Clinical Trials Register

Summary
EudraCT Number:	2011-001733-16
Sponsor's Protocol Code Number:	A3921083
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-12-22
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2011-001733-16

A.3

Full title of the trial

A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL
GROUP, MULTI-CENTRE STUDY TO INVESTIGATE THE SAFETY AND
EFFICACY OF CP-690,550 FOR INDUCTION THERAPY IN SUBJECTS WITH MODERATE TO SEVERE CROHN’S DISEASE

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A randomized, double-blind, placebo-controlled, parallel group, multi-centre study to investigate the safety and efficacy of CP-690,550 for induction therapy in subjects with moderate to severe Crohn’s disease

A.4.1

Sponsor's protocol code number

A3921083

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pfizer Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pfizer Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pfizer Inc.
B.5.2	Functional name of contact point	Clinical Trials.gov Call Center
B.5.3	Address:
B.5.3.1	Street Address	235 East 42nd Street,
B.5.3.2	Town/ city	New York,
B.5.3.3	Post code	NY 10017
B.5.3.4	Country	United States
B.5.4	Telephone number	0018007181021
B.5.5	Fax number	0013037391119
B.5.6	E-mail	clinicaltrials.govcallcenter@pfizer.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tofacitinib
D.3.2	Product code	CP-690,550-10
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	540737-29-9
D.3.9.2	Current sponsor code	CP-690,550-10
D.3.9.3	Other descriptive name	Tofacitinib
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Crohn's disease

E.1.1.1

Medical condition in easily understood language

Crohn's disease

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10011402
E.1.2	Term	Crohn's disease (colon)
E.1.2	System Organ Class	100000004856

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the study is to evaluate the dose-response of tofacitinib in inducing clinical remission in subjects with moderate to severe Crohn’s disease and to select effective dose(s).

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of tofacitinib induction therapy in subjects with moderate to severe Crohn’s disease.
 To evaluate the dose-response of tofacitinib in inducing clinical response in subjects with moderate to severe Crohn’s disease.
 To characterize the pharmacokinetics of tofacitinib in subjects with moderate to severe Crohn’s disease.
 To evaluate the effect of tofacitinib on quality of life in subjects with moderate to severe Crohn’s disease.
 To evaluate the effect of tofacitinib on CRP and fecal calprotectin.

E.2.3

Trial contains a sub-study

E.3

Principal 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. Male or female subjects between the ages of ≥18 and ≤75 years at screening.
2. Subjects with documented clinical diagnosis of Crohn’s disease (CD) for at least 6 months prior to screening.
3. Subjects with active moderate to severe ileal, ileocolic, or colonic CD defined by a baseline score of Crohn’s Disease Activity Index (CDAI) of ≥220 to ≤450 at baseline.
4. Subjects with a history of inadequate treatment response or intolerance (as defined by the Investigator) to at least one of the following therapies for Crohn’s disease:
• Corticosteroids.
• Azathioprine/6-Mercaptopurine.
• Methotrexate.
• Anti-TNF therapy (Infliximab; Adalimumab; Certolizumab pegol).
5. Subjects currently receiving any of the following treatments for Crohn’s disease are eligible provided they are on stable dose for designated period of time and throughout the study:
• Oral 5-ASA or sulfasalazine stable dose for at least 4 weeks prior to baseline.
• Oral corticosteroids (prednisolone up to 30 mg/day; budesonide up to 9 mg/day) stable dose for at least 2 weeks prior to baseline.
• Chronic treatment for Crohn’s disease with antibiotics (e.g. metronidazole, rifaximin) stable dose for at least 2 weeks prior to baseline.
• Rectally administered formulation of corticosteroids or 5-ASA stable dose for at least 2 weeks prior to baseline.
• Seton placement before enrollment must remain in place during the study.
6. Subjects with presence of ulceration at screening/baseline colonoscopy as documented by the Simple Endoscopic Score for Crohn’s Disease (SES-CD): aphthous ulcers (0.1 to 0.5 cm), large ulcers (0.5 to 2 cm), or very large ulcers (>2 cm).
7. No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB) as defined by all of the following:
• A chest radiograph taken at or within the 3 months prior to screening, without changes suggestive of active TB infection as determined by a qualified radiologist.
• No history of either untreated or inadequately treated latent or active TB infection.
• If a subject has previously received an adequate course of therapy for either latent (e.g., 9 months of isoniazid in a locale where rates of primary multi drug resistant TB infection are <5% or an acceptable alternative regimen) or active (acceptable multi drug regimen) TB infection, neither a PPD test nor a QFT G test is needed, but a negative chest radiograph must still be obtained if not performed within 3 months prior to screening. Documentation of adequate treatment for TB will be obtained prior to first dose of study drug.
• A subject who is currently being treated for active TB infection is to be excluded.
• A subject who is currently being treated for latent TB infection can only be enrolled with confirmation of current incidence rates of multi-drug resistant TB infection in the locale, documentation of an adequate treatment regimen, and with prior approval by the Sponsor.
8. Women of childbearing potential must test negative for pregnancy prior to study enrolment.
9. Sexually active females of childbearing potential are required to use adequate contraceptive methods during the study period and until completion of the follow-up procedures. (Further description of the requirements and a list of contraceptives considered effective and acceptable for use in this trial are found in Section 4.4 Life Style
Guidelines in the protocol).
10. Subjects receiving non-prohibited concomitant medications for any reason, must be on a stable regimen, which is defined as not starting a new medication or changing dosage of a current medication within 7 days or 5 half-lives (whichever is longer) prior to baseline.
11. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
12. 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.

E.4

Principal exclusion criteria

1.Diagnosis of indeterminate colitis, UC, or clinical findings suggestive of UC. 2.Subjects diagnosed with Crohn's disease but without previous exposure to treatment or having failed or been intolerant to treatment solely with 5 ASA containing compounds. 3.Subjects receiving treatment for Crohn's disease (see protocol for list of treatments). 4.Other investigational or marketed biologics with immunomodulatory properties within 3 months prior to baseline. 5.Subjects who have previously received natalizumab, or any anti adhesion molecule, within 1 year prior to baseline. 6.Leukocyte apheresis including selective lymphocyte, monocyte, or granulocyte apheresis, or plasma exchange within 6 months. 7.Subjects who have previously participated in any study of tofacitinib. 8.Participation in other interventional clinical studies within 3 months prior to baseline and/or during study. 9.History of symptomatic obstructive strictures unless the stricture has been surgically treated or treated with dilation without recurrence of symptoms for at least 6 months prior to enrollment, or an active ostomy. 10.History of total colectomy or subtotal colectomy to the extent that it precludes the subject from having any formed stool, extensive small bowel resection (>100 cm) or short bowel syndrome. 11.History of bowel surgery within 6 months prior to baseline. 12.Subjects likely to require any type of surgery during the study period. 13.Fecal culture/toxin assay indicating presence of pathogenic infection. 14.Presence of active (draining) fistulae, intra-abdominal or perineal collection or abscess.15.Subjects on elemental diet used for treating Crohn's disease within 7 days from baseline. 16.Subjects with blood dyscrasias at screening. 17.Subjects with evidence of or suspected liver disease eg, liver injury due to methotrexate or primary sclerosing cholangitis. 18.Subjects with estimated GFR <40 ml/min at screening, based on Cockcroft Gault calculation. 19.Subjects with total bilirubin, AST or ALT more than 1.5 times the upper limit of normal at screening. 20.Subjects with current or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, or neurological disease. 21.Subjects who
have been vaccinated with any live or attenuated virus vaccine within 6 weeks of baseline or scheduled to receive live virus vaccination during study period and for 6 weeks after last dose of study drug. 22.Subjects with history of any lymphoproliferative disorder, history of lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic disease. 23.Subjects with clinically significant infections currently or within 6 months of baseline, a history of any infection requiring antimicrobial therapy within 2 weeks of baseline, or a history of any infection otherwise judged by the investigator to have the potential for exacerbation by participation in the study. 24.Subjects with a history of more than one episode of herpes zoster, a history of disseminated herpes zoster or disseminated herpes simplex. 25.Subjects with prior treatment with lymphocyte depleting agents/therapies. Subjects who have received rituximab or other selective B lymphocyte depleting agents are eligible if they have not received such therapy for at least 1 year prior to baseline. 26.Subjects with any condition possibly affecting oral drug absorption. 27.Women who are pregnant or breastfeeding, or planning pregnancy during the study period. 28.History of alcohol or drug abuse with less than 6
months of abstinence prior to baseline. 29.Screening 12 lead ECG that demonstrates clinically relevant abnormalities which may affect subject safety or interpretation of study results. 30. Subjects with history of blood donation in excess of 500 mL within 8 weeks prior to baseline. 31.Subjects with history of blood transfusion within 4 weeks prior to baseline. 32.Subjects with a first degree relative with a hereditary immunodeficiency. 33.Subjects with any malignancies or with a history of malignancies with the exception of adequately treated or excised non metastatic basal cell or squamous cell cancer of the skin. 34.Significant trauma or major surgery within 4 weeks of screening visit. 35.Subjects infected with HIV or hepatitis B or C viruses. 36.Subjects receiving prohibited concomitant medications including medications that are either moderate to potent CYP3A4 inducers or inhibitors in the specified time periods prior to the first dose of study drug or are expected to receive any of these medications during the study period. See Protocol for additional criteria and details.

E.5 End points

E.5.1

Primary end point(s)

The proportion of subjects in clinical remission at week 8 as defined by a Crohn’s disease
activity index (CDAI) score of less than 150 points.

E.5.1.1

Timepoint(s) of evaluation of this end point

The proportion of subjects in clinical remission at week 8 as defined by a Crohn’s disease activity index (CDAI) score of less than 150 points

E.5.2

Secondary end point(s)

The proportions of subjects in clinical remission (CDAI<150) at Week 2 and 4.
The proportion of subjects achieving clinical response-70 at Week 2, 4, and 8 as defined by a decrease in CDAI score of at least 70 points from baseline.
The proportion of subjects achieving clinical response-100 at Week 2, 4, and 8 as defined by a decrease in CDAI score of at least 100 points from baseline.
The proportion of subjects achieving either clinical response-100 or clinical remission (CDAI<150) at Week 2, 4, and 8.
CDAI scores over time.
Serum CRP and fecal calprotectin levels over time.
Plasma tofacitinib concentration over time.

E.5.2.1

Timepoint(s) of evaluation of this end point

The proportions of subjects in clinical remission (CDAI<150) at week 2 and 4
The proportion of subjects achieving clinical response-70 at week 2, 4, and 8 as defined by a decrease in CDAI score of at least 70 points from baseline
The proportion of subjects achieving clinical response-100 at week 2, 4, and 8 as defined by a decrease in CDAI score of at least 100 points from baseline
The proportion of subjects achieving either clinical response-100 or clinical remission (CDAI<150) at week 2, 4, and 8
CDAI scores over time
Serum CRP and fecal calprotectin levels over time
Plasma tofacitinib concentration over time

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Austria

Bulgaria

Canada

Croatia

Czech Republic

France

Germany

Greece

Hungary

Israel

Japan

Korea, Republic of

Netherlands

South Africa

Spain

Ukraine

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

EOT in all participating countries is defined as LSLV. EOT in a Member State of the EU is defined as time at which it is deemed that sufficient subjects have been recruited & completed the study as stated in regulatory application (ie, Clinical Study Application) &ethics application in the Member State (MS). Poor recruitment (recruiting less than the anticipated number in the CTA) by a MS is not a reason for premature termination but is considered a normal conclusion to the study in that MS.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1