Effect of Ileal Bile Acid Transporter Inhibitor in Functional Constipation
Condition: Functional Constipation
MeSH terms: Constipation
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a single-center, randomized, parallel group, double-blind, placebo-controlled, dose
      response, pharmacodynamic and pharmacokinetic study evaluating the effects of A3309 on
      gastric, intestinal and colonic transit in patients with functional constipation.
    

Detailed description: 
      Study period Estimated date of first patient enrolled: January 2010 Study design This is a
      single-center, randomized, parallel group, double-blind, placebo-controlled, dose response,
      pharmacodynamic and pharmacokinetic study evaluating the effects of A3309 on gastric,
      intestinal and colonic transit in patients with functional constipation. Doses of 10 or 20 mg
      A3309 or matching placebo will be administered orally once daily for fourteen (14)
      consecutive days.

      Aim To assess the dose related effects of A3309 on small bowel and overall colonic transit
      and bowel function in patients with functional constipation.

      Number of patients planned Twelve completed female patients with functional constipation in
      each treatment group for a total of 36 patients.

      Diagnosis and main eligibility criteria Female patients with diagnosed functional
      constipation will be recruited from the local community by public advertisement placed within
      areas of Mayo Clinic or by a targeted mailing of an informational letter.

      Methodology Patients with functional constipation will be screened for eligibility and
      informed about the study during pre-screening dialogue and also at the initial Visit 1
      screen.

      Within seven (7) to fourteen (14) days of Visit 1, eligible patients will return for an
      abbreviated scintigraphy test with images obtained only at 4 and 24 hours following In111
      capsule ingestion. A geometric center at 24 hours must be less than or equal to 2.30 to
      qualify for randomization to study medication. The assigned medication is either 10 or 20 mg
      A3309 or placebo administered orally once daily for fourteen (14) consecutive days. The
      allocation to treatment group will be concealed.

      A urine pregnancy test will be performed for all females of child bearing potential at Visit
      1 and again within the 48 hours prior to the receipt of the isotopes by mouth for both the
      abbreviated and post-study medication transit scintigraphy tests at Visit 2 and Visit 4. Note
      that females who are status post-bilateral tubal ligation, hysterectomy or postmenopausal are
      exempted from this test.

      Patients will take study medication at home for eleven (11) consecutive days. Study
      medication will be administered at the Charlton 7 Clinical Research Unit (CRU) at Visit 4, 5,
      and 6, the days of scintigraphic assessment of gastric, small bowel and colonic transit of
      solids performed over a 48 hour period for a total dosing period of fourteen (14) consecutive
      days.

      Within seven (7) to ten (10) days of Visit 6, patients will return to the Charlton 7 CRU for
      final safety monitoring and an exit physical examination and interview with study staff.

      Investigational product, dosage and mode of administration

      Patients will take 15 or 20 mg of A3309 or placebo administered orally for eleven (11)
      consecutive days and report for post-study medication transit scintigraphy on day twelve (12)
      of dosing. Study medication will be administered once with the In111 capsule on Visit 4 and
      once immediately before the camera images obtained on Visits 5 and 6. Study medication will
      be administered at Charlton 7 CRU by a nurse on days 12-14.

      Duration of treatment

      A3309 or matching placebo will be administered orally once daily for fourteen (14)
      consecutive days.

      Duration of patients' involvement in the study

      Each patient will attend seven (7) visits at the clinic during a period of about thirty-one
      (31) to forty-one (41) days.

      Efficacy assessments

        -  Scintigraphic small bowel and colonic transit

        -  Assessment of stool frequency and consistency using the Bowel Pattern Diary

      Pharmacokinetic analysis Blood samples for analysis of pharmacokinetic (PK) parameters will
      be collected at Visit 4, before dosing and at 30, 60, 90, 120, 150, 180, 210, and 240 minutes
      post-dose. PK parameters will be analyzed.

      Safety assessments

      The following safety assessments will be performed:

        -  Laboratory safety tests, including a complete blood count (CBC), a comprehensive
           metabolic panel (CMP), coagulation studies (PT and APTT) and a urinalysis (UA) performed
           at Visit 1 study entry, Visit 6 completion of transit scintigraphy and final dose of
           study medication, and Visit 7 study completion. A urine screen for drugs of abuse will
           be performed once at Visit 1 study entry.

        -  A 12-lead ECG performed at Visit 1 study entry, Visit 6 completion of post-study
           medication transit scintigraphy and Visit 7 study completion.

        -  A physical examination by a study physician at Visit 1 study entry and Visit 7 study
           completion.

        -  Vital signs (including temperature, pulse, blood pressure and respiration rate) at every
           visit

        -  Urine pregnancy tests performed at Visit 1 study entry and within 48 hours prior to
           receipt of radiation during the abbreviated transit scintigraphy and post-study
           medication transit scintigraphy at Visit 2 and Visit 4, respectively

        -  Interview for concomitant medications and adverse events at every visit

      Statistical methods An analysis of covariance (ANCOVA) will be used to compare transit
      parameters among the treatment groups. The co-variates considered for inclusion in the
      analyses are age and body mass index (BMI). If necessary a suitable transformation for
      potential skewness in the distributions of measured volumes may be used (e.g., ANCOVA on
      ranks or log volumes).

      If ANCOVA shows a p value less than or equal to 0.10, then both the 10 mg and 20 mg doses
      will be compared to placebo (p value less than or equal to 0.025 to correct for 2 pairwise
      comparisons by Dunnett's Test). Since each of the secondary endpoints assesses a separate
      hypothesis regarding the effects of A3309, no adjustment in the alpha level for testing
      multiple types of endpoints is anticipated, and a two-sided significance level of 0.05 will
      be used in each ANCOVA model.

      Statistical Power Based on data acquired using the same methods in the laboratory, the sample
      size of 12 patients per group provides 80% power to detect differences of approximately 27%
      to 37% in colonic transit at 24 hours, the primary endpoint. This magnitude of change is
      considered clinically significant.

      PK analyses Plasma concentration vs time curves will be plotted for each subject, on both
      linear/linear and log10/linear scales. Mean plasma concentration vs time curves will also be
      presented by dose level. Summary statistics (n, mean, SD, minimum, median, maximum, geometric
      mean, and coefficient of variation) will be calculated for plasma concentrations at each time
      point by dose level.

      Summary statistics (n, mean, SD, minimum, median, maximum, geometric mean and coefficient of
      variation) will be presented for all pharmacokinetic parameters by dose level. Geometric mean
      and coefficient of variation will not be calculated for Tmax. The coefficient of variation
      will be calculated using the following formula: CV(%) =[exp(SD2)-1]1/2 * 100 where
      SD=standard deviation of the natural-logarithmically-transformed data.

      Analysis data sets The primary analyses will follow the intent to treat (ITT) paradigm with
      all patients randomized included in the analyses. Those patients with missing response values
      will have their missing values imputed via the overall (patients with non-missing data) mean
      and a corresponding adjustment in the ANCOVA residual error variance degrees of freedom
      (subtracting one for each missing value imputed).

      Safety data will be presented for all patients receiving investigational product.
    

Intervention name(s): A3309; placebo
Intervention type(s): Drug; Drug
Intervention description(s): A3390, a bile acid transport inhibitor was provided in either 15 mg or 20 mg oral tablets; placebo
Other intervention name(s): Elobixibat
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: functional constipation; bile acid