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GIC-1001 , 250 mg TID during 3 consecutive days + a last, 10th dose in the morning of Day 4 (colonoscopy day)

GIC-1001 , 375 mg TID during 3 consecutive days + a 10th dose in the morning of day 4 (colonoscopy day)

GIC-1001 , 500 mg TID during 3 consecutive days + a 10th dose in the morning of day 4 (colonoscopy day)

Placebo, TID during 3 consecutive days, + a 10 th dose in the morning of day 4 (colonoscopy day)

GIC-1001 oral tablet, white-coated, to be taken with water

GIC-1001

Mark V Larson, MD

Michael DeMicco, MD

Mark Lamet, MD

Taddese Desta, MD

Cynthia Schaeffer, MD

Vivek Gumaste, MD

Theadore Ptak, MD

Anand Sahai, MD

Umedchandra Shah, MD

Suryakanth R. Gurudu, MD

Robert Enns, MD

Narayanachar S Murali, MD

Vishal Gupta, MD

Albert Cohen, MD

Vitaly Fishbein, MD

Dennis Riff, MD

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.

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

A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Proof-of-Concept Study of GIC-1001 for the Management of Visceral Pain in Subjects Undergoing Sedation-Free, Full Colonoscopy

The Primary Outcomes Measure was the pain VAS 100-mm AUC (0mm = no pain; 100mm = worst pain), constructed from serial pain VAS measurements performed during colonoscopy. At least 8 pain VAS measurements were made, and the length of the colonoscope inserted (or removed on the way out) was recorded at every measurement. The X-axis of the VAS versus anatomical locations was defined accordingly: each VAS value corresponded to a relative length of inserted colonoscope (d/2Lc) of the X axis, where d was the actual length of the inserted colonoscope and 2Lc represented twice the total length of the colon examined (Lc). Before scope insertion the X value equaled zero. Once the caecum was reached, the X value was 0.5. Upon complete removal of the endoscope, the X value was 1. This allowed standardization of colonic length between study subjects. Visceral pain AUC (mm) was calculated from all serial measurements, where the length of inserted colonoscope determined the VAS measurement's location

Time to Caecum is the time taken by the physician to reach the caecum with the colonoscope, from the insertion in the anus. Time to Caecum was measured during colonoscopy, for which total duration of colonoscopy ranged between a minimum of 5.00 and a maximum of 50.10 minutes.

Qualitative outcome: colonoscopy completion is defined as a procedure performed entirely, from initial anal insertion, reaching of caecum, and complete removal of the scope. Completion rate is then the number of patient (%) with a complete colonoscopy (up to the caecum) divided by the number of trial participants.

A pharmacokinetic (PK) analysis was carried out on the first 24 patients randomized, equally distributed between treatment groups; 18 patients were assigned to active treatment

Defined as the time from endoscope insertion to complete removal of the endoscope; measured in minutes

Endoscopist's perception of the adequacy of analgesia, difficulty of insertion and withdrawal measured on a five-point Likert scale: Strongly Agree, Agree, Agree nor Disagree, Disagree, Strongly Disagree

Endoscopist's perception of the amount of colonic spasm on insertion and withdrawal measured on five-point Likert scale according to the following: Strongly Agree, Agree, Agree nor Disagree, Disagree, Strongly Disagree

Patients' willingness for repeat colonoscopy, was assessed with the Patient Willingness to Repeat Experience (P.W.R.E.) questionnaire (1 question), asking patients to rate their willingness to repeat the procedure according to a 5-point Likert scale: Strongly Agree, Agree, Agree nor Disagree, Disagree, Strongly Disagree. The P.W.R.E was administered after the colonoscopy during subject recovery.

Subject satisfaction and acceptability of the colonic analgesia modality offered by GIC-1001 was assessed with the Patient Global Impression of Abdominal Pain (P.G.I.A.P.) (1 question), asking patients to rate their pain during the procedure according to a 5-point Likert scale: Absent, Mild, Moderate, Severe, Intolerable. The P.G.I.A.P was administered after the colonoscopy during subject recovery.

JSS Medical Research Inc.

Algorithme Pharma Inc

gicare Pharma Inc.

Safety was assessed via performance of physical exams, vital signs, 12-lead ECG, laboratory safety tests (hematology, biochemistry and urinalysis) and the occurrence of adverse events.

GIC-1001 , 250 mg TID during 3 consecutive days + a last, 10th dose in the morning of Day 4 (colonoscopy day)

GIC-1001: GIC-1001 oral tablet, white-coated, to be taken with water

GIC-1001 Low Dose

GIC-1001 , 375 mg TID during 3 consecutive days + a 10th dose in the morning of day 4 (colonoscopy day)

GIC-1001: GIC-1001 oral tablet, white-coated, to be taken with water

GIC-1001 Mid-dose

GIC-1001 , 500 mg TID during 3 consecutive days + a 10th dose in the morning of day 4 (colonoscopy day)

GIC-1001: GIC-1001 oral tablet, white-coated, to be taken with water

GIC-1001 , High Dose

Placebo, TID during 3 consecutive days, + a 10 th dose in the morning of day 4 (colonoscopy day)

GIC-1001: GIC-1001 oral tablet, white-coated, to be taken with water

GIC-1001 Matching Placebo

Total

Age, Continuous

Sex: Female, Male

Asian/Oriental

Black

Caucasian

Hispanic

Other

Race/Ethnicity, Customized

Demographics provided for the Full Analysis Set (FAS; N=262), defined as all randomized patients who received at least one dose of study drug, had a baseline and at least one post-baseline VAS rating.

Patrick Colin

AUC Censored (Standardized)- PP Population

AUC- censorsed (standardized); FAS

AUC LOCF (standardized); FAS

AUC- censorsed (standardized); PP

AUC LOCF (standardized); PP

Primary endpoint assessed in the FAS (randomized patients who received at least one dose of study drug, had a baseline and at least one post-baseline VAS rating; N=262) and PP analysis sets (randomized patients in the FA population with ≥80% treatment compliance, who had at least 6/8 VAS ratings and no major protocol deviations; N=213)

Measurements of Visceral Pain, Using a 100-mm Visual Analog Scale (VAS)

FAS (randomized patients who received at least one dose of study drug, had a baseline and at least one post-baseline VAS rating; N=262)

Time to Caecum

Colonoscopy Completion Rate (%)

Plasma Concentration- Trimebutine

Plasma Concentration-N-Desmethyl-Trimebutine

Trimebutine and N-Desmethyl-Trimebutine plasma concentrations were assessed in all arms, with the exception of placebo

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Phase 2a, Proof-of-Concept Study of GIC-1001 in the Management of Visceral Pain During Sedation-Free, Full Colonoscopy	NCT01926444	Pain Cancer Colonic Disease...	GIC-1001	40 Years - 70 Years	gicare Pharma Inc.
A Phase 2a, Proof-of-Concept Study of GIC-1001 in the Management of Visceral Pain During Sedation-Free, Full Colonoscopy	NCT01926444	Pain Cancer Colonic Disease...	GIC-1001	40 Years - 70 Years	gicare Pharma Inc.

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