Evaluate PF-00547659 On Cerebrospinal Fluid Lymphocytes In Volunteers With Crohn's Disease Or Ulcerative Colitis Who Failed Or Did Not Tolerate Anti-TNFs (TOSCA)

A Multi-Center, Phase 1, Open-Label Evaluation Of The Effect Of PF-00547659 (Anti Madcam Monoclonal Antibody) On Cerebrospinal Fluid (CSF) Lymphocytes In Volunteers With Crohns Disease Or Ulcerative Colitis Who Are Anti-TNFInadequate Responders (TOSCA)

Study is designed to show a lack of effect on white blood cells circulating in the spinal fluid.

Study Overview

• Status: Completed
• Conditions: Crohn's Disease; Ulcerative Colitis; Ileitis; Granulomatous Colitis; Ileo-colonic and Colonic Crohn's Disease; Regional Enteritis
• Intervention / Treatment: Procedure: lumbar puncture; Drug: lumbar puncture

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 1

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria, 1090
    • AKH Wien Universitaetsklinik fuer Innere Medizin III Klinische Abteilung fuer Gastroenterologie und
• Belgium
  • Brussels, Belgium, B-1000
    • Hôpital Erasme
  • Leuven, Belgium, B-3000
    • UZ Gasthuisberg
• France
  • Lille Cedex, France, 59037
    • Hopital Huriez, CHRU de Lille
  • Lille Cedex, France, 59037
    • Hopital Cardiologique
  • Paris, France, 75010
    • Hôpital Saint-Louis
  • Paris, France, 75010
    • Hopital Saint-Louis - CIC
• Germany
  • Berlin, Germany, 13353
    • Charité, Universitaetsmedizin Berlin, Campus Virchow Klinikum,
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academic Medical Center - University of Amsterdam, Dept. of Gastroenterology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• males and females >=18 and =<75 years
• For CD subjects: hsCRP > 5 mg/L and Harvey-Bradshaw Index > 8 OR when HBI cannot be determined (ie if stoma is present) or hsCRP < 5mg/L then: active lesions on colonoscopy or flexible sigmoidoscopy or active Crohn's disease on CT or MR enterography
• For UC subjects: diagnosis of UC > 3 months; must have endoscopy to confirm active disease during screening; total mayo score of 6 to 12 points and moderate to severe disease on endoscopy

Exclusion Criteria:

• Pregnancy or breastfeeding
• TB or active enteric infections
• Entero vesicular fistulae
• Prior use of natalizumab or vedolizumab
• Right or left heart failure including symptomatic diastolic dysfunction or unexplained elevation of troponin I (>0.05 ng/mL)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Interventions prior to treatment. Control arm	Procedure: lumbar puncture; 2 lumbar punctures prior to treatment; study drug 225mg SC once a month X 3 doses.
Experimental: Cohort 2; Interventions prior to and after 3 monthly injections	Drug: lumbar puncture; 1 lumbar puncture before and after 3 doses; study drug 225mg SC once a month X 3 doses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort 2: Baseline Absolute Lymphocyte Count in Cerebrospinal Fluid (CSF)	The primary CSF endpoint of Cohort 2 was the percent change from baseline in absolute lymphocyte counts in CSF after 3 doses of PF-00547659. The hypothesis for the primary endpoint was evaluated using the CSF evaluable population in Cohort 2. CSF samples were obtained via lumbar puncture and analyzed by fluorescence-activated cell sorting (FACS) for total lymphocyte counts. Lumbar punctures were performed by a highly qualified physician using a 20-22 gauge needle, preferably an atraumatic needle.	Baseline
Cohort 2: Percent Change From Baseline in Absolute Lymphocyte Count in CSF at Month 3	The primary CSF endpoint of Cohort 2 was the percent change from baseline in absolute lymphocyte counts in CSF after 3 doses of PF-00547659. The hypothesis for the primary endpoint was evaluated using the CSF evaluable population in Cohort 2. CSF samples were obtained via lumbar puncture and analyzed by FACS for total lymphocyte counts. Lumbar punctures were performed by a highly qualified physician using a 20-22 gauge needle, preferably an atraumatic needle.	Baseline, Month 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohorts 1 and 2: Total Number of Participants With Non-Lumbar Puncture (LP) Related Treatment-Emergent Adverse Events (AEs), Withdrawals Due to AEs, and Serious Adverse Events (SAEs) During the 12-week Treatment Period	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An 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/birth defect. Treatment-emergent for this measure are events between first dose of study drug and up to 85 days (Week 12) after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included serious and non-serious AEs.	Baseline up to Week 12
Cohorts 1 and 2: Number of Participants Who Developed Anti-Drug Antibodies (ADAs) to PF-00547659	Serum samples were analysed for presence of ADAs to PF-00547659. Participants who showed positive results for PF-00547659 were reported.	Day 1; Weeks 4, 8, 9-11 (Cohort 2 only), 12, 20, 28, and 36; Early Withdrawal
Cohorts 1 and 2: Number of Participants With Injection Site Reactions by Severity	Injection site reaction AEs include: injection site irritation, injection site pain, injection site rash, contusion, and erythema.	Baseline till End of Study/Early Withdrawal, up to Week 12

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• Stuve O, Cataldi F, Pradhan V, Gorelick KJ. Normal intrathecal leukocyte cell number and composition do not decrease the incidence of post-lumbar puncture headache. J Neuroimmunol. 2017 Sep 15;310:69-71. doi: 10.1016/j.jneuroim.2017.06.011. Epub 2017 Jun 30.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2012
• Primary Completion (Actual): March 31, 2014
• Study Completion (Actual): November 26, 2015

Study Registration Dates

• First Submitted: June 30, 2011
• First Submitted That Met QC Criteria: June 30, 2011
• First Posted (Estimate): July 4, 2011

Study Record Updates

• Last Update Posted (Actual): June 3, 2021
• Last Update Submitted That Met QC Criteria: May 11, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Crohn's disease lumbar puncture anti-MAdCAM monoclonal antibody PF-00547659 Ulcerative Colitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ileal Diseases; Ulcer; Crohn Disease; Enteritis; Colitis; Colitis, Ulcerative; Ileitis
• Other Study ID Numbers: A7281008; 2011-001443-74 (EudraCT Number)