Supplementary Appendix
Supplementary Materials
Contents
Appendix 1 – Phase I studies of umeclidinium
Appendix 2 – Search Strategy
Appendix 3 - PRISMA Checklist
Appendix 4 – Funnel plot for assessment of publication bias for change in trough FEV 1.
1
Table 1. Phase I Umeclidinium Studies
Study
(Author,
journal, year),
National
Clinical Trial
number (NCT)
Cahn A et al.
2013 [14]
NCT00803673
Cahn A et al.
[16]
(No NCT#
provided)
Cahn A et al.
[16]
NCT00475436
Study Objective(s) and
Population
Study Design
and Duration
Interventions1
and Number of
Subjects (n)
Completing Study
Primary and Other
Endpoints
Outcomes/Results
Determine safety,
tolerability and PKs of
UMEC in persons with
normal CYP2D6
metabolism (HVL-NM)
and poor CYP2D6
metabolism (HVL-PM)
R, PC, single and
multiple dose
study for 7 days
UMEC 100 -1000
μg via DPI on Day
1 and Day 7 in
HVL-NM (n=20)
and HVL-PM
(n=16)
Primary: Safety (blood
chemistries,
hematology, VS, ECG,
Holter, lung function)
Primary: No SAEs, 13 subjects
reported AEs in each group. UMEC
caused dry mouth (n=5) No significant
abnormalities in VS, lung function,
laboratories or ECGs.
Determine safety,
tolerability, PKs, and
PD of UMEC in HVL
responsive to inhaled
ipratropium
R, DB, DD, PC
single dose,
cross-over study
Determine safety,
tolerability, PKs, and
PD of UMEC in HVL
(18-55 yo)
R, DB, PG, PC,
dose-escalation,
repeat dose study
for 7-14 days
Five treatment
periods. One
cohort – UMEC 10
μg , 60 μg and 250
μg via Diskus®,
TIO 18 μg DPI
and PBO
Second cohort –
UMEC 20 μg, 100
μg and 350 μg via
Diskus®, TIO 18
μg DPI and PBO
UMEC 250 μg
(cohort 1, n=12),
500 μg (cohort 2,
n=12), and 1000
μg (cohort 3,
n=12) via Diskus®
Other measures: Plasma
and urine PKs and PD
Primary: safety (blood
chemistries,
hematology, VS, ECG,
Holter, urine output.
Other measures: No differences in
plasma or urine PKs of UMEC
between HVL-NM and HVL-PM with
single or multiple doses. AUC ~ 30%
greater in HVL-PM with multiple
dosing at 1000 μg, but was NSS.
Primary: No SAEs, 11 AEs, 10 mild, 1
moderate (Rhabdomyolysis not drugrelated). No significant effects on
laboratories, VS, or CV measures.
Other measures:
Plasma and urine PK
analysis, PD, lung
function (FEV1 and
sGAW)
Other measures: ~ 1% of dose renally
excreted unchanged, slight evidence of
non-proportional PKs among different
doses. Greatest effect on sGAW and
FEV1 with higher UMEC doses
Primary:
Safety (blood
chemistries,
hematology, and CV,
urine output)
Secondary: PKs
Primary: No SAEs, 50 AEs, 56% drugrelated. HA most common, dry mouth
at 1000 μg dose (n=1). No significant
effects on laboratories or CV tests,
urinary retention.
Secondary: Cmax 5-7 minutes, t ½ ~ 27
hrs, PKs dose-disproportionate
between 250 and 1000 μg.
2
Adverse Events
See Outcomes/Results
See Outcomes/Results
See Outcomes/Results
Kelleher et al.
[17]
NCT00976144
GSK on file
AC4112014
Evaluate safety,
tolerability, pks, and PD
of UMEC and
UMEC/VIL
SC, DB, PC, R,
crossover study
Japanese HVL
Determine the excretion
balance and pks of
single doses of oral and
IV radiolabeled UMEC
Open-label, two
period study in
healthy males
(n=6)
Assess the safety and
Pks (bioavailability) of
IV, oral and inhaled
UMEC in HVL
Open-label,
sequential,
crossover,
escalating dose
study (n=9)
NCT01362257
GSK on file
AC4112008
NCT01110018
Mehta R et al.
[21]
(GSK#114633)
Mehta R et al
[22]
NCT01571999
Single doses of
UMEC 500 μg,
VIL 25 μg, and
UMEC/VIL
500/25 μg via
Ellipta® (n=16)
65 mcg 14Clabeled UMEC by
IV infusion and
1000 mcg 14Clabeled UMEC
oral solution
UMEC IV (20, 50,
65 μg), 1000 μg
oral, and inhaled
Evaluate effects of
hepatic impairment on
UMEC PKs in persons
with moderate liver
disease (Child Pugh
score 7-9)
Open-label, nonR study of
persons with
moderate hepatic
impairment (n=9)
and HVL (n=9)
UMEC/VIL
125/25 μg via
Ellipta® for 1
dose, then UMEC
125 μg X 7 days
Evaluate effects of
severe renal disease on
pks of UMEC and
UMEC/VIL in patients
with ClCr< 30 ml/min
and HVL
SB, non-R study
of patients with
ClCr < 30ml/min
(n==9) and HVL
(n=9) matched on
age, gender, BMI,
and race
Single doses of
UMEC 125 and
UMEC/VIL
125/25 via
Ellipta®
Primary: Safety and
tolerability (HR, BP,
ECG, biochemistries,
lung function)
Secondary: plasma PKs
of UMEC and VIL
Primary: Total
radioactivity of oral and
IV UMEC
Primary: Determine
safe IV dose of UMEC
Other measures: PKs
including absolute
bioavailability of
Inhaled and oral UMEC
Primary: Serum PKs
(AUC, Cmax) of UMEC
+/- VIL
Other: Urinary PKs of
UMEC and VIL, and
tolerability of UMEC
Primary:
UMEC and VIL plasma
PKs : area under the
curve (AUC)(0–0.25h),
AUC(0–2h), maximum
observed plasma concentration (Cmax), time
to Cmax (Tmax), AUC(0–
24h), AUC(0–∞), time
to last quantifiable
concentration (tlast),
terminal phase half-life
(t1/2)
Secondary: UMEC
urine PK parameters
safety and tolerability
assessments. clinical
3
Primary: No SAEs, 50% of subjects
experienced an AE, musculoskeletal in
2 subjects in each group
See Outcomes/Results
Primary: Oral bioavailability ~ 5%. ~
50% of dose excreted in feces over 48
hrs with oral administration. ~ 20%
excreted in urine in first 24 hrs
NO SAEs, HA and pain in
extremities in 1/3 of subjects
with both routes of
administration
Primary measures: No significant
SAEs with any IV dose, dizziness most
common AE(n=2 in oral group)
See Outcomes/Results
Secondary measures: 12% systemic
bioavailability with Inhaled UMEC,
plasma t ½ of inhaled UMEC ~ 2.5 hrs
No significant differences in UMEC
systemic exposure or urinary excretion
between persons with moderate liver
impairment compared to HVL. < 4%
unchanged UMEC excreted through
urine
Primary measures: Tmax ~ 5 minutes,
Tlast = 2 hrs in both groups. No increase
in AUC between groups. UMEC
plasma T ½ ~ 8-9 hrs in both groups, ~
90% excreted in urine in 24 hrs in both
groups. Renal excretion 9-fold lower in
renal disease pts, but no difference, not
associated with significant changes in
plasma AUC or Cmax.
No adverse effects reported
for any subject
No clinically relevant changes
in laboratories, VS, or ECG.
No SAEs
Mehta R et al.
[20]
NCT01128634
Hu C et al. [15]
(NCT01899638)
Assess effect of
concomitant verapamil
on UMEC systemic
exposure and AEs in
HVL 18-65 yo
R, open-label
study over 15
days
Assess PK, safety, and
tolerability of UMEC
and UMEC + VIL in
HVL Chinese subjects
18-45 yo
R, Open-label, 3
period cross-over,
single and repeat
doses over 10
days
UMEC 500 μg via
DPI X 15 days,
verapamil 240 mg
daily for days 1115 (n=14)
UMEC 500/VIL
25 μg via DPI X
15 days, verapamil
240 mg on Days
11-15 (n=15)
UMEC/VIL
62.5/25 μg,
UMEC/VIL
125/25 μg, UMEC
62.5 μg, UMEC
125 μg , and VIL
25 μg, single
doses and repeated
doses over 10 days
chemistry, hematology,
urinalysis, VS, and
12-lead ECG
Primary: UMEC
systemic exposure
(AUC) and Cmax
Other measures: HR,
QTc interval, serum
potassium
UMEC and VIL plasma
PKs, systemic exposure
of UMEC based on
AUC (0-2 hrs), Tmax,
time to last measurable
blood level, and Cmax
4
Verapamil increased AUC0-T of UMEC
by 39%, whether given alone in
combination with VIL. Decrease in HR
and increase in QTc with concomitant
verapamil consistent with effects of
verapamil
Most frequent AE was HA,
no difference among groups.
3 subjects withdrew due to
possibly drug-related AEs –
transient increase in LFTs,
GI, and psychiatric effects
Single dose UMEC/VIL 62.5/25
UMEC125/25, UMEC 62.5, and
UMEC 125 μg
(Cmax = 214, 471, 234, and 569 pg/ml;
Tmax = 0.08, 0.08, 0.08, and 0.08 hrs;
Tlast = 2.0, 4.0, 2.0, 4.0 hrs; AUC 0-2
hrs = 49.2, 134, 53.3, and 161
pg.hrs/ml
Repeated dosing: UMEC/VIL 62.5/25,
UMEC/VIL 125/25, UMEC 62.5, and
UMEC 125 μg
(Cmax = 245, 548, 258, and 759 pg/ml;
Tmax = 0.08, 0.08, 0.08, 0.08; Tlast = 48,
28, 48.0, and 48 hrs; AUC0-2 = 89.1,
192, 93.2, and 257 pg.hr/ml)
Most common AE in UMEC
groups was chest discomfort.
Dry throat reported in 1
UMEC 125 subject,
constipation reported in 2
UMEC or UMEC/VIL
subjects
Appendix 2: Search Strategy
PubMed search:
#1 " chronic obstructive pulmonary disease "[Mesh]
#2 “chronic obstructive pulmonary disease "
#3 COPD
#4 OR #1-#3
#5 Umeclidinium
#6 Incruse
#7 Ellipta
#8 Anoro
#9 "long-acting antimuscarinic "[Mesh]
#10 long-acting antimuscarinic
#11 LAMA
#12 OR #5-#11
#13 "randomised controlled trials"
#14 "randomized controlled trials"
#15 "Randomized Controlled Trial"[Publication Type]
#16 RCT
#17 random*[Title/Abstract]
#18 trial[Title/Abstract]
#19 registr*[Title/Abstract]
#20 OR #13-#19
#4 AND #12 AND #20
5
Appendix 3. Prisma Checklist
#
Checklist item
Reported on page #
1
Identify the report as a systematic review, meta-analysis, or both.
Title
2
Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria,
participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of
key findings; systematic review registration number.
Abstract
Rationale
3
Describe the rationale for the review in the context of what is already known.
Introduction
Objectives
4
Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons,
outcomes, and study design (PICOS).
Introduction
Protocol and registration
5
Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide
registration information including registration number.
No
Eligibility criteria
6
Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language,
publication status) used as criteria for eligibility, giving rationale.
Study selection
Information sources
7
Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional
studies) in the search and date last searched.
Literature search
Search
8
Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
Literature search
Study selection
9
State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included
in the meta-analysis).
Study selection, Appendix 1
Section/topic
TITLE
Title
ABSTRACT
Structured summary
INTRODUCTION
METHODS
Data collection process
10
Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for
obtaining and confirming data from investigators.
Data extraction
Data items
11
List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and
simplifications made.
Data extraction
Risk of bias in individual
studies
12
Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at
the study or outcome level), and how this information is to be used in any data synthesis.
Risk of bias/quality
assessment
Summary measures
13
State the principal summary measures (e.g., risk ratio, difference in means).
Data analysis
6
Synthesis of results
14
Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2)
for each meta-analysis.
Data analysis
Risk of bias across studies
15
Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting
within studies).
Data analysis, Risk of
bias/quality assessment
Additional analyses
16
Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which
were pre-specified.
Data analysis
Study selection
17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each
stage, ideally with a flow diagram.
RESULTS, the 1st paragraph
Study characteristics
18
For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide
the citations.
RESULTS, the 1st paragraph,
Appendix 3 (Table 3.1 &
3.2), Table1
Risk of bias within studies
19
Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).
Appendix 6
Results of individual studies
20
For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention
group (b) effect estimates and confidence intervals, ideally with a forest plot.
RESULTS, 2nd – 6th
paragraph, Appendix 4
(Figure 4.1-4.8);
Synthesis of results
21
Present results of each meta-analysis done, including confidence intervals and measures of consistency.
Appendix 4 (Figure 4.1-4.8),
Figure 2-3
Risk of bias across studies
22
Present results of any assessment of risk of bias across studies (see Item 15).
RESULTS, the 7th paragraph;
Appendix 6
Additional analysis
23
Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).
Subgroup analysis and metaregression, Time-cumulative
analysis, Sensitivity analysis
Summary of evidence
24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key
groups (e.g., healthcare providers, users, and policy makers).
DISCUSSION, the 1st
paragraph
Limitations
25
Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified
research, reporting bias).
Strength and Limitations
Conclusions
26
Provide a general interpretation of the results in the context of other evidence, and implications for future research.
DISCUSSION, the 1st – 3rd
paragraph
27
Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the
systematic review.
No
RESULTS
DISCUSSION
FUNDING
Funding
7
From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS
Med 6(6): e1000097. doi:10.1371/journal.pmed1000097
8
Appendix 4 – Funnel plot for assessment of publication bias for change in trough FEV1.
9