Effect of Methylnaltrexone on GI Transit in Healthy Volunteers

Study Overview
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Brief Summary
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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: Methylnaltrexone administered subcutaneously enhances gastrointestinal motility with acceleration of overall colonic transit, and ascending colon emptying of solids in healthy humans. Methylnaltrexone significantly accelerates colonic transit that is delayed by codeine

Detailed Description
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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 placebo + placebo (8 participants) placebo + codeine 120mg (8 participants) methylnaltrexone 0.30 mg/kg + placebo (16 participants) methylnaltrexone 0.30 mg/kg + codeine 120 mg (16 participants) Efficacy assessments Scintigraphic gastrointestinal and colonic transit 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.

Official Title
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Effect of Methylnaltrexone on Gastrointestinal and Colonic Transit in Health

Conditions
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Gastric Motility Disorder

Intervention / Treatment
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* Drug: Methylnaltrexone only
* Drug: Codeine only
* Drug: Methylnaltrexone + codeine
* Drug: Placebo + placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methylnaltrexone<br> | Drug: Methylnaltrexone only<br>* 0.30 mg/kg subcutaneous injection daily<br>* Other names: Relistor;|
| Experimental: Codeine<br> | Drug: Codeine only<br>* 30 mg taken orally four times daily for 5 days<br>|
| Experimental: Methylnaltrexone + codeine<br> | Drug: Methylnaltrexone + codeine<br>* Methylnaltrexone 0.30 mg/kg by subcutaneous injection once daily and codeine 30 mg taken orally four times daily for 5 days<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo + placebo<br>* Placebo subcutaneous injection once daily and placebo taken orally four times daily for 5 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T1/2 of Ascending Colon Emptying |  | 24 hours | 
| T1/2 of Gastric Emptying of Solid |  | 4 hours | 
| 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. | 4 hours | 
| 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. | 48 hours | 
| Colonic Filling at 6 Hours | Percent of solids reaching the colon at 6 hours | 6 hours | 
| Stool Frequency | Stool frequency was self reported in a daily bowel pattern diary for 13 days. | daily | 
| 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. | Daily | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methylnaltrexone, Codeine, Gastrointestinal motility, Colonic transit