Clinical Trials Register

Summary
EudraCT Number:	2011-005251-13
Sponsor's Protocol Code Number:	20110166
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-07-11
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

Denmark - DHMA

A.2

EudraCT number

2011-005251-13

A.3

Full title of the trial

A Randomized, Double blind, Multiple Dose Placebo Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of AMG 181 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 to find out more about the effect of AMG 181 in people with moderate to severe ulcerative colitis

A.4.1

Sponsor's protocol code number

20110166

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	Amgen 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	Amgen 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	Amgen (EUROPE) GmbH
B.5.2	Functional name of contact point	IHQ Medical Info - Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	Dammstrasse 23, P.O. Box 1557
B.5.3.2	Town/ city	Zug
B.5.3.3	Post code	CH-6300
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	N/A
B.5.5	Fax number	N/A
B.5.6	E-mail	MedinfoInternational@amgen.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	AMG 181
D.3.2	Product code	AMG 181
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AMG 181
D.3.9.2	Current sponsor code	AMG 181
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	70
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 injection
D.8.4	Route of administration of the placebo	Subcutaneous 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 Ulcerative Colitis

E.1.1.1

Medical condition in easily understood language

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	19.0
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 evaluate the effect of AMG 181 on induction of remission in subjects with moderate to severe UC at week 8 as assessed by a total Mayo Score ≤ 2 points, with no individual subscore > 1 point

E.2.2

Secondary objectives of the trial

Key Secondary Objectives:
- To evaluate the effects of AMG 181 on induction of response at week 8 as assessed by the total Mayo Score
- To evaluate the effects of AMG 181 on mucosal healing at week 8 as assessed by rectosigmoidoscopy

Other Secondary objective:
- To evaluate the effects of AMG 181 on sustained remission at both week 8 and week 24 as assessed by the total Mayo Score

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

There are 4 substudies for sites in Europe
- PK Substudy: Participation in the PK substudy is optional. Subjects will visit the clinic for additional pharmacokinetic samples
- Biomarker Development Blood and Stool Samples Substudy: A subgroup of subjects who provide additional informed consent will participate in the biomarker development substudy. Additional blood samples will be collected for assessment of transcript markers and plasma protein analytes. No additional stools samples will be collected other than those described for the main study
- Pharmacogenetic Substudy:A subgroup of subjects who provide additional informed consent will participate in the pharmacogenetic substudy. Participation in this substudy is optional. Subjects can only participate in the pharmacogenetic substudy if they have also provided consent for the biomarker substudy. No additional blood samples will be collected.
- Immunophenotyping and Absolute Counting (IPAC) PD Assay Substudy: A subgroup of subjects who provide additional informed consent will participate in the IPAC PD assay substudy for enumeration of, and assessment of α4β7 occupancy by AMG 181 on, naïve and memory CD4+ T cell subsets by flow cytometry. Participation in the IPAC substudy is limited to selected sites.

E.3

Principal inclusion criteria

■ Age 18 to 65 at screening (inclusive)
■ Diagnosis of UC established ≥ 3 months before baseline by clinical and endoscopic evidence and corroborated by a histopathology report
■ Moderate to severe active UC as defined by a total Mayo score of 6 to 12 with a centrally read rectosigmoidoscopy score ≥ 2 prior to baseline
■ Demonstrated an inadequate response to, loss of response to, or intolerance to immunomodulators or anti-TNF agents or to corticosteroids (non-US sites only)
■ Subjects can be receiving the following treatments:
• Azathioprine or 6 mercaptopurine if treatment initiated at least 12 weeks prior to baseline and if stable dosage for ≥ 8 weeks prior to baseline
• Methotrexate up to 25 mg/week if stable dosage for ≥ 8 weeks prior to baseline
• 5 aminosalicylates and/or oral prednisone or equivalent up to 20 mg/day, if stable dosage for ≥ 2 weeks prior to baseline
■ Neurological exam, free of clinically significant, unexplained signs or symptoms in the opinion of the investigator during screening and no clinically significant change prior to randomization
■ Subject has no known history of active tuberculosis
■ Subject has a negative test for tuberculosis during screening
■ Subject has provided informed consent

For full list of inclusion criteria, please refer to section 4.1 of the protocol

E.4

Principal exclusion criteria

Disease specific:
■ Disease limited to the rectum (ie, within 10 cm of the anal verge)
■ Toxic megacolon
■ Crohn’s Disease
■ History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Koch pouch, or ileostomy for UC
■ Stool positive for C. Difficile toxin at screening

Excluded Medications:
■ Immunosuppressive therapy with either cyclosporine A, tacrolimus, or mycophenolate mofetil, within 1 month prior to baseline
■ Prior exposure to anti TNF agents, within 2 months, or 5 times the respective elimination half life (whichever is longer) prior to baseline
■ Any prior exposure to vedolizumab, rituximab, efalizumab, natalizumab
■ Use of topical (rectal) aminosalicylic acid (eg, mesalamine) or topical (rectal) steroids within 2 weeks prior to baseline
■ Use of intravenous or intramuscular corticosteroids within 2 weeks prior to screening and during screening

Laboratory Abnormalities:
■ Abnormal laboratory results at screening:
•Liver tests: either aspartate aminotransferase (AST), alanine transaminase (ALT) or alkaline phosphatase (ALP) > 2.0 Upper Limit of Normal (ULN) OR total bilirubin (TBL) > 1.5 ULN (except for subjects with Gilbert Syndrome)
• White blood cell count < 3,000 cells/mm³(< 3 x 10^9/L in SI units)
•Hemoglobin < 10 g/dL

General:
■ Female subject is not willing to prevent pregnancy from occurring during treatment and for 7 months after the last dose of investigational product (except if ≥ 2 years postmenopausal or surgically sterile). Prevention of pregnancy involves a female subject not having intercourse during treatment and for 7 months after the last dose of investigational product, or the use of two methods of birth control. This means the simultaneous use of: Two highly effective methods of birth control, or one highly effective method of birth control and one effective method of birth control.
Highly effective methods (≥ 99% effective when used correctly) of birth control include: hormonal birth control methods (pills, shots, implants or patches), intrauterine devices, sexual activity with a male partner who has had a vasectomy, tubal sterilization (tie, clip, band, burn), or tubal occlusion (insert placed in tube after confirmed occlusion).
Effective methods (< 99% effective) of birth control include: barrier method of condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide.
■ Subject is pregnant or breast feeding, or might become pregnant within 7 months after the last dose of investigational product

For full list of exclusion criteria, please refer to section 4.2 of the protocol

E.5 End points

E.5.1

Primary end point(s)

Remission at week 8 defined by a total Mayo Score ≤ 2 points, with no individual subscore > 1 point

E.5.1.1

Timepoint(s) of evaluation of this end point

at week 8

E.5.2

Secondary end point(s)

Key Secondary Endpoints
- Response at week 8 as defined by a decrease from baseline in the total Mayo Score of ≥ 3 points and ≥ 30%, with an accompanying decrease in the subscore for rectal bleeding of ≥ 1 point or an absolute subscore for rectal bleeding of 0 or 1
- Mucosal healing at week 8 as defined by an absolute subscore for rectosigmoidoscopy of 0 or 1

Other Secondary Endpoints:
- Sustained remission at both week 8 and week 24

E.5.2.1

Timepoint(s) of evaluation of this end point

key secondary endpoints: at week 8
Other secondary endpoint (i.e. sustained remission): week 8 and week 24

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

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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

Yes

E.8.1.7.1

Other trial design description

placebo-controlled period followed by open label period (see Protocol section 3.1)

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

Belgium

Canada

Czech Republic

Denmark

France

Germany

Greece

Hungary

Italy

Netherlands

Norway

Poland

Switzerland

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

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

"LVLS"

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:

340

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

279

F.4.2.2

In the whole clinical trial

360

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)

Plans for treatment of care after the subject has ended participation
are not different from the expected normal treatment for this condition.

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

2012-07-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-08-16

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-04-10

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