Gastric Motility Disorder
Conditions
Keywords
Methylnaltrexone, Codeine, Gastrointestinal motility, Colonic transit
Brief summary
This is a single-center, randomized, double blind, placebo-controlled study evaluating the effects of placebo, codeine, methylnaltrexone and codeine with methylnaltrexone on gastrointestinal motility and colonic transit of solids in healthy human subjects. The hypotheses are: 1. Methylnaltrexone administered subcutaneously enhances gastrointestinal motility with acceleration of overall colonic transit, and ascending colon emptying of solids in healthy humans. 2. Methylnaltrexone significantly accelerates colonic transit that is delayed by codeine
Detailed description
Methodology Following the initial screening visit (visit 1), participants will be randomized to study medication, either 0.30mg/kg methylnaltrexone subcutaneously or placebo once daily and 30 mg codeine orally or placebo taken four times daily for a total of five days. Participants will be randomly assigned to study medication and allocation will be concealed. A urine pregnancy test will be performed for all females of child bearing potential within the 48 hours prior to the receipt of study medication. Note that females who are status post bilateral tubal ligation, hysterectomy or postmenopausal are exempted from this test. Study medication will be administered on study med days 1, 2 and 3 (visits 2, 3 and 4) at the Clinical Research Unit (CRU). Participants will return for scintigraphic assessment of gastric, small bowel and colonic transit of solids on study med days 4 and 5 (visits 5 and 6). The transit studies will be undertaken on over a 48 hour time period; no study medication is given on the final day of transit (visit 7). Investigational product, dosage, mode of administration, duration of treatment 0.30 mg/kg methylnaltrexone or placebo subcutaneously once daily and 30 mg codeine or placebo orally four times daily for five consecutive days. Treatment groups 1. placebo + placebo (8 participants) 2. placebo + codeine 120mg (8 participants) 3. methylnaltrexone 0.30 mg/kg + placebo (16 participants) 4. methylnaltrexone 0.30 mg/kg + codeine 120 mg (16 participants) Efficacy assessments 1. Scintigraphic gastrointestinal and colonic transit 2. Assessment of bowel pattern frequency and consistency made by the patient using the bowel pattern diary Safety assessments No safety assessments (routine laboratory analysis, ECG etc) will be performed as both methylnaltrexone and codeine are FDA approved medications Statistical analysis The overall effects of the methylnaltrexone treatment on the primary and secondary response measures will be assessed using an analysis of covariance (ANCOVA) with suitable transformation for skewness in the distributions of measured responses if necessary (e.g., ANCOVA on ranks or an arcsine square root transformation for the proportion of marker in the colon at 6 hours). The covariates considered for inclusion in the analyses will be age, gender and body mass index. An a priori anticipated contrast (overall drug vs. placebo) will be examined (α = 0.05). The specific comparisons of methylnaltrexone vs placebo and codeine vs codeine plus methylnaltrexone are of significant interest, and since they are related to specific hypotheses, no change in α from 0.05 is planned.
Interventions
DRUGMethylnaltrexone only
0.30 mg/kg subcutaneous injection daily
DRUGCodeine only
30 mg taken orally four times daily for 5 days
DRUGMethylnaltrexone + codeine
Methylnaltrexone 0.30 mg/kg by subcutaneous injection once daily and codeine 30 mg taken orally four times daily for 5 days
Placebo subcutaneous injection once daily and placebo taken orally four times daily for 5 days
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Males and non-pregnant, non-breastfeeding females * 18-65 years old * No functional GI disorders on the short Bowel Disease Questionnaire (BDQ) * A BMI greater than 22.0
Exclusion criteria
* Structural or metabolic diseases/conditions that affect the gastrointestinal system or functional gastrointestinal disorders. The short version of the Bowel Disease Questionnaire (BDQ) will be exclude functional GI disorders. More than three positive responses will exclude participation. * Unable to withdraw from the following medications 48 hours prior to study entry:Any medication that alters GI transit including but not limited to laxatives, magnesium or aluminum-containing antacids, prokinetics, erythromycin, narcotics, anticholinergics, tricyclic antidepressants, SSRI and newer antidepressants; analgesic drugs including opiates, NSAID, COX 2 inhibitors (note : Tylenol is permitted); GABAergic agents and benzodiazepines. Note: Concomitant medications will be reviewed on a case by case basis by the study physicians. * Subjects who are considered by the investigator to be alcoholics not in remission or known substance abusers. Alcohol must be avoided from seven days prior to beginning the study medication until the completion of the study. * Subjects who have participated in another clinical study within the past 30 days. * Clinical evidence (including physical exam and review of the medical history) of significant cardiovascular, respiratory, renal, hepatic, pulmonary, gastrointestinal, hematological, neurological, psychiatric, or other disease that interfere with the objectives of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Colonic Geometric Center at 24 Hours | 24 hours | The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit. A GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| T1/2 of Gastric Emptying of Solid | 4 hours | — |
| Colonic Geometric Center at 4 Hours | 4 hours | The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit. A GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. |
| Colonic Geometric Center at 48 Hours | 48 hours | The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit. A GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. |
| T1/2 of Ascending Colon Emptying | 24 hours | — |
| Stool Frequency | daily | Stool frequency was self reported in a daily bowel pattern diary for 13 days. |
| Stool Consistency as Reported From the Bristol Stool Scale | Daily | Bristol Stool Scale a medical aid designed to classify the form of human feces into seven categories or types. Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools especially the latter, as they are the easiest to defecate, and 5-7 tending towards diarrhea. |
| Colonic Filling at 6 Hours | 6 hours | Percent of solids reaching the colon at 6 hours |
Countries
United States
Participant flow
Recruitment details
Study participants included males and non-pregnant, non-breastfeeding females aged 18 to 55 years. All subjects had a minimum body mass index (BMI) of 22 kg/m2.
Pre-assignment details
Subjects were screened for eligibility within 28 days of Day 1 of the study. They were stratified based on gender and BMI (\<25, ≥25 kg/m2) and randomized into one of four treatment groups: Treatment groups were randomly assigned in fixed block sizes according to a schedule provided by the study statistician (ARZ). Allocation sequence was concealed
Participants by arm
| Arm | Count |
|---|---|
| Methylnaltrexone 0.30 mg/kg | 16 |
| Codeine 30 mg | 8 |
| Methylnaltrexone 0.30 mg/kg + Codeine 30 mg | 16 |
| Placebo | 8 |
| Total | 48 |
Baseline characteristics
| Characteristic | Methylnaltrexone 0.30 mg/kg | Codeine 30 mg | Methylnaltrexone 0.30 mg/kg + Codeine 30 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 8 Participants | 16 Participants | 8 Participants | 48 Participants |
| Age Continuous | 33.9 years STANDARD_DEVIATION 2.6 | 39.4 years STANDARD_DEVIATION 3.8 | 31.6 years STANDARD_DEVIATION 2.7 | 36.1 years STANDARD_DEVIATION 3.6 | 37.5 years STANDARD_DEVIATION 2.4 |
| Sex: Female, Male Female | 11 Participants | 5 Participants | 10 Participants | 5 Participants | 31 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 6 Participants | 3 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 16 | 7 / 8 | 11 / 16 | 5 / 8 |
| serious Total, serious adverse events | 0 / 16 | 0 / 8 | 0 / 16 | 0 / 8 |
Outcome results
Primary
Colonic Geometric Center at 24 Hours
The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit. A GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool.
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylnaltrexone 0.30 mg/kg | Colonic Geometric Center at 24 Hours | 2.3 Units on a scale | Standard Error 0.2 |
| Codeine 30 mg | Colonic Geometric Center at 24 Hours | 1.8 Units on a scale | Standard Error 0.2 |
| Methylnaltrexone 0.30 mg/kg + Codeine 30 mg | Colonic Geometric Center at 24 Hours | 1.9 Units on a scale | Standard Error 0.3 |
| Placebo | Colonic Geometric Center at 24 Hours | 2.3 Units on a scale | Standard Error 0.4 |
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.90295% CI: [-0.835, 0.739]ANCOVA
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.70995% CI: [-0.578, 0.841]ANCOVA
Secondary
Colonic Filling at 6 Hours
Percent of solids reaching the colon at 6 hours
Time frame: 6 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylnaltrexone 0.30 mg/kg | Colonic Filling at 6 Hours | 21.9 Percentage | Standard Error 5.7 |
| Codeine 30 mg | Colonic Filling at 6 Hours | 23.7 Percentage | Standard Error 11.2 |
| Methylnaltrexone 0.30 mg/kg + Codeine 30 mg | Colonic Filling at 6 Hours | 28.0 Percentage | Standard Error 6.9 |
| Placebo | Colonic Filling at 6 Hours | 34.5 Percentage | Standard Error 14.1 |
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI as covariatesp-value: 0.88995% CI: [-23.678, 27.223]ANCOVA
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.27495% CI: [-10.362, 35.577]ANCOVA
Secondary
Colonic Geometric Center at 48 Hours
The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit. A GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool.
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylnaltrexone 0.30 mg/kg | Colonic Geometric Center at 48 Hours | 3.9 Units on a scale | Standard Error 0.3 |
| Codeine 30 mg | Colonic Geometric Center at 48 Hours | 3.3 Units on a scale | Standard Error 0.4 |
| Methylnaltrexone 0.30 mg/kg + Codeine 30 mg | Colonic Geometric Center at 48 Hours | 2.8 Units on a scale | Standard Error 0.3 |
| Placebo | Colonic Geometric Center at 48 Hours | 4.1 Units on a scale | Standard Error 0.2 |
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.15195% CI: [-0.278, 1.734]ANCOVA
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.80695% CI: [-0.795, 1.017]ANCOVA
Secondary
Colonic Geometric Center at 4 Hours
The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit. A GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool.
Time frame: 4 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylnaltrexone 0.30 mg/kg | Colonic Geometric Center at 4 Hours | 0.236 Units on a scale | Standard Error 0.105 |
| Codeine 30 mg | Colonic Geometric Center at 4 Hours | 0 Units on a scale | Standard Error 0 |
| Methylnaltrexone 0.30 mg/kg + Codeine 30 mg | Colonic Geometric Center at 4 Hours | 0.379 Units on a scale | Standard Error 0.13 |
| Placebo | Colonic Geometric Center at 4 Hours | 0.347 Units on a scale | Standard Error 0.229 |
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.06495% CI: [-0.827, 0.025]ANCOVA
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.6195% CI: [-0.287, 0.482]ANCOVA
Secondary
Stool Consistency as Reported From the Bristol Stool Scale
Bristol Stool Scale a medical aid designed to classify the form of human feces into seven categories or types. Types 1 and 2 indicate constipation, with 3 and 4 being the ideal stools especially the latter, as they are the easiest to defecate, and 5-7 tending towards diarrhea.
Time frame: Daily
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylnaltrexone 0.30 mg/kg | Stool Consistency as Reported From the Bristol Stool Scale | 3.4 Units on a scale | Standard Error 0.3 |
| Codeine 30 mg | Stool Consistency as Reported From the Bristol Stool Scale | 3.1 Units on a scale | Standard Error 0.5 |
| Methylnaltrexone 0.30 mg/kg + Codeine 30 mg | Stool Consistency as Reported From the Bristol Stool Scale | 3.3 Units on a scale | Standard Error 0.3 |
| Placebo | Stool Consistency as Reported From the Bristol Stool Scale | 3.7 Units on a scale | Standard Error 0.3 |
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.19295% CI: [-1.255, 0.261]ANCOVA
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.85595% CI: [-0.756, 0.63]ANCOVA
Secondary
Stool Frequency
Stool frequency was self reported in a daily bowel pattern diary for 13 days.
Time frame: daily
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylnaltrexone 0.30 mg/kg | Stool Frequency | 1.1 Stools | Standard Error 0.1 |
| Codeine 30 mg | Stool Frequency | 0.63 Stools | Standard Error 0.2 |
| Methylnaltrexone 0.30 mg/kg + Codeine 30 mg | Stool Frequency | 0.7 Stools | Standard Error 0.1 |
| Placebo | Stool Frequency | 1.5 Stools | Standard Error 0.4 |
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.23695% CI: [-0.572, 0.145]ANCOVA
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.88595% CI: [-0.412, 0.357]ANCOVA
Secondary
T1/2 of Ascending Colon Emptying
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylnaltrexone 0.30 mg/kg | T1/2 of Ascending Colon Emptying | 17.1 hours | Standard Error 2.2 |
| Codeine 30 mg | T1/2 of Ascending Colon Emptying | 24.0 hours | Standard Error 3.9 |
| Methylnaltrexone 0.30 mg/kg + Codeine 30 mg | T1/2 of Ascending Colon Emptying | 23.6 hours | Standard Error 3.3 |
| Placebo | T1/2 of Ascending Colon Emptying | 14.1 hours | Standard Error 2.6 |
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.67595% CI: [-11.415, 7.472]ANCOVA
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.59195% CI: [-10.792, 6.233]ANCOVA
Secondary
T1/2 of Gastric Emptying of Solid
Time frame: 4 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylnaltrexone 0.30 mg/kg | T1/2 of Gastric Emptying of Solid | 102.7 Minutes | Standard Error 5.1 |
| Codeine 30 mg | T1/2 of Gastric Emptying of Solid | 104.0 Minutes | Standard Error 14.1 |
| Methylnaltrexone 0.30 mg/kg + Codeine 30 mg | T1/2 of Gastric Emptying of Solid | 126.8 Minutes | Standard Error 11.9 |
| Placebo | T1/2 of Gastric Emptying of Solid | 101.1 Minutes | Standard Error 6.2 |
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.02495% CI: [-64.097, -4.753]ANCOVA
Comparison: Data were analyzed using analysis of covariance (ANCOVA) with gender and/or BMI included as covariates.p-value: 0.98995% CI: [-26.962, 26.598]ANCOVA