Clinical Trials Register

Summary
EudraCT Number:	2015-005467-16
Sponsor's Protocol Code Number:	55995
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-03-09
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

Netherlands - Competent Authority

A.2

EudraCT number

2015-005467-16

A.3

Full title of the trial

Peppermint oil for the treatment of Irritable Bowel Syndrome: optimizing therapeutic strategies using targeted delivery

Pepermuntolie voor behandeling van het Prikkelbare Darm Syndroom: het optimaliseren van therapeutische strategieën door het gebruik van doelgerichte afgifte.

A.3.1

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

A new formulation of peppermint oil for the treatment of Irritable Bowel Syndrome

Een nieuwe formulering pepermuntolie voor de behandeling van het Prikkelbare Darm Syndroom

A.3.2

Name or abbreviated title of the trial where available

PERSUADE

A.4.1

Sponsor's protocol code number

55995

A.5.4

Other Identifiers

Name:

ABR form number (CCMO)

Number:

56000

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	Maastricht University
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Maastricht University
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	ZonMw
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Maastricht University
B.5.2	Functional name of contact point	Coordinating investigator, Z Weerts
B.5.3	Address:
B.5.3.1	Street Address	Universiteitssingel 50
B.5.3.2	Town/ city	Maastricht
B.5.3.3	Post code	6229 ER
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	00313882284
B.5.6	E-mail	z.weerts@maastrichtuniversity.nl

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	Tempocol®
D.2.1.1.2	Name of the Marketing Authorisation holder	WillPharma
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Tempocol®
D.3.2	Product code	CBG-rvg number 109856/115173
D.3.4	Pharmaceutical form	Capsule, soft
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	Peppermint Oil
D.3.9.3	Other descriptive name	PEPPERMINT OIL
D.3.9.4	EV Substance Code	SUB12550MIG
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	182
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	Yes
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	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	Tempocol-ColoPulse®
D.3.4	Pharmaceutical form	Capsule, soft
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	Peppermint Oil
D.3.9.3	Other descriptive name	PEPPERMINT OIL
D.3.9.4	EV Substance Code	SUB12550MIG
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	182
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	Yes
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, soft
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

Prikkelbare Darm Syndroom

E.1.1.1

Medical condition in easily understood language

IBS

PDS

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. To assess the efficacy and safety profile of treatment of IBS symptoms with peppermint oil compared to placebo. Thereby superiority of peppermint oil can be scientifically supported, leading to increased recognition of this therapy in IBS.
2. To ascertain whether treatment of IBS symptoms with colon-targeted-delivery peppermint oil results in a greater reduction of IBS symptoms and reduction of side effects, compared to enteric-coated capsules delivering the oil in the small intestine.

1. De werkzaamheid en het veiligheidsprofiel van behandeling van IBS symptomen met pepermuntolie te vergelijken met placebo. Daarbij hopen we superioriteit van pepermuntolie wetenschappelijk te kunnen ondersteunen, wat mogelijk leidt tot grotere erkenning van deze therapie in IBS.
2. Om te evalueren of de behandeling van IBS symptomen met colon-gerichte afgifte van pepermuntolie leidt tot een grotere afname van IBS symptomen en vermindering van bijwerkingen, in vergelijking met capsules die de pepermuntolie in de dunne darm afgeven.

E.2.2

Secondary objectives of the trial

1. To evaluate the costs-effectiveness of treatment of IBS symptoms with peppermint oil (both enteric-coated and colon-targeted-delivery formulation) compared to placebo according to the intention to treat principle.
2. To evaluate the effect of treatment with both peppermint formulations on (IBS related) quality of life.

1. Om de kosten-effectiviteit van de behandeling van IBS-symptomen met pepermuntolie (zowel volledig gecoate en colon darm gerichte-afgifte formulering) in vergelijking met placebo volgens de intention to treat principe te evalueren.
2. Om het effect van behandeling met beide pepermunt formuleringen op (IBS gerelateerde) kwaliteit van leven te beoordelen.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age between 18 and 75 years;
2. Diagnosed with Irritable Bowel Syndrome according to the Rome III criteria:
• Recurrent abdominal pain or discomfort, at least 3 days/month for the last 3 months;
• Symptom onset at least 6 months prior to diagnosis
• Associated with two or more of the following:
1. Improvement with defecation;
2. Onset associated with a change in frequency of stool;
3. Onset associated with a change in form (appearance/consistency) of stool;
3. Based on the medical history and previous examination, no other causes for the abdominal complaints can be defined. Especially no history of:
a. Inflammatory Bowel Disease;
b. Celiac Disease;
c. Thyroid dysfunction (if not well-regulated);
If alarm symptoms (including unexplained rectal blood loss or weight loss) are present, a colonoscopy has been performed and was negative for other causes.
4. Women in fertile age (<55 years old) must use contraception or be postmenopausal for at least two years.
5. Average worst abdominal pain score (on 11-point NRS) of > 3, during the two-week run-in period.

1. Leeftijd tussen de 18 en 75 jaar (deze hadden jullie wel ook al vanwege stratificatiefactor)
2. Gediagnosticeerd met het Prikkelbare Darm Syndroom (IBS) volgens de ROME-III criteria:
Recidiverende buikpijn of een ongemakkelijk gevoel in de buik voor ten minste 3 dagen/maand gedurende de laatste 3 maanden;
Symptomen zijn ten minste 6 maanden aanwezig;
Geassocieerd met twee of meer van de volgende criteria:
- Klachten verminderen na defecatie;
- Klachten zijn geassocieerd met een verandering in de frequentie van de defecatie;
- Klachten zijn geassocieerd met een verandering in de consistentie van de ontlasting;
3. Gebaseerd op de medische voorgeschiedenis en aanvullend onderzoek, zijn er geen oorzaken voor de buikklachten aan te wijzen. Er is ten minste geen sprake van:

a. Inflammatory Bowel Disease (IBD);

b. Coeliakie;

c. Schildklier aandoening; (a, b, c, mogen samen afgevinkt worden)

In het geval dat er alarmsymptomen aanwezig zijn, is een colonoscopie verricht om andere oorzaken uit te sluiten.

4. Gemiddelde ergste abdominale pijn score (op de 11-punts schaal) van > 3 (Gedurende twee weken van run-in period);

5. Vrouwen in vruchtbare leeftijd (<55 jaar) moeten anticonceptie gebruiken of voor ten minste twee jaar postmenopauzaal zijn. Vrouwen zijn niet zwanger en geven geen borstvoeding;

E.4

Principal exclusion criteria

1. Insufficient fluency of the Dutch language;
2. Any previous use (also incidental use) of peppermint oil capsules in the last 3 months prior to inclusion;
3. The inability to stop regular use of medication affecting the gastro-intestinal system (such as Non Steroidal Anti Inflammatory Drugs (NSAID), laxatives, prokinetics, opioids, smasmolytics and anti-diarrhoeal drugs);
a. The use of 1 antidepressant drug is allowed, providing dosing has been stable for > 6 weeks before enrollment;
b. The use of 1 proton pump inhibitors (PPI) is allowed, providing dosing has been stable > 6 weeks before enrollment;
4. Previous major abdominal surgery or radiotherapy interfering with gastrointestinal function:
a. Uncomplicated appendectomy, cholecystectomy and hysterectomy allowed unless within the past 6 months;
b. Other surgery upon judgment of the principle investigator;
5. History of liver disease, cholangitis, achlorhydria, gallstones or other diseases of the gallbladder/biliary system;
6. Pregnancy, lactation;
7. Using drugs of abuse;
8. Known allergic reaction to peppermint.

1. Er is onvoldoende vaardigheid van de Nederlandse taal;
2. Gebruik van pepermuntolie capsules in de laatste drie maanden;
3. Niet in staat om regelmatig gebruik van medicatie, die het maag- darm stelsel kan beïnvloeden, te stoppen (zoals NSAIDs, laxantia, prokinetica, opioiden, smasmolytica, anti-diarree medicijnen, drugs);
a. Het gebruik van 1 antidepressivum is toegestaan, mits de dosering reeds 6 weken stabiel is voor inclusie;
b. Het gebruik van 1 PPI is toegestaan, mits de dosering 6 weken stabiel is voor inclusie;
4. Historie van grote abdominale chirurgie of radiotherapie die de maag-darm functie zou kunnen beïnvloeden:
a. Ongecompliceerde appendectomie, cholecystectomie and hysterectomie zijn toegestaan mits deze niet in de voorgaande 6 maanden heeft plaatsgevonden;
b. Andere chirurgie wordt toegestaan naar inschatting van de onderzoeker;
5. Historie van leverziekten, cholangitis, achlorhydria, galstenen of andere aandoeningen van de galwegen
6. Zwangerschap, lactatie
7. Gebruik van drugs
8. Historie van een allergische reactie op pepermuntolie;

E.5 End points

E.5.1

Primary end point(s)

1. Abdominal pain response rate after 8 weeks of treatment.
a. A responder is defined as a patient who experiences at least a 30 percent decrease in the weekly average of worst daily abdominal pain (measured daily, on an 11 point NRS) compared to baseline weekly average in at least 50 percent of the weeks in which the treatment in given.

2. Degree of relief response rate after 8 weeks of treatment.
a. A responder is defined as a patient who experiences a weekly relief of 1 or 2 (on a 7 point NRS) in at least 50 percent of the weeks in which treatment is given.

1. Buikpijn responspercentage na 8 weken van de behandeling.
als.--> Een responder is gedefinieerd als een patiënt die ten minste 30 procent afname ervaart van het wekelijks gemiddelde van ergste dagelijkse buikpijn (dagelijks gemeten op een 11 punt NRS) vergeleken met de uitgangswaarde, in ten minste 50 procent van de weken waarin de behandeling gegeven.

2. Mate van opluchting - responspercentage na 8 weken van de behandeling.
als. --> Een responder is gedefinieerd als een patiënt die een wekelijkse verlichting van 1 of 2 (op 7 punt NRS) ervaart in ten minste 50 procent van de weken, waarin de behandeling wordt gegeven.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 8 weeks of treatment

Na 8 weken behandeling

E.5.2

Secondary end point(s)

Global symptom improvement, abdominal discomfort, bloating, regurgitation, nausea, urgency, abdominal cramps, average stool frequency and consistency at baseline and after treatment (number of complete spontaneous bowel movements (CSBMs) for IBS-C, more lumpy stools in case of IBS-D), cost-utility (as determined by calculations with EQ-5D, direct costs MCP, indirect costs PCQ and social tariff), quality of life (as determined by the EQ-5D and IBS-QoL), use of OTC and rescue medication, number and severity of side effects, responder rates following discontinuation of treatment at 4 and 6 months, different thresholds for the responder analysis of abdominal pain. Worst-case-analysis: imputing a non-response day for each day on which the electronic diary entry was missing.

Globale symptoon verbetering, abdominale dyscomfort, opgeblazen gevoel, oprispingen, misselijkheid, urgentie, buikkrampen, de gemiddelde stoelgang frequentie en consistentie (gemeten door de Bristol Stool Form Scale) bij aanvang en na de behandeling (aantal volledige spontane darmbewegingen (CSBM) voor IBS-C, meer vaste ontlasting in het geval van IBS-D), kosten-utiliteit (zoals bepaald door berekeningen met EQ-5D, directe kosten MCP, indirecte kosten PCQ en sociaal tarief), de kwaliteit van leven (zoals bepaald door de EQ-5D en IBS-QoL), het gebruik van OTC en noodmedicatie, het aantal en de ernst van bijwerkingen, responder tarieven na het staken van de behandeling bij 4 en 6 maanden, anderere cut off waarden voor de responder analyse van buikpijn. Worst-case-analyse.

E.5.2.1

Timepoint(s) of evaluation of this end point

6 months after start of the treatment period

6 maanden na start van de behandelperiode

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

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

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

6 months after the last subject (that has completed the treatment period) has begun the treatment period. This moment has been chosen because a 6 month follow up is part of the study.

6 maanden nadat de laatste proefpersoon (die de behandelingsperiode heeft afgerond) begonnen is aan de behandelperiode. Dit moment is gekozen omdat 6 maanden follow up onderdeel is van de studie.

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

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)

F.1.2.1

Number of subjects for this age range:

140

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

178

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)

None

Geen

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

2016-03-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-11-01

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