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

Study Overview
=================
Brief Summary
-----------------
Study is designed to show a lack of effect on white blood cells circulating in the spinal fluid.

Official Title
-----------------
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)

Conditions
-----------------
Crohn's Disease, Ileitis, Ileo-colonic and Colonic Crohn's Disease, Granulomatous Colitis, Regional Enteritis, Ulcerative Colitis

Intervention / Treatment
-----------------
* Procedure: lumbar puncture
* Drug: lumbar puncture


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Crohn's disease lumbar puncture anti-MAdCAM monoclonal antibody PF-00547659 Ulcerative Colitis