Clinical Trials Register

Summary
EudraCT Number:	2005-002441-39
Sponsor's Protocol Code Number:	D961DC00001
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2006-05-05
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

Germany - BfArM

A.2

EudraCT number

2005-002441-39

A.3

Full title of the trial

A randomised, double-blind, parallel-group, placebo controlled study of
esomeprazole i.v. (bolus infusion of 80 mg followed by a continuous infusion
of 8 mg per hour) administered for 72 hours to assess prevention of
rebleeding in subjects that have undergone successful primary endoscopic
haemostasis of a bleeding peptic ulcer – the PUB study

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

D961DC00001

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AstraZeneca AB
B.1.3.4	Country	Sweden
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Yes
D.2.1.1.1	Trade name	Nexium 40 mg powder for solution for injection/infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Astrazeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	Nexium 40 mg powder for solution for injection/infusion
D.3.2	Product code	Esomeprazole powder for solution for injection/inf
D.3.4	Pharmaceutical form	Powder for infusion*
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Esomeprazole sodium
D.3.9.1	CAS number	161796-78-7
D.3.9.2	Current sponsor code	Esomeprazole sodium
D.3.9.3	Other descriptive name	H 199/18 sodium
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Information not present in EudraCT
D.IMP: 2
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	Esomeprazole capsules 40 mg (unmarked capsules for clinical trial use)
D.3.2	Product code	Esomeprazole capsules 40 mg
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Esomeprazole magnesium trihydrate
D.3.9.1	CAS number	217087-09-7
D.3.9.2	Current sponsor code	Esomeprazole magnesium trihydrate
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	40
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Powder for 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

Gatrointestinal haemorrhages NEC. (Bleeding gastric or duodenal ulcer will be investigated).

MedDRA classification code Level: HLGT = High Level Group Term. See below.

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	8.0
E.1.2	Level	HLGT
E.1.2	Classification code	10017959

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 is to compare, in subjects with PUB after successful endoscopic haemostasis, the efficacy of 72 hours continuous i.v. infusion of either esomeprazole or placebo by assessment of the rate of clinically significant rebleeding during the i.v. treatment period.

E.2.2

Secondary objectives of the trial

To compare, in subjects with PUB after successful endoscopic haemostasis, 72 hours continuous i.v. infusion of either esomeprazole or placebo with regard to the following, where the time period begins at start of i.v. treatment:
1. The rate of clinically significant rebleeding within 7 days and 30 days.
2. Proportion of mortalities within 72 hours and 30 days.
3. Rate of “bleed-related” mortalities within 30 days, based on the assessments by the Endpoint Committee (EpC).
4. Proportion of subjects who, within 72 hours and 30 days, had surgery (except endoscopic treatment) due to rebleeding.
5. Proportion of subjects who within 72 hours and 30 days, had endoscopic re-treatment due to rebleeding.
6. Number of blood units transfused within 72 hours and 30 days.
7. Number of days hospitalised due to rebleeding within 30 days.
8. Safety and tolerability.
In addition, the safety and tolerability of open oral treatment of esomeprazole 40 mg for 27 days will be assessed.

E.2.3

Trial contains a sub-study

Information not present in EudraCT

E.3

Principal inclusion criteria

For inclusion in the study, subjects must fulfil all of the following criteria:
1. Provision of informed consent.
2. Female or male aged 18 years and over.
3. Upper gastrointestinal bleeding (haematemesis, melaena or haematochezia) or with such sign within the last 24 hours as judged by the investigator.
4. One endoscopically confirmed bleeding gastric or duodenal peptic ulcer, at least 5 mm in diameter, classified as Forrest Ia, Ib, IIa, or IIb. Photo documentation of the source of bleeding is required.

Forrest classification of PUB (Forrest et al 1974):
Ia = arterial bleeding
Ib = oozing bleeding
IIa = non-bleeding visible vessel
IIb = adherent clot

In case of Forrest IIb (adherent clot), all efforts should be made to remove the clot. If the clot cannot be removed, it is to be handled as follows:
- If the clot can be removed with 5 min of high-pressure water irrigation (Laine et al 1996) or by cold snare, the ulcer should be reclassified and only Forrest Ia, Ib and IIa should be included.
- If the clot cannot be removed despite these measures, the subject should be included as Forrest IIb.

5. Successful haemostasis (which is considered to have been established if bleeding has stopped and, if applicable, formerly bleeding vessels are flattened or cavitated) achieved by endoscopic treatment with:
- Injection therapy (epinephrine, dilution 1:10000)
and/or one of the following:
- Coagulation with heater probe
- Electrocautery
- Haemoclips.

E.4

Principal exclusion criteria

Any of the following is regarded as a criterion for exclusion from the study:
1. Malignancy or other advanced disease with a life expectancy of < 6 months as judged by the investigator.
2. The ASA classification (Appendix C) of physical status > 3 as judged by the investigator.
3. Severe hepatic disease defined as Child-Pugh B or C (Appendix D).
4. Severe renal disease, defined as subject requiring dialysis or subject in imminent need of dialysis as judged by the investigator.
5. Major cardiovascular event at enrolment or within 3 months prior to study start, such as stroke, myocardial infarction, or hospitalisation for treatment of unstable angina pectoris as judged by the investigator.
6. Haemorrhagic disorder, platelets <100x10e9/L, INR>1.5, APTT>1.5x upper limit of normal (ULN), or treatment with low-molecular weight heparin.
7. Endoscopic suspicion of gastric malignancy or juxta pyloric stenosis as judged by the investigator.
8. Sign of multiple bleeding peptic ulcers or concomitant other gastrointestinal bleeding from esophageal varices, reflux esophagitis, gastritis, Mallory Weiss rifts, ulcus simplex, Dieulafoy’s lesion, colon, small bowel, or ulcer distal to the stoma in Billroth-resected subjects.
9. Need for treatment during the first 7 days of the study with NSAIDs, Cyclooxygenase-2 (COX-2) inhibitors, acetyl salicylic acid (ASA) (including low dose) and clopidogrel.
10. Known or suspected hypersensitivity to any component of any PPI (esomeprazole, omeprazole, lansoprazole, rabeprazole, or pantoprazole).
11. Planned treatment with medication that could interact with esomeprazole; ie, phenytoin, clarithromycin, itraconazole, ketoconazole, warfarin (including other vitamin K antagonists), cisapride, atazanavir and ritonavir.
12. Chemotherapy or radiation therapies within 2 weeks prior to study start or planned during the course of the study.
13. Pregnancy, planned pregnancy or lactation. Women of childbearing potential must use reliable and medically accepted methods of birth control, as judged by the investigator.
14. Known or suspected alcohol, drug or medication abuse, or any condition associated with poor compliance as judged by the investigator.
15. Participation in any study of investigational drugs within the preceding 30 days prior to enrolment.
16. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the investigational site).
17. Previous enrolment in the present study.
18. Intravenous administration of a PPI (esomeprazole, omeprazole, lansoprazole, rabeprazole or pantoprazole) exceeding a total dose of 40 mg within 24 hours prior to enrolment.

E.5 End points

E.5.1

Primary end point(s)

There is no primary endpoint in this study.

Primary outcome variable: Clinically significant rebleeding within 72h of continues infusion of esomeprazole or placebo.

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

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)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

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.8.5

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

Information not present in EudraCT

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

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

End of study is defined as database lock, which is the time point after which no subject will be exposed to study related activities.

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

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.1.3

Elderly (>=65 years)

Yes

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

Information not present in EudraCT

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2006-05-05.

Yes

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

Yes

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

440

F.4.2.2

In the whole clinical trial

760

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)

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

2005-09-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2005-11-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2008-01-04

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