A Phase 2a, Proof-of-Concept Study of GIC-1001 in the Management of Visceral Pain During Sedation-Free, Full Colonoscopy

GIC-1001 is a novel, orally-administered, colonic analgesic drug developed as an alternative to i.v. sedation during full colonoscopy. It will be evaluated for efficacy and safety in a multi-center, randomized, double-blind, placebo controlled, dose-ranging, proof of concept Phase 2a trial. Up to 240 patients will receive one of 3 doses of GIC-1001 or its matching placebo. A pharmacokinetic evaluation will be carried out on a subset of patients (N: 24).

1. Study Objectives

   1.1 Primary objective: The primary objective of this Phase IIa study is to establish clinical Proof-of-Concept (POC) by providing clinically and statistically significant evidence that GIC-1001 is safe and effective in managing visceral pain in male and female patients who undergo sedation-free, full colonoscopy for preventive purposes.

   1.2 Secondary objectives: Secondary objectives will include the selection of the optimal dose of GIC-1001 from a safety/efficacy ratio point of view, establish a preliminary safety profile of the drug in patients, and obtain a preliminary general efficacy profile of GIC-1001 by assessing various secondary endpoints
2. Study Endpoints

   2.1 Primary endpoints:

   Visceral pain will be assessed using a 100-mm VAS, measured at various times and anatomical segments (N: 8) throughout the colon, i.e.:
   1. Prior to intra-rectal insertion of the endoscope;
   2. After insertion through the anus;
   3. After passage through the rectosigmoid segment;
   4. Immediately after passage through the splenic flexure;
   5. Immediately after passage through the hepatic flexure;
   6. Once the caecum is reached;
   7. Immediately after passage through the splenic flexure during scope withdrawal; and
   8. At the end of the procedure, once the colonoscope has been completely removed. Any additional episodes of pain experienced by the patient will also be assessed using the 100-mm VAS scale.

   The area under the curve (AUC) calculated from all serial measurements made will be used for statistical purposes, where the length of inserted colonoscope determines the VAS measurement's location.

   2.2 Secondary endpoints:
   1. Overall pain perception (100-mm VAS) at the end of the procedure;
   2. Time to reach the caecum with the endoscope (intubation time from rectum to caecum defined as time-to-caecum);
   3. Total examination time, defined at the time from introduction to removal of the colonoscope;
   4. Percentage of completed procedures;
   5. Endoscopist's perception of the adequacy of analgesia, difficulty of insertion, and amount of colonic spasm on insertion and withdrawal (five-point Likert scale);
   6. Use of rescue sedation (i.e. midazolam or midazolam followed by fentanyl)
   7. Safety as assessed by the incidence of treatment emergent adverse effects during the procedure and for 30 days after;
   8. Plasma determination of trimebutine and N-desmethyl-trimebutine moieties at GIC-1001 plasmatic steady state;
   9. Patient satisfaction with treatment (five-point Likert scale);
   10. Patient' willingness for repeat colonoscopy in the future (five-point Likert scale); and
   11. Safety of GIC-1001.
3. Study Design This is a randomized, double-blind, placebo-controlled parallel design 4-treatment arms study. Eligible patients will be randomized in a 1:1:1:2 ratio to one of 4 treatment arms: low (250 mg), mid (375 mg) or high (500 mg) dose of GIC-1001, or matching placebo. All potential study subjects will be screened and assessed for eligibility within maximum two (2) weeks prior to randomization. Bowel preparation will be performed using a polyethylene glycol (PEG) based regimen the night before the actual procedure.
4. Number of Clinical Sites: This trial will be conducted in both Canada and USA. Up to ten (10) clinical sites will participate in this trial. The lead Investigator for this trial is Dr Mark V. Larson MD, Head of Digestive Endoscopy, Mayo Clinic, Rochester MN, USA
5. Study population and sample size: Approximately 240 patients will be randomized in this study. Male and female patients having an indication for full colonoscopy, mainly for colorectal cancer screening and surveillance. Only naïve subjects, i.e. who never underwent colonoscopy before, will be eligible.
6. Inclusion Criteria See Eligibility Section
7. Exclusion Criteria See Eligibility Section
8. Study Drugs Administration and Schedule:

   GIC-1001, or its matching placebo will be administered as follows:
   1. One tablet TID on an empty stomach for three (3) consecutive days prior to colonoscopy.
   2. Last dose taken at the clinical site at least one (1) hour prior to beginning of procedure (endoscope insertion).
   3. Bowel preparation to be performed using PEG based regimen the day before the actual procedure.
   4. Three (3) different GIC-1001 dose levels will be studied:

      * 250 mg TID
      * 375 mg TID
      * 500 mg TID
      * Matching placebo TID
9. Concomitant Medications

   9.1 Prior to colonoscopy, the following medication will be permitted: Aspirin (ASA) at low levels for cardiovascular health, if dose and regimen stable for the last 6 months prior to colonoscopy.

   9.2 The following medications and foods will be prohibited:
   * Any prescription chronic analgesic narcotic, anti-spasmodic, anti-inflammatory medications are forbidden for 30 days prior to screening. (i.e. Washout ≥ 30 days)
   * Selective Serotonin Re-uptake Inhibitors (SSRIs) are forbidden for 30 days prior to screening, unless patient has been on a stable dose for 3 consecutive months prior to screening.
   * Over-the-counter analgesics, or anti-inflammatory medication, oral or topical used for acute pain treatment must be washed out for ≥ 7days prior to screening.
   * Acute or as needed prescription or non-prescription anti-inflammatory and/or analgesic treatment within one (1) week prior to colonoscopy.
   * Use of bowel stimulant laxatives, such bisacodyl, within one (1) week preceding randomization.
   * Use of antidiarrheic medication, such as diphenoxylate, loperamide, kaopectate or bismuth salts, within one (1) week preceding randomization.
   * Administration of barium enema within two (2) weeks preceding randomization.
   * Colonic irritant beverages or foods, such as caffeine-containing beverages (e.g. coffee, Coca-Cola), spices, as well as foods containing seeds (i.e. tomatoes, strawberries, kiwis, raspberries) within 24 hours preceding colonoscopy.
   * Use of any other investigational drug is prohibited unless discontinued, within at least 30 days prior to randomization.
   * Additionally, Prior and Concomitant Medications are to be recorded in the CRF starting 30 days prior to Screening Visit CLV1.
10. Efficacy Evaluation: Colonic analgesic clinical efficacy of GIC-1001 will be measured using a continuous, horizontal 100-mm VAS, at pre-determined times and colonic anatomical segments. At least 8 measurements will be done by the participating patients themselves (see Primary Endpoint section). Subjects will receive proper instructions on the use of the VAS prior to colonoscopy. Overall experience of visceral pain (if any) will be evaluated using the AUC constructed from all calculated VAS self-measurements for each patient. Additional, secondary, efficacy endpoints will also be measured, including time-to-caecum, colonoscopy completion rate and antispasmodic activity.
11. Safety Evaluation: Safety will be assessed using the performance of physical exams, ECG, various laboratory safety tests and the occurrence of adverse events. AEs will be mapped to MedDRA, version 16.
12. Sample Size Considerations: It has been reported in the medical literature that a MCID range of 10-15 mm on the 100-mm VAS is clinical significant in the evaluation of colonoscopy-related visceral pain. Using this value, with an alpha of 0.05 and a beta of 0.9, about 50 patients would be needed in each active arm considering a 90-patient placebo arm. Total study sample size is then estimated at approximately 240 randomized patients.
13. Statistical Analysis: The primary outcome measure will be the mean 100-mm VAS AUC in each treatment arm.

Eligibility Criteria:
Inclusion Criteria:

1. Signed and dated written Informed Consent obtained.
2. Males or females.
3. Aged 40-75 years.
4. Indication for full colonoscopy for colorectal cancer screening or investigation, including subjects presenting suggestive symptoms and who need a differential diagnosis.
5. Colonoscopy naïve subjects, i.e. who never underwent colonoscopy before, will be eligible, as well as non-naïve subjects who have previously undergone unsedated colonoscopy , or who had sedated colonoscopy at least 10 years prior (i.e. ≥ 10 years) to enrolment
6. Eligible for a procedure without sedation.
7. Able to complete questionnaires and use a Visual Analog Scale (VAS), including sufficient English, French or Spanish speaking skills as well as adequate eyesight and hearing
8. BMI ≥ 19, BMI ≤ 40 kg/m2.

Exclusion Criteria:

1. Known allergy or intolerance to trimebutine (Modulon® or generic).
2. Known allergy or intolerance to sulfur-containing drugs (e.g. N-acetylcysteine or captopril).
3. Previous gastrointestinal or gynecologic surgery, e.g. ileostomy, pelvic surgery,; however, patients with an appendectomy are eligible.Patients who have had a tubal ligation at least 10 years prior (i.e. ≥ 10 years) to enrolment are also eligible.
4. Diagnosed Inflammatory Bowel Disease (IBD).
5. Visceral hypersensitivity conditions such as Irritable Bowel Syndrome (IBS).
6. Clinically significant renal and/or hepatic impairment.
7. History of peritonitis.
8. Known severe diverticular disease.
9. Severe diverticulosis as documented by prior imaging series
10. Known or suspected stenosis of the colon.
11. Chronic pain syndrome such as fibromyalgia and endometriosis.
12. Any clinically-relevant abnormality identified on the screening, history, physical examination, 12-lead ECG or laboratory examination, which would, in the Investigator's opinion, preclude the administration of investigational drug product, GIC1001
13. Unexpected and significant visceral pain reported by subject prior to colonoscopy.
14. Dementia.
15. Diagnosed clinically significant psychiatric illness, including severe anxiety disorders that may affect the subject's perception of visceral pain or ability to participate in the study.
16. Patient is a lactating female.
17. Female is of childbearing potential sexually active who are unwilling or unable to use an acceptable method of contraception (which includes oral or implanted contraceptives, IUD, female condom, diaphragm with spermicide, cervical cap, use of a condom by the sexual partner or sterile sexual partner) throughout the duration of the study and 1 month following study completion.
18. Female is of childbearing potential, sexually abstinent who does not agree to continue abstinence or to use one of the acceptable methods of birth control should sexual activity commence.
19. Any serious medical condition that could increase the risk of adverse reactions with trimebutine.
20. Participation in another experimental drug trial within 30 days of randomization.