Plasma Concentration (Cmax) of PF-06480605 [ Time Frame: Baseline Week 0, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 26 ]
  • Evaluate trough plasma concentration (Ctrough) of PF-06480605 [ Time Frame: Baseline Week 0, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 26 ]
  • Evaluate Area under the Curve to the end of the dosing period (AUC tau) of PF-06480605 [ Time Frame: Baseline Weeks 0, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 26 ]
  • Evaluate steady-state plasma drug concentration (Cav) of PF-06480605 [ Time Frame: Baseline Week 0, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 26 ]
  • Evaluate anti-PF-06480605 antibodies (ADA) [ Time Frame: Baseline Week 0, Weeks, 2, 4, 8, 12, 16, 20, 24, 26 ]
  • Evaluate PF-06480605 neutralizing antibodies (NAbs) [ Time Frame: Baseline Week 0, Weeks 2, 4, 8, 12, 16, 20, 24, 26 ]
  • Evaluate efficacy of PF-06480605 in induction of endoscopic remission [ Time Frame: Week 14 ]
    Defined as Mayo endoscopic subscore of 0
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Efficacy, and Tolerability Study of PF-06480605 in Subjects With Moderate to Severe Ulcerative Colitis.
Official Title  ICMJE A PHASE 2A, MULTICENTER, SINGLE ARM, OPEN- LABEL, TWO-STAGE, STUDY TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY AND PHARMACOKINETICS OF PF-06480605 IN SUBJECTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS
Brief Summary The purpose of this study is to evaluate the safety, tolerability, and efficacy of PF-06480605 in subjects with moderate to severe ulcerative colitis.
Detailed Description This is a Phase 2a, single arm, two-stage study in subjects with moderate to severe ulcerative colitis. Subjects will receive 500 mg of PF-06480605 intravenously every 2 weeks for a total of 7 doses. Blood, stool, and tissue samples will be collected at various time points throughout the study to evaluate safety, tolerability, efficacy, pharmacokinetics, and immunogenicity. Duration of participation for subjects will be approximately 8 months.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Colitis, Ulcerative
Intervention  ICMJE Drug: PF-06480605
PF-06480605 500 mg IV Q2W x 7 Doses
Study Arms  ICMJE Experimental: PF-06480605
PF-06480605 500 mg IV Q2W X 7 doses
Intervention: Drug: PF-06480605
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 25, 2019)
50
Original Estimated Enrollment  ICMJE
 (submitted: July 18, 2016)
40
Actual Study Completion Date  ICMJE August 30, 2018
Actual Primary Completion Date May 31, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female subjects between ≥ 18 and ≤ 75 years of age at the time of informed consent
  • Male subjects able to father children and female subjects of childbearing potential must agree to use two highly effective methods of contraception throughout the study and until the Week 26 visit
  • Diagnosis of ulcerative colitis for ≥ 4 months
  • Subjects with moderate to severe active ulcerative colitis as defined by screening colonoscopy with total Mayo score of ≥ 6, with rectal bleeding subscore of ≥ 1, and an endoscopic subscore of ≥ 2 on the Mayo
  • Active disease beyond the rectum (> 15 cm of active disease at the screening colonoscopy)
  • Must have inadequate response to, loss of response to, or intolerance to at least one conventional therapy for ulcerative colitis such as: Steroids; Immunosuppressants (AZA, 6-MP, or MTX); Anti -TNF inhibitors (eg, infliximab, adalimumab, or golimumab); Anti-integrin inhibitors (eg, vedolizumab).
  • Subjects currently receiving the following treatment are eligible provided they have been on stable doses of Oral 5-ASA or sulfasalazine for at least 4 weeks prior to baseline; oral corticosteroids stable dose for at least 2 weeks prior to baseline; 6-MP or AZA stable dose for 8 weeks prior to baseline.

Exclusion Criteria:

  • Diagnosis of indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, microscopic colitis or Crohn's Disease. Subjects with clinical findings suggestive of Crohn's disease (eg, fistulae, granulomas on biopsy) are also excluded.
  • Subjects with colonic dysplasia or neoplasia, toxic megacolon, primary sclerosing cholangitis, known colonic stricture, history of colonic or small bowel stoma, history of colonic or small bowel obstruction or resection
  • Presence of active enteric infections (positive stool culture and sensitivity)
  • Known history of HIV based on documented history with positive serological test, or positive HIV serologic test at screening
  • Presence of a transplanted organ
  • Cancer or history of cancer or lymphoproliferative disease within the previous 5 years (other than resected cutaneous basal cell or squamous cell carcinoma that has been treated with no evidence of recurrence);
  • Acute coronary syndrome (eg., myocardial infarction, unstable angina pectoris);
  • Any history of cerebrovascular disease within 24 weeks before screening;
  • Subject with current or a history of QT prolongation
  • Class III or Class IV heart failure
  • Prior evidence of liver injury or toxicity due to methotrexate
  • Abnormality in hematology and/or chemistry profiles during screening (as detailed in the protocol)
  • Subjects receiving the following therapies within the designated time period:

    • > 9 mg/day of oral budesonide or >20 mg/day prednisone or equivalent 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
    • Biologics including anti-TNF inhibitors as described: Infliximab, Adalimumab, or Golimumab within 8 weeks prior to baseline
    • Anti-integrin inhibitors (eg, vedolizumab) within 12 weeks prior to baseline
    • Other investigational procedures or products, or live attenuated vaccine within 30 days prior to baseline.
  • Current or history (within 2 years) of serious psychiatric disease or alcohol or drug abuse
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Italy,   Korea, Republic of,   Netherlands,   Poland,   United States
Removed Location Countries France
 
Administrative Information
NCT Number  ICMJE NCT02840721
Other Study ID Numbers  ICMJE B7541002
TUSCANY ( Other Identifier: Alias Study Number )
2016-001158-16 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP