A Phase 2a, Proof-of-Concept Study of GIC-1001 in the Management of Visceral Pain During Sedation-Free, Full Colonoscopy
Condition: Pain; Cancer; Colonic Diseases
MeSH terms: Colonic Diseases; Visceral Pain
Study type: Interventional
Phase: Phase 2

Summary: 
      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).
    

Detailed description: 
      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.
    

Intervention name(s): GIC-1001
Intervention type(s): Drug
Intervention description(s): GIC-1001 oral tablet, white-coated, to be taken with water
Other intervention name(s): trimebutine 3-thiocarbamoylbenzenesulfonate; TB-905-02
Intervention MeSH terms: Trimebutine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: colonoscopy; sedation-free; colorectal cancer; CRC screening; prevention; analgesia; colonic; kappa; opioid agonist; pain management; oral; hydrogen sulfide; peripheral