Crohn's Disease, Granulomatous Colitis, Ileitis, Ileo-colonic and Colonic Crohn's Disease, Regional Enteritis, Ulcerative Colitis
Conditions
Keywords
Crohn's disease lumbar puncture anti-MAdCAM monoclonal antibody PF-00547659 Ulcerative Colitis
Brief summary
Study is designed to show a lack of effect on white blood cells circulating in the spinal fluid.
Interventions
PROCEDURElumbar puncture
2 lumbar punctures prior to treatment; study drug 225mg SC once a month X 3 doses.
Sponsors
Shire
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 2: Baseline Absolute Lymphocyte Count in Cerebrospinal Fluid (CSF) | Baseline | 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. |
| Cohort 2: Percent Change From Baseline in Absolute Lymphocyte Count in CSF at Month 3 | Baseline, 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline up to Week 12 | 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. |
| Cohorts 1 and 2: Number of Participants Who Developed Anti-Drug Antibodies (ADAs) to PF-00547659 | Day 1; Weeks 4, 8, 9-11 (Cohort 2 only), 12, 20, 28, and 36; Early Withdrawal | Serum samples were analysed for presence of ADAs to PF-00547659. Participants who showed positive results for PF-00547659 were reported. |
| Cohorts 1 and 2: Number of Participants With Injection Site Reactions by Severity | Baseline till End of Study/Early Withdrawal, up to Week 12 | Injection site reaction AEs include: injection site irritation, injection site pain, injection site rash, contusion, and erythema. |
Countries
Austria, Belgium, France, Germany, Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: PF-00547659 Participants who had Crohn's disease (CD) and who satisfied all study entry criteria were enrolled into the study. Prior to treatment, participants underwent 2 lumbar punctures (LP) 2-4 weeks apart. All participants received 3 monthly subcutaneous (SC) doses of PF-00547659 225 milligrams (mg) (Days 1, 29, 57). At Week 12, participants who had a clinical response to treatment could enter the open-label extension study. Otherwise, participants would enter a 6-month follow-up period onsite. | 10 |
| Cohort 2: PF-00547659 Participants who had Crohn's disease (CD) and who satisfied all study entry criteria were enrolled into the study. Participants underwent 2 lumbar punctures (LP), 1 prior to treatment and another 1-3 weeks after the last dose. All participants received 3 monthly subcutaneous (SC) doses of PF-00547659 225 milligrams (mg) on Days 1, 29, and 57. At Week 12, participants who had a clinical response to treatment could enter the open-label extension study. Otherwise, participants would enter a 6-month follow-up period onsite. | 39 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Cohort 1: PF-00547659 | Cohort 2: PF-00547659 | Total |
|---|---|---|---|
| Age, Continuous | 40.9 years STANDARD_DEVIATION 15.9 | 37.4 years STANDARD_DEVIATION 10.6 | 38.1 years STANDARD_DEVIATION 11.8 |
| Age, Customized 18-44 years | 6 Participants | 27 Participants | 33 Participants |
| Age, Customized 45-64 years | 4 Participants | 12 Participants | 16 Participants |
| Age, Customized More than or equal to (>=) 65 years | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 26 Participants | 28 Participants |
| Sex: Female, Male Male | 8 Participants | 13 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 10 | 37 / 39 |
| serious Total, serious adverse events | 1 / 10 | 3 / 39 |
Outcome results
Primary
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.
Time frame: Baseline
Population: All Cohort 2 participants who were enrolled, had 2 evaluable LPs, and who received all 3 doses of study drug.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Cohort 2: PF-00547659 | Cohort 2: Baseline Absolute Lymphocyte Count in Cerebrospinal Fluid (CSF) | 338.5 cells per milliliter (cells/mL) | Full Range 689.69 |
Primary
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.
Time frame: Baseline, Month 3
Population: All Cohort 2 participants who were enrolled, had 2 evaluable lumbar punctures, and who received all 3 doses of study drug.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Cohort 2: PF-00547659 | Cohort 2: Percent Change From Baseline in Absolute Lymphocyte Count in CSF at Month 3 | 35.2 percent change | Full Range 92.67 |
Comparison: The null hypothesis is the (median) percent decrease in total lymphocytes count is greater or equal to 50%, equivalently indicating that the geometric mean ratio (GMR: post-treatment/pretreatment) in total lymphocyte counts is less than or equal to 0.5.80% CI: [1.13, 1.56]
Secondary
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.
Time frame: Day 1; Weeks 4, 8, 9-11 (Cohort 2 only), 12, 20, 28, and 36; Early Withdrawal
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 2: PF-00547659 | Cohorts 1 and 2: Number of Participants Who Developed Anti-Drug Antibodies (ADAs) to PF-00547659 | 4 participants |
| Cohort 2: PF-00547659 | Cohorts 1 and 2: Number of Participants Who Developed Anti-Drug Antibodies (ADAs) to PF-00547659 | 11 participants |
Secondary
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.
Time frame: Baseline till End of Study/Early Withdrawal, up to Week 12
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 2: PF-00547659 | Cohorts 1 and 2: Number of Participants With Injection Site Reactions by Severity | Mild | 1 participants |
| Cohort 2: PF-00547659 | Cohorts 1 and 2: Number of Participants With Injection Site Reactions by Severity | Moderate | 0 participants |
| Cohort 2: PF-00547659 | Cohorts 1 and 2: Number of Participants With Injection Site Reactions by Severity | Severe | 0 participants |
| Cohort 2: PF-00547659 | Cohorts 1 and 2: Number of Participants With Injection Site Reactions by Severity | Mild | 6 participants |
| Cohort 2: PF-00547659 | Cohorts 1 and 2: Number of Participants With Injection Site Reactions by Severity | Moderate | 1 participants |
| Cohort 2: PF-00547659 | Cohorts 1 and 2: Number of Participants With Injection Site Reactions by Severity | Severe | 0 participants |
Secondary
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.
Time frame: Baseline up to Week 12
Population: All participants who received at least one dose of study drug were analyzed for AEs/safety. Combined data for both cohorts is presented.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 2: PF-00547659 | 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 | AEs | 9 participants |
| Cohort 2: PF-00547659 | 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 | Withdrawals due to AEs | 0 participants |
| Cohort 2: PF-00547659 | 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 | SAEs | 1 participants |
| Cohort 2: PF-00547659 | 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 | AEs | 36 participants |
| Cohort 2: PF-00547659 | 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 | Withdrawals due to AEs | 0 participants |
| Cohort 2: PF-00547659 | 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 | SAEs | 3 participants |