Clinical Trials Register

Summary
EudraCT Number:	2014-004132-20
Sponsor's Protocol Code Number:	D9423C00001
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2016-07-28
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
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2014-004132-20

A.3

Full title of the trial

A multicentre, double-blind, randomised, parallel-group, Phase III study to assess efficacy and safety of D9421-C 9 mg versus Mesalazine 3 g in patients with active Crohn’s Disease in Japan

A.3.1

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

Phase III study to assess efficacy and safety of D9421-C 9 mg with active Crohn’s Disease in Japan

A.4.1

Sponsor's protocol code number

D9423C00001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01514240

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	AstraZeneca K.K.
B.1.3.4	Country	Japan
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	Astrazeneca KK
B.4.2	Country	Japan
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca K.K.
B.5.2	Functional name of contact point	Clinical Operations Division
B.5.3	Address:
B.5.3.1	Street Address	Grand Front Osaka Tower B, 3-1
B.5.3.2	Town/ city	Ofuka-cho, Kita-ku, Osaka
B.5.3.3	Post code	530-0011
B.5.3.4	Country	Japan
B.5.4	Telephone number	+81677114657
B.5.5	Fax number	+81648023563
B.5.6	E-mail	Kazuhiko.Motono@astrazeneca.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	Entocort
D.3.2	Product code	D9421-C
D.3.4	Pharmaceutical form	Capsule
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.3.8	INN - Proposed INN	budesonide
D.3.9.1	CAS number	51333-22-3
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	3
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	Pentasa
D.2.1.1.2	Name of the Marketing Authorisation holder	Kyorin Pharmaceutical CO. Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	Japan
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.3.4	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.3.8	INN - Proposed INN	mesalazine
D.3.9.1	CAS number	0000089-57-6
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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	Capsule
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
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

Active Crohn’s Disease

E.1.1.1

Medical condition in easily understood language

Symptomatic 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	19.0
E.1.2	Level	PT
E.1.2	Classification code	10011401
E.1.2	Term	Crohn's disease
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

To evaluate the clinical efficacy of D9421-C 9 mg once daily compared to Mesalazine 1 g three times a day to patients with mild to moderate active Crohn’s disease affecting ileum, ileocecal region and/or ascending colon as defined by a score of 180-400 on the Crohn’s Disease Activity Index (CDAI) by assessment of the remission after 8-week treatment defined by a CDAI score of ≤150.

E.2.2

Secondary objectives of the trial

•To evaluate clinical efficacy of D9421-C compared to Mesalazine to patients with mild to moderate active Crohn’s disease affecting ileum, ileocecal region and/or ascending colon as defined by a score of 180-400 on the CDAIby assessment of the following variables:
− Remission (ie, CDAI score of ≤150) rate after 2-week and 4-week treatment
− Change in CDAI score
− Time to the first remission
− Clinical improvement defined by a remission (ie, CDAI score of ≤150) or a decrease in CDAI score of at least 100 from Visit 2 after 2-week, 4-week, and 8-week treatments

•To evaluate the change in disease specific health-related quality of life (HRQL) of D9421-C compared to Mesalazine to patients with mild to moderate active Crohn’s disease

•To evaluate the overall safety of D9421-C compared to Mesalazine to patients with mild to moderate active Crohn’s disease

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Female or male ≥15 years of age
2. Diagnosis of Crohn’s Disease, verified by X-ray, endoscopy or histology
3. Main active disease of the ileal, ileocecal region, and/or ascending colon
4. Signed informed consent has to be obtained from the patient, and patient’s legal representative additively if necessary, prior to conducting any study-related procedures.
5.　If patients treated with medication before entry, subjects should fulfil the following criteria:
If treated with partial nutrition treatment (≤1200 kcal/day), the treatment has to be on constant calories from 14 days prior to randomisation until the study completion or discontinuation (including tapering period).
If treated with azathioprine (≤2.0 mg/kg/day) or 6-mercaptopurine (≤1.2 mg/kg/day), the treatment has to be on constant dose from 12 weeks prior to randomisation until the study completion or discontinuation (including tapering period).
6.　Ability to read, write and to fill a diary card and HRQL questionnaire as instructed.

For randomisation in the study patients must fulfil all of the following criteria:
7.Having mild to moderate active Crohn’s disease, defined as CDAI score of 180-400 based on the patient’s condition for 7 consecutive days prior to the Visit 2

E.4

Principal exclusion criteria

1.　Having ileostomy or pouch and/or colostomy.
2.　Having active Crohn’s disease in the rectum and/or anus
3.　Having limited active Crohn’s disease in upper gastrointestinal only.
4.　Having resection of ileum totalling more than 100 cm.
5.　Having previous total gastrectomy.
6.　Having a known or suspected systemic infection (eg, HBV, HCV, HIV infection).
7.　Other complications such as abscess, obstruction, stricture with proximal dilatation, and/or active fistula.
8.　Being candidates for immediate major surgery (including endoscopic treatment, but excluding tooth extraction and cataract surgery) or unlikely to complete the trial due to a poor general condition.
9.　Having histological documented gastrointestinal malignancy or high-grade dysplasia within five years prior to randomisation.
10.　Having a history of carcinoma (excluding basal and squamous skin cell carcinoma) within five years prior to randomisation.
11.　Having uncontrolled diabetes. Patient needs to have his/her diabetes controlled by diet, exercise, and medical treatment and without complications such as neuropathy, nephropaty or retinopathy.
12.　Having active peptic disease, such as a verified diagnose of esophagitis, gastric, duodenal ulcers and infectious diarrhea.
13.　Having rheumatoid arthritis.
14.　Having ankylosing spondylitis.
15.　Having parathyroid disease.
16.　Any clinically relevant abnormal findings in physical examination, clinical chemistry, haematology, urinalysis at Visit 1, which, in the opinion of the investigator(s), may put the patient at risk because of his/her participation in the study.
17.　Having a clinically relevant renal, hepatic, cardiovascular or psychiatric disease as judged by the investigator.
18.　Have received or requiring glucocorticosteroids for any reason, or antibiotics for treatment of Crohn’s Disease (eg, sulfasalazine, metronidazol, and ciprofloxacin), within two weeks prior to randomisation and during study period. Use of topical steroids (eg, nasal steroids, eye drops and steroid ointments) is eligible.
19.　Having been administered or requiring Mesalazine (≥2251 mg/day) from 14 days before randomisation until the day before the randomisation.
20.　Have received infliximab within 8 weeks or adalimumab within 2 weeks prior to randomisation
21. Have received methotrexate, cyclosporine or tacrolimus hydrate within 12 weeks prior to randomisation
22.　Have received granulocytapheresis within 4 weeks prior to randomisation
23.　Have received immunisation with live viruses (eg, polio) or live bacteria (eg, tubercle bacilli) within 12 weeks prior to randomisation.
24.　Requiring concomitant medications listed in Section 5.6.3 during the study period.
25.　Being pregnant or breast-feeding. Female patients have to be postmenopausal, surgically sterile or using medically accepted contraceptive measures.
26.　Known hypersensitivity to budesonide, other glucocorticosteroids, any of the excipients of D9421-C capsule, salicylate esters such as Mesalazine, salicylates, or salazosulfapyridine.
27.　Scheduled to undergo any types of invasive treatment during the course of the study.
28.　Have participated in any clinical study involving an investigational product 4 weeks prior to randomisation.
29.　Have received any kind of experimental treatment within 12 weeks prior to randomisation eg, studies with new biologicals, surgical procedures in a clinical setting, leukocytapheresis and other experimental procedure.
30.　Having previously been randomised in this study
31.　Are alcohol or drug abusers, or any conditions associated with poor compliance.
32.　Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
33.　Clinical judgment by the investigator that the subject should not participate in the study

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable is the remission defined as CDAI score of ≤150. The primary analysis will be based on the FAS and the analysis based on the PPS will also be done as a sensitivity analysis. The patients who dropped out without any remission will be considered as no remission after dropout in this analysis.

E.5.1.1

Timepoint(s) of evaluation of this end point

after 8-week treatment

E.5.2

Secondary end point(s)

1. Remission rate after treatment
2. CDAI scores at Visit 2 onwards and the changes from Visit 2
3. Time to remission defined as the number of days from the randomisation
4. Clinical improvement rate assesed by CDAI score
-CDAI score of ≤150 or a decrease in CDAI score of at least 100 from Visit 2
-CDAI score of ≤150 or a decrease in CDAI score of at least 70 from Visit 2.
5. The canges of IBDQ scores
6. Safety variables
(a )Adverse events
(b)Clinical Laboratory variables
(c)Vital signs

E.5.2.1

Timepoint(s) of evaluation of this end point

1. 2-week and 4-week after randomization
2. at Visit 2 and the visits at post-dose
3. the day when the first remission is obtained
4. at Weeks 2, 4 and 8 after randomization
5. at baseline, Weeks 2, 4, 8 and 10
6. Safety variables
(a) during study period.
(b) at baseline, Weeks 2, 4, 8 and 10
(c) at baseline, Weeks 2, 4, 8 and 10

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

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

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

Will this trial be conducted at a single site globally?

Yes

E.8.4

Will this trial be conducted at multiple sites globally?

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

Japan

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

Request subject to come the investigational site for follow up visit even if out of the time window.

E.8.9 Initial estimate of the duration of the trial

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

109

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

F.3.3.1

Women of childbearing potential not using contraception