Abdominal Pain, Colonic Diseases, Irritable Bowel Syndrome, Visceral Pain
Conditions
Keywords
Peppermint oil, Menthol, Volatile oil, Plant oil, Visceral pain, Abdominal pain, Irritable bowel syndrome (IBS), Colonic disease
Brief summary
This is a pilot study to compare the relative bioavailability between two peppermint oil formulations, namely a ileocolonic release peppermint oil and an small intestinal release peppermint oil (Tempocol®). This study is conducted as part of a future multicenter randomized controlled trial that will assess the therapeutic effect of the new peppermint oil formulation in IBS patients.
Detailed description
Rationale: Peppermint oil has shown to be effective in the treatment of 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 plan to conduct a multicenter randomized controlled trial to investigate the possible beneficial effects of peppermint oil in IBS. To improve efficacy and to reduce side effects, the investigators aim to study the use of a new peppermint oil formulation that will slowly release the oil in the (ileo-) colonic region specifically. In order to demonstrate differences in pharmacokinetics, the subsidizing party, ZonMW, requested an additional pilot study (described in the present protocol) in which the investigators will investigate surrogate markers for local colon bioavailability, tolerability and side effects of the new ileocolonic release PO. Study design: a randomized, double blind, two-period, two-treatment crossover study with a wash out period of at least 14 days. Intervention: All study volunteers will receive a single dose of 182mg of both ileocolonic release peppermint oil and small intestinal release peppermint oil, each on a different test day. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Subjects may be confronted with certain inconveniences and minor risks. They are required to visit the MUMC+ 5 times, once for the screening and two times per test day for various non-invasive measurements (questionnaires, blood pressure and heart-rate measurement, urine and fecal sampling, pregnancy test in women in fertile ages, general physical exam) as well as for minor invasive venous blood sampling, after which a small haematoma can occur. Total time investment is +/- 30 hours, subjects will not benefit from participation.
Interventions
DRUGMenthae piperitae aetheroleum/peppermint oil (enteric coated capsule)
Peppermint oil capsule available as an over the counter prescription drug on the Dutch market.
DRUGMenthae piperitae aetheroleum/peppermint oil (colon-targeted-delivery capsule)
Peppermint oil capsule with a coating developed according to the ColoPulse® technology, ensuring a pulsatile and therefore slower release in a lower part of the intestinal tract compared to Tempocol, namely in the (ileo-)colonic region.
Sponsors
ZonMw: The Netherlands Organisation for Health Research and Development
Maastricht University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Based on medical history and previous examination, no gastrointestinal complaints can be defined * Age between 18 and 65 years * BMI between 18 and 25 kg/m2 and a weight of at least 50 kilograms * Women in fertile age (\<55 years old) must use contraception or be postmenopausal for at least two years
Exclusion criteria
* History of severe or chronic cardiovascular, respiratory, urogenital, gastrointestinal/ hepatic, hematological/immunologic, HEENT (head, ears, eyes, nose, throat), dermatological/connective tissue, musculoskeletal, metabolic/nutritional, endocrine, neurological/psychiatric diseases, allergy, major surgery and/or laboratory assessments which might limit participation in or completion of the study protocol * Use of medication, including vitamin and iron supplementation, except oral contraceptives, within 14 days prior to start of the study * Administration of investigational drugs or participation in any scientific intervention study which may interfere with this study (to be decided by the principle investigator), in the 180 days prior to the study * Major abdominal surgery interfering with gastrointestinal function (uncomplicated appendectomy, cholecystectomy and hysterectomy allowed, and other surgery upon judgment of the principle investigator) * Dieting (for example lactose-free, gluten-free, caloric-restrictive, vegetarian or vegan, macrobiotic diet) * Pregnancy, lactation * High alcohol consumption (\>15 alcoholic consumptions per week) * Smoking/ Using drugs of abuse * Self-admitted HIV-positive state * Known allergic reaction to peppermint * High intake of caffeine (\>8 cups coffee a day)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| T-max | 24 hours | Time to reach maximum menthol-glucuronide (main constituent of peppermint oil after conversion by the liver) concentration in plasma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| T-lag | 24 hours | Time until a measurable plasma concentration of menthol-glucuronide occurs after oral administration of peppermint oil (45ug/L) |
| AUC | 24 hours | Area under the plasma concentration-time curve from t=0 hrs until t=24 hrs. |
| T1/2 | 24 hours | elimination half-life; time required for the plasma concentration of menthol-glucuronide to reach half of its original value. |
| C-max | 24 hours | Menthol-glucuronide (main constituent of peppermint oil after conversion by the liver) peak plasma concentrations |
| L-Menthol Concentration in Feces | +/- 24 hours | — |
| Difference in Total Number of Side Effects Per Time Point. | 24 hours | — |
| Tolerability Assessed by Heart Rate, Blood Pressure and Reported Side Effects | 24 hours | Assessed by heart rate, blood pressure and reported side effects. |
| Menthol-glucuronide Urine Exretion Time Curve | 24 hours | — |
Countries
Netherlands
Participant flow
Pre-assignment details
This was a crossover design.
Participants by arm
| Arm | Count |
|---|---|
| Ileocolonic Release PO on First Test Day Ileocolonic release PO is a targeted ileocolonic release peppermint oil capsule that releases peppermint oil in the (ileo-) colonic region specifically.
Menthae piperitae aetheroleum/peppermint oil (colon-targeted-delivery capsule): Peppermint oil capsule with a coating developed according to the ColoPulse® technology, ensuring a pulsatile and therefore slower release in a lower part of the intestinal tract compared to Tempocol, namely in the (ileo-)colonic region. | 4 |
| Small Intestinal Release PO on First Test Day Small Intestinal Release PO (Tempocol®) is an enteric-coated peppermint oil capsule that delivers peppermint oil in the upper small intestine.
Menthae piperitae aetheroleum/peppermint oil (enteric coated capsule): Peppermint oil capsule available as an over the counter prescription drug on the Dutch market. | 4 |
| Total | 8 |
Baseline characteristics
| Characteristic | Ileocolonic Release PO on First Test Day | Small Intestinal Release PO on First Test Day | Total |
|---|---|---|---|
| Age, Continuous | 21.7 years | 24.1 years | 22.2 years |
| BMI | 21.5 kg/m^2 | 21.7 kg/m^2 | 21.5 kg/m^2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment Netherlands | 4 participants | 4 participants | 8 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 8 | 2 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
T-max
Time to reach maximum menthol-glucuronide (main constituent of peppermint oil after conversion by the liver) concentration in plasma
Time frame: 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ileocolonic Release PO | T-max | 360 minutes |
| Small Intestinal Release PO | T-max | 180 minutes |
Secondary
AUC
Area under the plasma concentration-time curve from t=0 hrs until t=24 hrs.
Time frame: 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ileocolonic Release PO | AUC | 2331 ug*h/L |
| Small Intestinal Release PO | AUC | 2623 ug*h/L |
Secondary
C-max
Menthol-glucuronide (main constituent of peppermint oil after conversion by the liver) peak plasma concentrations
Time frame: 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ileocolonic Release PO | C-max | 563.6 ug/L |
| Small Intestinal Release PO | C-max | 702 ug/L |
Secondary
Difference in Total Number of Side Effects Per Time Point.
Time frame: 24 hours
Secondary
L-Menthol Concentration in Feces
Time frame: +/- 24 hours
Secondary
Menthol-glucuronide Urine Exretion Time Curve
Time frame: 24 hours
Population: No urine analysis was performed due to lack in funding. In addition, it was felt that the systemic concentration of menthol glucuronide concentration provided enough information to answer the research question.
Secondary
T1/2
elimination half-life; time required for the plasma concentration of menthol-glucuronide to reach half of its original value.
Time frame: 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ileocolonic Release PO | T1/2 | 6.1 hours |
| Small Intestinal Release PO | T1/2 | 7.7 hours |
Secondary
T-lag
Time until a measurable plasma concentration of menthol-glucuronide occurs after oral administration of peppermint oil (45ug/L)
Time frame: 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ileocolonic Release PO | T-lag | 225 minutes |
| Small Intestinal Release PO | T-lag | 37 minutes |
Secondary
Tolerability Assessed by Heart Rate, Blood Pressure and Reported Side Effects
Assessed by heart rate, blood pressure and reported side effects.
Time frame: 24 hours