Clinical Trials Register

Summary
EudraCT Number:	2013-003342-16
Sponsor's Protocol Code Number:	Z338-01
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-01-20
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2013-003342-16

A.3

Full title of the trial

A Phase III, Multicentre, Single-arm, Open-label Study to Evaluate the Long-term Safety of Z-338 in Subjects with Functional Dyspepsia

A.3.1

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

Long-term safety of Z-338 in Patients with Functional Dyspepsia (Condition that causes an upset stomach or pain or discomfort in the upper abdomen).

A.4.1

Sponsor's protocol code number

Z338-01

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	Zeria Pharmaceutical Co., Ltd.
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	Zeria Pharmaceutical Co.,Ltd.
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	Zeria Pharmaceutical Co., Ltd. (UK)
B.5.2	Functional name of contact point	Tomoharu Miyagawa
B.5.3	Address:
B.5.3.1	Street Address	Building 3, Chiswick Park, 556 Chiswick High Road
B.5.3.2	Town/ city	London
B.5.3.3	Post code	W4 5YA
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44208849 8031
B.5.5	Fax number	+44208889 6001
B.5.6	E-mail	tomoharu-miyagawa@zeria.co.jp

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	Acofide
D.2.1.1.2	Name of the Marketing Authorisation holder	Zeria Pharmaceuticals 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.3.1	Product name	Acotiamide
D.3.2	Product code	Z-338
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	acotiamide
D.3.9.1	CAS number	773092-05-0
D.3.9.2	Current sponsor code	Z-338API
D.3.9.3	Other descriptive name	Z-338
D.3.9.4	EV Substance Code	SUB129868
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	100
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Functional Dyspepsia

E.1.1.1

Medical condition in easily understood language

Condition that causes an upset stomach or pain or discomfort in the upper abdomen

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10064536
E.1.2	Term	Functional dyspepsia
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 long-term safety of 100 mg Z-338 three times a day (TID) in subjects with Functional Dyspepsia.

E.2.2

Secondary objectives of the trial

To explore:
• The use of the Leuven Postprandial Distress Scale (LPDS) to measure Functional Dyspepsia symptom severity, and the effect of Z-338.
• The effect of Z-338 on the Quality of Life (QoL) in subjects with Functional Dyspepsia as measured by the Short Form-36 (SF-36) survey and the Short Form-Nepean Dyspepsia Index (SF-NDI).
• The effect of Z-338 on work productivity in subjects with Functional Dyspepsia as measured by the Work Productivity and Activity Impairment (WPAI).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria for run-in period:
Subjects will be eligible to enter the run-in period if all of the following criteria are met:
1. Subjects to provide written informed consent prior to any study procedures being performed.
2. Male or female subjects aged 18 years or over, inclusive, on the day the informed consent is signed.
3. Subjects with a diagnosis of FD (postprandial distress syndrome) as defined by the Rome III Criteria* (see Appendix A). Criteria must be fulfilled for the 3 months prior to informed consent with symptom onset at least 6 months prior to informed consent.
Symptoms must include one or both of the following:
i. Bothersome postprandial fullness (PPF), occurring after ordinary-sized meals, more than 1 day per week
ii. Early satiation (ES) that prevents finishing a regular meal, more than 1 day per week
There must be no evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms.
4. Subjects must have consulted for dyspeptic symptoms at least once during the 6 months prior to informed consent. If there are no medical records, the subject should be asked when the symptoms started.
5. Subjects must present PPF or ES as the most bothersome symptom during the 6 months prior to informed consent.
6. Subjects must have a normal endoscopy result within the 6 months (3 months in case of subjects who are H. pylori positive) prior to informed consent or during the screening period.
• If no normal endoscopy results are available from the 6 months (3 months for H. pylori positive subjects) prior to informed consent, an endoscopy must be conducted during the screening period and must be normal for the subject to be eligible. If H. pylori status is unknown, then a H. pylori test must be conducted during the screening period although H. pylori status (i.e., positive or negative) is not an eligibility criterion.
7. Subjects must be able to understand the study, comply with the study requirements, and return to the investigational site for assessments at specified times.
8. Subjects must be able to understand the symptom definitions and how to record their severity using the LPDS incorporated in an electronic Patient Reported Outcome (ePRO) device.
9. Female subjects of childbearing potential must provide a negative pregnancy test (urine dipstick) at screening (Visit 1 or 2). Female subjects of childbearing potential must agree to use acceptable contraceptive methods (i.e., contraceptive implant, injectable or patch hormone therapy, oral contraceptives in combination with barrier methods [e.g., condoms] supplemented with spermicidal foam/gel/film/cream/suppository, intrauterine device, sexual abstinence, or surgical sterilisation of the subject or the subject’s sexual partner) during the screening, run-in, treatment, and follow-up periods. Non-childbearing potential includes being surgically sterilized at least 6 months prior to informed consent, post-menopausal, or defined as amenorrhoea for at least 12 months prior to informed consent.
Male subjects with partners of childbearing potential must agree to use acceptable contraceptive methods (i.e., barrier method [e.g., condoms] supplemented with spermicidal foam/gel/film/cream/suppository in combination with another contraceptive measure as described above) during the screening, run-in, treatment, and follow-up periods.
Inclusion criteria for open-label treatment period
Subjects will be eligible to enter the open-label treatment period if all of the following criteria are met:
1. Subjects must present ES (Question 1 of LPDS) or PPF (Question 2 of LPDS) with a severity of at least moderate and a frequency of at least 2 days a week during the run-in period.
2. Female subjects of childbearing potential must provide a negative pregnancy test (urine dipstick) at Visit 3.

E.4

Principal exclusion criteria

1.Subjects on PPI(s) who are unable to discontinue PPI medication by the end of the screening period (Visit 2).
•Subjects taking PPIs at the time of informed consent will be asked to discontinue the medication and return after a 14- to 21-day washout period to complete screening assessments at Visit 2.
2. Subjects taking drugs that affect gut motility, gut sensitivity and/or acid secretion (see list of prohibited medications, Appendix B) who are unable to discontinue these drugs by the end of the screening period(Visit 2).
•Subjects taking drugs that affect gut motility, gut sensitivity and/or acid secretion* at the time of informed consent will be asked to discontinue the medication and return after a 14- to 21-day washout period to complete screening assessments at Visit 2.*Note: no washout is required for medications listed in the “antacids and cytoprotectors” category in Appendix B.
3.Subjects taking non-steroidal anti-inflammatory drugs (NSAIDs). However, aspirin administration not exceeding 500 mg per day for cardiovascular primary prophylaxis is allowed.
4.Subjects taking QT-time prolonging drugs, e.g., macrolide antibiotics and CYP3A4 inhibiting azole-type antimycotics.
5.Subjects who have received H. pylori eradication therapy during the 3 months prior to informed consent.
6.Subjects with confirmed organic gastrointestinal disease.
7.Subjects with a history of surgery that can affect gastrointestinal motility including endoscopic surgery for gastro-oesophageal reflux disease (GORD) and obesity.
•Subjects with former uncomplicated appendectomy, cholecystectomy, and/or laparoscopic surgery may be included.
8.Subjects presenting with predominant complaints relieved by stool movements(irritable bowel syndrome).
9.Subjects presenting with predominant GORD symptoms(e.g., heartburn, regurgitation, chest pain).
10.Subjects presenting with predominant complaints of chronic idiopathic nausea.
11.Subjects with Type I or Type II diabetes.
12.Subjects with active uncontrolled psychiatric and/or psychosomatic disorders, depression, alcohol, or substance abuse in the 2 years prior to informed consent.
•Subjects with a stable condition(as judged by the Investigator) taking one form of medication of standard dose antidepressant for at least 3 months prior to informed consent may be included. However, subjects taking Amitriptyline or Nortriptyline must be excluded even if prescribed as monotherapy.
•Subjects taking one anxiolytic alone, one sedative alone, or one hypnotic alone once a day at night for sleep problems may be included. However, subjects taking a combination of these drugs must be excluded.
13.Subjects with known hypersensitivity to gastroprokinetic drugs.
14.Subjects with cardiovascular problems, history of arrhythmias, clinically significant electrocardiogram (ECG) abnormalities, and/or subjects with any kind of risk of QT prolongation.
•Subjects who suffer from controlled and non-complicated hypertension, as judged by the Investigator, may be included. However subjects taking clonidine, alphamethyldopa beta blockers, and/or organonitrates must be excluded.
15.Subjects with any evidence of, or treatment for, malignancy(with the exception of basal cell carcinoma) within the 5 years prior to informed consent.
16.Subjects with body mass index(BMI) over 30 kg/m2.
17.Subjects with a clinically significant renal, hepatic, cardiovascular, pulmonary, endocrine, metabolic, or haematological condition, as judged by the Investigator.
18.Females who are pregnant or lactating at the time of informed consent.
19.Subjects who have received treatment with an investigational drug or device within 60 days prior to informed consent.
20.Subjects with any condition which, in the opinion of the Investigator, makes the subject unsuitable for entry into the study.
Open-label treatment period:
1.Subjects with either of the following:
•“Severe” or “Very Severe” Heartburn (Question 8 of LPDS) during the run-in period.
•“Mild” or “Moderate” Heartburn (Question 8 of LPDS) for >1 day during the run-in period.
2.Subjects with“Severe” or “Very Severe” Nausea(Question 6 of LPDS) for >2 days during the run-in period.
3.Subjects with a weekly average severity score of Epigastric Pain (Question 4 of LPDS) and Epigastric Burning(Question 5 of LPDS) of >1.0* during the run-in period.
* daily recorded severity converted into scores as follows: absent=0, mild=1, moderate=2, severe=3, very severe=4 (minimum of 5 days required [does not need to be consecutive days] with both Epigastric Pain(Q4) and Epigastric Burning(Q5) questions answered)
4.Subjects with a clinically significant ECG abnormality.
5.Subjects with a clinically significant renal, hepatic, cardiovascular, pulmonary, endocrine, metabolic, or haematological condition, as judged by the Investigator.
6.Subjects with any condition which, in the opinion of the Investigator, makes the subject unsuitable for entry into the open-label treatment period.

E.5 End points

E.5.1

Primary end point(s)

The long-term safety of Z-338 100 mg TID will be evaluated by assessment of:
• AEs
• ECGs
• Laboratory variables
• Vital signs
• Physical examination

E.5.1.1

Timepoint(s) of evaluation of this end point

58 weeks

E.5.2

Secondary end point(s)

The efficacy of Z-338 100 mg TID will be explored by assessment of the following Patient Reported Outcomes:
• Change of each individual symptom score of the subject measured by LPDS
• Global outcome of the subject measured by OTE
• Change of QoL score of the subject measured by the SF-36 survey and the SF-NDI
• Change of work productivity of the subject measured by WPAI

E.5.2.1

Timepoint(s) of evaluation of this end point

52 weeks

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

The study will be considered to be complete when the last subject has completed their final study assessment.

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:

500

F.1.3

Elderly (>=65 years)

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

F.3.3.2

Women of child-bearing potential using contraception

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

500

F.4.2.2

In the whole clinical trial

500

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)

All subjects who enter the open-label treatment period and receive at least one dose of the study drug will have a follow-up assessment for adverse events (including assessment of concomitant medications taken) either by phone contact or visit to the study site, if required, two weeks after the subject's End of treatment (52 weeks) visit, or early termination visit, as applicable.

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

2014-02-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-02-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-09-30

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