Peppermint Oil for the Treatment of Irritable Bowel Syndrome: Optimizing Therapeutic Strategies Using Targeted Delivery (PERSUADE)

Study Description

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Brief Summary:

Peppermint oil has shown to be effective in the treatment of Irritable Bowel Syndrome (IBS) symptoms in several meta-analyses. However, the level of evidence is moderate and peppermint oil remains relatively under-used in IBS. Therefore, the investigators will conduct a multicenter randomized, placebo controlled trial to investigate the effects of an eight-week peppermint oil treatment in IBS patients according to current European Medicines Agency (EMA) / US Food and Drug Administration (FDA) guidelines. To improve efficacy and to reduce side effects, the investigators aim to study the use of a new peppermint oil formulation, a colon-targeted-delivery capsule that will release the oil in the (ileo-) colonic region specifically.

Condition or disease	Intervention/treatment	Phase
Irritable Bowel Syndrome; Abdominal Pain; Colonic Diseases, Functional	Drug: Ileocolonic release peppermint oil; Drug: Placebo; Drug: Small intestinal release peppermint oil	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	190 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Peppermint Oil for the Treatment of Irritable Bowel Syndrome: Optimizing Therapeutic Strategies Using Targeted Delivery
Actual Study Start Date :	August 17, 2016
Actual Primary Completion Date :	May 1, 2018
Actual Study Completion Date :	October 1, 2018

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Ileocolonic release peppermint oil; Colon-targeted-delivery capsule containing 182mg of Peppermint Oil, to be taken orally, 3 times daily for 8 weeks (first week, dosing will be titred).	Drug: Ileocolonic release peppermint oil; Peppermint oil, menthae piperitae aetheroleum
Experimental: Small intestinal release peppermint oil (Tempocol®); Enteric-coated capsule containing 182mg of Peppermint Oil that release the oil in the small intestine, to be taken orally, 3 times daily for 8 weeks (first week, dosing will be titred).	Drug: Small intestinal release peppermint oil; Peppermint oil, menthae piperitae aetheroleum; Other Name: Tempocol
Placebo Comparator: Placebo; Capsule containing microcrystalline cellulose, to be taken orally, 3 times daily for 8 weeks (first week, dosing will be titred).	Drug: Placebo; Placebo capsule, containing microcrystalline cellulose

Outcome Measures

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Primary Outcome Measures :

1. Abdominal pain response rate after 8 weeks of treatment [ Time Frame: 8 weeks ]
   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. [ Time Frame: 8 weeks ]
   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.

Secondary Outcome Measures :

1. Global symptom improvement [ Time Frame: 8 weeks ]
   As determined by IBS-SSS (IBS symptom severity scale)
2. Abdominal Discomfort [ Time Frame: 8 weeks ]
   As determined by symptom diary
3. Bloating [ Time Frame: 8 weeks ]
   As determined by IBS-SSS (IBS - symptom severity scale)
4. Regurgitation [ Time Frame: 8 weeks ]
   As determined by symptom diary
5. Nausea [ Time Frame: 8 weeks ]
   As determined by symptom diary
6. Urgency [ Time Frame: 8 weeks ]
   As determined by symptom diary
7. Abdominal cramps [ Time Frame: 8 weeks ]
   As determined by symptom diary
8. Average stool frequency and consistency [ Time Frame: 8 weeks ]
   Measured by bristol stool chart
9. Indirect costs [ Time Frame: 8 weeks, 3 and 6 months ]
   Determined by Production Cost Questionnaire (PCQ) questionnaire
10. Direct costs [ Time Frame: 8 weeks, 3 and 6 months ]
    Determined by Medical Cost Questionnaire (MCQ) questionnaire
11. General Quality of Life [ Time Frame: 8 weeks, 3 and 6 months ]
    As determined by Euro-Qol-5D (EQ-5D)
12. IBS related Quality of Life [ Time Frame: 8 weeks, 3 and 6 months ]
    As determined by IBS-Quality of life questionnaire (IBS-QoL)
13. Use of Over the counter medication and rescue medication [ Time Frame: 8 weeks ]
    Number of drugs taken as rescue medication (This is not an intervention)
14. Number and severity of side effects [ Time Frame: 8 weeks ]
    Determined by daily diary
15. Responder rates following discontinuation of treatment at 3 and 6 months, different thresholds for the responder analysis of abdominal pain (e.g. 40 and 50 percent improvement); [ Time Frame: 3 and 6 months after discontinuation of treatment ]
16. Responder rates when missing are interpreted as "no effect" [ Time Frame: 8 weeks ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Age between 18 and 75 years;

2. Diagnosed with Irritable Bowel Syndrome according to the Rome IV criteria:

   (Recurrent abdominal pain, at least 1 day/week for the last 3 months; Symptom onset at least 6 months prior to diagnosis; Associated with two or more of the following:

   1. Pain related to defecation;
   2. Pain associated with a change in frequency of stool;
   3. Pain 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:

   1. Inflammatory Bowel Disease;
   2. Celiac Disease;
   3. 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.

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 (the use of peppermint tea, menthol candy etc. is allowed);

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). This use should be halted at least 1 week before enrollment into the run-in period;

   1. The use of 1 antidepressant drug is allowed, providing dosing has been stable for > 6 weeks before enrollment;
   2. The use of 1 proton pump inhibitor (PPI) is allowed, providing dosing has been stable > 6 weeks before enrollment;

4. Previous major abdominal surgery or radiotherapy interfering with gastrointestinal function:

   1. Uncomplicated appendectomy, cholecystectomy and hysterectomy allowed unless within the past 6 months;
   2. 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.

Contacts and Locations

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Locations

Netherlands
Medical Center Leeuwarden
Leeuwarden, Friesland, Netherlands, 8934 AD
Gelderse Vallei Hospital
Ede, Gelderland, Netherlands, 6716 RP
Alrijne Hospital
Leiden, Zuid Holland, Netherlands, 2334 CK
Maastricht University Medical Center
Maastricht, Netherlands, 6229 ER

Sponsors and Collaborators

Maastricht University Medical Center

ZonMw: The Netherlands Organisation for Health Research and Development

Investigators

Principal Investigator:	A Masclee, Prof., PhD., MD.	Maastricht University Medical Center

More Information

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Publications:

Schellekens RC, Stellaard F, Olsder GG, Woerdenbag HJ, Frijlink HW, Kosterink JG. Oral ileocolonic drug delivery by the colopulse-system: a bioavailability study in healthy volunteers. J Control Release. 2010 Sep 15;146(3):334-40. doi: 10.1016/j.jconrel.2010.05.028. Epub 2010 May 31.

Maurer JM, Schellekens RC, van Rieke HM, Stellaard F, Wutzke KD, Buurman DJ, Dijkstra G, Woerdenbag HJ, Frijlink HW, Kosterink JG. ColoPulse tablets perform comparably in healthy volunteers and Crohn's patients and show no influence of food and time of food intake on bioavailability. J Control Release. 2013 Dec 28;172(3):618-24. doi: 10.1016/j.jconrel.2013.09.021. Epub 2013 Oct 2.

Khanna R, MacDonald JK, Levesque BG. Peppermint oil for the treatment of irritable bowel syndrome: a systematic review and meta-analysis. J Clin Gastroenterol. 2014 Jul;48(6):505-12. doi: 10.1097/MCG.0b013e3182a88357. Review.

Enck P, Junne F, Klosterhalfen S, Zipfel S, Martens U. Therapy options in irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2010 Dec;22(12):1402-11. doi: 10.1097/MEG.0b013e3283405a17. Review.

Ford AC, Talley NJ, Spiegel BM, Foxx-Orenstein AE, Schiller L, Quigley EM, Moayyedi P. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ. 2008 Nov 13;337:a2313. doi: 10.1136/bmj.a2313. Review. Erratum in: BMJ.2009;338:b1881.

Weerts ZZRM, Keszthelyi D, Vork L, Aendekerk NCP, Frijlink HW, Brouwers JRBJ, Neef C, Jonkers DMAE, Masclee AAM. A Novel Ileocolonic Release Peppermint Oil Capsule for Treatment of Irritable Bowel Syndrome: A Phase I Study in Healthy Volunteers. Adv Ther. 2018 Nov;35(11):1965-1978. doi: 10.1007/s12325-018-0802-1. Epub 2018 Oct 4.

Responsible Party:	Maastricht University Medical Center
ClinicalTrials.gov Identifier:	NCT02716285 History of Changes
Other Study ID Numbers:	NL56000.068.16; METC162009; 2015-005467-16 ( EudraCT Number )
First Posted:	March 23, 2016
Last Update Posted:	November 2, 2018
Last Verified:	October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Maastricht University Medical Center:

Irritable Bowel Syndrome; Abdominal pain; Targeted Delivery; Peppermint oil

Additional relevant MeSH terms:

Syndrome; Irritable Bowel Syndrome; Abdominal Pain; Colonic Diseases; Colonic Diseases, Functional; Disease; Pathologic Processes; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Pain	Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Signs and Symptoms, Digestive; Peppermint oil; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Parasympatholytics