A Phase 2 interventional study of A3309 and placebo in Functional Constipation, sponsored by Michael Camilleri, MD. Completed at 1 site in United States. Open to female participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2020-09-04.
Sponsored by Michael Camilleri, MD · Phase 2, Interventional, and Treatment
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.
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
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:
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.
1,018 studies on the registry are indexed under Constipation; 139 are open to participants now.
This study's enrollment of 36 is below the median of 80 across 850 interventional studies indexed under Constipation.
Browse Constipation studies →Michael Camilleri, MD is the lead sponsor of 3 studies on the registry; none are open to participants now.
Counted across the registry records on this site, refreshed daily.
A diagnosis of functional constipation as defined by two or more of the following:
Females of child-bearing potential (those who have not experienced a bilateral tubal ligation, hysterectomy or menopause) must use an acceptable method of contraception during the study. Acceptable methods are surgical sterilization, hormonal methods such as oral contraceptives, Norplant and Depo-Provera, double barrier method such as a condom and spermicide, and an IUD.
Abstinent females may participate if they agree to use the double barrier method should they become sexually active during the study.
EXCLUSION CRITERIA
Unable to withdraw all medications 48 hours prior to Visit 1; any medication that alters GI transit including but not limited to laxatives, magnesium or aluminum-containing antacids. prokinetics, erythromycin, narcotics, anticholinergics, tricyclic antidepressants and SNRIs; analgesic drugs including opiates, NSAIDs, and COX-2 inhibitors (Note: Tylenol is permitted), GABAergic agents and benzodiazepines.
Note: All other concomitant medications will be reviewed on a case by case basis by the study physicians.
Patients randomized to this arm received one oral tablet daily of 15 mg A3309 for a period of 14 consecutive days.
Drug: A3309
Patients randomized to this arm received one oral tablet daily of 20 mg A3309 for a period of 14 consecutive days.
Drug: A3309
Patients randomized to this arm received one oral tablet daily of a matching placebo for a period of 14 consecutive days.
Drug: placebo
A3390, a bile acid transport inhibitor was provided in either 15 mg or 20 mg oral tablets
Also known as: Elobixibat
placebo
Colonic Transit at 24 Hours
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Colonic transit was measured by quantification of radioactive counts via abdominal scintiscans. Overall colonic transit was computed as the colonic geometric center (GC), which is the weighted average of counts in the different colonic regions (ascending, transverse, descending, rectosigmoid and stool), respectively numbered 1 to 5. At any time point, the GC equals the proportion of counts in each colonic region multiplied by its weighting factor: (%ACx1+%TCx2+%DCx3+%RSx4+%stoolx5)/100. As such, a higher GC reflects faster colonic transit. A GC of 1 implies all the isotope is in the ascending colon and a GC of 5 implies all the isotope is in the stool.
Time frame: 24 hours post-radiolabeled meal
Colonic Filling
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Colonic filling was measured by scintigraphy as the percentage of the radiolabeled meal that reached the colon at 6 hours.
Time frame: 6 hours post-radiolabeled meal
Gastric Emptying , T1/2
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Gastric emptying (GE t 1/2) was measured by scintigraphy and defined as the time required for 50% of the radiolabeled tracer to empty from the stomach.
Time frame: post-treatment, approximately 12-14 days
Ascending Colon Emptying t 1/2
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Ascending colon emptying t 1/2 was measured by scintigraphy and defined as the time required for 50% of the radiolabeled tracer to empty from the ascending colon.
Time frame: post-treatment, approximately 12-14 days
Colonic Transit at 8 Hours
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Colonic transit was measured by quantification of radioactive counts via abdominal scintiscans. Overall colonic transit was computed as the colonic geometric center (GC), which is the weighted average of counts in the different colonic regions (ascending, transverse, descending, rectosigmoid and stool), respectively numbered 1 to 5. At any time point, the GC equals the proportion of counts in each colonic region multiplied by its weighting factor: (%ACx1+%TCx2+%DCx3+%RSx4+%stoolx5)/100. As such, a higher GC reflects faster colonic transit. A GC of 1 implies all the isotope is in the ascending colon and a GC of 5 implies all the isotope is in the stool.
Time frame: 8 hours post-radiolabeled meal
Colonic Transit at 48 Hours
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Colonic transit was measured by quantification of radioactive counts via abdominal scintiscans. Overall colonic transit was computed as the colonic geometric center (GC), which is the weighted average of counts in the different colonic regions (ascending, transverse, descending, rectosigmoid and stool), respectively numbered 1 to 5. At any time point, the GC equals the proportion of counts in each colonic region multiplied by its weighting factor: (%ACx1+%TCx2+%DCx3+%RSx4+%stoolx5)/100. As such, a higher GC reflects faster colonic transit. A GC of 1 implies all the isotope is in the ascending colon and a GC of 5 implies all the isotope is in the stool.
Time frame: 48 hours post-radiolabeled meal
Stool Frequency
Subjects maintained a validated daily bowel diary and recorded the number of bowel movements each day during treatment.
Time frame: 14 days
Stool Consistency
Subjects maintained a validated daily bowel diary during treatment and recorded stool consistency according to the Bristol Stool Form Scale, where: 1= separate hard lumps; 2= lumpy sausage-shape; 3= cracked sausage; 4= smooth and soft sausage; 5=soft blobs; 6=mushy, fluffy pieces; 7= watery, no solid pieces.
Time frame: 14 days
Treatment Effectiveness of A3309
Subject perception of treatment efficacy was measured using a 5 point numerical scale where 1=not at all effective to 5=extremely effective.
Time frame: Day 14
| Milestone | A3309 15 mg | A3309 20 mg | Placebo |
|---|---|---|---|
| Started | 12 | 11 | 13 |
| Completed | 12 | 9 | 12 |
| Not completed | 0 | 2 | 1 |
| Withdrew: Adverse event | 0 | 2 | 1 |
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Colonic transit was measured by quantification of radioactive counts via abdominal scintiscans. Overall colonic transit was computed as the colonic geometric center (GC), which is the weighted average of counts in the different colonic regions (ascending, transverse, descending, rectosigmoid and stool), respectively numbered 1 to 5. At any time point, the GC equals the proportion of counts in each colonic region multiplied by its weighting factor: (%ACx1+%TCx2+%DCx3+%RSx4+%stoolx5)/100. As such, a higher GC reflects faster colonic transit. A GC of 1 implies all the isotope is in the ascending colon and a GC of 5 implies all the isotope is in the stool.
| units on a scale | A3309 15 mg | A3309 20 mg | Placebo |
|---|---|---|---|
| Colonic Transit at 24 Hours | 2.68 ± 0.07 | 3.12 ± 0.07 | 1.93 ± 0.09 |
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Colonic filling was measured by scintigraphy as the percentage of the radiolabeled meal that reached the colon at 6 hours.
| percentage of colonic filling | A3309 15 mg | A3309 20 mg | Placebo |
|---|---|---|---|
| Colonic Filling | 55.8 ± 9.3 | 60.0 ± 6.1 | 50.4 ± 9.6 |
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Gastric emptying (GE t 1/2) was measured by scintigraphy and defined as the time required for 50% of the radiolabeled tracer to empty from the stomach.
| minutes | A3309 15 mg | A3309 20 mg | Placebo |
|---|---|---|---|
| Gastric Emptying , T1/2 | 165.4 ± 14.4 | 159.4 ± 12.8 | 130.8 ± 5.9 |
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Ascending colon emptying t 1/2 was measured by scintigraphy and defined as the time required for 50% of the radiolabeled tracer to empty from the ascending colon.
| hours | A3309 15 mg | A3309 20 mg | Placebo |
|---|---|---|---|
| Ascending Colon Emptying t 1/2 | 14.0 ± 3.6 | 5.8 ± 1.9 | 14.8 ± 1.6 |
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Colonic transit was measured by quantification of radioactive counts via abdominal scintiscans. Overall colonic transit was computed as the colonic geometric center (GC), which is the weighted average of counts in the different colonic regions (ascending, transverse, descending, rectosigmoid and stool), respectively numbered 1 to 5. At any time point, the GC equals the proportion of counts in each colonic region multiplied by its weighting factor: (%ACx1+%TCx2+%DCx3+%RSx4+%stoolx5)/100. As such, a higher GC reflects faster colonic transit. A GC of 1 implies all the isotope is in the ascending colon and a GC of 5 implies all the isotope is in the stool.
| units on a scale | A3309 15 mg | A3309 20 mg | Placebo |
|---|---|---|---|
| Colonic Transit at 8 Hours | 1.98 ± 0.55 | 2.82 ± 0.55 | 1.20 ± 0.09 |
Subjects ingested a Technetium-99m sulfur colloid radiolabeled meal and Indium-111 absorbed on to activated charcoal particles and delivered to the colon by an oral methacrylate-coated capsule. Colonic transit was measured by quantification of radioactive counts via abdominal scintiscans. Overall colonic transit was computed as the colonic geometric center (GC), which is the weighted average of counts in the different colonic regions (ascending, transverse, descending, rectosigmoid and stool), respectively numbered 1 to 5. At any time point, the GC equals the proportion of counts in each colonic region multiplied by its weighting factor: (%ACx1+%TCx2+%DCx3+%RSx4+%stoolx5)/100. As such, a higher GC reflects faster colonic transit. A GC of 1 implies all the isotope is in the ascending colon and a GC of 5 implies all the isotope is in the stool.
| units on a scale | A3309 15 mg | A3309 20 mg | Placebo |
|---|---|---|---|
| Colonic Transit at 48 Hours | 3.64 ± 0.07 | 3.91 ± 0.07 | 2.18 ± 0.09 |
Subjects maintained a validated daily bowel diary and recorded the number of bowel movements each day during treatment.
| bowel movements | A3309 15 mg | A3309 20 mg | Placebo |
|---|---|---|---|
| Stool Frequency | 1.33 ± 0.15 | 2.14 ± 0.39 | 1.43 ± 0.24 |
Subjects maintained a validated daily bowel diary during treatment and recorded stool consistency according to the Bristol Stool Form Scale, where: 1= separate hard lumps; 2= lumpy sausage-shape; 3= cracked sausage; 4= smooth and soft sausage; 5=soft blobs; 6=mushy, fluffy pieces; 7= watery, no solid pieces.
| units on a scale | A3309 15 mg | A3309 20 mg | Placebo |
|---|---|---|---|
| Stool Consistency | 4.17 ± 0.32 | 4.42 ± 0.32 | 2.69 ± 0.24 |
Subject perception of treatment efficacy was measured using a 5 point numerical scale where 1=not at all effective to 5=extremely effective.
| score on a scale | A3309 15 mg | A3309 20 mg | Placebo |
|---|---|---|---|
| Treatment Effectiveness of A3309 | 3.7 ± 0.3 | 2.4 ± 0.4 | 4.3 ± 0.3 |
Collected over Adverse events were collected on each subject from enrollment until 7-10 days after the last day of the study medication, for approximately one month.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| A3309 15 mg | 0/12 (0%) | 0/12 (0%) | 12/12 (100%) |
| A3309 20 mg | 0/11 (0%) | 0/11 (0%) | 11/11 (100%) |
| Placebo | 0/13 (0%) | 0/13 (0%) | 13/13 (100%) |
| Event | A3309 15 mg | A3309 20 mg | Placebo |
|---|---|---|---|
| HeadacheGeneral disorders | 0/12 | 0/11 | 10/13 |
| Abdominal cramps/painGastrointestinal disorders | 4/12 | 6/11 | 0/13 |
| DiarrheaGastrointestinal disorders | 1/12 | 4/11 | 1/13 |
| SinusitisGeneral disorders | 0/12 | 0/11 | 4/13 |
| NauseaGastrointestinal disorders | 1/12 | 2/11 | 2/13 |
| BorboygmiGastrointestinal disorders | 2/12 | 1/11 | 0/13 |
| FlatulenceGastrointestinal disorders | 1/12 | 1/11 | 2/13 |
| StressGeneral disorders | 0/12 | 0/11 | 2/13 |
| LightheadnessGeneral disorders | 0/12 | 0/11 | 2/13 |
| Stomach upsetGastrointestinal disorders | 0/12 | 1/11 | 1/13 |
| Age, Continuous(years) | A3309 15 mg | A3309 20 mg | Placebo | Total |
|---|---|---|---|---|
| Mean | 38.7 ± 2.4 | 46.7 ± 1.9 | 47.5 ± 2.6 | 44.3 ± 1.5 |
| Sex: Female, Male(Participants) | A3309 15 mg | A3309 20 mg | Placebo | Total |
|---|---|---|---|---|
| Female | 12 | 11 | 13 | 36 |
| Male | 0 | 0 | 0 | 0 |
| Race and Ethnicity Not Collected(Participants) | A3309 15 mg | A3309 20 mg | Placebo | Total |
|---|---|---|---|---|
| Count of participants | — | — | — | 0 |
| Region of Enrollment(participants) | A3309 15 mg | A3309 20 mg | Placebo | Total |
|---|---|---|---|---|
| United States | 12 | 11 | 13 | 36 |
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