Effect of Methylnaltrexone on GI Transit in Healthy Volunteers
Condition: Gastric Motility Disorder
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Methylnaltrexone only; Codeine only; Methylnaltrexone + codeine; Placebo + placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 0.30 mg/kg subcutaneous injection daily; 30 mg taken orally four times daily for 5 days; 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
Other intervention name(s): MNTX; Relistor
Intervention MeSH terms: Naltrexone; Codeine; Methylnaltrexone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Methylnaltrexone; Codeine; Gastrointestinal motility; Colonic transit