Download GIC-1001 375 mg - Algorithme Pharma

Algorithme Pharma, 575 Armand-Frappier, Laval (Montréal), Québec, Canada
algopharm.com | [email protected]
PAIN THRESHOLDS OBSERVED FOLLOWING THE ADMINISTRATION OF PLACEBO, GIC-1001 AND GIC-1002 IN
HEALTHY VOLUNTEERS UNDERGOING RECTAL DISTENSIONS USING THE BAROSTAT METHOD
J-M. Paquette, M. Iovu Niculita, M. Rufiange, S. Boily, E. Sicard, J. Massicotte, M. Lefebvre; Algorithme Pharma Inc., Laval, QC, Canada. O. Uresandi, P. Colin, M.Ranger; gIcare Pharma Inc., Montreal, QC, Canada.
Overview
Key Inclusion & Exclusion Criteria
Analysis Population
Phase 1B, Randomized, Double-Blind (double dummy), Placebo Controlled, Parallel Group Administration Design.
GIC-1001 and GIC-1002 are being developed for the management of visceral pain in patients undergoing sedation-free
full colonoscopy. This poster will highlight the study design and results of the Phase IB barostat study in healthy
volunteers.
Ninety healthy male or female subjects aged between 18 and 65 years with a BMI between 18.5 and 35 kg/m2 and
having a normal anorectal area as confirmed by digital rectal examination were included in this Phase IB study. Subjects
with diagnosis of IBS or any other functional bowel disorder were to be excluded. Subjects with history of abdominal or
rectal surgery, including gynaecological surgery for females subjects, were also to be excluded.
Full analysis population: all randomized subjects who received at least one dose of study medication, had a baseline
VAS measurement, reached stage IV of the barostat experiment, and had at least one VAS measurement at stage IV.
Safety population: all randomized subjects who took at least one dose of study drugs.
Background
Study Design
GIC-1001 (trimebutine 3-thiocarbamoyl-benzenesulfonate) is an innovative and dual action single drug substance that
gIcare Pharma intends to develop as an orally-administered alternative to parenteral sedation. It is intended to manage
visceral pain in subjects undergoing full colonoscopy. GIC-1001 is a novel drug salt of trimebutine, a non-centrally acting
opioid agonist, which bears a counterion capable of releasing an active metabolite, hydrogen sulfide (H2S).
This study was designed as a single center, Phase Ib, randomized, double-blind, placebo controlled, parallel group
administration design. Fully blinded for both GIC-1001 and GIC-1002, with double dummy technique. Subjects were
randomized in five treatment arms (n =18); GIC-1001 (375 or 500 mg), equimolar doses of GIC-1002 (345 or 460 mg) or
matching placebo.
GIC-1002 developed as the active control of GIC-1001. GIC-1002’s drug substance is trimebutine tosylate. GIC-1002 is
a salt in which the cation is the protonated form of trimebutine and the counterion is tosylate. The counterion is the part
of the drug substance which has no ability to release hydrogen sulfide in vivo.
Ten administrations of GIC-1001, GIC-1002 and/or matching placebo were administered as follows:
•
One administration tid on an empty stomach for 3 consecutive days prior to barostat procedure, last administration
on the 4th day in the morning at least 1 hour prior to beginning of the procedure (Barostat rectal insertion)
•
Bowel preparation to be performed using Fleet enema following the last administration (approximately 2 hours before
the barostat procedure)
In the morning of Day 4, subjects completed a barostat procedure comprised of 4 different stages in about one hour:
I.
Balloon Unfolding: single distension at a balloon pressure of 20 mmHg for 60 sec.
II. Rectal Conditioning Distension: staircase distension protocol with pressure steps of 4 mmHg with a duration of
30 seconds each and a range from 0 to 40 mmHg.
Figure 1. GIC-1001 molecular structure
Figure 2. GIC-1002 molecular structure
A double blind, placebo-controlled, parallel design Phase IIA trial was completed in subjects undergoing sedation-free full
colonoscopy. While GIC 1001 has been shown to be completely safe in the study subject population, only the mid dose
(375 mg tid regimen x 3 days) induced a clinically significant reduction in the overall periprocedural pain experience, as
measured with a 100-mm VAS. The apparent U-shaped dose-response curve suggested an interaction between
released H2S and the trimebutine component of GIC-1001. In light of this non-conclusive efficacy evidence, the clinical
exploration of the true analgesic effects of GIC-1001, especially at 375 mg tid, gIcare pharma proposed to study the
antinociceptive properties of trimebutine as well as the contribution of H2S in the context of a barostat study.
Rectal and sigmoid distensions have been used to test visceral perception, notably in Irritable Bowel Syndrome (IBS).
Predefined and standardized distensions of the bowel wall using a barostat device are widely accepted, and represent
the current standard for the assessment of sensorimotor function in experimental trials in healthy and diseased subjects.
The barostat is a computer-driven air pump connected to a double-lumen catheter, on which a highly compliant balloon is
securely fixed. The balloon is introduced in the rectum and is used to measure the tone, compliance and sensory
thresholds. Rectal distension can be done according to a certain protocol, during which different pressures are applied to
the rectal wall. The intensity and quality of perception can be measured by means of rating scales (typically VAS).
Besides perception scores (pain, urge and discomfort), parameters such as first sensation, minimal distension pressure,
and rectal capacity may also be evaluated in these studies.
Method
III. Compliance, Sensory Thresholds and Ratings: staircase distension protocol with pressure steps of 4 mmHg with a
duration of 60 seconds each and a pressure range of 0–60 mmHg
IV. Visceral Pain Perception: automatic distensions from 0 to a maximal pressure limit of 60 mmHg. Distensions were
randomly increased by increments of 6 mmHg with an isobar duration of 60 seconds. Randomization of pressures
were split into two series: (a) 6 to 42 mmHg and (b) 48 to 60 mmHg. The balloon was deflated down to 6 mmHg for a
period of 60 seconds after each distension.
Study Endpoints
Primary Objective
•
Secondary Objectives Included
•
•
To determine the barostat intra-balloon pressure required to elicit pre defined rectal sensory symptoms (i.e. first
sensation, need to defecate, urgency to defecate and pain) following the oral administration of GIC 1001 or
GIC-1002, respectively, at two equimolar doses.
To assess the rectal sensory symptom ratings during rectal compliance assessment following the administration of
GIC-1001 and GIC-1002, respectively at two equimolar doses.
Demographic
Ninety subjects were included in this study. All subjects received all 10 doses of the allocated study product.
Fifty nine males and 31 females subjects aged between 19 and 65 years were included. Most subjects were white and
had a BMI < 30 kg/m2.
Sensory Threshold
Eighty-eight subjects were included in the full analysis population. Excluded subjects 503 and 704 received the placebo.
These subjects did not complete stage III and/or stage IV due to equipment malfunction/technical difficulty.
Mean visceral pain intensity score in millimeters (mm) on a 100-mm Visual Analog Scale (VAS) based on
seven measurements collected at increasing rectal distension pressures from 24 to 60 mmHg following the oral
administration of the GIC-1001 375 mg tid x 3 days regimen, and comparing it to placebo.
Secondary Endpoints Included
•
•
Barostat intra-balloon pressure in mmHg required to elicit pre-defined rectal sensory symptoms (i.e. first sensation,
need to defecate, urgency to defecate and pain) following the oral administration of GIC-1001 or GIC 1002,
respectively at two equimolar doses.
Rectal sensory intensity score (i.e. first sensation, need to defecate, urgency to defecate and pain) in mm on a
100-mm VAS following the oral administration of GIC-1001 or GIC-1002, respectively at two equimolar doses.
Figure 4. Percentage of Placebo Subjects Reporting Sensory Thresholds
Statistical analyses were performed to evaluate if gender, body weight and BMI had an impact on pain rating. Despite
more females reporting pain at lower pressures than men, there was no significant gender difference in intra-balloon
pressure required to elicit pain. The statistical analysis also confirmed that there was no significant relationship between
body weight (70 kg), BMI (25 kg/m2) and mean pressure eliciting pain in healthy subjects receiving placebo.
Table 2. Mean Barostat Pressure (mmHg) Eliciting Pain in Healthy Subjects
Table 1. Intra-Balloon Pressure and VAS Score Associated to Pre-Determined Sensory Thresholds
Pressure (mmHg)
p-value
First Sensation
Pressure (mmHg)
p-value [1]
Need to Defecate
Pressure (mmHg)
p-value [1]
Urgency to Defecate Pressure (mmHg)
p-value [1]
Pain
Pressure (mmHg)
p-value [1]
No Sensation
VAS Score (mm)
p-value [1]
First Sensation
VAS Score (mm)
p-value [1]
Need to Defecate
VAS Score (mm)
p-value [1]
Urgency to Defecate VAS Score (mm)
p-value [1]
Pain
VAS Score (mm)
p-value [1]
[1] Compared to Placebo.
Placebo
(N=16)
-0.6 (5.6)
[1]
Primary Endpoint
To assess the analgesic effect of GIC-1001 via the assessment of visceral pain intensity under rectal distension
following the oral administration of a dose regimen of GIC-1001 375 mg tid over three successive days.
Results
No Sensation
Figure 3. Schematic Representation of the Four Barostat Stages
In order to maximize data obtained during the study, data of subjects receiving placebo was analyzed to characterize
sensory thresholds in healthy volunteers.
Subjects were instructed of usual rectal sensory thresholds : (1) first sensation of balloon distension, (2) need to
defecate, and (3) urge to defecate, followed by the pain threshold. Subjects were asked to report such rectal sensory
thresholds during Stage III in addition to reporting the respective rectal sensory intensity on a 100-mm VAS scale (where
0 mm meant no discomfort or pain at all, and 100 mm meant severe pain). The lowest pressure reported for each of five
rectal sensory symptoms (i.e. no sensation, first sensation, need to defecate, urgency to defecate and pain) was used for
each subject to estimate the mean barostat intra-balloon pressure for each treatment group. The Mean VAS difference
between each active drug dose and placebo groups were assessed using an ANOVA model (with a significance level of
α = 0.05). During Stage III, the data for non-painful or painful sensory thresholds that were not recorded were imputed
using a “censored” data approach: when a sensation threshold was not perceived, this threshold pressure was imputed
using the next perceived threshold. When the pain threshold was not perceived , it was imputed to the highest pressure
reached in Stage III. Descriptive statistics were used to summarize pressure and VAS results. Statistical analyses were
generated with SAS version 9.4 and figures were generated using Phoenix WinNonlin version 6.3.
Mean (SD)
Objectives
•
Sensory Threshold Evaluation
Subjects dosed with 345 mg and 460 mg of GIC-1002 reported first sensation to a statistically significant (p< 0.05) higher
intra-balloon pressure than subjects dosed with placebo. However, no other sensation showed a statistically significant
difference (p<0.05) between treatments. The difference between the mean VAS value for active drug dose and placebo
groups, for each of the five rectal sensory thresholds, did not show any statistical significance (p > 0.05).
8.4 (3.6)
19.9 (9.5)
32.0 (12.1)
41.0 (12.6)
1.1 (1.1)
10.7 (8.0)
29.0 (16.5)
54.4 (19.0)
80.7 (20.7)
GIC-1001
375 mg
(N=18)
GIC-1001
500 mg
(N=18)
GIC-1002
345 mg
(N=18)
GIC-1002
460 mg
(N=18)
0.7 (1.1)
1.2 (1.7)
0.7 (1.4)
1.4 (1.6)
0.616
8.0 (4.3)
0.857
19.3 (9.0)
0.928
31.0 (10.3)
0.514
37.8 (11.6)
0.555
2.4 (3.5)
0.120
12.0 (9.6)
0.657
33.6 (15.6)
0.353
60.9 (15.9)
0.284
83.1 (16.1)
0.733
0.631
9.5 (5.5)
0.589
20.1 (11.6)
0.910
33.1 (13.9)
0.874
39.2 (12.2)
0.772
2.1 (2.4)
0.232
10.7 (7.8)
0.994
37.8 (12.6)
0.087
65.2 (16.1)
0.076
87.0 (8.7)
0.391
0.841
11.1 (3.5)
0.021
22.7 (8.8)
0.320
33.1 (9.9)
0.890
42.0 (5.3)
0.892
1.1 (0.9)
0.934
11.0 (10.1)
0.910
28.6 (14.8)
0.939
60.3 (15.4)
0.326
79.8 (14.0)
0.910
0.275
10.7 (3.2)
0.020
17.4 (5.3)
0.706
30.2 (10.3)
0.651
37.9 (12.4)
0.554
2.2 (2.8)
0.179
11.1 (8.4)
0.893
29.1 (13.0)
0.979
54.3 (18.2)
0.980
75.0 (23.5)
0.406
Treatment
Statistic
Female
Male
Placebo
n
6
7
(N=13)
Mean (SD)
42.7 (13.8)
46.9 (12.4)
p-value
0.5792
p-values were estimated based on Satterwaite t-test method
Weight ≤ 70 kg Weight > 70 kg BMI ≤ 25 kg/m2 BMI > 25 kg/m2
6
7
46.0 (15.3)
44.0 (11.1)
0.7966
8
5
45.0 (15.2)
44.8 (8.7)
0.9765
Discussion and Conclusion
Data from placebo subjects provided important information on rectal sensory thresholds in healthy volunteers.
Interestingly, not all subjects reported pain during stage III (staircase distensions at increasing pressures). Of the
16 subjects receiving placebo and included in the analysis, 13 reported pain. Two subjects (female, ≈50 years, BMI of
≈20 kg/m2) asked to stop the barostat procedures following the urgency to defecate at a pressure of 44 mmHg, and one
subject (male, 50 years, BMI of ≈31 kg/m2) completed stage III (pressure up to 60 mmHg) without reporting pain.
The barostat experiment using intra-rectal balloon distensions was well tolerated by the subjects, as evaluated by the
assessment of adverse events, the measurement of clinical laboratory parameters, concomitant medication, vital signs,
physical examination, and 12-lead ECG. The assessment of visceral pain intensity, under rectal distension following the
oral administration of four different dose regimens of GIC-1001 and GIC-1002 over three successive days failed to show
a significant analgesic effect of the investigational products, as measured with a 100-mm VAS. The large intra- and intersubject variability of VAS values observed might have contributed to this lack of apparent efficacy. However, the study
allowed to characterize important physiological thresholds in healthy male and female volunteers.
Acknowledgement: We thank Dr Albert Cohen, Dr Anand Sahai, Dr Serge Mayrand and Dr Michel Gagnon for their
participation as gastroenterologist during this study.