Effects of ROSE-010 on GI Transit in Constipation Predominant Irritable Bowel Syndrome (C-IBS) Patients

Methodology

Female patients with C-IBS will be screened for eligibility and informed about the study at the initial screening visit Visit 1. Within two weeks of Visit 1, eligible patients will be randomized to study medication, either 30 mcg, 100 mcg or 300 mcg ROSE-010 or placebo administered via abdominal subcutaneous (s.c.) injection for a total of four days, three consecutive days during transit scintigraphy and once prior to SPECT imaging. The allocation to treatment group will be concealed.

Study medication will be administered at Visits 2, 3, and 4, the days of scintigraphic assessment of gastric, small bowel and colonic transit of solids performed over a 48 hour period.

Within two to seven days of Visit 4, patients will be instructed to return for administration of a final injection of study medication followed by SPECT gastric accommodation measurements (Visit 5). Within seven to ten days of Visit 5, patients will return for Visit 6, final safety monitoring and an exit interview with study staff.

Investigational product, dosage and mode of administration

Patients will receive placebo or 30 mcg, 100 mcg or 300 mcg ROSE-010 administered s.c. in the abdomen once on Visit 2, immediately before the standardized breakfast meal, fifteen minutes before the first camera image is obtained. Study medication will be administered fifteen minutes before camera images obtained on Visits 3 and 4. Study medication will be administered immediately after the first fasting scan is obtained and before the second fasting scan during SPECT at Visit 5.

Duration of treatment

ROSE-010 or matching placebo will be administered via abdominal s.c injection once daily for three consecutive days and one final day two to seven days later, over a ten-day interval.

Duration of patients involvement in the study

Each patient will attend six visits at the clinic during a period of two to four weeks.

Efficacy assessments

• Scintigraphic gastrointestinal and colonic transit
• Technetium-99m (99mTc) SPECT measurement of gastric volumes
• Assessment of stool frequency and consistency made by the patient using the Bowel Pattern Diary

Safety assessments

The following safety assessments will be performed:

• Laboratory safety tests, including a complete blood count (CBC), a comprehensive metabolic panel (CMP), and urinalysis (UA) at Visit 1 (study entry) and Visit 6 (study exit)
• A physical examination by a study physician at Visit 1
• Weight and vital signs (including temperature, pulse, blood pressure and respiration rate) at every visit
• Urine pregnancy tests performed at Visit 1 and within 48 hours prior to receipt of radiation at Visit 2 transit test and Visit 5 SPECT test
• Interview for concomitant medications and adverse events at every visit

Statistical methods

An analysis of covariance (ANCOVA) will be used to compare transit parameters and gastric volumes among the treatment groups. 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 100 mcg and 300 mcg doses will be compared to placebo (p value less than or equal to 0.25). Dunnett's Test will be used to compare each dose group with placebo. Since each of the primary endpoints assesses a separate hypothesis regarding the effects of ROSE-010, 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.

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.

Inclusion criteria

• Female aged 18-65 years old inclusive.
• A previous diagnosis of IBS according to Rome III criteria to include those patients who have had recurrent abdominal pain or discomfort for the at least the six months prior to diagnosis and currently at least three days per month in the last three months associated with two or more of the following:

• improvement with defecation
• onset associated with a change in the frequency of stool
• onset associated with a change in form (appearance) of stool.
• Constipation predominant type IBS as defined by one or more of the following:

• fewer than three spontaneous complete bowel movements per week
• hard or lumpy stools more than 25% of the time
• straining during a bowel movement more than 25% of the time.
• A normal rectal exam result on file within the past two years or performed at screen to exclude the possibility of an evacuation disorder. Examination must exclude findings suggestive of an evacuation disorder such as high sphincter tone at rest, failure of perineal descent by more than one centimeter on straining and last, spasm, tenderness or paradoxical contraction of the puborectalis muscles.
• 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 intrauterine device (IUD). Abstinent females may participate if they agree to use the double barrier method should they become sexually active during the study.
• Able to provide written informed consent prior to any study procedures being performed.

Exclusion criteria

• Female patients who are pregnant or breast-feeding.
• Structural or metabolic diseases/conditions that affect the gastrointestinal system, or functional gastrointestinal disorders other than C-IBS.
• Unable to withdraw medications 48 hours prior to the study: any medication that alters GI transit including but not limited to laxatives, magnesium or aluminum-containing antacids, prokinetics, erythromycin, narcotics, anticholinergics, tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors (SNRIs); analgesic drugs including opiates, nonsteroidal anti-inflammatory drugs (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.
• Clinical evidence (including but not limited to a clinically significant abnormal physical exam, ECG or laboratory result in the past medical record) or current clinically significant abnormal physical exam or laboratory test result that could indicate significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric, or other diseases that interfere with the objectives of the study. If a laboratory test result is abnormal and clinically significant, it may be repeated once at the discretion of the PI. If the laboratory test result remains abnormal and clinically significant, the patient will be referred to a primary care physician for further evaluation.
• Patients who are considered by the Investigator to be alcoholics not in remission or known substance abusers.
• Patients who have participated in another clinical study within the past 30 days.