-
In February 2013, GlaxoSmithKline (GSK) announced a commitment
to further clinical transparency through the public disclosure of
GSK Clinical Study Reports (CSRs) on the GSK Clinical Study
Register.
The following guiding principles have been applied to the
disclosure: Information will be excluded in order to protect the
privacy of patients and all named
persons associated with the study
Patient data listings will be completely removed* to protect
patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further
information please see the Patient Level Data section of the GSK
Clinical Study Register.
Aggregate data will be included; with any direct reference to
individual patients excluded
*Complete removal of patient data listings may mean that page
numbers are no longer consecutively
numbered
-
Division: Worldwide Development
Information Type: Clinical Study Report
Control:
No active control placebo
Title: 201135: A randomised, double-blind, multicenter,
parallel-group study to compare the efficacy and safety of
fluticasone furoate (FF) 100mcg once daily with fluticasone
propionate (FP) 250μg twice daily and FP 100μg twice daily in
well-controlled asthmatic subjects stepped down from a maintenance
therapy with Relvar®100 Ellipta® (FF/VI) 100μg once-daily in
Japanese subjects.
Additional Study Design Information:
Double-Blind Treatment Period:12 weeks
Phase: III
Compound Number: GW685698
Effective Date: 7-Dec-2016
Subject: Asthma, adults, Relvar® Ellipta®, fluticasone furoate,
fluticasone propionate, patients with well-controlled asthma,
step-down prescription, switching prescription
Author(s):
Indication Studied: Bronchial Asthma
Initiation Date: 27-Mar-2014
Completion Date: 28-Aug-2015
Earlier CSRs:
201135: A randomised, double-blind, multicenter, parallel-group
study to compare the efficacy and safety of fluticasone furoate
(FF) 100mcg once daily with fluticasone propionate (FP) 250μg twice
daily and FP 100μg twice daily in well-controlled asthmatic
subjects stepped down from a maintenance therapy with Relvar®100
Ellipta® (FF/VI) 100μg once-daily in Japanese subjects.(Document
No.: 2015N239011_00, Date of Report: Feb 2016)
Clinical Study Report Revision History:
Original: 2015N239011_00 (Effectvie Date: 05-Feb-2016)
Amendment 01: 2015N239011_01 (Effectvie Date: 7-Dec-2016)
After the approval of the original CSR, it was found that
“asthma worsening/exercabation” for evaluating co-primary endpoints
of proportion of subjects “well controlled” at the end of Period 2
and time to withdrawal due to “poorly-controlled (requires
step-up)” during Period 2 was evaluated using only “severe asthma”,
although “asthma worsening/exercabation” had to be evaluated using
“severe asthma” and “worsening asthma.” Therefore, co-primary
endpoints as well as two ‘other’ endpoints (proportion of subjects
“well controlled” at the end of Period 1and time to withdrawal due
to “ poorly-controlled (requires step-up)” during Period 1) were
re-analyzed using “severe asthma” and
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CONFIDENTIAL 2015N239011_01201135
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“worsening asthma” for evaluating “asthma
worsening/exercabation”, and the CSR was amended to reflect the
results of re-analysis.
Sponsor’s Medical Expert(s):GlaxoSmithKline K.K.Head, Medicines
Development
Sponsor Signatory: Kihito TakahashiGlaxoSmithKline K.K.Head,
Japan Development & Medical Affairs
This clinical trial was executed in compliance with the Good
Clinical Practice (GCP) of
pharmaceutical product research and Standard Operating
Procedures (SOP) of GlaxoSmithKline K.K.
All documents and materials concerning the clinical trial have
been stored according to methods
described in the Study Protocol.
Copyright 2016 the GlaxoSmithKline group of companies. All
rights reserved.
Unauthorised copying or use of this information is
prohibited.
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CONFIDENTIAL 2015N239011_01201135
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Table of Contents Page TITLE PAGE
..........................................................................................................
LIST OF DEFINITIONS FOR ABBREVIATIONS AND TERMS
............................. ETHICS AND GCP
.................................................................................................
1. Introduction
.......................................................................................................
2. Study Objectives
..............................................................................................
3. Investigators and Clinical Trial Management
.................................................
3.1. Sponsor and Representatives
.........................................................................
3.2. Study Center and the
Investigators..................................................................
3.3. Testing Facility
.................................................................................................
3.4. Study Period
....................................................................................................
4. Study Plan
.........................................................................................................
4.1. Study Design
...................................................................................................
4.2. Consideration for the Study Design
.................................................................
4.3. Revision of the Study Protocol
.........................................................................
4.4. Selection of The Analysis Set
..........................................................................
4.4.1. Inclusion/Exclusion Criteria
.........................................................................
4.4.2. Withdrawal Criteria
......................................................................................
4.5. Treatment
........................................................................................................
4.5.1. Investigational Product and related Treatments
.......................................... 4.5.2. Allocation to
Treatment Groups
...................................................................
4.5.3. Blinding
........................................................................................................
4.5.4. Pre-treatment drugs, concomitant drugs and non-drug
therapies ............... 4.5.5. Compliance with Treatments
.......................................................................
4.6. Study Evaluations and Procedures
..................................................................
4.6.1. Efficacy Endpoints
.......................................................................................
4.6.2. Safety Evaluations
.......................................................................................
4.6.3. Health Outcomes
.........................................................................................
4.6.4. Pharmacokinetics
........................................................................................
4.6.5. Pharmacogenetics Research
......................................................................
4.7. Quality Assurance of Data
...............................................................................
4.7.1. Data Management
.......................................................................................
4.7.2. Quality Control
.............................................................................................
4.7.3. Quality Assurance
.......................................................................................
4.8. Data Analysis Method
......................................................................................
4.8.1. Hypotheses
.................................................................................................
4.8.2. Determination of the Sample Size
...............................................................
4.8.3. Analysis Population
.....................................................................................
4.8.4. Interim Analysis
...........................................................................................
4.8.5. Final Analysis
..............................................................................................
4.8.6. Changes to the Analysis of Study Implementation or the
Analysis
Protocol
..................................................................................................
5. Analysis Results of Analysis Populations
.....................................................
5.1. Breakdown of Subjects
....................................................................................
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5.2. Deviations from the Study Protocol
..................................................................
5.3. Analysis Population
.........................................................................................
5.4. Demographic and Other Baseline Characteristics
........................................... 5.5. Pre-Treatment and
Concomitant Therapy
....................................................... 5.6.
Exposure and Compliance with Treatment
......................................................
6. Efficacy Results
................................................................................................
6.1. Primary Endpoints
...........................................................................................
6.1.1. Time to withdrawal due to “poorly-controlled (requires
step-up)” (Period 2)
............................................................................................................
6.1.2. Proportion of Subjects with “Well-controlled Asthma”
(Period 2) ................. 6.2. Secondary Endpoints
.......................................................................................
6.2.1. FEV1 Trough value (Period 2)
.....................................................................
6.2.2. Daily AM and PM PEF (Period 2)
................................................................
6.2.3. Percentage of Symptom-free 24-Hour Periods (Period 2)
........................... 6.2.4. Percentage of Rescue-free
24-Hour Periods (Period 2) .............................. 6.2.5.
ACT Score (Period 2)
..................................................................................
6.2.6. Proportion of Subjects with ACT Score ≥ 20 (Period 2)
...............................
6.3. Others
..............................................................................................................
6.3.1. Proportion of Subjects with “Well-controlled Asthma” (Period
1) ................. 6.3.2. Time to Withdrawal due to
“Poorly-controlled (Requires Step-up)”
(Period 1)
................................................................................................
6.3.3. FEV1 Trough Value (Period 1)
....................................................................
6.3.4. Daily AM and PM PEF (Period 1)
................................................................
6.3.5. Percentage of Symptom-free 24-Hour Periods (Period 1)
........................... 6.3.6. Percentage of Rescue-free
24-Hour Periods (Period 1) .............................. 6.3.7.
ACT Score (Period 1)
..................................................................................
6.3.8. Proportion of Subjects with ACT Score ≥20 (Period 1)
................................ 6.3.9. Unscheduled Healthcare
Visits or Utilization Due to Severe Asthma
Exacerbations or Other Treatment for Asthma (Period 1 and Period
2) . 7. Safety Results
...................................................................................................
7.1. Period 2
...........................................................................................................
7.1.1. Adverse Events
...........................................................................................
7.1.2. Serious Adverse Events and Other Important Adverse Events
................... 7.1.3. Evaluation of Clinical Laboratory Values
..................................................... 7.1.4. Other
Safety Evaluations
.............................................................................
7.2. Period 1
...........................................................................................................
7.2.1. Adverse Events
...........................................................................................
7.2.2. Serious Adverse Events and Other Important Adverse Events
................... 7.2.3. Evaluation of Clinical Laboratory Values
..................................................... 7.2.4. Other
Safety Evaluations
.............................................................................
7.3. Accidents and Failures of Medical Equipment and Improvement
Measures .... 7.4. Pregnancy
.......................................................................................................
8. Pharmacokinetics
.............................................................................................
9. Discussion and Conclusion
.............................................................................
9.1. Discussion
.......................................................................................................
9.2 Conclusion (in CSR body)
................................................................................
59626368697171
7172737374757576777777
77777878787878
787979798285868686889191919191939394
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10. References
......................................................................................................
11. Description of Cases
......................................................................................
STUDY POPULATION DATA SOURCE TABLES
................................................
Table 5.010 Summary of Subject Populations during Period 1 (All
Subjects Enrolled
Population).................................................................................
Table 5.020 Summary of Subject Populations during Period 2 (ITT
Population) .... Table 5.030 Summary of Reasons for Failure at
Visit 1 (All Subjects Enrolled
Population)
...............................................................................................
Table 5.040 Summary of Reasons for Failure at Visit 2 (All Subjects
Enrolled
Population)
...............................................................................................
Table 5.050 Summary of Reasons for Failure at Visit 5 (Open Label
Population) .. Table 5.060 Summary of Subject Disposition during
Period 1 (Open Label
Population)
...............................................................................................
Table 5.070 Summary of Subject Disposition during Period 2 (ITT
Population) ..... Table 5.080 Summary of Attendance at Each Clinic
Visit during Period 1 (Open
Label Population)
.....................................................................................
Table 5.090 Summary of Attendance at Each Clinic Visit during
Period 2 (ITT
Population)
...............................................................................................
Table 5.100 Summary of Inclusion/Exclusion Criteria Deviations at
Visit 1 (All
Subjects Enrolled Population)
..................................................................
Table 5.101 Summary of Inclusion/Exclusion Criteria Deviations at
Visit 2 (All
Subjects Enrolled Population)
..................................................................
Table 5.110 Summary of Randomisation Criteria Deviations at Visit 5
(Open
Label Population)
.....................................................................................
Table 5.120 Summary of Protocol Deviations during Period 1 (Open
Label
Population)
...............................................................................................
Table 5.130 Summary of Protocol Deviations during Period 2 (ITT
Population) ..... Table 5.140 Summary of Demographic
Characteristics Open Label Population
(Open Label Population)
..........................................................................
Table 5.150 Summary of Demographic Characteristics Intent-to-Treat
Population
(ITT Population)
.......................................................................................
Table 5.160 Summary of Demographic Characteristics Per Protocol
Population
(Per Protocol Population)
.........................................................................
Table 5.170 Summary of Race and Racial Combination Details for
Period 1
(Open Label Population)
..........................................................................
Table 5.180 Summary of Race and Racial Combination Details for
Period 2 (ITT
Population)
...............................................................................................
Table 5.190 Summary of Current Medical Conditions for Period 1
(Open Label
Population)
...............................................................................................
Table 5.200 Summary of Current Medical Conditions for Period 2 (ITT
Population)
.................................................................................................................
Table 5.210 Summary of Past Medical Conditions for Period 1 (Open
Label
Population)
...............................................................................................
Table 5.220 Summary of Past Medical Conditions for Period 2 (ITT
Population) ... Table 5.230 Summary of Asthma Concomitant
Medications Taken Pre-Treatment
during Period 1 (Open Label Population)
.................................................
9596100
100101
102
103104
105106
107
108
109
111
112
113114
115
118
121
124
125
126
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Table 5.240 Summary of Asthma Concomitant Medications Taken
On-Treatment during Period 1 (Open Label Population)
.................................................
Table 5.250 Summary of Asthma Concomitant Medications Taken
Post-Treatment during Period 1 (Open Label Population)
...............................
Table 5.260 Summary of Asthma Concomitant Medications Taken
Pre-Treatment during Period 2 (ITT Population)
..............................................................
Table 5.270 Summary of Asthma Concomitant Medications Taken
On-Treatment during Period 2 (ITT Population)
..............................................................
Table 5.280 Summary of Asthma Concomitant Medications Taken
Post-Treatment during Period 2 (ITT Population)
.............................................
Table 5.290 Summary of Non-Asthma Concomitant Medications Taken
Pre-Treatment during Period 1 (Open Label Population)
...............................
Table 5.300 Summary of Non-Asthma Concomitant Medications Taken
On-Treatment during Period 1 (Open Label Population)
...............................
Table 5.310 Summary of Non-Asthma Concomitant Medications Taken
Post-Treatment during Period 1 (Open Label Population)
...............................
Table 5.320 Summary of Non-Asthma Concomitant Medications Taken
Pre-Treatment during Period 2 (ITT Population)
.............................................
Table 5.330 Summary of Non-Asthma Concomitant Medications Taken
On-Treatment during Period 2 (ITT Population)
.............................................
Table 5.340 Summary of Non-Asthma Concomitant Medications Taken
Post-Treatment during Period 2 (ITT Population)
.............................................
Table 5.350 Summary of Screening and Baseline Lung Function Test
Results during Period 1 (Open Label Population)
.................................................
Table 5.360 Summary of Screening and Baseline Lung Function Test
Results during Period 2 (ITT Population)
..............................................................
Table 5.370 Summary of Exposure during Period 1 (Open Label
Population) ....... Table 5.380 Summary of Exposure during Period 2
(ITT Population) .................... Table 5.390 Summary of
Overall Treatment Compliance (%) during Period 1
(Open Label Population)
..........................................................................
Table 5.400 Summary of Overall Treatment Compliance (%) during
Period 2 (ITT
Population)
...............................................................................................
EFFICACY DATA SOURCE
FIGURES..................................................................
Figure 6.010 Cox Proportional Hazards Model Cumulative Incidence
Curve for Time to Withdrawal Due to Poorly-Controlled during Period
2 (ITT Population)
...............................................................................................
Figure 6.020 Kaplan-Meier Cumulative Incidence Curve for Time to
Withdrawal Due to Poorly-Controlled during Period 2 (ITT
Population) .....................
Figure 6.030 Line Plot of % Subjects Well-Controlled during
Period 1 and Period 2 (ITT Population)
....................................................................................
Figure 6.040 Line Plot of % Subjects Well-Controlled during
Period 1 (Open Label Population)
...............................................................................................
Figure 6.050 Line Plot of Mean Change from Baseline in FEV1 (L)
during Period 1 (Open Label Population)
.......................................................................
Figure 6.060 Line Plot of Mean Change from Baseline in ACT Score
during Period 1 (Open Label Population)
............................................................
131
132
134
135
136
139
155
174
180
181
202
217
219221222
223
224225
225
226
227
228
229
230
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Figure 6.070 Line Plot of Mean Change from Baseline in AM PEF
(L/min) during Period 1 (Open Label Population)
............................................................
Figure 6.080 Line Plot of Mean Change from Baseline in PM PEF
(L/min) during Period 1 (Open Label Population)
............................................................
Figure 6.090 Line Plot of Daily AM PEF Averaged (L/min) during
Period 1 (Open Label Population)
.....................................................................................
Figure 6.100 Line Plot of Daily PM PEF Averaged (L/min) during
Period 1 (Open Label Population)
.....................................................................................
Figure 6.110 Line Plot of the Percentage of Symptom-free 24-hour
during Period 1 (Open Label Population)
.......................................................................
Figure 6.120 Line Plot of the Percentage of Rescue-free 24-hour
during Period 1 (Open Label Population)
..........................................................................
Figure 6.130 Line Plot of Asthma Control Test (ACT) Score during
Period 1 (Open Label Population)
..........................................................................
Figure 6.140 Line Plot of Trough (pre-dose of Sultanol Inhaler
and investigational product) FEV1 (L) during Period 1 (Open Label
Population) ...................
Figure 6.150 Line Plot of Mean Change from Baseline in FEV1 (L)
during Period 2 (ITT Population)
....................................................................................
Figure 6.160 Line Plot of Mean Change from Baseline in ACT Score
during Period 2 (ITT Population)
.........................................................................
Figure 6.170 Line Plot of Mean Change from Baseline in AM PEF
(L/min) during Period 2 (ITT Population)
.........................................................................
Figure 6.180 Line Plot of Mean Change from Baseline in PM PEF
(L/min) during Period 2 (ITT Population)
.........................................................................
Figure 6.190 Line Plot of Daily AM PEF Averaged (L/min) during
Period 2 (ITT Population)
...............................................................................................
Figure 6.200 Line Plot of Daily PM PEF Averaged (L/min) during
Period 2 (ITT Population)
...............................................................................................
Figure 6.210 Line Plot of the Percentage of Symptom-free 24-hour
during Period 2 (ITT Population)
....................................................................................
Figure 6.220 Line Plot of the Percentage of Rescue-free 24-hour
during Period 2 (ITT Population)
.......................................................................................
Figure 6.230 Line Plot of Asthma Control Test (ACT) Score during
Period 2 (ITT Population)
...............................................................................................
Figure 6.240 Line Plot of Trough (pre-dose of Sultanol Inhaler
and investigational product) FEV1 (L) during Period 2 (ITT
Population) ................................
Figure 6.250 Box Plot of Mean Change from Baseline in Daily AM
PEF Averaged (L/min) during Period 2 (ITT Population)
.................................................
Figure 6.260 Box Plot of Mean Change from Baseline in Daily PM
PEF Averaged (L/min) during Period 2 (ITT Population)
.................................................
Figure 6.270 Box Plot of Mean Change from Baseline in the
Percentage of Symptom-free 24-hour Periods during Period 2 (ITT
Population) ............
Figure 6.280 Box Plot of Mean Change from Baseline in the
Percentage of Rescue-free 24-hour Periods during Period 2 (ITT
Population) ...............
Figure 6.290 Box Plot of Mean Change from Baseline in Asthma
Control Test (ACT) Score during Period 2 (ITT Population)
.........................................
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
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CONFIDENTIAL 2015N239011_01201135
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Figure 6.300 Box Plot of Mean Change from Baseline in Clinic
Visit Trough (pre-dose of Sultanol Inhaler and investigational
product) FEV1 (L) at Visit 11 (ITT Population)
.......................................................................................
Figure 6.310 Forest Plot for LS Mean from Change from Baseline
of FEV1 (L) at End of Period 2 (Intent-to-treat Population)
.............................................
Figure 6.320 Forest Plot for LS Mean from Change from Baseline
of Asthma Control Test (ACT) Score at End of Period 2
(Intent-to-treat Population)
Figure 6.330 Forest Plot for LS Mean from Change from Baseline
of Symptom-Free 24-Hour Periods (%) and Rescue-Free 24-Hour Periods
(%) at Weeks 9-20 (Intent-to-treat Population)
...................................................
Figure 6.340 Forest Plot for LS Mean from Change from Baseline
of AM PEF (L/min) and PM PEF (L/min) at Weeks 9-20 (Intent-to-treat
Population) ..
Figure 6.350 Cox Proportional Hazards Model Cumulative Incidence
Curve for Time to Withdrawal Due to Poorly-Controlled during Period
2 including Asthma Aggravated subjects into the assessment (ITT
Population) ........
Figure 6.360 Kaplan-Meier Cumulative Incidence Curve for Time to
Withdrawal Due to Poorly-Controlled during Period 2 including
Asthma Aggravated subjects into the assessment (ITT Population)
........................................
Figure 6.370 Line Plot of % Subjects Well-Controlled during
Period 1 and Period 2 including Asthma Aggravated into the
assessment (ITT Population) ...
Figure 6.380 Line Plot of % Subjects Well-Controlled during
Period 1 including Asthma Aggravated into the assessment (Open
Label Population) .........
EFFICACY DATA SOURCE TABLES
...................................................................
Table 6.010 Cox Proportional Hazards Analysis of Time to Withdrawal
Due to
Poorly-Controlled during Period 2, Intent-to Treat (ITT
Population) ......... Table 6.020 Cox Proportional Hazards Analysis
of Time to Withdrawal Due to
Poorly-Controlled during Period 2, Per Protocol (Per Protocol
Population)
...............................................................................................
Table 6.030 Logistic Regression Analysis of Proportion of
Subjects who Achieved Well-Controlled at Visit11, Intent-to Treat
(ITT Population) ......................
Table 6.040 Logistic Regression Analysis of Proportion of
Subjects who Achieved Well-Controlled at Visit 11, Per Protocol
(Per Protocol Population) .........
Table 6.050 Analysis of Mean Change from Baseline in Clinic
Visit Trough (pre-dose of Sultanol Inhaler and investigational
product) FEV1 (L) at the end of Period 2 (ITT Population)
.....................................................................
Table 6.060 Summary of FEV1 (L) by Visit during Period 2 (ITT
Population) ......... Table 6.070 Summary of Mean Change from
Baseline in Clinic Visit Trough (pre-
dose of Sultanol Inhaler and investigational product) FEV1 (L)
by Visit during Period 2 (ITT Population)
..............................................................
Table 6.080 Analysis of Mean Change from Baseline in Daily AM
PEF Averaged (L/min) during Period 2 (ITT Population)
..................................................
Table 6.090 Analysis of Mean Change from Baseline in Daily PM
PEF Averaged (L/min) during Period 2 (ITT Population)
..................................................
Table 6.100 Summary of Daily AM PEF Averaged (L/min) during
Period 2 (ITT Population)
...............................................................................................
254
255
256
257
258
259
260
261
262263
263
264
265
266
267268
270
271
272
273
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CONFIDENTIAL 2015N239011_01201135
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Table 6.120 Summary of Daily PM PEF Averaged (L/min) during
Period 2 (ITT Population)
...............................................................................................
Table 6.130 Summary of Mean Change from Baseline in Daily AM PEF
Averaged (L/min) by Assessment Period during Period 2 (ITT
Population) .............
Table 6.140 Summary of Mean Change from Baseline in Daily PM PEF
Averaged (L/min) by Assessment Period during Period 2 (ITT
Population) .............
Table 6.150 Analysis of Mean Change from Baseline in the
Percentage of Symptom-free 24-hour Periods during Period 2 (ITT
Population) ............
Table 6.160 Summary of Symptom-free 24-hour Periods (%) by
Assessment Period during Period 2 (ITT Population)
...................................................
Table 6.170 Summary of Mean Change from Baseline in the
Percentage of Symptom-free 24-hour Periods by Assessment Period
during Period 2 (ITT Population)
.......................................................................................
Table 6.180 Analysis of Mean Change from Baseline in the
Percentage of Rescue-free 24-hour Periods during Period 2 (ITT
Population) ...............
Table 6.190 Summary of Rescue-free 24-hour Periods (%) by
Assessment Period during Period 2 (ITT Population)
..............................................................
Table 6.200 Summary of Mean Change from Baseline in the
Percentage of Rescue-free 24-hour Periods by Assessment Period
during Period 2 (ITT Population)
.......................................................................................
Table 6.210 Analysis of Mean Change from Baseline in Asthma
Control Test (ACT) Score at the end of Period 2 (ITT Population)
...............................
Table 6.220 Summary of Asthma Control Test (ACT) Score by Visit
during Period 2 (ITT Population)
....................................................................................
Table 6.230 Summary of Mean Change from Baseline in Asthma
Control Test (ACT) Score by Visit during Period 2 (ITT Population)
.............................
Table 6.240 Logistic Regression Analysis of ACT Score >= 20
at Visit11 (ITT Population)
...............................................................................................
Table 6.250 Summary of Categorization of ACT Score by Visit
during Period 2 (ITT Population)
.......................................................................................
Table 6.260 Summary of Proportion of Subjects Well-Controlled at
the end of Period 1 (Open Label Population)
............................................................
Table 6.270 Summary of Time to Withdrawal Due to
Poorly-Controlled during Period 1 (Open Label Population)
............................................................
Table 6.280 Summary of Mean Change from Baseline in Clinic Visit
Trough (pre-dose of Sultanol Inhaler and investigational product)
FEV1 (L) by Visit during Period 1 (Open Label Population)
.................................................
Table 6.290 Summary of Mean Change from Baseline in Daily AM PEF
Averaged (L/min) during Period 1 (Open Label Population)
.....................................
Table 6.300 Summary of Mean Change from Baseline in Daily PM PEF
Averaged (L/min) during Period 1 (Open Label Population)
....................
Table 6.310 Summary of Mean Change from Baseline in the
Percentage of Symptom-free 24-hour Periods during Period 1 (Open
Label Population)
Table 6.320 Summary of Mean Change from Baseline in the
Percentage of Rescue-free 24-hour Periods during Period 1 (Open
Label Population) ..
278
283
288
293
294
299
304
305
310
315
316
317
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319
321
322
323
324
327
330
333
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CONFIDENTIAL 2015N239011_01201135
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Table 6.330 Summary of Mean Change from Baseline in Asthma
Control Test (ACT) Score by Visit during Period 1 (Open Label
Population) ...............
Table 6.340 Summary of Asthma Control Test (ACT) Score by Visit
during Period 1 (Open Label Population)
.......................................................................
Table 6.350 Summary of Categorization of ACT Score by Visit
during Period 1 (Open Label Population)
..........................................................................
Table 6.360 Unscheduled Visits or Utilization of a Physician's
Office associated with Severe Asthma Exacerbations or Other
Asthma-Related Healthcare during Period 1 and Period 2 (Open Label
Population) ............................
Table 6.370 Summary of Subjects Who Withdraw Due to
Poorly-Controlled during Period 1 (Open Label Population)
............................................................
Table 6.380 Summary of Subjects Who Withdraw Due to
Poorly-Controlled during Period 2 (ITT Population)
.........................................................................
Table 6.390 Logistic Regression Analysis of Proportion of
Subjects who Achieved Well-Controlled at Visit11, excluding
Unevaluable data Intent-to Treat (Intent-to-treat Population)
.......................................................................
Table 6.400 Cox Proportional Hazards Analysis of Time to
Withdrawal Due to Poorly-Controlled during Period 2 including
Asthma Aggravated Subjects into the assessment, Intent-to Treat
(ITT Population) ...............
Table 6.410 Cox Proportional Hazards Analysis of Time to
Withdrawal Due to Poorly-Controlled during Period 2 including
Asthma Aggravated Subjects into the assessment, Per Protocol (Per
Protocol Population) ....
Table 6.420 Logistic Regression Analysis of Proportion of
Subjects who Achieved Well-Controlled at Visit11 including Asthma
Aggravated into the assessment, Intent-to Treat (ITT Population)
...........................................
Table 6.430 Logistic Regression Analysis of Proportion of
Subjects who Achieved Well-Controlled at Visit 11 including Asthma
Aggravated into the assessment, Per Protocol (Per Protocol
Population) ...............................
Table 6.440 Summary of Proportion of Subjects Well-Controlled at
the end of Period 1 including Asthma Aggravated into the assessment
(Open Label Population)
...............................................................................................
Table 6.450 Summary of Time to Withdrawal Due to
Poorly-Controlled during Period 1 including Asthma Aggravated
Subjects into the assessment (Open Label Population)
..........................................................................
Table 6.460 Summary of Subjects Who Withdraw Due to
Poorly-Controlled during Period 1 including Asthma Aggravated into
the assessment (Open Label Population)
...............................................................................................
Table 6.470 Summary of Subjects Who Withdraw Due to
Poorly-Controlled during Period 2 including Asthma Aggravated into
the assessment (ITT Population)
...............................................................................................
Table 6.480 Logistic Regression Analysis of Proportion of
Subjects who Achieved Well-Controlled at Visit11 including Asthma
Aggravated into the assessment, excluding Unevaluable data
Intent-to Treat (ITT Population)
...............................................................................................
SAFETY DATA SOURCE FIGURES
.....................................................................
336
337
338
340
341
342
343
344
345
346
347
348
349
350
351
352353
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Figure 7.010 Most Frequent On-Treatment Adverse Events Sorted by
Relative Risk for Period 2 (>=3% in any treatment group) for FF
100 vs. FP 100 BD (ITT Population)
.................................................................................
Figure 7.011 Most Frequent On-Treatment Adverse Events Sorted by
Relative Risk for Period 2 (>=3% in any treatment group) for FF
100 vs. FP 250 BD (ITT Population)
.................................................................................
SAFETY DATA SOURCE TABLES
.......................................................................
Table 7.010 On Treatment Adverse Event Overview during Period 1
(Open Label
Population)
...............................................................................................
Table 7.020 On and Post Treatment Adverse Event Overview during
Period 2
(ITT Population)
.......................................................................................
Table 7.030 Summary of On-Treatment Adverse Events during Period 1
(Open
Label Population)
.....................................................................................
Table 7.040 Summary of On-Treatment Adverse Events during Period 2
(ITT
Population)
...............................................................................................
Table 7.050 Summary of On-Treatment Adverse Events during Period 1
for
randomized treatment groups (ITT Population)
....................................... Table 7.060 Summary of
Post-Treatment Adverse Events during Period 1 (Open
Label Population)
.....................................................................................
Table 7.070 Summary of Post-Treatment Adverse Events during Period
2 (ITT
Population)
...............................................................................................
Table 7.080 Summary of On and Post-Treatment Adverse Events during
Period 2
(ITT Population)
.......................................................................................
Table 7.090 Summary of 10 Most Frequent On-Treatment Adverse Events
during
Period 1 (Open Label Population)
............................................................ Table
7.100 Summary of 10 Most Frequent On-Treatment Adverse Events
during
Period 2 (ITT Population)
.........................................................................
Table 7.110 Summary of On-Treatment Common Adverse Events during
Period 1
(>=3% in any treatment group) (Open Label
Population)......................... Table 7.120 Summary of
On-Treatment Common Adverse Events during Period 2
(>=3% in any treatment group) (ITT Population)
...................................... Table 7.130 Summary of On
and Post-Treatment Common Adverse Events
during Period 2 (>=3% in any treatment group) (ITT
Population) ............ Table 7.140 Summary of On-Treatment
Adverse Events (Non-SAE>=5%) during
Period 1 and Period 2(for FDAAA) (Open Label Population)
................... Table 7.150 Summary of On-Treatment Adverse
Events during Period 1 by
maximum severity (Open Label Population)
............................................ Table 7.160 Summary of
Post-Treatment Adverse Events during Period 1 by
maximum severity (Open Label Population)
............................................ Table 7.170 Summary of
On-Treatment Adverse Events during Period 2 by
maximum severity (ITT Population)
......................................................... Table
7.180 Summary of Post-Treatment Adverse Events during Period 2
by
maximum severity (ITT Population)
......................................................... Table
7.190 Summary of On-Treatment Drug-Related Adverse Events
during
Period 1 (Open Label Population)
............................................................
353
354355
355
356
358
363
368
373
374
375
380
381
383
384
385
386
387
392
393
403
405
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Table 7.200 Summary of On-Treatment Drug-Related Adverse Events
during Period 2 (ITT Population)
.........................................................................
Table 7.210 Summary of On-Treatment Drug-Related Adverse Events
during Period 1 for randomized treatment groups (ITT Population)
....................
Table 7.220 Summary of Drug-Related Adverse Events for
Post-Treatment Period during Period 1 (Open Label Population)
.....................................
Table 7.230 Summary of Drug-Related Adverse Events for
Post-Treatment Period during Period 2 (ITT Population)
...................................................
Table 7.240 Summary of Drug-Related Adverse Events for On and
Post-Treatment Period during Period 2 (ITT Population)
.................................
Table 7.250 Summary of On-Treatment Adverse Events Leading to
Permanent Discontinuation of Study Drug or Withdrawal From the
Study during Period 1 (Open Label Population)
............................................................
Table 7.260 Summary of On-Treatment Adverse Events Leading to
Permanent Discontinuation of Study Drug or Withdrawal From the
Study during Period 2 (ITT Population)
.........................................................................
Table 7.270 Summary of On-Treatment Serious Adverse Events
during Period 1 (Open Label Population)
..........................................................................
Table 7.280 Summary of Post-Treatment Serious Adverse Events
during Period 1 (Open Label Population)
..........................................................................
Table 7.290 Summary of On-Treatment Serious Adverse Events
during Period 2 (ITT Population)
.......................................................................................
Table 7.300 Summary of Post-Treatment Serious Adverse Events
during Period 2 (ITT Population)
.......................................................................................
Table 7.310 Summary of On-Treatment Fatal Adverse Events during
Period 1 (Open Label Population)
..........................................................................
Table 7.320 Summary of Post-Treatment Fatal Adverse Events
during Period 1 (Open Label Population)
..........................................................................
Table 7.330 Summary of On-Treatment Fatal Adverse Events during
Period 2 (ITT Population)
.......................................................................................
Table 7.340 Summary of Post-Treatment Fatal Adverse Events
during Period 2 (ITT Population)
.......................................................................................
Table 7.350 Summary of On-Treatment Drug-Related Serious Adverse
Events during Period 1 (Open Label Population)
.................................................
Table 7.360 Summary of Post-Treatment Drug-Related Serious
Adverse Events during Period 1 (Open Label Population)
.................................................
Table 7.370 Summary of On-Treatment Drug-Related Serious Adverse
Events during Period 2 (ITT Population)
..............................................................
Table 7.380 Summary of Post-Treatment Drug-Related Serious
Adverse Events during Period 2 (ITT Population)
..............................................................
Table 7.390 Summary of On-Treatment Drug-Related Fatal Adverse
Events during Period 1 (Open Label Population)
.................................................
Table 7.400 Summary of On-Treatment Drug-Related Fatal Adverse
Events during Period 2 (ITT Population)
..............................................................
Table 7.410 Summary of On-Treatment Fatal Serious Adverse Events
during Period 1 (Open Label Population)
............................................................
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
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Table 7.420 Summary of On-Treatment Non-Fatal Serious Adverse
Events during Period 1 (Open Label Population)
............................................................
Table 7.430 Summary of On-Treatment Fatal Serious Adverse Events
during Period 2 (ITT Population)
.........................................................................
Table 7.440 Summary of On-Treatment Non-Fatal Serious Adverse
Events during Period 2 (ITT Population)
.........................................................................
Table 7.450 Summary of On-Treatment and Post-Treatment Adverse
Events of Special Interest during Period 1 (Open Label Population)
.......................
Table 7.460 Summary of On-Treatment and Post-Treatment Adverse
Events of Special Interest during Period 2 (ITT Population)
....................................
Table 7.470 Relationship of Adverse Event System Organ Class,
Preferred Term and Verbatim Text (Open Label Population)
............................................
Table 7.480 Summary of Clinical Chemistry Data during Period 1
(Open Label Population)
...............................................................................................
Table 7.490 Summary of Clinical Chemistry Data during Period 2
(ITT Population)
.................................................................................................................
Table 7.500 Summary of Clinical Chemistry Data Outside the
Reference Range during Period 2 (ITT Population)
..............................................................
Table 7.510 Summary of Change from Baseline in Clinical
Chemistry Data during Period 2 (Shift Table) (ITT Population)
....................................................
Table 7.520 Summary of On-Treatment Severe Asthma Exacerbations
during Period 1 (Open Label Population)
............................................................
Table 7.530 Summary of Post-Treatment Severe Asthma
Exacerbations during Period 1 (Open Label Population)
............................................................
Table 7.540 Summary of On-Treatment Severe Asthma Exacerbations
during Period 2 (ITT Population)
.........................................................................
Table 7.550 Summary of Post-Treatment Severe Asthma
Exacerbations during Period 2 (ITT Population)
.........................................................................
Table 7.560 Record of all Preferred Terms That Could Have Mapped
to Special Interest Terms during Period 1 (Open Label Population)
.........................
Table 7.570 Record of all Preferred Terms That Could Have Mapped
to Special Interest Terms during Period 2 (ITT Population)
......................................
PHARMACOKINETIC DATA SOURCE TABLES
.................................................. Table 8.010
Summary of Plasma FF Concentrations (PK Population)
...................
428
429
430
431
434
436
445
449
461
482
545
546
547
548
549
592615615
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LIST OF DEFINITIONS FOR ABBREVIATIONS AND TERMS
Abbreviations
Symbol/Abbreviation Definition / Unabbreviated Name
ACT Asthma Control Test
ALT Alanine Transaminase
ANCOVA Analysis of Covariance
AST Aspartate aminotransferase
BD Twice daily
BUN Blood Urea Nitrogen
Cmax Maximum blood plasma concentration
CPK Creatinine Phosphokinase
CT Computed Tomography
CYP Cytochrome P450
DNA Deoxyribonucleic Acid
eCRF electronic Case Report Form
EW Early Withdrawal
FEV1 Forced Expiration Volume in 1 second
FF Fluticasone Furoate
FP Fluticasone Propionate
GCP Good Clinical Practice standards
GCSP Global Clinical Safety & Pharmacovigilance
GGT γ-glutamyltranspeptidase
GINA Global Initiative for Asthma
GSK GlaxoSmithKline
hCG Human Chorionic Gonadotrophin
ICS Inhaled Corticosteroids
IgE Immunoglobulin E
IgG Immunoglobulin G
IgM Immunoglobulin M
INR International Normalized Ratio
ITT Intent-to-Treat
IUD Intrauterine Device
IVRS Interactive Voice Response System
LABA Long-Acting β2 Agonists
LDH Lactate Dehydrogenase
LLQ Lower Limit of Quantification
MAO Monoamine oxydase
MCHC Mean Corpuscular Hemoglobin Concentration
MedDRA ICH International Pharmaceutical Glossary
MRI Magnetic Resonance Imaging
NHANES National Health and Nutrition Examination Survey
NIH National Institutes of Health
NQ Not quantifiable
PEF Peak Expiratory Flowrate
PGx Pharmacogenetics
PK Pharmacokinetics
PMDA Pharmaceuticals and Medical Devices Agency
PP Per Protocol
PT Preferred Term
QTc Corrected QT Interval
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QTcF QT Interval corrected with the heart rate using Fridericia
‘s formula
RNA Ribonucleic Acid
RR RR Interval
SABA Short-Acting β2 Agonist
SCR Screening
SD Standard Deviation
SE Standard Error
SMQ Standardised MedDRA Queries
SOC System Organ Class
t1/2 Half-life
ULN Upper Limit of Normal
VI Vilanterol
Trademark Information
Non-GSK Trademarks
Xolea®
Asthma Control Test (ACT™)
GSK ‘s Trademarks
Adolair®
Relvar®
Allermist®
Nasal SpraySaltanol®
Inhaler Diskus®
Ellipta®
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ETHICS AND GCP
The Study Protocol, its revisions, Informed Consent Forms and
other information requiring prior approval have been reviewed and
approved by an Institutional Review Board / Independent Ethics
Committee stipulated in Article 27 of “Ministerial Ordinance on
Standards of Good Clinical Practice”.
A copy of the notification / approval with the date from the
Institutional Review Board or the Independent Ethics Committee has
been stored by the Study Sponsor.
This clinical trial was implemented while complying with
Standards for Good Clinical Practice (GCP), Article 14(3) and
Article 80(2) of laws related to ensuring the quality, efficacy and
safety of pharmaceutical products and medical equipment, privacy
protection requirements for all applicable subjects and the basic
principles of the Declaration of Helsinki (2008). This clinical
trial was monitored in accordance with GCP.
The Principal Investigator and Subinvestigators have received
training on executing this clinical trial according to GCP and the
Study Protocol. We acquired an agreement form from the Principal
Investigator to conduct this study in accordance with GCP and the
Study Protocol.
Prior to the Clinical Trial, the Principal Investigator and
Subinvestigators have provided sufficient explanations to those
considered appropriate to be subjects and/or their legal
representatives using the Written Information document. During this
process, sufficient time and opportunities to ask questions were
provided for the subjects, and the investigators obtained consent
forms that were signed and dated with the date of consent from the
subject and/or their legal representatives. The Sponsor has
provided CRFs to record data for each subject.
There were 3 revisions to the Informed Consent Form (sample)
since the start of the clinical trial, and for those subjects who
were already part of the ongoing study at the time, revised consent
forms were provided and their consents were re-acquired.
Revisions to the Informed Consent Form (sample)
Version Date Created Main Content of Revision
Version 1 10-January-2014 (Initial version)
Version 2 10-June-2014 Revisions associated to safety
information updates
Version 3 16-September-2014 Corrections to components in the
placebo, due to false imports of the placebo for Fluticasone
Furoate (FF)1
Version 4 3-October-2014 Increase in volume of blood collected
during Visit 1 (2 mL increase from 7 to 9 mL); Partial addition of
the primary inclusion criteria; maintaining descriptions of
contraceptive methods
1. Please see “5.2 Deviations from the Study Protocol” for
details of this case.
There was 1 case of GCP violation in this study.
Partial loss of source documents for study data was identified
for Subject prior to unblinding, and this was reported as a GCP
violation. Lost data concerned visit dates and adverse events. For
details, see “5.2 Deviations from the Study Protocol”.
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1. IntroductionAsthma is a chronic disease of the lungs with
characteristics of inflammation of the airways,
bronchoconstriction and increased reactivity of the airways
[Global Initiative for Asthma (GINA), 2011].
Although the prevalence of asthma varies between 1 to 18%
depending on the country (reason for
differences in prevalence remains unknown), there is an
estimated 300 million asthma patients around the
world [Beasley, 2004; Masoli, 2004]. While the number of deaths
does not necessarily correlate with the
number of patients, there is an estimated 250,000 deaths
annually due to asthma [Beasley, 2004; Masoli,
2004]. The number of morbidity and deaths related to asthma
represents the large economic burden that
includes direct medical expenses and indirect costs from lost
productivity costs.
Inhaled corticosteroids (ICS) are the most effective
anti-inflammatory drugs for persistent asthma,
regardless of its severity [Global Initiative for Asthma (GINA),
2011]. ICS treatments reduces the
frequency of asthma exacerbations and asthma severity by
controlling asthma symptoms, improving
Quality of Life and lung function, suppressing increased airway
reactivity and controlling airway
inflammation, as a result leading to decreased mortality rates
due to asthma. Dose of ICS is selected
depending on the severity of asthma.
Fluticasone Furoate (FF) is an ICS that has been developed in 2
doses, namely 100 and 200μg, for once
daily dosing in adult asthma patients undergoing maintenance
therapy, and it has been approved for the
indication of bronchial asthma since August 20, 2014 in US. In
Japan, it has already been developed as the
ICS component of FF/Vilanterol (FF/VI), a once daily
ICS/Long-Acting β2-Agonist (LABA) that is being
marketed for asthma patients. FF 100μg has been developed as a
low to medium dose inhaled
corticosteroid for those patients that have used non-steroidal
monotherapy agents [e.g. short-acting β2-
Agonist (SABA), Leukotriene antagonist] or low to medium dose
ICS. FF 200μg has been developed as
an ICS for patients that have used medium to high dose ICS. For
patients with whom FF 100μg does not
show sufficient effect, asthma control may improve in a
dose-dependent manner by increasing to FF
200μg.
Although FF/VI has been approved in Japan for the indication of
bronchial asthma since
September 2013, approval reviews by the Pharmaceuticals and
Medical Devices Agency (PMDA)
indicated that while the efficacy of FF/VI 100/25μg was
estimated to correspond to mild persistent to
moderate persistent asthma (treatment step 2 to 3), further
information about the relationship between
FV/VI 100/25μg and mild-persistent asthma is required.
Although the early market entry of FF is desirable in order to
enable step-down from FF/VI to FF, it was
pointed out that in developing FF, it is necessary to clarify
the positioning of FF relative to existing
treatments, by studying the dose of FF that corresponds to
existing low-dose ICS and medium-dose ICS.
Based on the above, we planned this clinical trial thinking that
it is important to clarify the position of FF
100μg and FF/VI 100/25μg relative to existing therapies for
Japanese asthma patients, by studying the
proportion of patients with well-controlled asthma when they
switch to FF/VI 100/25μg, as well as the
effect of FF 100μg relative to existing low dose and medium dose
ICS, after stepping down from FF/VI
100/25μg in Japanese asthma patients being treated with
medium-dose ICS/LABA equivalent to Adoair®
Diskus® 250μg.
This report is an amendment of the original CSR to reflect the
results of re-analysis of co-primary
endpoints (proportion of subjects “well controlled” at the end
of Period 2 and time to withdrawal due
to “poorly-controlled (requires step-up)” during Period 2) and
two ‘other’ endpoints (proportion of
subjects “well controlled” at the end of Period 1and time to
withdrawal due to “ poorly-controlled
(requires step-up)” during Period 1). After the approval of the
original CSR, it was found that “asthma
worsening/exercabation” for evaluating co-primary endpoints was
evaluated using only “severe
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asthma”, although “asthma worsening/exercabation” had to be
evaluated using “severe asthma” and
“worsening asthma.” Therefore, co-primary endpoints and two
‘other’ endpoints were re-analyzed
using “severe asthma” and “worsening asthma” for evaluating
“asthma worsening/exercabation.”
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2. Study ObjectivesPrimary Objective
To clarify the positioning of FF 100μg in medical practice by
evaluating time to withdrawal due to
“poorly-controlled (requires step-up) asthma” and to evaluate
the proportion of subjects “well-
controlled” in fluticasone furcate (FF) 100μg once daily (OD),
fluticasone propionate (FP) 250μg twice
daily (BD), or FP 100μg BD for 12 weeks (Period-2) after
stepping down in Japanese subjects with
asthma who have been well-controlled on FF/VI 100/25μg OD.
Secondary ObjectiveTo evaluate the proportion of subjects
“well-controlled” after switching from the middle-dose
ICS/LABA, which is equivalent to Adoair Diskus 250μg, to
once-daily FF/VI 100/25μg for 8 weeks
(Period-1) in Japanese subjects with asthma who have been
well-controlled on the middle-dose Inhaled
Corticosteroid/ long-acting β2-agonist (ICS/LABA).
Other objectives To evaluate safety of FF 100μg in Japanese
subjects with asthma.
To evaluate Pharmacokinetic (PK) of FF 100μg in Japanese
subjects with asthma.
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3. Investigators and Clinical Trial Management
3.1. Sponsor and Representatives
Sponsor
GlaxoSmithKline K.K. (GSK)
4-6-15 Sendagaya, Shibuya-ku, Tokyo, Japan 151-8566
Chief Executive of the Study:
Chief, Development Headquarters / Pharmaceutical Product
Development
Department Office of Development in the Respiratory Field
Sponsor Contact Information
Study Protocol Creation Leader:
Development Headquarters / Pharmaceutical Product Development
Department Office of
Development in the Respiratory Field
Monitoring Leader:
Development Headquarters / Clinical Operations Department
Medical Monitor (Physician from Sponsor) / Specialist from
Sponsor
M.D., Director, Development Headquarters / Pharmaceutical
Product
Development Department GlaxoSmithKline K.K.
3.2. Study Center and the InvestigatorsThis study was a
multicentre study held in a total of 34 study centers within Japan,
with a total of 34
Investigators participating in it.
3.3. Testing Facility
Clinical Laboratory Testing Contract Research Organization
SRL Medisearch Inc.
Responsible person: Department Head, Clinical Trial Testing
Department
6-5-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, Japan 163-1310
Clinical Laboratory Testing Agency
SRL Inc.
Responsible Person: Department Head, Clinical Testing
Department
2-1-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, Japan 163-0409
Drug Concentration Measuring Facility
Shin Nippon Biomedical Laboratories, Ltd.
Drug Metabolism Analysis Center
Responsible Person:
16-1 Minami-akasaka, Kainan-shi, Wakayama, Japan 642-0017
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PPD
PPD
PPD
PPD
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3.4. Study Period
The first subject was registered on March 27th 2014, and the
last subject completed his/her final stipulated observation on
August 28th, 2015.
4. Study Plan
4.1. Study Design
Figure 1 shows the study design.
Figure 1 Study design
This study was a multi-center study which comprised Period 1
conducted in an uncontrolled, open-
label manner and Period-2 conducted in a randomized,
double-blind, active-controlled, parallel-group
manner. This study was comprised of a run-in period (4 weeks),
an open-label treatment period
(Period-1: 8 weeks), a double-blind treatment period (Period-2:
12 weeks), and a follow-up period
(1 week). The total period was 25 weeks. Subjects complying with
the inclusion/exclusion criteria at
Visit 1 were registered in the run-in period (4 weeks). Subjects
whose asthma was assessed as “well-
controlled” (as defined in “4.4.1.1. Inclusion Criteria”) were
switched at Visit 2 from the middle-dose
ICS/LABA equivalent dose of Adoair® Diskus® 250μg to once-daily
FF/VI 100/25μg (PM) for an 8-
week treatment period (Period-1: open-label treatment period).
Subjects whose asthma was assessed as
well-controlled were randomized at Visit 5 in a 1:1:1 ratio to
one of FF 100μg OD, FP 250μg BD, or
FP 100μg BD and entered the 12 week double blind treatment
period (Period-2: double blind period).
There was a 1-week follow-up period following completion of, or
early withdrawal from, the 12-week
period in Period-2.
Subjects avoided using Sultanol® Inhaler within 6 hours prior to
each visit.
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4.2. Consideration for the Study Design
This study was planned, having considered that it is important
to clarify the position of FF and FF/VI 100/25μg relative to
existing therapies for Japanese patients, taking into account the
indications of the PMDA that information for Japanese asthma
patients are lacking with regards to the corresponding relationship
between FF/VI 100/25μg and each step of mild/moderate persistent
asthma (in particular the mild persistent type), the relationship
between FF 100μg and FP 250μg BD in subject groups requiring
middle-dose ICS, as well as the relationship between FF 100μg and
FP 100μg BD in patient groups requiring low-dose ICS.
As to the number of enrolled subjects, 360 subjects (120
subjects in each treatment group) were randomized in Period-2. In
Period-1, in order to secure the target number of subjects for
randomization (360 subjects) for Period-2, screenings were carried
out while observing the proportion of “well-controlled” asthma
subjects, and the clinical trial was carried on while adjusting the
number of registered subjects.
As switching from middle-dose ICS/LABA equivalent to Adoair
Diskus 250μg to FF/VI 100/25μg and stepping down from FF/VI
100/25μg to ICS monotherapy requires these subjects to have
sufficiently stable asthma symptoms [“Asthma Prevention /
Management Guideline 2012” creating committee, 2012], we setup
criteria to standardize the conditions of well-controlled
asthma.
It would be appropriate to use strict standards to evaluate the
3 dosing regimes FP 100μg BD, FP 250μg BD and FF 100μg OD until
withdrawal due to “poorly-controlled (needing step-up)” in
Period-2. Therefore, based on the fact that the Asthma Prevention /
Management Guideline (2012) says “For the therapeutic measure, if
asthma is not well-controlled under the current treatment step,
strengthen treatment with the current treatment step if asthma
symptoms do not occur every week, and step-up the content of
treatment by 1 or 2 levels from the current treatment if asthma
symptoms occur every week or every day”, the definition of
“poorly-controlled (needing step-up)” asthma was to be evaluated
using the similar items of observations as those defining
“well-controlled asthma”.
In order to evaluate whether or not well-controlled asthma can
be maintained after subjects with “well-controlled” asthma enters
and switches from middle-dose ICS/LABA to FF/VI 100/25μg, the
8-week treatment period in Period-1 should be sufficient to
demonstrate the safety and efficacy of FF/VI 100/25μg. Furthermore,
according to the Asthma Prevention / Management Guideline for Adult
Asthma(2012), the 12-week treatment period in Period-2 should be
sufficient to study the safety and tolerability of ICS monotherapy
in presumed target groups, taking into consideration the general
step-down in asthma treatments after 3 to 6 months of continued
good control of asthma [“[“Asthma Prevention / Management Guideline
2012” creating officers, 2012] Tokyo: Kyowa Project; 2012].
4.3. Revision of the Study Protocol
The main revisions made in the protocol of this clinical trial
are shown in Table 1 Main Revisions to the Study Protocol 1.
The first version of the Study Protocol (Version 00) was created
on 10-January-2014, and this clinical trial was started based on
it. There were 4 revisions after the start of the study. The main
revisions made the first time (Version 01_00) are shown in Table 1
Main Revisions to the Study Protocol 1. Furthermore, the study
period was changed from March 2014 – June 2015 to March 2014
–October 2015 in the third revision (Version 01_02). Other
revisions were about organizational changes and personnel
changes.
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Table 1 Main Revisions to the Study Protocol 1Version 01_00
(revised on 18-September-2014)
Section Before After Reason for Revision
4.8 Re-screening criteria
(p.36)
Screen failure subjects that did not meet the inclusion criteria
may be re-screened. However, each subject can only be re-screened
once, after 30 days pass from the initial screening. During
re-screening, the subject will undergo the assessments and
procedures stipulated for Visit 1 on the Protocol. Subjects that
can be re-screened are those who have stable asthma symptoms, but
could not perform the appropriate lung function measurements on
Visit 1. Subjects that dropped out after commencing the run-in
period cannot be re-screened.
Subjects that failed to perform the appropriate lung function
measurements during Visit 1 may be re-screened. However, each
subject can only be re-screened once. Subjects that dropped out
after commencing the run-in period cannot be re-screened. During
re-screening, the inclusion criteria (Visit 1) stipulated in the
Protocol are re-checked before performing Visit 1 assessments and
procedures.
As subjects eligible for re-screening are limited to those that
fit the inclusion criteria but “failed to perform the appropriate
lung function measurements”, the “30 days pass”was deleted and the
description was consolidated.
5.1Investigational product and rescue medications(p.37)
The Sponsor will provide investigational product and rescue
medications to be used in this study, except for the middle-dose
ICS/LABA equivalent Adoair® Diskus® 250μg
The Sponsor will provide investigational product and rescue
medications to be used in this study, via their storage place at
the Mitsubishi Logistics Co., Ltd., except for the middle-dose
ICS/LABA equivalent Adoair® Diskus® 250μg
Clarified the process of providing the investigational
products.
5.1.1Investigational product
(p.38)
【FF Placebo】1 inhalation per time, OD(PM)
【Front】
“Formulation”: Single-strip packing:
Contains lactose
“Dosage form”: Ellipta® containing 30 blisters (30 blisters in 1
strip, 1 strip packaged)
【FF Placebo】1 inhalation per time, OD(PM)
【Front】
“Formulation”: First strip packaging: contains lactose hydrate,
second strip packaging: mixture of lactose hydrate and Magnesium
stearate
“Dosage form”:Ellipta® containing 30 blisters (30 blisters in 1
strip, 2 strips packaged)
As it was discovered that the actual FF placebo formulations are
two-strip packages rather than the single-strip 1 this was
corrected appropriately.
5.1.1Investigational product
(p.38)
【FP 250μg, FP 100μg】1 inhalation per time, BD (AM/ PM)
【Front】
“Formulation”:−
【FP 250μg, FP 100μg】1 inhalation per time, BD (AM/ PM)
【Front】
“Formulation”:combination of pulverized FP and lactose
hydrate
Formulations contained were clearly appended.
5.1.1Investigational product
(p.38)
【FP Placebo】1 inhalation per time, BD (AM/ PM)
【Front】
“Formulation”:−
【FP 250μg, FP 100μg】1 inhalation per time, BD (AM/ PM)
【Front】
“Formulation”:Contains lactose hydrate
Same as above
5.6.2 Prohibited drugs and therapies
(p.41)
Asthma treatment drugs that are prohibited for concomitant use
from 12
weeks before Visit 1 to Visit 11:
�Oral or non-oral steroids including sustained (depot-type)
drugs
Asthma treatment drugs that are prohibited for concomitant use
from
12 weeks before Visit 1 to Visit 11:
�Oral or non-oral steroids including sustained (depot-type)
drugs
(However, female hormone agents including oral contraceptives
may continue to be used throughout the study period as long as the
prescription is not changed.)
Appended to maintain consistency with the inclusion criteria for
enrolment.
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Section Before After Reason for Revision
5.6.2 Prohibited drugs and therapies (p.41)
Non-asthma Drugs Prohibited for Concomitance between Visit 1 and
Visit 11:
Anticonvulsants (Barbituric acid, hydantoin, carbamazepine)
Polycyclic antidepressants
β blockers
Phenothiazine drugs
Monoamine oxidase (MAO) inhibitors
Non-asthma Drugs Prohibited for Concomitance between Visit 1 and
Visit 11:
Anticonvulsants (Barbituric acid, hydantoin, carbamazepine)
Polycyclic antidepressants
β blockers
Phenothiazine drugs
Monoamine oxidase (MAO) inhibitors
Allermist Nasal®Spray
The proviso [Non-asthma drugs prohibited for concomitant use]
was made clear.
8.3.1 Analysis Population(p.66–67)
All Subjects Enrolled Populationcomprised all subjects, for whom
a record existed in the study database, including screen failures
and any subject who was not screened but experienced an SAE between
the date of informed consent and the planned date of the Screening
Visit. This population was used when reporting serious adverse
events concerning reasons for withdrawal before randomization
(drop-out reason), deviation from inclusion/exclusion/randomization
criteria, and for subjects who were not randomized.
All Subjects Enrolled Population comprised all subjects, for
whom a record existed in the study database, including screen
failures and any subject who was not screened but experienced an
SAE between the date of informed consent and the planned date of
the Screening Visit. This population was used when reporting
serious adverse events concerning reasons for withdrawal before
investigational product administration (drop-out reason), deviation
from inclusion/exclusion criteria, and for subjects to whom the
investigational product was not administered during Period-1.
Description was clarified in association with the review of the
definition of the analysis population.
8.3.1 Analysis Population(p.66–67)
N/A Open Label Population comprised all subjects who received at
least one dose of study medication in Period-1. This population was
used for all data analyses and results presented for Period-1.
Furthermore, this population was used when reporting serious
adverse events concerning reasons for withdrawal before
randomization (drop-out reason), deviation from
inclusion/exclusion/randomization criteria, and for subjects who
were not randomized during Period-2.
Same as above
8.3.1 Analysis Population(p.66–67)
Intent-to-Treat (ITT) Population comprised all subjects
randomized to treatment who received at least one dose of
randomized investigational product in the treatment period.
Randomized subjects were assumed to have received investigational
product unless definitive evidence to the contrary exists. Results
were reported based on the randomized treatment group. This was the
main population for all data analysis and display of analysis
results.
Intent-to-Treat (ITT) Population comprised all subjects
randomized to treatment who received at least one dose of
randomized investigational product in the treatment period.
Randomized subjects were assumed to have received investigational
product unless definitive evidence to the contrary exists. Results
on efficacy were reported based on the randomized treatment group.
This was the main population for all data analysis and display of
analysis results for Period-2.
Same as above
1. Details concerning the erroneous delivery issue of
investigational product is described in “5.2. Deviations from the
Study Protocol”.
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4.4. Selection of The Analysis Set
4.4.1. Inclusion/Exclusion Criteria
4.4.1.1. Inclusion Criteria
Inclusion Criteria at Enrolment (Visit 1)
Only those who fulfil all of the following were included for
enrolment in this study.
1. Consent: Possible to acquire written consent from the patient
him/herself.
2. Type of subject: Outpatient subjects aged 18 years or older
who had a diagnosis of asthma as
defined by the diagnostic criteria of National Institutes of
Health [NIH, 2007] at least 1 year prior
to Visit 1.
3. Gender: Male or eligible female
Non-childbearing potential females of or childbearing potential
females who used an acceptable
method of birth control, as shown below, consistently and
correctly.
The male partner of the subject is azoospermic prior to
subject’s study enrolment, and that
this is the only male partner that they have
Oral contraceptives (Estrogen / progestin mixed formulation)
Intrauterine device (IUD) with contraceptive failure rate below
1% according to literature
Double-barrier method: Spermicide + physical barrier (spermicide
+ condom, or spermicide
+ pessary)
Females of childbearing potential must maintain complete
abstinence during the study
period and during the period until the investigational product
disappears from the system
(more than 6 days after the last dose).
Pregnant women, breastfeeding women, or those women who plan on
becoming pregnant
during the study period cannot be enrolled in the study. Serum
pregnant tests are done on
female patients of childbearing potential on the registration
visit (Visit 1) and on Visit
11/Early Withdrawal Visit. All female patients of childbearing
potential must undergo urine
pregnancy tests when switching to FF/VI 100/25μg (Visit 2),
randomization visit (Visit 5)
and follow-up visit (Visit 12).
4. Severity of disease: A best pre-bronchodilator FEV1 of ≥80%
of the predicted normal value at
Visit 1. Predicted values were based on NHANES III [Hankinson,
1999] values adjusted for Asian
race related variations [Hankinson, 2010].
5. Stable Asthma: Subjects who had stable asthma, as judged
comprehensively by the Investigator/
Subinvestigator. This included no change in asthma medication
for at least 8 weeks prior to Visit 1
and an Asthma Control Test (ACT) score of ≥20 at Visit 1.
6. Current anti-Asthma Therapy: Subjects who used the
middle-dose ICS/LABA which was
equivalent to twice-daily Adoair Diskus 250μg for at least 12
weeks prior to Visit 1. In addition,
the prescription of the middle-dose ICS/LABA could not be
changed at least 8 weeks prior to
Visit 1.
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7. SABA: Subjects who, during the study, were able to use the
Sultanol Inhaler, provided as rescue
medication on Visit 1 when needed. However, subjects were able
to avoid the use of the Sultanol
Inhaler 6 hours prior to every study visit.
8. 12-Lead Electrocardiogram: Subjects had no clinically
problematic abnormalities in the 12-Lead
Electrocardiogram test conducted during Visit 1, according to
judgments made by the Investigator/
Subinvestigator(s). The following conditions had to be met about
the QT interval.
Inclusion Criteria at Switching of Medications/Randomization
(Visit 2 and Visit 5)
1. Subjects whose asthma met the criterion of “well-controlled”
(as defined in “Well-controlled”) and who were allowed to be
“switched” or “randomized” at the discretion of the Investigator/
Subinvestigator at Visit 2 or Visit 5 respectively.
Definition of Well-controlled Asthma (assessed in one week prior
to Visits 2 and 5)
Observation item Well-controlled
Assess weekly Asthma symptom score 1)
(Day-time)Two or more of the 3 criteria*
AND
1 or greater on no more than one day
Rescue salbutamol use No more than 1 day of use
Morning PEF ≥80% the best effort value every day
At visits A best pre-bronchodilator FEV1 Meet all of the
criteria*
≥80% predicted
Assess daily Asthma symptom score 1) (Night-time)
0
Asthma worsening/ exacerbation 2) No
*Both should be met for ‘well-controlled’.
1) The following will be recorded every day in the eDiary in the
evening (PM) before taking any rescue or study medication and
before PEF measurement:
Day-time Symptom Score:0 = No symptoms during the day1 =
Symptoms for one short period during the day2 = Symptoms for two or
more short periods during the day3 = Symptoms for most of the day
which did not affect my normal daily activities4 = Symptoms for
most of the day which did affect my normal daily activities5 =
Symptoms so severe that I could not go to work or perform normal
daily Activities
The following will be recorded every day in the eDiary in the
morning (AM) before taking any rescue medication and before PEF
measurement:
Night-time Symptom Score:0 = No symptoms during the night1 =
Symptoms causing me to wake once (or wake early)2 = Symptoms
causing me to wake twice or more (including waking early)3 =
Symptoms causing me to be awake for most of the night4 = Symptoms
so severe that I did not sleep at all
QTcF
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2) See Exacerbation of Asthma Symptoms: “Asthma exacerbation” of
“4.6.2.9 Other Safety Endpoints”.
2. Subjects with compliance rate >80% for use of middle-dose
ICS/LABA compounding agents equivalent to Adoair Diskus 250μg
(Visit 1 to 2) and FF/VI 100/25μg (Visit 2 to 5)
3. Subjects that make more than 5 days of entries into the
electronic diary (“4.6.1.2 Patient Diary”) in the morning and
night, during the 1 week immediately before Visit 2 and Visit 5
4.4.1.2 Exclusion Criteria
Exclusion Criteria at Enrolment (Visit 1) Subjects were not
enrolled to the study if they corresponded to any of the following
conditions.
1. Life-threatening history of Asthma: Subject who had a
life-threatening episode of asthma.
Definition of a life-threatening episode of asthma: Asthma
episodes needing endotracheal intubation and/or asthma episodes
involving hypercapnia, respiratory arrest or hypoxicconvulsions
within the past 10 years.
2. Respiratory tract infection: Subject who had positive or
suspected positive response in culture
tests of bacterial infection or viral infection in the upper
respiratory tract, lower respiratory tract,
paranasal sinus or the middle ear and had not been healed of it
within 8 weeks prior to Visit 1,
which had led to make changes to asthma treatments, or these
infections could affect the condition
of asthma or subject’s participation in the study, based on
judgments made by the Investigator/
Subinvestigator.
3. Asthma Exacerbation: Subject who received treatments with
systemic oral steroids or steroidal
injections within 12 weeks before Visit 1, or was hospitalized
for more than 1 night for asthma
exacerbation that required additional treatments, within 6
months of Visit 1.
4. Complications of the respiratory tract: Subject who had
pneumonia, pneumothorax, atelectasis,
pulmonary fibrosis, bronchopulmonary dysplasia, chronic
bronchitis, emphysema, chronic
obstructive pulmonary disease or complications with any other
respiratory disorders other than
asthma.
5. Other complications/abnormalities: Subject who had clinically
significant symptoms or illnesses
that are unmanaged, and who might risk their safety by
participating in the study, or should these
symptoms/illnesses worsen during the study, the interpretation
of results concerning efficacy
might be interfered, based on the judgment of the Investigator/
Subinvestigator.
Other symptoms/illnesses which exclude subjects from being
enrolled to this study are shown in, but not limited to the table
below.
Congestive heart failure Existing aortic aneurysm
Clinically significant coronary heart disease Clinically
significant arrhythmia
Stroke within 3 months before Visit 1 Unmanaged
hypertension1
Recently developed, unmanaged gastric ulcer Hematological,
liver, kidney diseases
Lack of immunity Malignant tumor2
Tuberculosis (active or untreated)3 Cushing’s disease
Addison’s disease Unmanaged diabetes
Unmanaged thyroid disease Recent history of drug or alcohol
abuse
1. If measurements of systolic blood pressure >160mmHg or
diastolic blood pressure >100mmHg were taken more than
twice.
2. Subjects with history of malignant tumors were allowed to
enrol as long as the cancer has been in remission for 1 year prior
to Visit 1 (remission means that there are no signs of the
malignant tumor 12 months prior to Visit 1, and the subject has not
received any treatments for it).
3. Patients with tuberculosis were allowed for enrolment
provided that they are receiving appropriate treatments with
antituberculotic drugs and show no clinical signs of relapsing or
active tuberculosis.
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6. Oropharyngeal Examination: Subjects who had clinically
visible oral candidiasis during Visit 1,
they were not subjected to enrolment during the run-in
period.
7. Investigational Product Treatments: Subject who had used the
investigational product within 30
days prior to Visit 1, or 5 times the half-life (t1/2) of the
investigational product had not passed
(whichever was longer of these two periods).
8. Allergy:
Drug Allergy: Subject who had a history of immediate or
delayed-type sensitivity to β2
agonists, sympathomimetic agents or intranasal, inhaled,
systemic steroid therapies.
Subject who had or was suspected of having sensitivities against
excipients of the
investigational product (Lactose hydrate, magnesium
stearate).
Allergies against milk proteins: Subject who had a history of
severe allergies against milk
proteins.
9. Concomitant drugs:
Subjects who were using prescription drugs or general
pharmaceutical products like
anticonvulsants (Barbituric acid, hydantoin, carbamazepine),
polycyclic antidepressants
(tricyclic or tetracyclic), β-blockers (both heart-selective and
non-selective), phenothiazine
drugs and monoamine oxidase (MAO) inhibitors that have large
impact on the progress of
asthma, or that have risks of drug interactions with the
investigational product.
Immunosuppressants:Subjects who was using immunosuppressant
drugs or expected to
use immunosuppressants during the study period.
Note: Immunotherapy towards allergy treatments during the study
period was
allowed as long as it had started more than 4 weeks before Visit
1 and continued
during the study period with