The primary objective is to determine the number of subjects that experience a decrease in CDAI (Crohn*s Disease Activity Index) of at least 70 points by the Week 8 or Week 12 assessment.
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
CDAI-70 response rate at Week 8 or Week 12.
Secondary outcome
Main secondary endpoints
* Safety and tolerability of PF-00547659 dose levels versus placebo: the
frequency of treatment adverse events, withdrawal due to adverse events, and
serious adverse events (SAEs) will be reported. Any subject who receives at
least 1 dose of investigational product will be included in the evaluation for
safety.
* Percent of subjects with a CDAI remission (CDAI <150), CDAI-70 and CDAI-100
responses Weeks 2 through 12 (Day 14 to Day 84).
Other Secondary Endpoints
* Immunogenicity assessments of antidrug antibodies (ADAs).
* The PK of PF 00547659 will be analyzed by non-compartmental approach as data
permit. PK parameters including but not limited to area under the curve (AUC),
clearance (CL) and half-life will be summarized descriptively by dose, along
with listings and plots.
* Eploratory Endpionts
* Percent of subjects with a flare (CDAI increase * 70 points) at week 12.
* Mean change and/ or fold change from baseline for high sensitivity C reactive
protein (hsCRP), fecal calprotectin and CDAI score.
Exploratory Biomarkers
* Percent of subjects with a flare (CDAI increase *70 points) at Week 12.
* Mean change from baseline for high sensitivity C-reactive protein (hsCRP) and
fecal calprotectin.
Other Exploratory Biomarkers (blood)
* *4*7+ T-cells, CD34+, and B-cell precursors by Florescence Activated Cell
Sorting (FACS) (baseline, Week 8, Week 12, and Week 24).
* Soluble MAdCAM (baseline, Week 2, Week 10, and Week 12).
* Gene expression profiling (mRNA) at baseline only.
Other Exploratory Biomarkers: from Optional Colonic tissue Biopsies at
Screening and Week 10
* Membrane bound MAdCAM levels in the intestinal mucosa by immunohistochemistry
(IHC).
* *4*7+ T-cells, CD34+, and B-cell precursor levels in the intestinal mucosa by
IHC.
* Gene expression profiling (mRNA).
Health Outcomes
* Change in the mean IBDQ domain and total scores from baseline to Week 12.
* Proportion of subjects with a clinically meaningful change in the IBDQ total
score (*16 points) at Week 12.
* Proportion of subjects with an IBDQ total score of *170 at Week 12.
* Changes in the European Quality of Life 5 Dimensions questionnaire (EQ-5D)TM
and EQ-5D visual analog scale (VAS) scores from baseline to Week 12.
Background summary
Crohn*s Disease (CD) is a chronic granulomatous inflammation of the
gastrointestinal tract. Although the exact cause of CD remains unclear,
increased trafficking of T-lymphocytes to the gut has been demonstrated.
Improved treatments are needed for CD for the majority of subjects who have
active disease despite currently available therapies. Please see chapter 1
(Introduction) of the protocol for detailed information.
Study objective
The primary objective is to determine the number of subjects that experience a
decrease in CDAI (Crohn*s Disease Activity Index) of at least 70 points by the
Week 8 or Week 12 assessment.
Study design
This is a Phase 2, parallel, dose ranging, randomized, double-blind,
placebo-controlled clinical trial.
Intervention
Subjects will be randomly assigned to 1 of 4 treatment arms for the 12-week
induction period stratified by the status of anti-TNF experience and background
immunosuppressant therapy. Three subcutaneous (SC) doses (22.5, 75 and 225 mg)
of PF-00547659 versus placebo (in a 1:1:1:1 ratio) will be investigated. Study
medication or placebo will be administered as three SC injections at Day 1, Day
28 and D56.
Study burden and risks
The results of the nonclinical toxicity and safety pharmacology studies,
together with the clinical experience obtained to date with PF- 00547659,
support the continued development of PF-00547659 for the treatment of Crohn*s
Disease and support the initiation of phase 2 clinical study A7281006. Subjects
will be monitored closely for neurologic symptoms, evidence of infection,
evidence of allergy, and evidence of myocardial changes. Please see the OVERALL
RISK-BENEFIT ASSESSMENT which is part of the IMPD (D2 in submission package)
for further information.
East 42nd Street 235
New York 10017
US
East 42nd Street 235
New York 10017
US
Listed location countries
Age
Inclusion criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator*s study team before subjects are included in the study. Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study.;1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.;2. Subjects are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.;3. Male and/or female subjects between the ages of *18 and *75 years. The subject must meet the age criteria at the time of the baseline visit.;4. Active moderate to severe ileal (terminal ileum), ileocolonic, or colonic CD (CDAI scores 220 450). ;5. Subjects must have a history of treatment failure or intolerance to either immunosuppressant therapy with azathioprine, 6-mercaptopurine or methotrexate AND/OR anti-TNF monoclonal antibodies:
For Immunosuppressants:
* Treatment failure means continued disease activity despite treatment with a therapeutic dose of azathioprine, 6-mercaptopurine and/or methotrexate.
* Intolerance means that the subject has a history of having experienced an unacceptable or dose limiting toxicity associated with the use of the agent. Examples of intolerance include:
o For azathioprine: severe leucopenia, thrombocytopenia, anemia, severe bone marrow suppression; serious infection; gastrointestinal hypersensitivity; hypersensitivity pancreatitis; or hepatotoxicity manifested by elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases.
o For 6-mercaptopurine: bone marrow suppression including anemia, leucopenia, thrombocytopenia or hepatotoxicity.
o For methotrexate: immunosuppression, bone marrow, liver (including fibrosis or cirrhosis), lung (including interstitial fibrosis), skin and kidney toxicities.
For anti-TNF Monoclonal Antibodies:
* Treatment failure is characterized as either primary non-responsive or relapse.
o Primary Non-Response: Subject experienced no clinical response to at least 1 treatment regimen with an anti TNF with an adequate dose and regimen.
o Relapse: Subject experienced relapse after an initial clinical response or remission to at least 1 anti TNF with an adequate dose and regimen.
* Intolerance is defined as: Clinically significant side effect(s) (including hypersensitivity and development of anti-drug antibodies) to at least 1 treatment regimen with an anti TNF.
6. hsCRP >3.0 mg/L. ;7. Ulcerations on colonoscopy performed during screening as defined by the Simple Endoscopic Score * Crohn*s Disease (SES CD). Colonoscopy performed within 8 weeks of screening documenting ulceration and able to retrospectively complete the SES-CD is acceptable.
Note: Colonoscopy to be completed after signing ICD and verification of eligible lab values if required.;8. All women of childbearing potential (WOCBP) must have a negative serum pregnancy test result at screening and a negative urine pregnancy test result at baseline.
Note: A negative urine pregnancy test will also be required for WOCBP prior to each dose.
* WOCBP are defined as women who are biologically capable of becoming pregnant, including women who are using contraceptives or whose sexual partners are either sterile or using contraceptives.
* Women of non childbearing potential (WONCBP) are defined as either postmenopausal (history of amenorrhea for *52 weeks and confirmation by FSH level) or who are surgically sterile, such as after hysterectomy, bilateral oophorectomy, or tubal ligation (procedure performed *52 weeks before screening). This information must be documented in the subject's source documents.
* WONCBP do not require a serum and urine pregnancy test.;Please refer to the protocol for the full list of inclusion criteria
Exclusion criteria
Subjects presenting with any of the following will not be included in the study:;1. Pregnant or breastfeeding women.;2. Entero vesicular (ie, between the bowel and urinary bladder) fistulae are prohibited. Other fistulae are allowed (eg enterocutaneous fistulae). Documentation of active and inactive fistulae are required.;3. Multiple small bowel resections resulting in clinically significant short bowel syndrome who require TPN.;4. Previous bowel surgery resulting in an existing or current stoma Subjects who have a j-pouch are excluded as a j-pouch can result in a stoma. ;5. Surgical bowel resection within the past 3 months. ;6. History of diverticulitis or currently symptomatic diverticulosis.;7. Abnormal findings on the chest x ray film, performed routinely before initiating a new biologic therapy, such as presence of tuberculosis (TB), general infections, heart failure, or malignancy. (Chest x ray examination may be performed up to 12 weeks prior to study entry. Documentation of the official reading must be located and available in the source documentation).;8. Any history or current evidence of latent or active tuberculosis infection, evidence of prior or currently active tuberculosis by chest radiography, residing with or frequent close contact with an individual with active tuberculosis. Subjects who have a positive Mantoux (PPD) tuberculin skin test or a positive Interferon Gamma Release Assay performed locally (the following are acceptable assay: QuantiFERON® TB Gold test (QFT G), QuantiFERON® TB Gold In Tube test (QFT GIT) and T SPOT® TB test) during screening or within 12 weeks prior to randomization.
* A positive Mantoux tuberculin skin test is defined as *5 mm of induration (or as defined by country specific or local standards) at 48 72 hours without consideration of prior Bacillus Calmette-Guérin (BCG) vaccination. Documentation of the dose and product used as well as the official test reading must be obtained and available in the subject's study file.
* An IGRA is preferred for subjects with a prior Bacillus Calmette Guérin (BCG) vaccination (to be tested by the site*s local lab). Documentation of IGRA product used and the test result must be in the subject*s source documentation.;9. Presence of active enteric infections (positive stool culture and sensitivity). The presence of Clostridium difficile or pseudomembranous colitis. Known active invasive fungal infections such as histoplasmosis. Subjects with a clinically significant underlying disease that could predispose the subject to infections. A history of serious infection (requiring parenteral antibiotic and/or hospitalization) within 4 weeks before the randomization visit or baseline visit. Pyoderma gangrenosum is allowed.;10. Preexisting demyelinating disorder such as Multiple Sclerosis or new onset seizures, unexplained sensory, motor, or cognitive, behavioral, neurological deficits, or significant abnormalities noted during screening.;11. Known history of HIV based on documented history with positive serological test, or positive HIV serologic test at screening, tested at the site*s local lab. (Note: a documented negative HIV test within one year of screening is acceptable and does not need to be repeated).;12. Significant concurrent medical conditions at the time of screening or baseline visit, including, but not limited to, the following:
* Any major illness/condition or evidence of an unstable clinical condition (eg, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, immunologic [eg, Felty syndrome], or local active infection/infectious illness) that, in the investigator*s judgment, will substantially increase the risk to the subject if he or she participates in the study.
* 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).
* Right or left heart failure including symptomatic diastolic dysfunction or unexplained elevation of troponin I (>0.05 ng/mL). Subjects with screening or baseline value of NPproBNP >124 pg/mL must have an echocardiogram and cardiology consult that exclude right or left heart failure.
* Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) and any history of significant cerebrovascular disease within 24 weeks before screening. ;13. Presence of a transplanted organ. Skin grafts to treat pyoderma gangrenosum are allowed.;14. Any major elective surgery scheduled to occur during the study.;15. Prior evidence of liver injury or toxicity due to methotrexate.;Please refer to the protocol for the full list of exclusion criteria
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2010-023437-30-NL |
ClinicalTrials.gov | NCT01276509 |
CCMO | NL36139.018.11 |