Effect of Methylnaltrexone on GI Transit in Healthy Volunteers

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.

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.