Amitiza ® Slide Kit V - PowerPoint Presentation

342 views
Uploaded On 2022-08-01

Amitiza ® Slide Kit V - PPT Presentation

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

sbm patients week frequency patients sbm frequency week test constipation lubiprostone study hours dose bid change treatment proportion endpoints

Link:

Copy

Embed:

<iframe width="560" height="315" src="https://www.docslides.com/embed/931653" frameborder="0" allowfullscreen></iframe>

Download Presentation from below link

Download Presentation The PPT/PDF document "Amitiza ® Slide Kit V" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.

Presentation Transcript

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

Slide2

1. Basic data

Slide3

History 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

Slide4

Amitiza® 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

Molecular weight: 390.46

Profile

Slide5

Trade 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

Lubiprostone Profile

Profile

Molecular weight: 390.46

Slide6

Conceptual 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

ClC-2

Chloride channel

Mucosal

epithelial cells

Intestinal

lumen

(Apical membrane)

(Basal membrane)

Na+Water

Sodium pump

-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。

Slide7

Clinical 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

Slide8

World 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)

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)

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)

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)

μg

/capsule

Irritable bowel syndrome with constipation

September 2017 (approved)

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)

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

Slide9

Japanese Phase II Dose-response StudyLubiprostone Clinical Studies (1)

Slide10

Japanese 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

Slide11

Lubiprostone16

μg/dayn=41

Lubiprostone

32 μg/day

n=43Analysis Populations

Discontinued

n=1

Discontinued

n=1

Placebo

n=42

Lubiprostone

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

Slide12

Patient Demographics

Placebo

Lubiprostone

16 μg/day

Lubiprostone32 μg/day

Lubiprostone

μg

/day

Test

No. of patients

Sex (men)

3 (7.1%)

4 (9.8%)

6 (14.0%)

3 (6.8%)

Age (years)

38.4±11.6

38.8±11.0

40.0±11.3

40.7±12.9

Height (cm)

160.9±5.7

160.8±6.5

160.9±7.0

158.4±7.4

Body weight (kg)

54.7±7.3

54.3±8.3

56.3±9.7

52.6±8.3

BMI (kg/m

)

21.2±2.7

20.9±2.5

21.7±3.3

20.9±2.6

*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

Analysis plan

Jonckheere

test.

Japanese Phase II

Dose-response Study

Slide13

Dose 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)

μg

/day

(n=43)

(Times/week)

Lubiprostone

Change in SBM frequency

(Week 1)

***

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

Analysis plan

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

Slide14

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 weeksPrimary endpoint

:Change in the frequency of spontaneous bowel movement (SBM) at Week 1Secondary endpoints:

Fukudo S, et al. Neurogastroenterol Motil. 23(6): 544-e205, 2011.

This study was supported by funding from Sucampo Pharma.

[Stool consistency assessment]

Separate hard lumps like nuts (difficult to pass)

Sausage

shaped but lumpy

Like a sausage

but with cracks on its surface

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

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

Slide15

Adverse 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

μg

/day

Lubiprostone

μg

/day

Lubiprostone

μg

/day

Diarrhea

4 (9.3)

8 (18.2)

Nausea

3 (7.0)

7 (15.9)

Stomach discomfort

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

Analysis plan

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

Slide16

Japanese Phase III Double-blind Controlled StudyLubiprostone Clinical Studies (2)

Slide17

Japanese 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.

Slide18

Analysis 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

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

Slide19

Patient Demographics

Placebo

Lubiprostone 48 μg/day

Test

No. of patients

Sex (men)

9 (14.5%)

6 (9.7%)

Age (years)

41.5±14.2

42.7

16.4

Height (cm)

159.5

7.5

158.5

6.6

Body weight (kg)*1

54.7±8.4

54.2±8.9

BMI (kg/m

)

21.5

2.5

21.5

2.5

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)

25.2

15.2

26.3

16.4

History of treatment for constipation (yes)

41 (66.1%)

34 (54.8%)

IBS (yes)

0 (0.0%)

*1:

Mean

, *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

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

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

Slide20

Lubiprostone 48 μg/day

(n=60)

Placebo(n=62)

(Times/week)

Mean ± SD, ***: p < 0.001 (two-sample t-test)

Change in SBM frequency

(Week 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

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

Slide21

Change in SBM frequency(Primary endpoint, secondary endpoint)Week 1

Week 3

Week 4

Week 2

(Times/week)

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

2.7

1.6

2.6

***

3.7

2.7

1.5

2.8

1.6

2.6

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

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

Japanese Phase III Double-blind Controlled Study

Slide22

Time to first SBM after first dose(Secondary endpoint)140

Placebo

(n=60)

Lubiprostone 48 μg/day(n=59)

(Hours)

Mean ± SD, *: p < 0.05 (two-sample t-test)

120

100

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

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

Japanese Phase III Double-blind Controlled Study

Slide23

Proportion of patients who had SBM within 24 hours after first dose(Secondary endpoint)Placebo

(n=62)

Lubiprostone 48 μg/day(n=62)

100

(%)

Patients who had SBM within 24 hours after the first dose

58.1

30.6

**: p<0.01

(Fisher's exact 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

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

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

Japanese Phase III Double-blind Controlled Study

Slide24

Proportion 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)

(%)

***: p < 0.001 vs. placebo (chi-square test)

(%)

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

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.

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

Slide25

Change in SBM frequency over time (secondary endpoint)

Week 1

Baseline

Week 2

Week 3

Week 4

SBM frequency

(Times/week)

***

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

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

Slide26

Change in stool consistency over time (secondary endpoint)[Stool consistency assessment]

Week 1

Week 2

Week 3

Week 4

Stool consistency

Baseline

Placebo (n = 62)

Lubiprostone 48

μg

/day (n = 62)

Mean ± SD, ***: p < 0.001, **: p < 0.01 (two-sample t-test)

***

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

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

Japanese Phase III Double-blind Controlled Study

Separate hard lumps like nuts (difficult to pass)

Sausage

shaped but lumpy

Like a sausage

but with cracks on its surface

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

Slide27

Changes in abdominal bloating over time(secondary endpoint)

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

None

Very severe

Baseline

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

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

Japanese Phase III Double-blind Controlled Study

Slide28

Changes in abdominal discomfort over time(secondary endpoint)

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]

Abdominal discomfort

Very severe

Week 1

Week 2

Week 3

Week 4

Baseline

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

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

Japanese Phase III Double-blind Controlled Study

Slide29

Change in feeling of incomplete evacuation after defecation over time (secondary endpoint)[Assessment of feeling of incomplete evacuation]

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

No feeling of incomplete evacuation

Very strong feeling of incomplete evacuation

Baseline

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

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

Japanese Phase III Double-blind Controlled Study

Slide30

Change in the degree of straining during defecationover time (secondary endpoint)

Baseline

Week 1

Week 2

Week 3

Week 4

No straining

Mild straining

Moderate straining

Severe straining

Very severe straining

Degree of straining

No straining

Very severe straining

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

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

Japanese Phase III Double-blind Controlled Study

Slide31

Changes in the severity of constipation over time (patient's global assessment)(Secondary endpoint)0

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)

Baseline

Week 1

Week 2

Week 4

***

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

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

Japanese Phase III Double-blind Controlled Study

Slide32

Adverse 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

10 (16.1)

Nasopharyngitis

4 (6.5)

7 (11.3)

Vomiting

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

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

Slide33

Japanese Phase III Long-term Treatment studyLubiprostone Clinical Studies (3)

Slide34

Japanese 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.

Slide35

Analysis 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

Slide36

Patient 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

)

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

Slide37

SBM 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

SBM frequency

Baseline

(Times/week)

(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

Slide38

Stool consistency in patients treated with lubiprostone (change over 48 weeks)

Nut-like

Stool consistency

Watery

(Weeks)

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

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

）

Separate hard lumps like nuts (difficult to pass)

Sausage

shaped but lumpy

Like a sausage

but with cracks on its surface

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

Slide39

Abdominal bloating in patients treated with lubiprostone (change over 48 weeks)Abdominal bloating

None

Baseline

Very severe

(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)

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

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

Slide40

Abdominal 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

Baseline

(Weeks)

Lubiprostone 48

μg

/day (n = 209)

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

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

Slide41

Feeling 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

Change in feeling of incomplete evacuation: p < 0.001 for all weeks (one-sample t-test, vs. baseline)

[Assessment of feeling of incomplete evacuation]

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)

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

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

Slide42

Degree of straining during defecation in patients treated with lubiprostone(changes over 48 weeks)

Degree of straining

No straining

(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)

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

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

Slide43

Severity of constipation in patients treated with lubiprostone (change over 48 weeks)2

Severity of constipation

(patient's global assessment)

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

Baseline

(Weeks)

Lubiprostone 48

μg

/day (n = 209)

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

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

Slide44

Effect 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

***

***: 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

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

Slide45

Effect 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)

***

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

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

Slide46

Change 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)

Change in SBM frequency

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

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

Slide47

Change in SBM frequency (Week 1): Stratified analysis by age0

< 65 years

(n=186)

≥ 65 years(n=15)

Mean ± SD (two-sample t-test)

Change in SBM frequency

(Week 1)

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

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

Slide48

Adverse Drug ReactionsData submitted for approval application

This study was supported by funding from Sucampo Pharma.

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

Slide49

Clinical Equivalence StudyLubiprostone Clinical Studies (4)

Slide50

Study 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

Slide51

Endpoints 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.

Slide52

Patient DispositionData submitted for approval application

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

Slide53

Group 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

*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

Slide54

Patient DemographicsData submitted for approval application

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

)

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

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

Slide55

Change in SBM frequency at Week 1 (primary endpoint)Data submitted for approval application

Treatment difference (95% CI) by ANCOVA: -0.4 (-1.4 to 0.2)

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

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

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

Slide56

Proportion of patients who had SBM within 24/48 hours after the first dose (secondary endpoint)Data submitted for approval application

0100

(%)Within 24 hoursWithin 48 hours

*Likelihood-ratio chi-square test

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

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

Slide57

Severity 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

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)

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

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

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

Slide58

SBM/BM/CSBM frequency at Week 1(Secondary endpoint)Data submitted for approval application

010

SBM frequencyBM frequency

CSBM frequency(Times/week)

0.5 (-0.7 to 1.7)*

SBM/BM/CSBM frequency

4.8

4.9

2.6

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

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

Slide59

Change in BM/CSBM frequency at Week 1(Secondary endpoint)Data submitted for approval application

(Times/week)Change in BM/CSBM frequencyChange in BM frequency

Change in CSBM frequency

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

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

Slide60

Adverse 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)

　Abdominal bloating

1 (1.4)

Abdominal pain

1 (1.6)

　Upper abdominal pain

1 (1.4)

　Soft stools

1 (1.6)

　Gastrointestinal hypermotility

1 (1.6)

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

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

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

Slide61

Adverse events: Other than gastrointestinal disordersData submitted for approval application

n (%)

Two 12-μg capsules BID(n=64)

One 24-μg capsule BID(n=71)Infections and infestations

(

4.7)

(

7.0)

　Nasopharyngitis

(

1.6)

(

2.8)

　Oral herpes

(1.6)

(

1.4)

　Bronchitis

1 (1.4)

　Influenza

01 (1.4)

　Pharyngitis

1 (1.6)

0General disorders and administration site conditions

(1.6)3 (

4.2)　Chest discomfort

1 (1.6)

0　Feeling abnormal

1 (1.4)　Peripheral edema

(

1.4)

　Thirst

(

1.4)

Respiratory, thoracic and mediastinal disorders

(

1.6)

(

1.4)

　Dyspnea

(

1.4)

　Upper respiratory tract inflammation

(

1.6)

n (%)

Two 12-μg capsules

BID

(n=64)

One 24-μg capsule

BID

(n=71)

Cardiac disorders

(

1.4)

　Palpitations

(

1.4)

Ear and labyrinth disorders

(

1.4)

　Dizziness

(

1.4)

Investigations

(

1.4)

　Blood creatine phosphokinase increased

(

1.4)

Metabolism and nutrition disorders

(

1.6)

　Appetite impaired

(

1.6)

Nervous system disorders

(

1.4)

　Headache

(

1.4)

Reproductive system and breast disorders

(

1.4)

　Dysmenorrhea

(

1.4)

Skin and subcutaneous tissue disorders

(

1.6)

　Eczema

(

1.6)

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

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

n (%)

Two 12-μg capsules BID(n=64)

One 24-μg capsule BID(n=71)Nausea

(

17.2)

(

9.9)

　Not related to study treatment

(

1.6)

　Related to study treatment

(

15.6)

(

9.9)

　　　Possibly related

(4.7)

4 (5.6)

　　　Probably related3

(4.7)1 (1.4)

　　　Definitely related

4 (6.3)2 (

2.8)Diarrhea

(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

(

3.1)

(

4.2)

　　　Probably related

(

4.7)

(

5.6)

　　　Definitely related

(

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

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

Slide63

Discussion 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

Slide64

Adverse Drug Reactions in Japanese Clinical Studies (at time of approval)Lubiprostone: Safety

Slide65

Adverse 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

Slide66

Adverse 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

(

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

(

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

(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

(

0.6%)

Reflux esophagitis

(

0.6%)

Defecation frequency increased

(

0.3%)

Gastritis hemorrhagic

(

0.3%)

Epigastric discomfort

(

0.3%)

Hemorrhoidal hemorrhage

(

0.3%)

Skin and subcutaneous tissue disorders

(

1.0%)

Eczema

(

0.6%)

Erythema

(

0.3%)

ADRs

No. of patients

Musculoskeletal and connective tissue disorders

(

1.0%)

Musculoskeletal stiffness

(

0.6%)

Back pain

(

0.3%)

Limb discomfort

(

0.3%)

General disorders and administration site conditions

(9.2%)

Chest discomfort

17 (5.4%)

Malaise

(

1.0%)

Edema

(

1.0%)

Feeling abnormal

(

0.6%)

Chest pain

(

0.6%)

Thirst

(

0.6%)

Discomfort

(

0.3%)

Investigations

10 (3.2%)

Blood triglycerides increased

(

0.6%)

Blood creatine phosphokinase increased

(

0.3%)

Blood glucose increased

(

0.3%)

Blood bilirubin increased

(

0.3%)

Blood urea increased

(

0.3%)

Blood gamma-glutamyltransferase increased

(

0.3%)

Glucose urine present

(

0.3%)

Hemoglobin decreased

(

0.3%)

Weight gain

(

0.3%)

White blood cell count increased

(

0.3%)

Blood phosphorus increased

(

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.

Amitiza ® Slide Kit V - PowerPoint Presentation

Amitiza ® Slide Kit V - PPT Presentation

Share:

Link:

Embed:

Related Contents