Clinical Trials Register

Summary
EudraCT Number:	2013-000895-14
Sponsor's Protocol Code Number:	NAK-07
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-11-29
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

Czechia - SUKL

A.2

EudraCT number

2013-000895-14

A.3

Full title of the trial

A 52-week, double-blind, randomised, placebo-controlled, parallel-group
phase III study with re-randomisation at week 25 to evaluate the efficacy and safety of oral ibodutant 10 mg once daily in female patients with irritable bowel syndrome with diarrhoea (IBS-D).

52týdenní, dvojitě zaslepená, randomizovaná, placebem kontrolovaná studie fáze III paralelních skupin s opětovnou randomizací po 25 týdnech k posouzení účinnosti a bezpečnosti perorálního užívání ibodutantu 10 mg jednou denně u pacientek se syndromem dráždivého tračníku s průjmem

A.3.1

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

A Clinical study assessing the treatment with ibodutant for Irritable Bowel Syndrome with diarrhoea.

A.3.2

Name or abbreviated title of the trial where available

IRIS-4

A.4.1

Sponsor's protocol code number

NAK-07

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	Menarini Ricerche S.p.A.
B.1.3.4	Country	Italy
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	Menarini Ricerche S.p.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Menarini Ricerche S.p.A.
B.5.2	Functional name of contact point	Clinical Research
B.5.3	Address:
B.5.3.1	Street Address	Via Sette Santi, 1
B.5.3.2	Town/ city	Florence
B.5.3.3	Post code	50131
B.5.3.4	Country	Italy
B.5.4	Telephone number	+3905556809990
B.5.5	Fax number	+390555680597
B.5.6	E-mail	acapriati@menarini-ricerche.it

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	ibodutant
D.3.2	Product code	MEN15596
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	ibodutant
D.3.9.1	CAS number	522664-63-7
D.3.9.2	Current sponsor code	MEN 15596
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	10
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	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

Irritable bowel syndrome with diarrhoea (IBS-D) in female patients.

E.1.1.1

Medical condition in easily understood language

Gastrointestinal disorder mainly characterised by abdominal pain and diarrohea and, hence, called irritable bowel syndrome with Diarrhoea (IBS-D), in female patients.

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	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10060849
E.1.2	Term	Diarrhoea predominant irritable bowel syndrome
E.1.2	System Organ Class	100000004856

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10060845
E.1.2	Term	Diarrhea predominant irritable bowel syndrome
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 efficacy of ibodutant on IBS symptoms as compared to placebo in IBS-D female patients over a 24-week oral treatment period.

E.2.2

Secondary objectives of the trial

· To assess the safety and tolerability of ibodutant on 12, 24 and 52-week treatment course with oral 10 mg dose once daily in IBS-D female patients.
· To evaluate the sustained effect of ibodutant on IBS symptoms in IBS-D female patients.
· To evaluate ibodutant population pharmacokinetics in IBS-D female patients.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Female patients aged 18 years or older.
- Clinical diagnosis of IBS-D according to the following symptom-based criteria as per Rome III modular questionnaire criteria:
- Recurrent abdominal pain or discomfort for at least 3 days per month in the last 3 months associated with at least 2 of the
following characteristics:
a) improvement with defecation;
b) onset associated with a change in the frequency of stool;
c) onset associated with a change in form (appearance) of stool. - Symptom-onset at least 6 months prior to diagnosis. - Loose or watery stools at least 25% of the time in the last 3 months AND hard or lumpy stools less than 25% of the time in the last 3 months. - Additional criterion: more than 3 bowel movements per day at least 25% of the time in the last 3 months.
- For patients older than 50 years OR patients with positive family
history of colorectal cancer: normal results from colonoscopy/flexible sigmoidoscopy performed within the last 5 years and after the onset of IBS symptoms, and completed before the start of the Screening period.
- For patients aged 65 years or older: absence of ischaemic colitis, microscopic colitis, or any other organic gastrointestinal (GI) disease as evidenced by the results of a colonoscopy/ flexible sigmoidoscopy with biopsy performed within 6 months before the start of the Screening period.
- Patient willing to refrain from using any anti-diarrhoeal loperamide within 3 days prior to the Run-in visit and during the Run-in period (to be re-checked prior to randomisation).
At the end of Run in period, ONLY patients meeting the following e-diary criteria and all the other inclusion criteria will be eligible to progress to randomisation:
- Patient has during both weeks of the Run-in period a weekly average of worst abdominal pain in the past 24 hours with a score of ≥ 3.0 on a 0 to 10 point scale (Abdominal Pain Intensity).
- Patient has during both weeks of the Run-in period at least one bowel movement on each day.
- Patient has during both weeks of the Run-in period a weekly average of at least 3 bowel movements per day.
- Patient has during both weeks of the Run-in period at least one stool with a consistency of Type 6 or Type 7 according to the Bristol Stool Scale (BSS) on at least 2 days per week (Stool Consistency).
- Patient has during both weeks of the Run-in period less than 2 bowel movements with a consistency of Type 1 or Type 2 according to the BSS per week.
- Adequate compliance with the e-diary recording procedure defined as at least 11 of 14 days (≥75%) of the nominal daily entry considering the last consecutive 14 days prior the randomisation [NOTE: Run-in duration is 14 days (+3 days)].

E.4

Principal exclusion criteria

NOTE: Patient with any alarm signs (e.g. fever, rectal bleeding other than haemorrhoids, unintentional weight loss, anaemia) deserve special consideration to exclude any organic GI disease.
- Male gender.
- Patient has a diagnosis of IBS with a subtype of constipation, mixed IBS, or unsubtyped IBS according to the Rome III criteria.
- Patient has had surgery that meets any of the following criteria:
a) Colonic or major abdominal surgery, i.e. bariatric surgery and stomach, small/large bowel or large vessel abdominal surgery (except appendicectomy, hysterectomy, cholecystectomy, caesarean section, or laparoscopic surgery).
b) Any other major abdominal surgery in the previous 6 months.
-Patient has any elective major surgery planned or expected at any time during the study.
- Patient has a history of inflammatory bowel diseases, complicated diverticulosis (i.e. diverticulitis), ischaemic colitis, microscopic colitis.
- Patient has a history of organic abnormalities of the GI tract, intestinal obstruction, stricture, toxic megacolon, GI perforation, faecal impaction, gastric banding, adhesions or impaired intestinal circulation (e.g. aortoiliac disease).
- Patient has a history of pancreatitis of any aetiology, cholecystitis or of symptomatic gallbladder stone disease in the previous 6 months.
- Patient has an active biliary duct disease or a history of Sphincter of Oddi dysfunction.
- Patient has a history of gluten enteropathy.
- Patient has a history of lactose intolerance as assessed by response to diet.
- Patient has a current or previous diagnosis of neoplasia (except non-GI neoplasia in complete remission ≥ 5 years, squamous and basal cell carcinomas and cervical carcinoma in situ).
- Patient has a history of ectopic endometriosis.
- Patient has a history of positive tests for ova or parasites, or clostridium difficile toxin or occult blood in the stool in the previous 6 months.
- Relevant changes in dietary habits, lifestyle, or exercise regimen in the previous 2 months . NOTE: dietary habits, lifestyle and exercise regimen should be maintained for the duration of the study.
- Use of prohibited concurrent medication within the previous month, namely: Antibiotics (4 months in the case of rifaximin); 5-HT3 antagonist alosetron.
- Use of prohibited concurrent medication within the previous 7 days, namely (for details see protocol): Antimuscarinic drugs, Drugs enhancing GI motility, Analgesic drugs, Fibre products and herbal preparations, Antidepressants, Benzodiazepines

E.5 End points

E.5.1

Primary end point(s)

Primary Efficacy Endpoint:
Weekly response for abdominal pain intensity AND stool consistency over the first 24 weeks of treatment in at least 50% of the weeks of treatment (12
out of 24 weeks). The patient will be considered a weekly responder if she meets BOTH of the following criteria in the same week:
Abdominal pain response: decrease in weekly average of worst
abdominal pain score in past 24 hours of at least 30% compared with baseline (2-week Run-in period).
NOTE: “Worst abdominal pain score in past 24 hours” hereafter will be called “abdominal pain intensity”.
Stool consistency response: decrease of at least 50% in the number of days per week with at least one stool that has a consistency of Type 6 or 7 compared with baseline (2-week Run-in period).

E.5.1.1

Timepoint(s) of evaluation of this end point

weekly response over 24 weeks of treatment.

E.5.2

Secondary end point(s)

Sustained efficacy evaluated as weekly response for abdominal pain intensity AND stool consistency over the first 24 weeks of treatment applying the 50% rule with at least 2 weeks in the last 4 weeks of treatment (weeks 21 to 24). The patient will be considered a weekly responder as defined in the primary endpoint.
· Weekly response for abdominal pain intensity over the first 24 weeks of treatment in at least 50% of the weeks of treatment (12 out of 24 weeks). The patient will be considered a weekly responder as defined in the primary endpoint in terms of abdominal pain intensity. The same end-point will be evaluated over the first 12 weeks of treatment
· Weekly response for stool consistency over the first 24 weeks of treatment in at least 50% of the weeks of treatment (12 out of 24 weeks). The patient will be considered a weekly responder as defined in the primary endpoint in terms of stool consistency. The same end-point will be evaluated over the first 12 weeks of treatment.
· Weekly abdominal pain responder defined as a patient with a decrease of at least 30% versus baseline in the weekly average of abdominal pain intensity from randomisation until the end of first 24 weeks.
Additionally the same endpoint will be considered with the thresholds of 40% and 50%.
· Weekly stool consistency responder defined as a patient with a decrease versus baseline of at least 50% in the number of days per week with at least one stool that has the consistency of type 6 or 7 from randomisation until the end of first 24 weeks.

Weekly Response for relief of IBS symptoms over the first 24 weeks of treatment in at least 50% of the weeks of treatment (12 out of 24 weeks). The patient will be considered a weekly responder if she has an IBS degree-of-relief equal to “Completely relieved/improved” or “Considerably relieved/improved”.
· Change in IBS-SSS from baseline after 12 and 24 weeks of the first treatment period.
· Change of weekly average for each week during the first 24 weeks treatment period versus baseline (2-week Run-in period) of specific symptoms of IBS-D i.e.:
- Abdominal pain intensity.
- Abdominal discomfort intensity.
- Abdominal bloating intensity.
- Stool urgency intensity.
- Stool incontinence episodes.
- Stool frequency.
- Abdominal pain-free days.
- Stool consistency score.
· Weekly response for abdominal pain intensity and stool consistency over the first 12 weeks of treatment in at least 50% of the weeks of treatment (6 out of 12 weeks). The patient will be considered a weekly responder as defined in the primary endpoint.

E.5.2.1

Timepoint(s) of evaluation of this end point

weekly or as per protocol.

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

Yes

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.8.2.4

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

Czech Republic

Germany

Hungary

Latvia

Poland

Slovakia

Sweden

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:

450

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

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

285

F.4.2.2

In the whole clinical trial

558

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)

After end of study participation the patient may resume/start any IBS medication according to Investigator's recommendation and according to standard of care.

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

2014-02-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-11

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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