Revised in July 2020 When using the drug products listed herein refer to the package insert of each product Section 2 Product 1 Basic data History of development of Amitiza Capsules 12 ID: 931653
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Slide1
Amitiza
® Slide Kit V
Revised in July 2020
*When using the drug products listed herein, refer to the package insert of each product.
Section 2: Product
Slide21. Basic data
Slide3History of development of Amitiza® Capsules 12 μgDuring the review process for the approval of Amitiza
® Capsules 24 μg, the applicant was requested to consider developing a low-strength formulation to meet the needs in clinical settings so that the appropriate dose levels could be selected according to symptoms. The applicant therefore developed “Amitiza® Capsules 12 μg” (lubiprostone capsule 12
μg) as a low-strength formulation that enables dose adjustment and filed an application for approval.
This dose level is based on the identified risks associated with lubiprostone and provides alternative dosing options allowing for dose adjustment, especially for long-term use in elderly patients with chronic constipation.
Amitiza®Capsules 12 μg
Data submitted for approval application
Profile
O
H
H
HO
O
H
F
F
CH
3
CO
2
H
Slide4Amitiza® Capsules 12 μgGeneric name: Lubiprostone
Dosage form: White opaque soft capsule(major axis: 9.5 mm, minor axis: 6.0 mm, weight: 0.2 g)Structural formula:
Molecular formula: C20H32F
2O5
O
H
H
HO
O
H
F
F
CH
3
CO
2
H
Molecular weight: 390.46
Profile
Slide5Trade name:Amitiza® Capsules 12 μg
Amitiza® Capsules 24 μgGeneric name:Lubiprostone
Mechanism of action:ClC-2 chloride channel activationTarget disease
:Chronic constipation (excluding constipation due to organic disease)Dosage form
:12 μg: White opaque soft capsule(major axis: 9.5 mm, minor axis: 6.0 mm, weight: 0.2 g)24 μg: Pale orange soft capsule
(major axis: 9.5 mm, minor axis: 6.0 mm, weight: 0.2 g)
Structural formula
:
Molecular formula: C
20
H
32
F
2
O
5
Lubiprostone Profile
Profile
Molecular weight: 390.46
O
H
H
HO
O
H
F
F
CH
3
CO
2
H
Slide6Conceptual image of Cl
- transport in small intestinal mucosal epithelial cells and the site of action of Amitiza®
Movement of chloride ions (Cl-) is involved in intestinal fluid secretion.Lubiprostone activates ClC-2 chloride channels present in the apical membrane of the small intestine epithelium.Lubiprostone
promotes fluid secretion into the intestinal tract and softens the stool, thereby promoting intestinal motility and aiding defecation.Mechanism of action
Lubiprostone activates chloride channels present in the small intestinal epithelial cells and thereby promotes fluid secretion into the intestinal tract.Edited under supervision of: Dr. Shinichi Uchida, Professor, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
Amitiza
®
Cl
-
Cl
-
Cl
-
Cl
-
ClC-2
Chloride channel
Mucosal
epithelial cells
Intestinal
lumen
Na
+
(Apical membrane)
(Basal membrane)
Na
+
Na+Water
Sodium pump
Na
+
-K
+
-2Cl-Co-transporter
K+ channelChloride ion
K+Na+K+K+
Cl-Cl-ノート内●2つ目文章:
Chloride ions(Cl-)が変な上付きになっていますので修正ください。→申し訳ございません。修正いたしました。
Slide7Clinical Pharmacological Characteristics of LubiprostoneThe world's first chloride channel activator indicated for the treatment of chronic constipation (excluding constipation due to organic disease) by promoting fluid secretion from the small intestineSignificantly increases the frequency of spontaneous bowel movement (vs. placebo)Significantly increases spontaneous bowel movement within 24 hours after administration (vs. placebo)
Improves various symptoms associated with constipationProvides sustained improvement for a long period (48 weeks)Clinical equivalence of the 12-μg and 24-μg capsules when administered at the same dose levelAt time of approval: Adverse drug reactions (ADRs) including abnormal laboratory values were observed in 196 (62%) of 315 patients included in the safety evaluation (patients treated at 48 μg/day)Most common ADRs included diarrhea in 95 patients (30%) and nausea in 73 patients (23%)
Characteristics of Lubiprostone
Slide8World Marketing Status of Amitiza®CountryDateStrength
IndicationsU.S.April 2006 (launched)
24 μg/capsuleChronic idiopathic constipation
May 2008 (launched)8 μg/capsule
Irritable bowel syndrome with constipationMay 2013 (launched)
24 μg/capsule
Opioid-induced constipation in non-cancer patients
Canada
October 2015 (approved)
24
μg
/capsule
Chronic idiopathic constipation
Japan
November 2012 (launched)
24 μ
g/capsuleChronic constipation **
November 2018 (launched)
12 μ
g/capsule
Chronic constipation **
Switzerland
February 2012 (launched)
24
μg
/capsuleChronic idiopathic constipation
July 2014 (launched)24 μg/capsuleOpioid-induced constipation and associated symptoms in non-cancer patients
U.K.January 2014 (launched)24 μg/capsule
Chronic idiopathic constipationIrelandFebruary 2015 (approved)
24 μg/capsuleBelgium
March 2015 (approved)24 μg/capsule
LuxembourgApril 2015 (approved)24 μg/capsule
Netherlands
April 2015 (approved)24 μg/capsule
AustriaMay 2015 (approved)
24 μg/capsuleGermany
May 2015 (approved)24 μg/capsule
ItalyJuly 2015 (approved)24 μg/capsule
SpainOctober 2015 (approved)24 μg/capsule
Israel
January 2017 (launched)
24
μg
/capsule
January 2017 (launched)
8 μg/capsule
Irritable bowel syndrome with constipation
January 2017 (launched)
24 μg/capsule
Opioid-induced constipation in non-cancer patients
Kazakhstan
January 2017 (approved)
24 μg/capsule
Chronic idiopathic constipation
January 2017 (approved)
8 μg/capsule
Irritable bowel syndrome with constipation
January 2017 (approved)
24 μg/capsule
Opioid-induced constipation in non-cancer patients
Singapore
*
September 2017 (approved)
24 μg/capsule
Chronic idiopathic constipation
September 2017 (approved)
8
μg
/capsule
Irritable bowel syndrome with constipation
September 2017 (approved)
24
μg
/capsule
Opioid-induced constipation in non-cancer patients
Philippines
November 2017 (approved)
24 μg/capsule
Chronic idiopathic constipation
November 2017 (approved)
8 μg/capsule
Irritable bowel syndrome with constipation
November 2017 (approved)
24
μg
/capsule
Opioid-induced constipation in non-cancer patients
In-house data of
Sucampo
Pharma
As of August 2018
Related Information
*Indicated for irritable bowel syndrome with constipation in both male and female adult patients.
In other countries where the drug is indicated for irritable bowel syndrome with constipation, it is indicated only in women.
** Excluding constipation due to organic diseases
Slide9Japanese Phase II Dose-response StudyLubiprostone Clinical Studies (1)
Slide10Japanese Phase II Dose-response StudyPatients, Dosing regimen, EndpointsPatients:170 patients with chronic constipation of unknown cause*(41 patients treated with lubiprostone
16 μg/day, 43 with lubiprostone 32 μg/day, 44 with lubiprostone 48 μg/day, and 42 with placebo)Dosing regimen
:Patients were randomized into 4 groups to receive either 8, 16, or 24 μg lubiprostone or placebo orally BID (after breakfast and dinner) for 2 weeks.Primary endpoint:
Change in the frequency of spontaneous bowel movement (SBM) at Week 1Secondary endpoints:SBM frequency at each week, change in SBM frequency at Week 2, bowel movement (BM) frequency and change in BM frequency, number of additional rescue doses, proportion of patients who had SBM within 24/48 hours after the first dose, time to first SBM, proportion of responders, degree of straining, stool consistency, abdominal symptoms, feeling of incomplete evacuation
, severity of constipation, overall rating of the treatment effect, and quality of life (QOL).Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hoursAnalysis plan:For the primary endpoint and major secondary endpoints, dose responsiveness was assessed using analysis of variance (ANOVA), and those endpoints for which a dose response was observed were compared with placebo using t-test. For other endpoints, comparison with placebo was performed using the chi-square test or Wilcoxon test, and dose responsiveness was assessed using the Cochran-Armitage test or Jonckheere test.
*Major patient inclusion/exclusion criteria
•
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
•
Patients with organic or secondary constipation (drug-induced and symptomatic) were excluded
Data from a dose finding study submitted for approval application
Fukudo
S, et al.
Neurogastroenterol
Motil
. 23(6): 544-e205, 2011.
This study was supported by funding from Sucampo Pharma.
Japanese Phase II
Dose-response Study
Slide11Lubiprostone16
μg/dayn=41
Lubiprostone
32 μg/day
n=43Analysis Populations
Discontinued
n=1
Discontinued
n=1
Placebo
n=42
Lubiprostone
48
μg
/day
n=44
Completed Week 1
n=42
Completed Week 1
n=41
Completed Week 1
n=43
Completed Week 1
n=43
Completed Week 2
n=42
Completed Week 2
n=41
Completed Week 2
n=42
Completed Week 2
n=43
Enrolled patients
n=170
Created from
Fukudo
S, et al.
Neurogastroenterol
Motil
. 23(6): 544-e205, 2011.
This study was supported by funding from
Sucampo
Pharma.
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Patients
:
170 patients with chronic constipation of unknown cause
*
Methods
:
Patients were treated with either 8, 16, or 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 2 weeks
Primary endpoint
:
Change in the frequency of spontaneous bowel movement (SBM) at Week 1
Secondary endpoints
:
SBM frequency, number of additional rescue doses, proportion of patients who had SBM within 24/48 hours after the first dose, time to first SBM, proportion of responders, degree of straining, stool consistency, abdominal symptoms, feeling of incomplete evacuation, severity of constipation, QOL, etc.
Analysis plan
:
For the primary endpoint and major secondary endpoints, dose responsiveness was assessed using analysis of variance (ANOVA), and those endpoints for which a dose response was observed were compared with placebo using t-test. For other endpoints, comparison with placebo was performed using the chi-square test or Wilcoxon test, and dose responsiveness was assessed using the Cochran-Armitage test or
Jonckheere
test.
Japanese Phase II
Dose-response Study
Slide12Patient Demographics
Placebo
Lubiprostone
16 μg/day
Lubiprostone32 μg/day
Lubiprostone
48
μg
/day
Test
No. of patients
42
41
43
44
-
Sex (men)
3 (7.1%)
4 (9.8%)
6 (14.0%)
3 (6.8%)
NS
*
2
Age (years)
*
1
38.4±11.6
38.8±11.0
40.0±11.3
40.7±12.9
NS
*
3
Height (cm)
*
1
160.9±5.7
160.8±6.5
160.9±7.0
158.4±7.4
NS
*
3
Body weight (kg)
*
1
54.7±7.3
54.3±8.3
56.3±9.7
52.6±8.3
NS
*
3
BMI (kg/m
2
)
*
1
21.2±2.7
20.9±2.5
21.7±3.3
20.9±2.6
NS
*
3
*1: Mean ± SD
*2: Chi-square test *3: One-way analysis of variance
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Created from
Fukudo
S, et al.
Neurogastroenterol
Motil
. 23(6): 544-e205, 2011.
This study was supported by funding from
Sucampo
Pharma.
Patients
:
170 patients with chronic constipation of unknown cause
*
Methods
:
Patients were treated with either 8, 16, or 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 2 weeks
Primary endpoint
:
Change in the frequency of spontaneous bowel movement (SBM) at Week 1
Secondary endpoints
:
SBM frequency, number of additional rescue doses, proportion of patients who had SBM within 24/48 hours after the first dose, time to first SBM, proportion of responders, degree of straining, stool consistency, abdominal symptoms, feeling of incomplete evacuation, severity of constipation, QOL, etc.
Analysis plan
:
For the primary endpoint and major secondary endpoints, dose responsiveness was assessed using analysis of variance (ANOVA), and those endpoints for which a dose response was observed were compared with placebo using t-test. For other endpoints, comparison with placebo was performed using the chi-square test or Wilcoxon test, and dose responsiveness was assessed using the Cochran-Armitage test or
Jonckheere
test.
Japanese Phase II
Dose-response Study
Slide13Dose response in increased frequency of spontaneous bowel movement by lubiprostone(Primary endpoint)Japanese Phase II
Dose-response StudyCreated from Fukudo
S, et al. Neurogastroenterol Motil. 23(6): 544-e205, 2011.This study was supported by funding from Sucampo Pharma.
Placebo(n=42)
16 μg/day(n=41)
32 μg/day
(n=43)
48
μg
/day
(n=43)
(Times/week)
Lubiprostone
Change in SBM frequency
(Week 1)
9
0
6
4
2
7
5
3
1
**
***
8
6.8
3.5
2.3
1.5
Mean ± SE
Dose response: p<0.0001 (ANOVA)
vs. placebo: *** p < 0.001, ** p < 0.01 (t-test)
Patients
:
170 patients with chronic constipation of unknown cause
*
Methods
:
Patients were treated with either 8, 16, or 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 2 weeks
Primary endpoint
:
Change in the frequency of spontaneous bowel movement (SBM) at Week 1
Secondary endpoints
:
SBM frequency, number of additional rescue doses, proportion of patients who had SBM within 24/48 hours after the first dose, time to first SBM, proportion of responders, degree of straining, stool consistency, abdominal symptoms, feeling of incomplete evacuation, severity of constipation, QOL, etc.
Analysis plan
:
For the primary endpoint and major secondary endpoints, dose responsiveness was assessed using analysis of variance (ANOVA), and those endpoints for which a dose response was observed were compared with placebo using t-test. For other endpoints, comparison with placebo was performed using the chi-square test or Wilcoxon test, and dose responsiveness was assessed using the Cochran-Armitage test or
Jonckheere
test.
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Slide14Patients:170 patients with chronic constipation of unknown cause*Dosing regimen
:Patients were treated with either 8, 16, or 24 μg lubiprostone or placebo orally BID (after breakfast and dinner) for 2 weeksPrimary endpoint
:Change in the frequency of spontaneous bowel movement (SBM) at Week 1Secondary endpoints:
SBM frequency, number of additional rescue doses, proportion of patients who had SBM within 24/48 hours after the first dose, time to first SBM, proportion of responders, degree of straining, stool consistency, abdominal symptoms, feeling of incomplete evacuation, severity of constipation, QOL, etc.Analysis plan:
For the primary endpoint and major secondary endpoints, dose responsiveness was assessed using analysis of variance (ANOVA), and those endpoints for which a dose response was observed were compared with placebo using t-test. For other endpoints, comparison with placebo was performed using the chi-square test or Wilcoxon test, and dose responsiveness was assessed using the Cochran-Armitage test or Jonckheere test.
Fukudo S, et al. Neurogastroenterol Motil. 23(6): 544-e205, 2011.
This study was supported by funding from Sucampo Pharma.
[Stool consistency assessment]
1
2
3
4
5
6
7
Separate hard lumps like nuts (difficult to pass)
Sausage
shaped but lumpy
Like a sausage
but with cracks on its surface
Like
a sausage or snake, smooth and soft
Soft blobs with clear-cut edges (passed easily)
Fluffy pieces with ragged edges, a mushy stool
Watery, no solid pieces, entirely liquid
5
1
6
7
4
3
2
**
Baseline
Week 1
Week 2
Stool consistency
Watery
***
***
Placebo
Lubiprostone 48
μg
/day
Lubiprostone 32
μg
/day
Lubiprostone 16
μg
/day
Mean ± SD
Dose response: p < 0.0001
(
Jonckheere
test)
vs. placebo: *** p < 0.001
* p < 0.01
(Wilcoxon test)
Stool consistency (secondary endpoint)
Nut-like
Japanese Phase II
Dose-response Study
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Slide15Adverse drug reactions (ADRs), including abnormal laboratory values, occurred in 19.4% (33/170) of all patients and, by treatment group, in 4.8% (2/42) in the placebo group, 2.4% (1/41) in the lubiprostone 16 μg/day group, 30.2% (13/43) in the 32 μg/day group, and 38.6% (17/44) in the 48 μg/day group. Although the incidence was dose dependent, the majority of events were gastrointestinal symptoms likely due to the pharmacological action of lubiprostone, and resolved after dose reduction or discontinuation.
Adapted with modifications from Fukudo S, et al. Neurogastroenterol Motil. 23(6): 544-e205, 2011.This study was supported by funding from Sucampo Pharma.Adverse Drug Reactions
Two patients discontinued the study treatment: one owing to adverse events (AEs; palpitations, headache, and nausea) and the other owing to lack of efficacy.There were no deaths or serious adverse events.
n (%)
Placebo
Lubiprostone
16
μg
/day
Lubiprostone
32
μg
/day
Lubiprostone
48
μg
/day
Diarrhea
0
0
4 (9.3)
8 (18.2)
Nausea
0
0
3 (7.0)
7 (15.9)
Stomach discomfort
0
0
2 (4.7)
3 (6.8)
Patients
:
170 patients with chronic constipation of unknown cause
*
Dosing regimen
:
Patients were treated with either 8, 16, or 24 μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 2 weeks
Primary endpoint
:
Change in the frequency of spontaneous bowel movement (SBM) at Week 1
Secondary endpoints
:
SBM frequency, number of additional rescue doses, proportion of patients who had SBM within 24/48 hours after the first dose, time to first SBM, proportion of responders, degree of straining, stool consistency, abdominal symptoms, feeling of incomplete evacuation, severity of constipation, QOL, etc.
Analysis plan
:
For the primary endpoint and major secondary endpoints, dose responsiveness was assessed using analysis of variance (ANOVA), and those endpoints for which a dose response was observed were compared with placebo using t-test. For other endpoints, comparison with placebo was performed using the chi-square test or Wilcoxon test, and dose responsiveness was assessed using the Cochran-Armitage test or
Jonckheere
test.
Japanese Phase II
Dose-response Study
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Slide16Japanese Phase III Double-blind Controlled StudyLubiprostone Clinical Studies (2)
Slide17Japanese phase III study (double-blind controlled study)Patients, Dosing regimen, EndpointsPatients:124 patients with chronic constipation of unknown cause*
(62 patients treated with lubiprostone 48 μg/day, 62 with placebo)Dosing regimen:Patients were randomized into 2 groups to receive either 24 μg
lubiprostone or placebo orally BID (after breakfast and dinner) for 4 weeks. Patients were followed up for 2 weeks after the end of the treatment period for safety evaluation.Primary endpoint:Change in the frequency of spontaneous bowel movement (SBM) at Week 1Secondary endpoints
:Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medicationsNote) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hoursAnalysis plan
:The primary endpoint (change in SBM frequency at Week 1) was analyzed using two-sample t-test and the results between the groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).Japanese Phase III Double-blind Controlled Study
*Major patient inclusion/exclusion criteria
•
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
•
Patients with organic or secondary constipation (drug-induced and symptomatic) were excluded
Fukudo
S, et al.
Clin
Gastroenterol
Hepatol. 13(2): 294-301. e5, 2015.This study was supported by funding from Sucampo Pharma.
Slide18Analysis Populations
Discontinuedn=2Completed Week 4
n=61Completed Week 4
n=59Completed Week 1
n=62Completed Week 1
n=60
Enrolled patients
n=124
Placebo
n=62
Lubiprostone 48
μg
/day
n=62
Discontinued
n=1
Discontinued
n=1
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone or placebo orally BID (after breakfast and dinner) for 4 weeksPrimary endpoint: Change in SBM frequency at Week 1Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medicationsAnalysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study*Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Slide19Patient Demographics
Placebo
Lubiprostone 48 μg/day
Test
No. of patients
62
62
-
Sex (men)
9 (14.5%)
6 (9.7%)
NS
*
2
Age (years)
*
1
41.5±14.2
42.7
±
16.4
NS
*
3
Height (cm)
*
1
159.5
±
7.5
158.5
±
6.6
NS
*
3
Body weight (kg)*1
54.7±8.4
54.2±8.9
NS
*
3
BMI (kg/m
2
)
*
1
21.5
±
2.5
21.5
±
2.5
NS
*
3
Medical history (yes)
9 (14.5%)
14 (22.6%)
Not performed
Comorbidities (yes)
37 (59.7%)
42 (67.7%)
Not performed
Age of onset of constipation (years)
*
1
25.2
±
15.2
26.3
±
16.4
NS
*
3
History of treatment for constipation (yes)
41 (66.1%)
34 (54.8%)
NS
*
2
IBS (yes)
0 (0.0%)
0 (0.0%)
NS
*
2
*1:
Mean
±
SD
, *2: Fisher's exact test, *3: Two-sample t-test
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 4 weeks
Primary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Slide20Lubiprostone 48 μg/day
(n=60)
Placebo(n=62)
(Times/week)
7
0
Mean ± SD, ***: p < 0.001 (two-sample t-test)
Change in SBM frequency
(Week 1)
6
5
4
3
2
1
***
3.7
1.3
Change in SBM frequency at Week 1
of treatment with
lubiprostone
(Primary endpoint)
Fukudo
S, et al.
Clin
Gastroenterol
Hepatol
. 13(2): 294-301. e5, 2015.
This study was supported by funding from
Sucampo
Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24 μg lubiprostone or placebo orally BID (after breakfast and dinner) for 4 weeksPrimary endpoint: Change in SBM frequency at Week 1Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medicationsAnalysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Slide21Change in SBM frequency(Primary endpoint, secondary endpoint)Week 1
Week 3
Week 4
Week 2
7
(Times/week)
0
Placebo (n = 62)
Lubiprostone 48
μg
/day (n = 62)
Mean ± SD, ***: p < 0.001, **: p < 0.01, *: p < 0.05 (two-sample t-test)
Change in SBM frequency
5
4
3
2
1
6
2.7
1.6
2.6
***
**
*
3.7
2.7
1.5
2.8
1.6
2.6
1.3
1.3
***
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 4 weeks
Primary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study
Slide22Time to first SBM after first dose(Secondary endpoint)140
0
Placebo
(n=60)
Lubiprostone 48 μg/day(n=59)
(Hours)
Mean ± SD, *: p < 0.05 (two-sample t-test)
120
80
40
100
60
20
Time to first SBM
23.5
48.0
*
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 4 weeks
Primary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study
Slide23Proportion of patients who had SBM within 24 hours after first dose(Secondary endpoint)Placebo
(n=62)
Lubiprostone 48 μg/day(n=62)
100
(%)
0
40
20
Patients who had SBM within 24 hours after the first dose
**
58.1
30.6
**: p<0.01
(Fisher's exact test)
60
80
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from
Sucampo
Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 4 weeks
Primary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study
Slide24Proportion of patients who had SBM within 24 hours after first dose(Secondary endpoint)Japanese Phase II Dose-response Study/Japanese Phase III Double-blind Controlled Study
[Japanese Phase II Dose-response Study1)]
[Japanese Phase III Double-blind Controlled Study
2)]
**: p < 0.01 vs. placebo (Fisher's exact test)
80
(%)
***: p < 0.001 vs. placebo (chi-square test)
80
(%)
Patients: Patients with chronic constipation of unknown cause*
Methods: Patients were treated with either 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 2 weeks (phase II) or 4 weeks (phase III)
Primary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: SBM frequency, number of additional rescue doses, proportion of patients who had a bowel movement within 24/48 hours after the first dose, stool consistency, abdominal symptoms, QOL, etc.
Analysis plan: [Phase II] For the primary endpoint and major secondary endpoints, dose responsiveness was assessed using ANOVA, and those endpoints for which a dose response was observed were compared with placebo using t-test. For other endpoints, comparison with placebo was performed using the chi-square test or Wilcoxon test, and dose responsiveness was assessed using the Cochran-Armitage test or
Jonckheere
test. [Phase III] The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Placebo (n = 42)
Lubiprostone 48
μg
/day
(n=44)
Patients who had SBM within 24 hours after the first dose
70
10
0
20
30
40
50
60
70
10
0
20
30
40
50
60
75.0
26.2
58.1
30.6
***
**
1) Created from
Fukudo
S, et al.
Neurogastroenterol
Motil
. 23(6): 544-e205, 2011.
2) Data submitted for approval application
This study was supported by funding from
Sucampo
Pharma.
90
100
90
100
Lubiprostone 48
μg
/day
(n=62)
Placebo (n = 62)
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Slide25Change in SBM frequency over time (secondary endpoint)
Week 1
Baseline
Week 2
Week 3
Week 4
SBM frequency
6
5
4
3
2
1
9
8
7
0
(Times/week)
NS
**
*
***
***
3.31
3.18
2.98
2.93
1.68
5.37
4.44
4.43
4.32
1.65
Mean ± SD, ***: p < 0.001, **: p < 0.01, *: p < 0.05 (two-sample t-test)
Placebo (n = 62)
Lubiprostone 48
μg
/day (n = 62)
Japanese Phase III Double-blind Controlled Study
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from
Sucampo
Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 4 weeks
Primary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Slide26Change in stool consistency over time (secondary endpoint)[Stool consistency assessment]
6
Week 1
Week 2
Week 3
Week 4
Stool consistency
2
4
1
3
5
7
Baseline
Placebo (n = 62)
Lubiprostone 48
μg
/day (n = 62)
Mean ± SD, ***: p < 0.001, **: p < 0.01 (two-sample t-test)
NS
***
***
***
**
1.99
2.36
2.51
2.55
2.22
3.78
3.49
3.37
3.66
2.60
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Fukudo S, et al. Clin Gastroenterol Hepatol. 13(2): 294-301. e5, 2015.
This study was supported by funding from Sucampo Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 4 weeks
Primary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study
1
2
3
4
5
6
7
Separate hard lumps like nuts (difficult to pass)
Sausage
shaped but lumpy
Like a sausage
but with cracks on its surface
Like
a sausage or snake, smooth and soft
Soft blobs with clear-cut edges (passed easily)
Fluffy pieces with ragged edges, a mushy stool
Watery, no solid pieces, entirely liquid
Slide27Changes in abdominal bloating over time(secondary endpoint)
0
1
2
3
4
None
(No abdominal bloating at all)
Mild
(Slight abdominal bloating)
Moderate
(Obvious abdominal bloating)
Severe
(Severely swollen abdomen)
Very severe
(The abdomen is swollen almost to the bursting point)
[Assessment of abdominal bloating]
Abdominal bloating
Week 1
Week 2
Week 3
Week 4
0
1
2
3
4
None
Very severe
Baseline
NS
NS
NS
NS
*
Mean ± SD, *: p < 0.05 (two-sample t-test)
Placebo (n = 62)
Lubiprostone 48
μg
/day (n = 62)
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from
Sucampo
Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 4 weeks
Primary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study
Slide28Changes in abdominal discomfort over time(secondary endpoint)
0
1
2
3
4
None
(No abdominal discomfort at all)
Mild
(Slight abdominal discomfort)
Moderate
(Obvious abdominal discomfort)
Severe
(Abdominal discomfort with pain)
Very severe
(Abdominal discomfort with severe pain)
[Assessment of abdominal discomfort]
0
1
2
4
Abdominal discomfort
Very severe
3
Week 1
Week 2
Week 3
Week 4
Baseline
NS
NS
NS
NS
NS
Mean ± SD (two-sample t-test)
Placebo (n = 62)
Lubiprostone 48
μg
/day (n = 62)
None
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 4 weeks
Primary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study
Slide29Change in feeling of incomplete evacuation after defecation over time (secondary endpoint)[Assessment of feeling of incomplete evacuation]
0
1
2
3
4
No feeling of incomplete evacuation after defecation
Mild feeling of incomplete evacuation after defecation
Moderate feeling of incomplete evacuation after defecation
Strong feeling of incomplete evacuation after defecation
Very strong feeling of incomplete evacuation after defecation
Mean ± SD, *: p < 0.05 (two-sample t-test)
Feeling of incomplete evacuation
Week 1
Week 2
Week 3
Week 4
0
1
2
3
4
No feeling of incomplete evacuation
Very strong feeling of incomplete evacuation
Baseline
NS
NS
NS
NS
*
Placebo (n = 62)
Lubiprostone 48
μg
/day (n = 62)
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 4 weeks
Primary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study
Slide30Change in the degree of straining during defecationover time (secondary endpoint)
0
1
2
3
4
Baseline
Week 1
Week 2
Week 3
Week 4
0
1
2
3
4
No straining
Mild straining
Moderate straining
Severe straining
Very severe straining
Degree of straining
No straining
Very severe straining
NS
NS
NS
*
*
Mean ± SD, *: p < 0.05 (two-sample t-test)
[Assessment of degree of straining]
Lubiprostone 48
μg
/day (n = 62)
Placebo (n = 62)
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 4 weeks
Primary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study
Slide31Changes in the severity of constipation over time (patient's global assessment)(Secondary endpoint)0
1
2
3
4
None
(No symptom of constipation at all)
Mild
(Slight symptoms of constipation)
Moderate
(Constipation is present, but with only moderate symptoms)
Severe
(Having severe constipation with difficulty in defecation, or having only a slight feeling of evacuation in the bathroom)
Very severe
(Stubborn constipation with almost no bowel movement, or almost no feeling of evacuation in the bathroom)
[Assessment of severity of constipation (patient's global assessment)]
Mean ± SD
***: p<0.001
**: p<0.01
*: p<0.05
(Two-sample t-test)
Severity of constipation
(patient's global assessment)
0
1
2
4
Baseline
Week 1
Week 2
Week 4
3
NS
***
**
*
Very severe
None
Placebo (n = 62)
Lubiprostone 48
μg
/day (n = 62)
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone
or placebo orally BID (after breakfast and dinner) for 4 weeks
Primary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study
Slide32Adverse EventsData submitted for approval application
This study was supported by funding from Sucampo Pharma.Adverse events (AEs) were observed in 35.5% (22/62 patients) in the placebo group and 64.5% (40/62 patients) in the lubiprostone 48 μg/day group. Adverse drug reactions (ADRs) were observed in 16.1% (10/62 patients) in the placebo group and 41.9% (26/62 patients) in the lubiprostone 48 μg/day group. As a serious adverse event (SAE), spontaneous abortion occurred in 1 patient in the lubiprostone 48 μg/day group and was considered unrelated to the study treatment. One AE (in one patient) led to treatment discontinuation: chest discomfort.
n (%)
Placebo(n=62)
Lubiprostone 48 μg/day(n = 62)
Nausea
1 (1.6)
11 (17.7)
Diarrhea
0
10 (16.1)
Nasopharyngitis
4 (6.5)
7 (11.3)
Vomiting
0
4 (6.5)
AEs reported in ≥5% of patients in any group
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Patients: 124 patients with chronic constipation of unknown cause* (62 patients treated with
lubiprostone
48
μg
/day, 62 with placebo)
Methods: Patients were treated with either 24
μg
lubiprostone or placebo orally BID (after breakfast and dinner) for 4 weeksPrimary endpoint: Change in SBM frequency at Week 1
Secondary endpoints: Change in SBM frequency at Weeks 2 to 4, SBM frequency at each week, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medicationsAnalysis plan: The primary endpoint was analyzed using two-sample t-test and the results between groups were compared. Secondary endpoints were analyzed using two-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables).
Japanese Phase III Double-blind Controlled Study
Slide33Japanese Phase III Long-term Treatment studyLubiprostone Clinical Studies (3)
Slide34Japanese Phase III (Long-term Treatment) Study Patients, Dosing regimen, EndpointsPatients:209 patients with chronic constipation of unknown cause*
Dosing regimen:Patients were treated with 24 μg lubiprostone orally BID (after breakfast and dinner) for 48 weeksEndpoints:
SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medicationsNote) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hoursAnalysis plan:Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
Japanese Phase III Long-term Treatment study
*
Major patient inclusion/exclusion criteria
•
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
•
Patients with organic or secondary constipation (drug-induced and symptomatic) were excluded
Fukudo S, et al. Clin Gastroenterol Hepatol. 13(2): 294-301. e5, 2015.
This study was supported by funding from Sucampo Pharma.
Slide35Analysis PopulationsDiscontinuedn=36
Discontinuedn=10
Enrolled patientsn=209
Completed Week 48n=163
Completed Week 24n=173*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 209 patients with chronic constipation of unknown cause*
Methods: Patients were treated with 24
μg
lubiprostone
orally BID (after breakfast and dinner) for 48 weeks
Endpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
Japanese Phase III Long-term Treatment study
Slide36Patient Demographics*: Mean ± SD VariablesLubiprostone
No. of patients209Sex (men)
30 (14.4%)Age (years)*
41.8±13.3Height (cm)*
159.4±7.0Body weight (kg)*
55.4
±
9.8
BMI (kg/m
2
)
*
21.7
±3.2
Medical history (yes)
30 (14.4%)Comorbidities (yes)
164 (78.8%)Age of onset of constipation (years)*
25.4±14.0
History of treatment for constipation (yes)
107 (51.4%)
IBS (yes)
35 (16.8%)
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 209 patients with chronic constipation of unknown cause*Methods: Patients were treated with 24 μg lubiprostone orally BID (after breakfast and dinner) for 48 weeksEndpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medicationsAnalysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
Japanese Phase III Long-term Treatment study
Slide37SBM frequency in patients treated with lubiprostone (change over 48 weeks)*Patients with a mean SBM frequency of less than 3 times/week for at least 6 months Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Patients: 209 patients with chronic constipation of unknown cause*Methods: Patients were treated with 24 μg lubiprostone orally BID (after breakfast and dinner) for 48 weeksEndpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medicationsAnalysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
SBM frequency
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
Baseline
(Times/week)
0
2
4
6
7
5
3
1
8
(Weeks)
Change in SBM frequency: p < 0.001 for all weeks (one-sample t-test, vs. baseline)
Lubiprostone 48
μg
/day (n = 209)
Fukudo S, et al. Clin Gastroenterol Hepatol. 13(2): 294-301. e5, 2015.
This study was supported by funding from Sucampo Pharma.
Japanese Phase III Long-term Treatment study
Slide38Stool consistency in patients treated with lubiprostone (change over 48 weeks)
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
Nut-like
Stool consistency
Watery
(Weeks)
1
2
3
4
5
7
6
Baseline
Lubiprostone 48
μg
/day (n = 209)
Change in stool consistency: p < 0.001 for all weeks (one-sample t-test, vs. baseline)
[Stool consistency assessment]
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 209 patients with chronic constipation of unknown cause*
Methods: Patients were treated with 24
μg
lubiprostone
orally BID (after breakfast and dinner) for 48 weeks
Endpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
Japanese Phase III Long-term Treatment study
ブリストル便形状スケールの
rabbit dropping-like
を修正ください
。
→修正いたしました。
(スライド14もご確認く
ださい
)
1
2
3
4
5
6
7
Separate hard lumps like nuts (difficult to pass)
Sausage
shaped but lumpy
Like a sausage
but with cracks on its surface
Like
a sausage or snake, smooth and soft
Soft blobs with clear-cut edges (passed easily)
Fluffy pieces with ragged edges, a mushy stool
Watery, no solid pieces, entirely liquid
Slide39Abdominal bloating in patients treated with lubiprostone (change over 48 weeks)Abdominal bloating
None
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
Baseline
Very severe
1
2
3
4
0
(Weeks)
Change in abdominal bloating: p < 0.01 for Weeks 1 and 2, p < 0.001 for Weeks 3 through 48
(one-sample t-test, vs. baseline)
[Assessment of abdominal bloating]
Lubiprostone 48
μg
/day (n = 209)
0
1
2
3
4
None
(No abdominal bloating at all)
Mild
(Slight abdominal bloating)
Moderate
(Obvious abdominal bloating)
Severe
(Severely swollen abdomen)
Very severe
(The abdomen is swollen almost to the bursting point)
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 209 patients with chronic constipation of unknown cause*
Methods: Patients were treated with 24
μg
lubiprostone
orally BID (after breakfast and dinner) for 48 weeks
Endpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
Japanese Phase III Long-term Treatment study
Slide40Abdominal discomfort in patients treated with lubiprostone (change over 48 weeks)Abdominal discomfort
Change in abdominal discomfort: p < 0.01 for Week 2, p < 0.001 for Weeks 3 through 48
(one-sample t-test, vs. baseline)
[Assessment of abdominal discomfort]
None
Very severe
1
2
3
4
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
Baseline
(Weeks)
Lubiprostone 48
μg
/day (n = 209)
0
1
2
3
4
None
(No abdominal discomfort at all)
Mild
(Slight abdominal discomfort)
Moderate
(Obvious abdominal discomfort)
Severe
(Abdominal discomfort with pain)
Very severe
(Abdominal discomfort with severe pain)
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 209 patients with chronic constipation of unknown cause*
Methods: Patients were treated with 24
μg
lubiprostone
orally BID (after breakfast and dinner) for 48 weeks
Endpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
Japanese Phase III Long-term Treatment study
Slide41Feeling of incomplete evacuation after defecation in patients treated with lubiprostone (change over 48 weeks)No feeling of incomplete evacuation
Feeling of incomplete evacuation
Very strong feeling of incomplete evacuation
1
2
3
4
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
Change in feeling of incomplete evacuation: p < 0.001 for all weeks (one-sample t-test, vs. baseline)
[Assessment of feeling of incomplete evacuation]
0
1
2
3
4
No feeling of incomplete evacuation after defecation
Mild feeling of incomplete evacuation after defecation
Moderate feeling of incomplete evacuation after defecation
Strong feeling of incomplete evacuation after defecation
Very strong feeling of incomplete evacuation after defecation
(Weeks)
Baseline
Lubiprostone 48
μg
/day (n = 209)
0
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 209 patients with chronic constipation of unknown cause*
Methods: Patients were treated with 24
μg
lubiprostone
orally BID (after breakfast and dinner) for 48 weeks
Endpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
Japanese Phase III Long-term Treatment study
Slide42Degree of straining during defecation in patients treated with lubiprostone(changes over 48 weeks)
Degree of straining
No straining
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
(Weeks)
Baseline
Very severe straining
Lubiprostone 48
μg
/day (n = 209)
Change in the degree of straining: p < 0.001 for all weeks (one-sample t-test, vs. baseline)
1
2
3
4
0
0
1
2
3
4
No straining
Mild straining
Moderate straining
Severe straining
Very severe straining
[Assessment of degree of straining]
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 209 patients with chronic constipation of unknown cause*
Methods: Patients were treated with 24
μg
lubiprostone
orally BID (after breakfast and dinner) for 48 weeks
Endpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
Japanese Phase III Long-term Treatment study
Slide43Severity of constipation in patients treated with lubiprostone (change over 48 weeks)2
4
8
12
16
20
24
28
36
40
44
Severity of constipation
(patient's global assessment)
1
32
48
Change in the severity of constipation (patient's global assessment):
p < 0.001 at all time points
(one-sample t-test, vs. baseline)
[Assessment of severity of constipation (patient's global assessment)]
None
Very severe
1
2
3
4
0
Baseline
(Weeks)
Lubiprostone 48
μg
/day (n = 209)
0
1
2
3
4
None
(No symptom of constipation at all)
Mild
(Slight symptoms of constipation)
Moderate
(Constipation is present, but with only moderate symptoms)
Severe
(Having severe constipation with difficulty in defecation, or having only a slight feeling of evacuation in the bathroom)
Very severe
(Stubborn constipation with almost no bowel movement, or almost no feeling of evacuation in the bathroom)
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 209 patients with chronic constipation of unknown cause*
Methods: Patients were treated with 24
μg
lubiprostone
orally BID (after breakfast and dinner) for 48 weeks
Endpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
Japanese Phase III Long-term Treatment study
Slide44Effect of lubiprostone on QOL:Evaluation with SF-36® (scores based on the Japanese version scoring program)*1: SF-36
® is a registered trademark of Medical Outcomes Trust.SF-36
®*1 subscale score
Baseline (n = 208)
Week 48 (n = 207)
Week 24 (n = 173)
Physical functioning
Role physical
Bodily pain
General health
Vitality
Social functioning
Role emotional
Mental health
46
56
48
50
54
52
55
53
51
49
47
***
***
***
**
**
**
*
*
*
***: p < 0.001, **: p < 0.01, *: p < 0.05 (one-sample t-test, vs. baseline)
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Fukudo S, et al. Clin Gastroenterol Hepatol. 13(2): 294-301. e5, 2015.
This study was supported by funding from Sucampo Pharma.
Patients: 209 patients with chronic constipation of unknown cause*
Methods: Patients were treated with 24
μg
lubiprostone
orally BID (after breakfast and dinner) for 48 weeks
Endpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
Japanese Phase III Long-term Treatment study
Slide45Effect of lubiprostone on QOL:Evaluation with IBS-QOL-JDysphoria
Interference with activity
Body image
Health worry
Food avoidance
Social reaction
Sexual concerns
Interpersonal relations
Total score
100
***: p < 0.001 (one-sample t-test, vs. baseline)
60
70
80
90
***
***
***
***
***
***
***
***
***
***
***
***
***
***
***
***
***
***
IBS-QOL-J score
-
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Fukudo S, et al. Clin Gastroenterol Hepatol. 13(2): 294-301. e5, 2015.
This study was supported by funding from Sucampo Pharma.
Baseline (n = 208)
Week 48 (n = 207)
Week 24 (n = 173)
Patients: 209 patients with chronic constipation of unknown cause*
Methods: Patients were treated with 24
μg
lubiprostone
orally BID (after breakfast and dinner) for 48 weeks
Endpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
Japanese Phase III Long-term Treatment study
50
Slide46Change in SBM frequency (Week 1): Analysis by presence or absence of IBS0
With IBS(n=34)
Without IBS(n=167)
Mean ± SD (two-sample t-test)
4
10
Change in SBM frequency
14
8
6
2
12
NS
4.3
6.1
(Times/week)
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 209 patients with chronic constipation of unknown cause*
Methods: Patients were treated with 24
μg
lubiprostone
orally BID (after breakfast and dinner) for 48 weeks
Endpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
Japanese Phase III Long-term Treatment study
Slide47Change in SBM frequency (Week 1): Stratified analysis by age0
< 65 years
(n=186)
≥ 65 years(n=15)
Mean ± SD (two-sample t-test)
4
10
Change in SBM frequency
(Week 1)
12
8
6
2
NS
4.5
5.1
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Re-analysis from the data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 209 patients with chronic constipation of unknown cause*
Methods: Patients were treated with 24
μg
lubiprostone
orally BID (after breakfast and dinner) for 48 weeks
Endpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.
(Times/week)
Japanese Phase III Long-term Treatment study
Slide48Adverse Drug ReactionsData submitted for approval application
This study was supported by funding from Sucampo Pharma.
Patients: 209 patients with chronic constipation of unknown cause*Methods: Patients were treated with 24 μg lubiprostone orally BID (after breakfast and dinner) for 48 weeksEndpoints: SBM frequency at each week, change in SBM frequency, proportion of patients who had SBM within 24/48 hours after the first dose, proportion of responders, time to first SBM, stool consistency, severity of symptoms associated with constipation, severity of constipation, QOL, and frequency of use of rescue medications
Analysis plan: Endpoints were analyzed using one-sample t-test, Wilcoxon rank sum test (continuous variables), and Fisher's exact test (categorical variables) and compared with baseline.The incidence of ADRs including abnormal laboratory values was 73.2% (n = 153) in 209 patients included in the safety evaluation. The most common ADRs included diarrhea in 37.3% (n = 78), nausea in 27.3% (n = 57), chest discomfort in 7.2% (n = 15), abdominal pain in 5.3% (n = 11), and vomiting in 4.8% (n = 10).SAEs included vertigo and hypoesthesia in 1 patient each, which were assessed as “possibly related” to the study treatment and considered as serious ADRs. Thirty-three AEs (in 24 patients) led to treatment discontinuation: nausea (12 events); palpitation (3 events); abdominal discomfort, diarrhea, malaise, and vertigo (2 events each); and nasopharyngitis
, enterocolitis viral, hypersensitivity, dizziness, headache, somnolence, syncope, upper abdominal pain, chest discomfort, and hypoesthesia (1 event each).No. of patients (%)
Interim analysis up to Week 24 (n = 209)
Overall 48-week treatment period
(n=209)
Diarrhea
68 (32.5)
78 (37.3)
Nausea
55 (26.3)
57 (27.3)
Chest discomfort
14 (6.7)
15 (7.2)
Abdominal pain
10 (4.8)
11 (5.3)
ADRs reported in ≥ 5% of patients at any time point
*
Patients with a mean SBM frequency of less than 3 times/week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Japanese Phase III Long-term Treatment study
Slide49Clinical Equivalence StudyLubiprostone Clinical Studies (4)
Slide50Study OverviewObjectives:To evaluate the clinical equivalence of 2 capsule formulations of lubiprostone when administered at the same dose level in patients with chronic constipation of unknown cause.
Patients:135 patients aged ≥ 20 years with a diagnosis of constipation*(64 patients treated with two 12-μg capsules BID and 71 treated with one 24-μg capsule BID)
Dosing regimen:Two 12-μg lubiprostone capsules or one 24-μg lubiprostone capsule plus one placebo capsule were orally administered BID for 7 days.
*Major patient inclusion/exclusion criteria
• Patients with less than 3 SBMs per week for at least 6 months were included • Patients with secondary constipation (drug-induced and symptomatic) or organic disorder were excluded
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Clinical Equivalence Study
Slide51Endpoints and Analysis PlanClinical Equivalence Study
Primary endpoint:Change from baseline in SBM frequency at Week 1Secondary endpoints
:Frequency of SBM/bowel movement (BM)/complete spontaneous bowel movement (CSBM) at Week 1, proportion of patients who had SBM within 24/48 hours after the first dose, change from baseline in BM/CSBM frequency at Week 1, severity of symptoms associated with constipation (stool consistency/straining during defecation/abdominal bloating/abdominal discomfort) at Week 1*, and frequency of use of rescue medications at Week 1Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hoursCSBM: SBM without feeling of incomplete evacuation
Analysis plan:The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with treatment group as a factor, study site as a co-factor, and baseline SBM frequency (< 1.5 or ≥ 1.5) as a covariate to estimate the treatment difference between the 2 treatment groups and its corresponding two-sided 95% confidence interval (CI). The 2 treatments were considered clinically equivalent if the treatment difference was within the specified range of clinical significance (-1.6 to 1.6) and the 95% CI included 0. The proportion of patients who had SBM within 24/48 hours after the first dose was determined from the life-table estimates derived by the Kaplan-Meier method, with the p value calculated by the likelihood-ratio chi-square test.
*Evaluation scales for symptoms associated with constipation• Stool consistency: Bristol Stool Form Scale (7 levels, types 1 to 7)
•
Straining during defecation, abdominal bloating, abdominal discomfort: 0 (no symptom), 1 (mild), 2 (moderate), 3 (severe),
4 (very severe)
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
Slide52Patient DispositionData submitted for approval application
This study was supported by funding from Sucampo Pharma.*Patients with less than 3 SBMs per week for at least 6 months Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Patients: 135 patients aged ≥ 20 years with a diagnosis of constipation* (64 patients treated with two 12-μg capsules BID and 71 treated with one 24-μg capsule BID)Methods: Two 12-μg lubiprostone capsules or one 24-μg lubiprostone capsule plus one placebo capsule were orally administered BID for 7 daysPrimary endpoint: Change from baseline in SBM frequency at Week 1Secondary endpoints: SBM/BM/CSBM frequency at Week 1, proportion of patients who had SBM within 24/48 hours after the first dose, change from baseline in BM/CSBM frequency at Week 1, severity of symptoms associated with constipation at Week 1*, and frequency of use of rescue medications at Week 1
Analysis plan: The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with treatment group as a factor, study site as a co-factor, and baseline SBM frequency as a covariate to estimate the treatment difference between the 2 treatment groups and its corresponding two-sided 95% confidence interval (CI). The 2 treatments were considered clinically equivalent if the treatment difference was within the specified range of clinical significance (-1.6 to 1.6) and the 95% CI included 0. The proportion of patients who had SBM within 24/48 hours after the first dose was determined from the life-table estimates derived by the Kaplan-Meier method, with the p value calculated by the likelihood-ratio chi-square test.*Due to improper use of rescue medications
Treatment completedn=63 (98.4%)
Randomized
N=135 (100%)
Two 12-μg
lubiprostone
capsules BID
n=64 (100%)
Premature treatment discontinuation
n=1 (1.6%)
Sponsor request
*
n = 1 (1.6%)
One 24-μg lubiprostone
capsule BIDn=71 (100%)
Treatment completed
n=70 (98.6%)
Premature treatment discontinuation
n=1 (1.4%)
AE, n = 1 (1.4%)
Study completed
N=133 (98.5%)
Premature withdrawal from study
n=2 (1.5%)
Clinical Equivalence Study
Slide53Group 1Two 12-μg capsules BID*Evaluation of eligibilitySafety evaluation after completion of treatmentGroup 2
One 24-μg capsule plus one placebo capsule BID*Study Design
Data submitted for approval applicationThis study was supported by funding from Sucampo Pharma.*Each patient took 2 capsules after every breakfast and dinner
Screening periodDay -14 (-4 days)Treatment period
Day 1 to Day 7Follow-up periodDay 8 to Day 14 (+3 days)
Randomized
R
*Patients with less than 3 SBMs per week for at least 6 months
Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Patients: 135 patients aged ≥ 20 years with a diagnosis of constipation* (64 patients treated with two 12-μg capsules BID and 71 treated with one 24-μg capsule BID)
Methods: Two 12-μg
lubiprostone
capsules or one 24-μg
lubiprostone
capsule plus one placebo capsule were orally administered BID for 7 days
Primary endpoint: Change from baseline in SBM frequency at Week 1
Secondary endpoints: SBM/BM/CSBM frequency at Week 1, proportion of patients who had SBM within 24/48 hours after the first dose, change from baseline in BM/CSBM frequency at Week 1, severity of symptoms associated with constipation at Week 1*, and frequency of use of rescue medications at Week 1Analysis plan: The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with treatment group as a factor, study site as a co-factor, and baseline SBM frequency as a covariate to estimate the treatment difference between the 2 treatment groups and its corresponding two-sided 95% confidence interval (CI). The 2 treatments were considered clinically equivalent if the treatment difference was within the specified range of clinical significance (-1.6 to 1.6) and the 95% CI included 0. The proportion of patients who had SBM within 24/48 hours after the first dose was determined from the life-table estimates derived by the Kaplan-Meier method, with the p value calculated by the likelihood-ratio chi-square test.
Clinical Equivalence Study
Slide54Patient DemographicsData submitted for approval application
This study was supported by funding from Sucampo Pharma.*Patients with less than 3 SBMs per week for at least 6 months Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
Disease characteristicsTwo 12-μg capsules BID(n=64)
One 24-μg capsule BID
(n=71)BM frequency*
1.9
±
0.52
1.9
±
0.55
SBM frequency
*
1.8
±
0.60
1.8±
0.58
< 1.5 times [n (%)]
11 (17.2)
13 (18.3)
≥ 1.5 times [n (%)]
53 (82.8)
58 (81.7)
CSBM frequency
*
0.3
±
0.540.2±0.51
Stool consistency*1, *
2.2±0.96
2.2±1.16
Straining during defecation*2, *
2.3±0.69
2.2±0.89
Abdominal bloating*2, *
1.8±0.821.7
±0.95Abdominal discomfort*2, *
1.7±0.88
1.6
±
0.95
Number of days of use of rescue medications
*
2.6
±
2.44
1.3
±
0.49
* Mean ± SD
*1: Based on the Bristol Stool Form Scale (types 1 to 7)
*2: Evaluated as 0 (no symptom), 1 (mild), 2 (moderate), 3 (severe), or 4 (very severe)
Demographic characteristics
Two 12-μg capsules BID
(n=64)
One 24-μg capsule BID
(n=71)
Age (years)
*
45.1
±
13.07
44.2
±
11.14
Sex [n (%)]
Female
54 (84.4)
53 (74.6)
Male
10 (15.6)
18 (25.4)
Height (cm)
*
160.1
±
7.57
161.5
±
7.25
Body weight (kg)
*
55.7
±
11.31
56.9
±
10.01
BMI (kg/m
2
)
*
21.7
±
3.67
21.7
±
2.84
Patients: 135 patients aged ≥ 20 years with a diagnosis of constipation* (64 patients treated with two 12-μg capsules BID and 71 treated with one 24-μg capsule BID)
Methods: Two 12-μg
lubiprostone
capsules or one 24-μg
lubiprostone
capsule plus one placebo capsule were orally administered BID for 7 days
Primary endpoint: Change from baseline in SBM frequency at Week 1
Secondary endpoints: SBM/BM/CSBM frequency at Week 1, proportion of patients who had SBM within 24/48 hours after the first dose, change from baseline in BM/CSBM frequency at Week 1, severity of symptoms associated with constipation at Week 1*, and frequency of use of rescue medications at Week 1
Analysis plan: The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with treatment group as a factor, study site as a co-factor, and baseline SBM frequency as a covariate to estimate the treatment difference between the 2 treatment groups and its corresponding two-sided 95% confidence interval (CI). The 2 treatments were considered clinically equivalent if the treatment difference was within the specified range of clinical significance (-1.6 to 1.6) and the 95% CI included 0. The proportion of patients who had SBM within 24/48 hours after the first dose was determined from the life-table estimates derived by the Kaplan-Meier method, with the p value calculated by the likelihood-ratio chi-square test.
Clinical Equivalence Study
Slide55Change in SBM frequency at Week 1 (primary endpoint)Data submitted for approval application
This study was supported by funding from Sucampo Pharma.*Patients with less than 3 SBMs per week for at least 6 months Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours(Times/week)Mean ± SD
Treatment difference (95% CI) by ANCOVA: -0.4 (-1.4 to 0.2)
0
8Two 12-μg capsules BID(n=60)One 24-μg capsule BID
(n=65)
Analysis in the per-protocol set (PPS) of 125 patients
Change in SBM frequency
1
2
3
4
5
6
7
3.0
3.5
Patients: 135 patients aged ≥ 20 years with a diagnosis of constipation* (64 patients treated with two 12-μg capsules BID and 71 treated with one 24-μg capsule BID)
Methods: Two 12-μg
lubiprostone
capsules or one 24-μg
lubiprostone
capsule plus one placebo capsule were orally administered BID for 7 days
Primary endpoint: Change from baseline in SBM frequency at Week 1
Secondary endpoints: SBM/BM/CSBM frequency at Week 1, proportion of patients who had SBM within 24/48 hours after the first dose, change from baseline in BM/CSBM frequency at Week 1, severity of symptoms associated with constipation at Week 1*, and frequency of use of rescue medications at Week 1
Analysis plan: The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with treatment group as a factor, study site as a co-factor, and baseline SBM frequency as a covariate to estimate the treatment difference between the 2 treatment groups and its corresponding two-sided 95% confidence interval (CI). The 2 treatments were considered clinically equivalent if the treatment difference was within the specified range of clinical significance (-1.6 to 1.6) and the 95% CI included 0. The proportion of patients who had SBM within 24/48 hours after the first dose was determined from the life-table estimates derived by the Kaplan-Meier method, with the p value calculated by the likelihood-ratio chi-square test.
Clinical Equivalence Study
Slide56Proportion of patients who had SBM within 24/48 hours after the first dose (secondary endpoint)Data submitted for approval application
This study was supported by funding from Sucampo Pharma.*Patients with less than 3 SBMs per week for at least 6 months Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
0100
(%)Within 24 hoursWithin 48 hours
*Likelihood-ratio chi-square test
10
20
30
40
50
60
70
80
90
Proportion of patients with SBM
p=0.7264*
p=0.8250*
73.4
76.1
87.5
88.7
Two 12-μg capsules BID (n = 63) One 24-μg capsule BID (n = 71)
Patients: 135 patients aged ≥ 20 years with a diagnosis of constipation* (64 patients treated with two 12-μg capsules BID and 71 treated with one 24-μg capsule BID)
Methods: Two 12-μg
lubiprostone
capsules or one 24-μg
lubiprostone
capsule plus one placebo capsule were orally administered BID for 7 days
Primary endpoint: Change from baseline in SBM frequency at Week 1
Secondary endpoints: SBM/BM/CSBM frequency at Week 1, proportion of patients who had SBM within 24/48 hours after the first dose, change from baseline in BM/CSBM frequency at Week 1, severity of symptoms associated with constipation at Week 1*, and frequency of use of rescue medications at Week 1
Analysis plan: The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with treatment group as a factor, study site as a co-factor, and baseline SBM frequency as a covariate to estimate the treatment difference between the 2 treatment groups and its corresponding two-sided 95% confidence interval (CI). The 2 treatments were considered clinically equivalent if the treatment difference was within the specified range of clinical significance (-1.6 to 1.6) and the 95% CI included 0. The proportion of patients who had SBM within 24/48 hours after the first dose was determined from the life-table estimates derived by the Kaplan-Meier method, with the p value calculated by the likelihood-ratio chi-square test.
Clinical Equivalence Study
Slide57Severity of symptoms associated with constipation at Week 1 (secondary endpoint) <Stool consistency*1/straining during defecation/abdominal bloating/abdominal discomfort*2>
Data submitted for approval applicationThis study was supported by funding from Sucampo Pharma.*Patients with less than 3 SBMs per week for at least 6 months Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
0
0Rabbit dropping-likeNoneAbdominal discomfort
Abdominal bloatingStraining during defecationStool consistency*1: Evaluated based on the Bristol Stool Form Scale (types 1 to 7), *2: Evaluated as 0 (no symptom), 1 (mild), 2 (moderate), 3 (severe), or 4 (very severe)
Mean ± SD
* Treatment difference (95% CI) by ANCOVA
(n=62)
(n=71)
(62)
(71)
(64)
(71)
(64)
(71)
1
2
3
4
5
6
7
1
2
3
4
Watery
Stool consistency
Severity of symptoms associated with constipation
Very severe
-0.1 (-0.4 to 0.3)*
0.0 (-0.2 to 0.3)*
0.1 (-0.2 to 0.4)*
1.3
1.5
1.6
4.0
3.8
1.3
1.4
1.4
Two 12-μg capsules BID One 24-μg capsule BID
0.0 (-0.5 to 0.6)*
Patients: 135 patients aged ≥ 20 years with a diagnosis of constipation* (64 patients treated with two 12-μg capsules BID and 71 treated with one 24-μg capsule BID)
Methods: Two 12-μg
lubiprostone
capsules or one 24-μg
lubiprostone
capsule plus one placebo capsule were orally administered BID for 7 days
Primary endpoint: Change from baseline in SBM frequency at Week 1
Secondary endpoints: SBM/BM/CSBM frequency at Week 1, proportion of patients who had SBM within 24/48 hours after the first dose, change from baseline in BM/CSBM frequency at Week 1, severity of symptoms associated with constipation at Week 1*, and frequency of use of rescue medications at Week 1
Analysis plan: The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with treatment group as a factor, study site as a co-factor, and baseline SBM frequency as a covariate to estimate the treatment difference between the 2 treatment groups and its corresponding two-sided 95% confidence interval (CI). The 2 treatments were considered clinically equivalent if the treatment difference was within the specified range of clinical significance (-1.6 to 1.6) and the 95% CI included 0. The proportion of patients who had SBM within 24/48 hours after the first dose was determined from the life-table estimates derived by the Kaplan-Meier method, with the p value calculated by the likelihood-ratio chi-square test.
Clinical Equivalence Study
Slide58SBM/BM/CSBM frequency at Week 1(Secondary endpoint)Data submitted for approval application
This study was supported by funding from Sucampo Pharma.*Patients with less than 3 SBMs per week for at least 6 months Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
010
SBM frequencyBM frequency
CSBM frequency(Times/week)
1
2
3
4
5
6
7
8
9
0.5 (-0.7 to 1.7)*
SBM/BM/CSBM frequency
4.8
4.9
2.6
5.5
5.5
2.2
Two 12-μg capsules BID (n = 63) One 24-μg capsule BID (n = 71)
-0.6 (-2.0 to 0.7)*
-0.5 (-1.9 to 0.9)*
Mean ± SD
* Treatment difference (95% CI) by ANCOVA
Patients: 135 patients aged ≥ 20 years with a diagnosis of constipation* (64 patients treated with two 12-μg capsules BID and 71 treated with one 24-μg capsule BID)
Methods: Two 12-μg
lubiprostone
capsules or one 24-μg
lubiprostone
capsule plus one placebo capsule were orally administered BID for 7 days
Primary endpoint: Change from baseline in SBM frequency at Week 1
Secondary endpoints: SBM/BM/CSBM frequency at Week 1, proportion of patients who had SBM within 24/48 hours after the first dose, change from baseline in BM/CSBM frequency at Week 1, severity of symptoms associated with constipation at Week 1*, and frequency of use of rescue medications at Week 1
Analysis plan: The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with treatment group as a factor, study site as a co-factor, and baseline SBM frequency as a covariate to estimate the treatment difference between the 2 treatment groups and its corresponding two-sided 95% confidence interval (CI). The 2 treatments were considered clinically equivalent if the treatment difference was within the specified range of clinical significance (-1.6 to 1.6) and the 95% CI included 0. The proportion of patients who had SBM within 24/48 hours after the first dose was determined from the life-table estimates derived by the Kaplan-Meier method, with the p value calculated by the likelihood-ratio chi-square test.
Clinical Equivalence Study
Slide59Change in BM/CSBM frequency at Week 1(Secondary endpoint)Data submitted for approval application
This study was supported by funding from Sucampo Pharma.*Patients with less than 3 SBMs per week for at least 6 months Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
08
(Times/week)Change in BM/CSBM frequencyChange in BM frequency
Change in CSBM frequency
1
2
3
4
5
6
7
0.4 (-0.8 to 1.6)*
3.6
2.3
2.0
3.1
Two 12-μg capsules BID (n = 63) One 24-μg capsule BID (n = 71)
-0.5 (-1.9 to 0.9)*
Patients: 135 patients aged ≥ 20 years with a diagnosis of constipation* (64 patients treated with two 12-μg capsules BID and 71 treated with one 24-μg capsule BID)
Methods: Two 12-μg
lubiprostone
capsules or one 24-μg
lubiprostone
capsule plus one placebo capsule were orally administered BID for 7 days
Primary endpoint: Change from baseline in SBM frequency at Week 1
Secondary endpoints: SBM/BM/CSBM frequency at Week 1, proportion of patients who had SBM within 24/48 hours after the first dose, change from baseline in BM/CSBM frequency at Week 1, severity of symptoms associated with constipation at Week 1*, and frequency of use of rescue medications at Week 1
Analysis plan: The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with treatment group as a factor, study site as a co-factor, and baseline SBM frequency as a covariate to estimate the treatment difference between the 2 treatment groups and its corresponding two-sided 95% confidence interval (CI). The 2 treatments were considered clinically equivalent if the treatment difference was within the specified range of clinical significance (-1.6 to 1.6) and the 95% CI included 0. The proportion of patients who had SBM within 24/48 hours after the first dose was determined from the life-table estimates derived by the Kaplan-Meier method, with the p value calculated by the likelihood-ratio chi-square test.
Mean ± SD
* Treatment difference (95% CI) by ANCOVA
Clinical Equivalence Study
Slide60Adverse EventsData submitted for approval application
This study was supported by funding from Sucampo Pharma.*Patients with less than 3 SBMs per week for at least 6 months Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hoursA total of 45 patients (33.3%) experienced at least one AE, including 20 patients (31.3%) in the two 12-μg capsules BID group and 25 patients (35.2%) in the one 24-μg capsule BID group. Among AEs, gastrointestinal disorders occurred in 16 patients (25.0%) in the two 12-μg capsules BID group and 17 patients (23.9%) in the one 24-μg capsule BID group.
n (%)
Two 12-μg capsules BID(n=64)
One 24-μg capsule BID(n=71)
Gastrointestinal disorders
16 (25.0)
17 (23.9)
Nausea
11 (17.2)
7 (9.9)
Diarrhea
6 (9.4)
11 (15.5)
Abdominal discomfort
2 (3.1)
1 (1.4)
Vomiting
2 (3.1)
0
Abdominal bloating
0
1 (1.4)
Abdominal pain
1 (1.6)
0
Upper abdominal pain
0
1 (1.4)
Soft stools
1 (1.6)
0
Gastrointestinal hypermotility
1 (1.6)
0
n (%)
Two 12-μg capsules BID
(n=64)
One 24-μg capsule
BID
(n=71)
At least one AE
20 (31.3)
25 (35.2)
Treatment-related AEs
16 (25.0)
21 (29.6)
AEs leading to treatment discontinuation
0
1 (1.4)
All AEs
Gastrointestinal disorders
Palpitations in 1 patient was the only AE leading to discontinuation of study treatment.
There were no deaths or
serious adverse events
(SAEs).
Patients: 135 patients aged ≥ 20 years with a diagnosis of constipation* (64 patients treated with two 12-μg capsules BID and 71 treated with one 24-μg capsule BID)
Methods: Two 12-μg
lubiprostone
capsules or one 24-μg
lubiprostone
capsule plus one placebo capsule were orally administered BID for 7 days
Primary endpoint: Change from baseline in SBM frequency at Week 1
Secondary endpoints: SBM/BM/CSBM frequency at Week 1, proportion of patients who had SBM within 24/48 hours after the first dose, change from baseline in BM/CSBM frequency at Week 1, severity of symptoms associated with constipation at Week 1*, and frequency of use of rescue medications at Week 1
Analysis plan: The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with treatment group as a factor, study site as a co-factor, and baseline SBM frequency as a covariate to estimate the treatment difference between the 2 treatment groups and its corresponding two-sided 95% confidence interval (CI). The 2 treatments were considered clinically equivalent if the treatment difference was within the specified range of clinical significance (-1.6 to 1.6) and the 95% CI included 0. The proportion of patients who had SBM within 24/48 hours after the first dose was determined from the life-table estimates derived by the Kaplan-Meier method, with the p value calculated by the likelihood-ratio chi-square test.
Clinical Equivalence Study
Slide61Adverse events: Other than gastrointestinal disordersData submitted for approval application
This study was supported by funding from Sucampo Pharma.*Patients with less than 3 SBMs per week for at least 6 months Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
n (%)
Two 12-μg capsules BID(n=64)
One 24-μg capsule BID(n=71)Infections and infestations
3
(
4.7)
5
(
7.0)
Nasopharyngitis
1
(
1.6)
2
(
2.8)
Oral herpes
1
(1.6)
1
(
1.4)
Bronchitis
0
1 (1.4)
Influenza
01 (1.4)
Pharyngitis
1 (1.6)
0General disorders and administration site conditions
1
(1.6)3 (
4.2) Chest discomfort
1 (1.6)
0 Feeling abnormal
0
1 (1.4) Peripheral edema
0
1
(
1.4)
Thirst
0
1
(
1.4)
Respiratory, thoracic and mediastinal disorders
1
(
1.6)
1
(
1.4)
Dyspnea
0
1
(
1.4)
Upper respiratory tract inflammation
1
(
1.6)
0
n (%)
Two 12-μg capsules
BID
(n=64)
One 24-μg capsule
BID
(n=71)
Cardiac disorders
0
1
(
1.4)
Palpitations
0
1
(
1.4)
Ear and labyrinth disorders
0
1
(
1.4)
Dizziness
0
1
(
1.4)
Investigations
0
1
(
1.4)
Blood creatine phosphokinase increased
0
1
(
1.4)
Metabolism and nutrition disorders
1
(
1.6)
0
Appetite impaired
1
(
1.6)
0
Nervous system disorders
0
1
(
1.4)
Headache
0
1
(
1.4)
Reproductive system and breast disorders
0
1
(
1.4)
Dysmenorrhea
0
1
(
1.4)
Skin and subcutaneous tissue disorders
1
(
1.6)
0
Eczema
1
(
1.6)
0
Other than gastrointestinal disorders, the following AEs were observed:
Patients: 135 patients aged ≥ 20 years with a diagnosis of constipation* (64 patients treated with two 12-μg capsules BID and 71 treated with one 24-μg capsule BID)
Methods: Two 12-μg
lubiprostone
capsules or one 24-μg
lubiprostone
capsule plus one placebo capsule were orally administered BID for 7 days
Primary endpoint: Change from baseline in SBM frequency at Week 1
Secondary endpoints: SBM/BM/CSBM frequency at Week 1, proportion of patients who had SBM within 24/48 hours after the first dose, change from baseline in BM/CSBM frequency at Week 1, severity of symptoms associated with constipation at Week 1*, and frequency of use of rescue medications at Week 1
Analysis plan: The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with treatment group as a factor, study site as a co-factor, and baseline SBM frequency as a covariate to estimate the treatment difference between the 2 treatment groups and its corresponding two-sided 95% confidence interval (CI). The 2 treatments were considered clinically equivalent if the treatment difference was within the specified range of clinical significance (-1.6 to 1.6) and the 95% CI included 0. The proportion of patients who had SBM within 24/48 hours after the first dose was determined from the life-table estimates derived by the Kaplan-Meier method, with the p value calculated by the likelihood-ratio chi-square test.
Clinical Equivalence Study
Slide62(Reference) Adverse events: nausea and diarrheaData submitted for approval application
This study was supported by funding from Sucampo Pharma.*Patients with less than 3 SBMs per week for at least 6 months Note) SBM: Bowel movement that occurs without the use of laxatives, suppositories, or enema within 24 hours
n (%)
Two 12-μg capsules BID(n=64)
One 24-μg capsule BID(n=71)Nausea
11
(
17.2)
7
(
9.9)
Not related to study treatment
1
(
1.6)
0
Related to study treatment
10
(
15.6)
7
(
9.9)
Possibly related
3
(4.7)
4 (5.6)
Probably related3
(4.7)1 (1.4)
Definitely related
4 (6.3)2 (
2.8)Diarrhea
6
(9.4)11 (15.5)
Not related to study treatment
1 (1.6)
0 Related to study treatment
5 (7.8)
11 (15.5) Possibly related
2
(
3.1)
3
(
4.2)
Probably related
3
(
4.7)
4
(
5.6)
Definitely related
0
4
(
5.6)
The most common AEs were nausea and diarrhea, both occurring in about 13% of all patients.
Patients: 135 patients aged ≥ 20 years with a diagnosis of constipation* (64 patients treated with two 12-μg capsules BID and 71 treated with one 24-μg capsule BID)
Methods: Two 12-μg
lubiprostone
capsules or one 24-μg
lubiprostone
capsule plus one placebo capsule were orally administered BID for 7 days
Primary endpoint: Change from baseline in SBM frequency at Week 1
Secondary endpoints: SBM/BM/CSBM frequency at Week 1, proportion of patients who had SBM within 24/48 hours after the first dose, change from baseline in BM/CSBM frequency at Week 1, severity of symptoms associated with constipation at Week 1*, and frequency of use of rescue medications at Week 1
Analysis plan: The primary efficacy endpoint was analyzed using analysis of covariance (ANCOVA) with treatment group as a factor, study site as a co-factor, and baseline SBM frequency as a covariate to estimate the treatment difference between the 2 treatment groups and its corresponding two-sided 95% confidence interval (CI). The 2 treatments were considered clinically equivalent if the treatment difference was within the specified range of clinical significance (-1.6 to 1.6) and the 95% CI included 0. The proportion of patients who had SBM within 24/48 hours after the first dose was determined from the life-table estimates derived by the Kaplan-Meier method, with the p value calculated by the likelihood-ratio chi-square test.
Clinical Equivalence Study
Slide63Discussion and Overall ConclusionThe efficacy analysis confirmed the clinical equivalence of the 2 capsule formulations of lubiprostone when administered at the same dose level. The safety analysis showed that the safety profile was similar between the 2 treatment groups.
Patient data at study entry were balanced and comparable between the 2 treatment groups. Exposure and compliance to study treatment were also comparable between the 2 treatment groups.Analysis of the primary efficacy endpoint in the 2 treatment groups confirmed the clinical equivalence of the two 12-μg capsules BID and the one 24-μg capsule BID regimens.Analysis of the secondary efficacy endpoints in the 2 treatment groups confirmed the clinical equivalence of the two 12-μg capsules BID and the one 24-μg capsule BID regimens for all endpoints.The safety profile was similar to those observed in previous clinical trials, with no statistically significant differences in the incidence of AEs between the 2 treatment groups. All events of nausea and diarrhea observed in about 13% of all patients resolved during the study period.
No SAE was observed. An AE of palpitations in 1 patient led to discontinuation of study treatment.Overall conclusion
Clinical Equivalence Study
Slide64Adverse Drug Reactions in Japanese Clinical Studies (at time of approval)Lubiprostone: Safety
Slide65Adverse drug reactions in Japanese clinical studies of lubiprostone (at time of approval)Summary by age groupNo. of patients with ADRs/No. of patients with stratification factors*
Incidence of ADRsAge< 65 years
182/28464.1%
≥ 65 years14/31
45.2%
Incidence of ADRs
(by age at approval)
Tabulated from the data submitted for approval application
This study was supported by funding from Sucampo Pharma.
*: Patients treated with a 24-μg capsule BID
Slide66Adverse drug reactions in Japanese clinical studies of lubiprostone (at time of approval)No. of safety evaluable patients*315
No. of patients with ADRs (%)196(62.2%)
ADRsNo. of patientsBlood and lymphatic system disorders
1 (0.3%)Anemia1
(0.3%)Immune system disorders2 (0.6%)
Hypersensitivity
2
(
0.6%)
Nervous system disorders
15 (4.8%)
Headache
8 (2.5%)
Dizziness
3 (1.0%)
Hypoesthesia
3 (1.0%)
Dizziness postural1
(0.3%)
Somnolence
1 (0.3%)
Syncope
1
(
0.3%)
Ear and labyrinth disorders3 (1.0%)Vertigo
3 (1.0%)Cardiac disorders
7 (2.2%)Palpitations6 (1.9%)
Tachycardia1 (0.3%)
ADRsNo. of patientsVascular disorders1
(0.3%)Hot flush1 (0.3%)
Respiratory, thoracic and mediastinal disorders5 (1.6%)Dyspnea
5
(1.6%)Gastrointestinal disorders172 (54.6%)
Diarrhea95 (30.2%)Nausea
73 (23.2%)Abdominal pain18 (5.7%)
Abdominal discomfort14 (4.4%)Vomiting
12 (3.8%)Abdominal bloating8 (2.5%)
Dyspepsia2 (0.6%)
Hemorrhoids
2
(
0.6%)
Reflux esophagitis
2
(
0.6%)
Defecation frequency increased
1
(
0.3%)
Gastritis hemorrhagic
1
(
0.3%)
Epigastric discomfort
1
(
0.3%)
Hemorrhoidal hemorrhage
1
(
0.3%)
Skin and subcutaneous tissue disorders
3
(
1.0%)
Eczema
2
(
0.6%)
Erythema
1
(
0.3%)
ADRs
No. of patients
Musculoskeletal and connective tissue disorders
3
(
1.0%)
Musculoskeletal stiffness
2
(
0.6%)
Back pain
1
(
0.3%)
Limb discomfort
1
(
0.3%)
General disorders and administration site conditions
29
(9.2%)
Chest discomfort
17 (5.4%)
Malaise
3
(
1.0%)
Edema
3
(
1.0%)
Feeling abnormal
2
(
0.6%)
Chest pain
2
(
0.6%)
Thirst
2
(
0.6%)
Discomfort
1
(
0.3%)
Investigations
10 (3.2%)
Blood triglycerides increased
2
(
0.6%)
Blood creatine phosphokinase increased
1
(
0.3%)
Blood glucose increased
1
(
0.3%)
Blood bilirubin increased
1
(
0.3%)
Blood urea increased
1
(
0.3%)
Blood gamma-glutamyltransferase increased
1
(
0.3%)
Glucose urine present
1
(
0.3%)
Hemoglobin decreased
1
(
0.3%)
Weight gain
1
(
0.3%)
White blood cell count increased
1
(
0.3%)
Blood phosphorus increased
1
(
0.3%)
Incidence of ADRs
(at approval)
Data submitted for approval application
This study was supported by funding from Sucampo Pharma.
*: Patients treated with a 24-μg capsule BID
Note) In the package insert, ADRs were summarized as follows: “hypersensitivity” -> “airway hypersensitivity,” “feeling abnormal” -> “feeling abnormal (feeling bad)”
ADRs including abnormal laboratory values were observed in 196 (62%) of 315 patients included in the safety evaluation (patients treated at 48
μg
/day) at the time of approval. The most common ADRs included diarrhea in 95 patients (30%) and nausea in 73 patients (23%). SAEs were observed in 2 patients (spontaneous abortion in 1 and vertigo/hypoesthesia in 1 patient). The causal relationship with
lubiprostone
could not be ruled out for vertigo/hypoesthesia in 1 patient.