Clinical Trials Register

Summary
EudraCT Number:	2011-004579-35
Sponsor's Protocol Code Number:	A3921095
National Competent Authority:	Latvia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-01
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

Latvia - SAM

A.2

EudraCT number

2011-004579-35

A.3

Full title of the trial

A MULTICENTRE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY OF ORAL CP-690,550 AS AN INDUCTION THERAPY IN SUBJECTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS

A.3.1

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

A study of oral CP-690,550 as an induction therapy in subjects with moderate to severe ulcerative colitis.

A.4.1

Sponsor's protocol code number

A3921095

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, 235 East 42nd Street, New York, New York 10017
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	001303739 1119
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	CP-690,550-10
D.3.2	Product code	CP-690,550-10
D.3.4	Pharmaceutical form	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	10
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	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

Moderate to severe active Ulcerative Colitis

E.1.1.1

Medical condition in easily understood language

Moderate to severe active Ulcerative Colitis

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	10045365
E.1.2	Term	Ulcerative colitis
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

To demonstrate the efficacy of tofacitinib in inducing remission in subjects with moderately to severely active UC.

E.2.2

Secondary objectives of the trial

• To evaluate the safety and tolerability of tofacitinib in subjects with
moderately to severely active UC.
• To evaluate the efficacy of tofacitinib in achieving mucosal healing in subjects with moderately to severely active UC.
• To evaluate the effect of tofacitinib induction therapy on clinical outcomes in subjects with moderately to severely active UC.
• To evaluate the tofacitinib pharmacokinetic (PK) exposure during induction therapy in subjects with moderately to severely active UC.
• To evaluate the effect of induction treatment of tofacitinib on quality of life in subjects with moderately to severely active UC.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Subject must be at least 18 years of age.
2. Males and females with a diagnosis (endoscopic or radiographic and histological) of UC >4 months prior to entry into the study. A biopsy report supporting the diagnosis prior to the baseline visit must be available in the source documents.
3. Subjects with moderately to severely active UC as defined by a total Mayo score of >6, with a rectal bleeding score of >1 and an endoscopic
subscore of >2 on the Mayo score determined within 10 days of baseline visit (Visit 2).
4. Subjects must have failed or be intolerant (discontinued the medication due to an
adverse event as determined by the investigator) of at least one of the following treatments for UC:
- Oral or intravenous corticosteroids.
Azathioprine or 6-mercaptopurine (6-MP).
- Anti-TNF-alpha therapy: infliximab or adalimumab.
5. Subjects currently receiving the following treatment for UC are eligible providing they have been and are anticipated to be on stable
dose for designated period of time:
- Oral 5-ASA or sulfasalazine stable dose for at least 4 weeks prior to baseline and during the study period.
- Oral corticosteroids (prednisone equivalent up to 25 mg/day;
budesonide up to 9 mg/day) stable dose for at least 2 weeks prior to baseline and during the study period.
- Chronic treatment for UC with antibiotics (eg, metronidazole, rifaximin) stable dose for at least 2 weeks prior to baseline and during the study period.
6. No evidence of active or latent or inadequately treated infection with
Mycobacterium tuberculosis (TB) prior to randomization as defined by all of the following:
- A negative QuantiFERON-TB Gold (QFT-G) In-Tube test documented within 3 months prior to or during screening. If initial and repeat QFT-G
tests are indeterminate, a negative Mantoux/Purified Protein Derivative
(PPD) tuberculin skin test(with a result of <5 mm of induration) documented within 3 months prior to or during screening is required.
[Subjects with a history of Bacille Calmette Guérin (BCG) vaccination must have a
negative QFT-G test].
- A chest radiograph, taken within the 3 months prior to or during 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 (9 months of isoniazid in a locale where rates of primary multi-drug TB resistance are <5% or an acceptable alternative regimen) or active (acceptable multi-drug regimen) TB infection, neither a QFT-G
test nor a PPD test is needed, but a chest radiograph must still be
obtained if not performed within 3 months prior to a given Screening
visit. 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.
7. Female subjects of childbearing potential must agree to use a highly
effective method of contraception throughout the study and for at least 4
weeks after the last dose of assigned treatment.
8. Women of childbearing potential must have a negative pregnancy test prior to study enrollment.
9. Subjects receiving non-prohibited concomitant medications for any
reason, must be on a stable regimen, which is defined as not starting a new drug or changing dosage within 7 days or 5 half-lives (whichever is longer) prior to first study dose.
10. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, daily bowel movement diary call, and other study procedures. 11. 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. Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, or clinical findings suggestive of Crohn's disease.
2. Subjects with disease limited to distal 15 cm.
3. Subjects without previous treatment for UC (ie, treatment-naïve).
4. Subjects receiving the following therapy within the designated time period or are expected to receive any of these therapies during the study period:
- Azathioprine, 6-mercaptopurine, or methotrexate within 2 weeks prior
to baseline.
- Anti-TNF-alpha therapy (eg, infliximab, adalimumab, or certolizumab)
within 8 weeks prior to baseline.
- Cyclosporine, mycophenolate mofetil/mycophenolic acid, or tacrolimus
within 4 weeks prior to baseline.
- Interferon therapy within 8 weeks prior to baseline.
- Intravenous corticosteroids within 2 weeks prior to baseline.
- Rectally administered formulation of corticosteroids or 5-ASA within 2
weeks prior to baseline.
- Anti-adhesion molecule therapy taken within 1 year (eg, natalizumab or any investigational anti-adhesion molecule therapy).
- Subjects with prior treatment with lymphocyte-depleting agents/
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.
- Other marketed immunosuppressants or biologics with
immunomodulatory properties within 3 months prior to baseline.
5. Subjects displaying clinical signs of fulminant colitis or toxic megacolon.
6. Subjects with evidence of colonic adenomas or dysplasia. However, subjects with prior history of adenomatous polyps will be eligible if the polyps have been completely removed and the subjects are free of polyps at baseline.
7. Subjects at risk for colorectal cancer must have a colonoscopy. Colonoscopy report and pathology report (if biopsies are obtained) must
be available in the source document:
- If the subject is >50 years of age, a colonoscopy within 10 years of the screening visit is required to exclude adenomatous polyps. Subjects whose adenomas have been completely excised at baseline will be
eligible.
- If the subject has extensive colitis for >8 years or disease limited to
left side of colon (ie, distal to splenic flexure) for >10 years, regardless of age, a colonoscopy within 1 year of the screening visit is required to survey for dysplasia. Subjects with dysplasia or cancer identified on
biopsies will be excluded.
8. Subjects who have had surgery for UC or in the opinion of the Investigator, are likely to require surgery for UC during the study period
9. Subjects who have positive stool examinations for enteric pathogens,
pathogenic ova or parasites, or Clostridium difficile toxin at screening.
10. Subjects with clinically significant infections currently or within 6 months of baseline (eg, those requiring hospitalization or parenteral
antimicrobial therapy or opportunistic infections), 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
11. Subjects with a history of more than one episode of herpes zoster, a
history of disseminated herpes zoster or disseminated herpes simplex.
12. Subjects infected with human immunodeficiency virus (HIV) or
hepatitis B or C viruses (Subjects with positive HCV antibody must have
further testing for HCV RNA by PCR13. Subjects who have been vaccinated with live or attenuated vaccine within 6 weeks of baseline or
scheduled to receive these vaccines during study period or within 6 weeks after last dose of study medication
14. Subjects with history of any lymphoproliferative disorder (such as
EBV-related lymphoproliferative disorder, as reported in some subjects
on other immunosuppressive drugs), history of lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic disease.
15. Subjects with malignancies or a history of malignancies, with the exception of adequately treated or excised non-metastatic basal cell or
squamous cell cancer of the skin
16. Subjects receiving prohibited concomitant medications, including moderate to potent CYP3A 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.
- For moderate to potent CYP3A inducers, within 28 days or 5 half-lives,
whichever is longer, prior to first dose of study drug;
- For moderate to potent CYP3A inhibitors, within 7 days or 5 half-lives,
whichever is longer, prior to first dose of study drug.
17. Subjects with a history of bowel surgery within 6 months prior to baseline.
18. Subjects with significant trauma or major surgery within 4 weeks of screening visit.
19. Subjects likely to require any type of surgery during the study period.

E.5 End points

E.5.1

Primary end point(s)

The proportion of subjects in remission at Week 8. Remission is defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a rectal bleeding subscore of 0.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 8 of treatment

E.5.2

Secondary end point(s)

Key Secondary Endpoint:
The proportion of subjects achieving mucosal healing at Week 8. Mucosal healing is
defined by Mayo endoscopic subscore of 0 or 1.

Other Secondary Endpoints:
 The proportion of subjects achieving clinical response at Week 8. Clinical response is
defined by a decrease from baseline in Mayo score of at least 3 points and at least
30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or absolute subscore for rectal bleeding of 0 or 1.
 The proportion of subjects in endoscopic remission at Week 8. Endoscopic remission is defined by Mayo endoscopic subscore of 0.
 The proportion of subjects in clinical remission at Week 8. Clinical remission is defined
by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point.
 The proportion of subjects in symptomatic remission at Week 8. Symptomatic remission is defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, and both rectal bleeding and stool frequency subscore of 0.
 The proportion of subjects achieving deep remission at Week 8. Deep remission is
defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding
1 point and a zero on both endoscopic and rectal bleeding subscores.
 Partial Mayo scores and change from baseline over time.
 Change from baseline at Week 8 in total Mayo score.
other exploratory, pharmacokinetic, biomarker, Health Outcome and safety endpoints are described within the protocol

E.5.2.1

Timepoint(s) of evaluation of this end point

All secondary endpoints are evaluated at Week 8 of treatment

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability, Quality of life

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Information not present in EudraCT

E.8.4

The trial involves multiple sites in the Member State concerned

Information not present in EudraCT

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

Belgium

Brazil

Canada

Colombia

Croatia

Czech Republic

Denmark

Estonia

France

Germany

Hungary

India

Israel

Italy

Korea, Republic of

Latvia

Netherlands

New Zealand

Poland

Romania

Russian Federation

Serbia

Slovakia

South Africa

Spain

Taiwan

Ukraine

United Kingdom

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

Last visit last subject

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.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

445

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

204

F.4.2.2

In the whole clinical trial

545

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Subjects who complete the double-blind treatment and achieve clinical response at Week 8 are eligible to enter a double-blind maintenance study (A3921096).

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-05-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-06-09

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