Clinical Trials Register

Summary
EudraCT Number:	2008-002783-33
Sponsor's Protocol Code Number:	C13007
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-10-28
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

Austria - BASG

A.2

EudraCT number

2008-002783-33

A.3

Full title of the trial

A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab (MLN0002) in Patients with Moderate to Severe Ulcerative Colitis

A.3.1

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

Study of Vedolizumab (MLN0002) in Patients With Moderate to Severe Crohn's Disease

A.4.1

Sponsor's protocol code number

C13007

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00783692

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	Millennium Pharmaceuticals, 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	Millennium Pharmaceuticals, 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	Millennium Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Drug Information Call Center
B.5.3	Address:
B.5.3.1	Street Address	n/a
B.5.3.2	Town/ city	n/a
B.5.3.3	Post code	n/a
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 510 740 2412
B.5.5	Fax number	+1 800 881 6092
B.5.6	E-mail	medical@mlnm.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	VEDOLIZUMAB
D.3.2	Product code	MLN0002
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VEDOLIZUMAB
D.3.9.1	CAS number	943609-66-3
D.3.9.2	Current sponsor code	MLN0002
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	300mg
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous 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 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	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10013099
E.1.2	Term	Disease Crohns
E.1.2	System Organ Class	10017947 - Gastrointestinal disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Co-Primary Objective for the Induction Phase

• To determine the effect of MLN0002 induction treatment on clinical remission at 6 weeks (primary)

• To determine the effect of MLN0002 induction treatment on enhanced clinical response at 6 weeks (co-primary)

Primary Objective for the Maintenance Phase

• To determine the effect of MLN0002 maintenance treatment on clinical remission at 52 weeks

E.2.2

Secondary objectives of the trial

Secondary Objectives for the Induction Phase

• To determine the effect of MLN0002 induction treatment on enhanced clinical response at 6 weeks

• To determine the effect of MLN0002 induction treatment on serum C-reactive protein (CRP) levels at 6 weeks in patients with elevated CRP levels at baseline

Secondary Objectives for the Maintenance Phase

• To determine the effect of MLN0002 maintenance treatment on enhanced clinical response at 52 weeks

• To determine the effect of MLN0002 maintenance treatment on corticosteroid-free remission at 52 weeks

• To determine the effect of MLN0002 maintenance treatment on durability of clinical remission over 52 weeks

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Age 18-80. 2.Male/female patient voluntarily able to give consent 3.Female patients must:be post-menopausal for ≥1year before screening visit,OR be surgically sterile,OR(of childbearing potential)agree to practice 2 effective methods of contraception,at the same time,from time of signing informed consent form through to 6months after last dose of study drug,OR agree to completely abstain from heterosexual contact.Male patients,even if surgically sterilized, must agree to practice effective barrier contraception during entire study treatment period and through 6months after last dose of study drug,OR agree to completely abstain from heterosexual contact. 4.Diagnosis of Crohn’s disease established at least 3 months prior to enrollment by clinical & endoscopic evidence & corroborated by histopathology report.Cases of Crohn’s disease established ≥6 months prior to enrollment for which a histopathology report is not available will be considered.5. Moderate to severe CD determined by CDAI score of 220-450 within 7days of first administration of study drug and 1 of the following:a)CRP level>2.87mg/L during the screening period OR b)Ileocolonoscopy with photographic documentation of a minimum of 3 nonanastomotic ulcerations (each>0.5cm in diameter)or 10 aphthous ulcerations(involving a minimum 10 contiguous cm of intestine) consistent with CD ≥4 months prior to randomization OR c)Fecal calprotectin>250mcg/g stool during the screening period in conjunction with CT enterography,MR enterography, contrast-enhanced small bowel radiography,or wireless capsule endoscopy revealing Crohn’s ulcerations (aphthae not sufficient),4months prior to screening.(Patients with evidence of fixed stenosis or small bowel stenosis with prestenotic dilation should not be included.).6.CD involvement of ileum and/or colon,atat minimum 7.Patients with extensive colitis or pancolitis of>8years duration or left-sided colitis of>12years duration must have evidence of a surveillance colonoscopy within 12months of initial screening visit. 8.Patients with family history of colorectal cancer, personal history of increased colorectal cancer risk,age>50 years,or other known risk factor must be up-to-date on colorectal cancer surveillance. 9.Over the previous 5year period, an inadequate response to,loss of reponse to,or intolerance of at least one of the following agents as defined below:•Corticosteroids,Symptoms of persistently active disease despite a history of at least one 4-week induction regimen that included a dose equivalent to prednisone 30mg daily orally for 2weeks or intravenously for 1 week OR Two failed attempts to taper corticosteroids to below a dose equivalent to prednisone 10mg daily orally on two separate occasions OR History of intolerance of corticosteroids (including Cushing’s syndrome,osteopenia/osteoporosis, hyperglycemia, insomnia,infection) •Immunomodulators. Symptoms of persistently active disease despite history of ≥8week regimen of oral azathioprine (≥1.5mg/kg)or 6-mercaptopurine mg/kg (≥0.75mg/kg)OR Symptoms of persistently active disease despite a history of at least one 8week regimen of methotrexate (≥12.5 mg/week)OR History of intolerance of at least one immunomodulator(including nausea/vomiting,abdominal pain,pancreatitis,LFT abnormalities,lymphopenia,TPMT genetic mutation,infection)•TNF antagonists. Symptoms of persistently active disease despite history of at least one 4week induction regimen of one of the following agents:Infliximab 5mg/kg IV, 2doses at least 2weeks apart. Adalimumab one 80mg SC dose followed by one 40mg dose at least 2weeks apart.Certolizumab pegol 400mg SC,2 doses at least 2weeks apart OR Recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify) OR History of intolerance of at least one TNF antagonist (including, but not limited to infusion-related reaction, demyelination, congestive heart failure, infection).10.May be receiving therapeutic dose of the following drugs:a)Oral 5-ASA compounds provided that dose has been stable for 2 weeks immediately prior to enrollment b)Oral corticosteroid therapy(prednisone at stable dose 30mg/day, budesonide at a stable dose 9mg/day,or equivalent steroid) provided that dose has been stable for 4weeks immediately prior to enrollment if corticosteroids have just been initiated,or 2weeks immediately prior to enrollment if corticosteroids were in process of being tapered c)Probiotics provided that dose has been stable for 2weeks immediately prior to enrollment d)Antidiarrhoeals (e.g.loperamide, diphenoxylate with atropine) for control of chronic diarrhea e)Azathioprine or 6-mercaptopurine provided that dose has been stable for 8weeks immediately prior to enrollment f)Methotrexate provided that dose has been stable for 8weeks immediately prior to enrollment g)Antibiotics used for treatment of CD provided that dose has been stable for 2weeks immediately prior to enrollment

E.4

Principal exclusion criteria

Gastrointestinal Exclusion Criteria
1. Evidence of abdominal abscess at the initial screening visit
2. Extensive colonic resection, subtotal or total colectomy
3. History of >3 small bowel resections or diagnosis of short bowel syndrome
4. Have received tube feeding, defined formula diets, or parenteral alimentation within 21 days prior to the administration of the first dose of study drug
5. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
6. Within 30 days prior to enrollment, have received any of the following for the treatment of underlying disease:
a) Non-biologic therapies (eg, cyclosporine, thalidomide) other than those permitted
b) A non-biologic investigational therapy
c)An approved non-biologic therapy in an investigational protocol
7. Within 60 days prior to enrollment, have received any of the following:
a) Infliximab, adalimumab, or certolizumab pegol
b)Other investigational or approved biological agent
8. Any prior exposure to natalizumab, efalizumab or rituximab
9. Use of topical (rectal) treatment with 5-ASA or corticosteroid enemas/suppositories within 2 weeks of the administration of the first dose of study drug
10. Evidence of or treatment for C. difficile infection or other intestinal pathogen within 28 days prior to enrollment
11. Currently require or are anticipated to require surgical intervention for CD during the study
12. History or evidence of adenomatous colonic polyps that have not been removed
13. History or evidence of colonic mucosal dysplasia
14. Diagnosis of ulcerative colitis or indeterminate colitis
Infectious Disease Exclusion Criteria
1. Any chronic hepatitis B or C infection
2. Active or latent tuberculosis, regardless of treatment history, as evidenced by any of the following:
a) History of tuberculosis
b) A positive diagnostic tuberculosis (TB) test within one month of enrollment defined as:
i) a positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests OR
ii)a tuberculin skin test reaction ≥ 10 mm (≥ 5 mm in patients receiving the equivalent of > 15 mg/day prednisone).
c) Chest x-ray within 3 months of enrollment in which active or latent pulmonary tuberculosis cannot be excluded
3. Any identified congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation)
4. Any live vaccinations within 30 days prior to study drug administration except for the influenza vaccine
5. Clinically significant extra-intestinal infection (eg, pneumonia, pyelonephritis) within 30 days of the initial screening visit
General Exclusion Criteria
1. Previous exposure to MLN0002
2. Female patients who are lactating or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 prior to study drug administration.
3. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, would confound the study results or compromise patient safety
4. Had any surgical procedure requiring general anesthesia within 30 days prior to enrollment or is planning to undergo surgery during the study period
5. Any history of malignancy, except for the following:
• adequately-treated non-metastatic basal cell skin cancer; Squamous cell skin cancer that has been adequately treated and has not recurred for at least 1 year prior to enrollment; and history of cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years prior to enrolment. Patients with remote history of malignancy (eg, >10 years since completion of curative therapy without recurrence) will be considered based on the nature of the malignancy and the therapy received and must be discussed with the sponsor on a case-by-case basis prior to enrollment.
6. History of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease
7. Positive PML subjective symptom checklist prior to the administration of the first dose of study drug
8. Any of the following laboratory abnormalities during the screening period:
a) Hemoglobin level <8 g/dL b) WBC count <3 x 10exp9/L c) Lymphocyte count <0.5 x 10exp9/L d)Platelet count <100 x 10exp9/L or >1200 x 10exp9/L e) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x the upper limit of normal (ULN) f) Alkaline phosphatase >3 x ULN g) Serum creatinine >2 x ULN
9. Current or recent history (within one year prior to enrollment) of alcohol dependence or illicit drug use
10. Active psychiatric problems that, in the investigator’s opinion, may interfere with compliance with the study procedures
11. Unable to attend all the study visits or comply with study procedures

E.5 End points

E.5.1

Primary end point(s)

C0-Primary Endpoint for the Induction Phase

• Proportion of patients in clinical remission at Week 6 (primary)

• Proportion of patients with enhanced clinical response at Week 6 (co-primary)

Primary Endpoint for the Maintenance Phase

• Proportion of patients in clinical remission at Week 52

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 6 and Week 52

E.5.2

Secondary end point(s)

Proportion of patients with enhanced clinical response

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 6 and Week 52

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

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)

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

Yes

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

222

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

Bulgaria

Canada

Czech Republic

Denmark

Estonia

France

Germany

Greece

Hong Kong

Hungary

Iceland

India

Ireland

Israel

Italy

Korea, Republic of

Latvia

Malaysia

Netherlands

New Zealand

Norway

Poland

Romania

Russian Federation

Serbia

Singapore

Slovakia

South Africa

Spain

Sweden

Switzerland

Taiwan

Turkey

Ukraine

United Kingdom

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

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

Number of subjects for this age range:

F.1.1.1

In Utero