Respiratory Medicine 161 (2020) 105809

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Respiratory Medicine
journal homepage: http://www.elsevier.com/locate/rmed

Efficacy and safety of inhaled once-daily low-dose indacaterol acetate/

mometasone furoate in patients with inadequately controlled asthma:
Phase III randomised QUARTZ study findings
Oliver Kornmann a, *, Janos Mucsi b, Nadezda Kolosa c, Lorraine Bandelli d, Biswajit Sen e,
Lisa C. Satlin d, Peter D’Andrea d
a
IKF Pneumologie Frankfurt, Clinical Research Centre Respiratory Diseases, Frankfurt, Germany
b
Erzs�ebet Gondoz�
oh�
az, G€od€
oll}
o, Hungary
c
Daugavpils Regional Hospital LTD, Daugavpils, Latvia
d
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
e
Novartis Healthcare Pvt. Ltd, Hyderabad, India

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Global initiative for asthma (GINA) 2019 recommends adding a long-acting β2-agonist (LABA) to an
Asthma inhaled corticosteroid (ICS) as a maintenance controller therapy in patients with inadequately controlled asthma.
Treatment Indacaterol acetate (IND, a LABA) in combination with mometasone furoate (MF, an ICS) is under development
Long acting beta agonists
for the treatment of these patients.
Inhaled corticosteroids
Objective: This phase III QUARTZ was a multicentre, randomised, double-blind, double-dummy and parallel-
group study to assess the efficacy and safety of low-dose IND/MF 150/80 μg once daily (o.d.) versus MF
200 μg o.d. in adult and adolescent patients with inadequately controlled asthma.
Methods: Eligible patients (n ¼ 802) were randomised (1:1) to receive either low-dose IND/MF 150/80 μg o.d. via
Breezhaler® or MF 200 μg o.d. via Twisthaler® for 12 weeks. Primary endpoint was trough forced expiratory
volume in 1 s (FEV1) and key secondary endpoint was Asthma Control Questionnaire (ACQ-7) treatment
difference after 12-week treatment. Other secondary endpoints included ACQ-7 responder analysis, morning and
evening peak expiratory flow, Asthma Quality of Life Questionnaire total score, rescue medication use, daily
symptom score, nighttime awakenings and rate of exacerbations, evaluated over 12-week treatment. Safety was
also assessed including serious asthma outcomes.
Results: Low-dose IND/MF significantly improved trough FEV1 (least squares mean treatment difference
[LSMTD]: 0.182 L; p < 0.001) and ACQ-7 (LSMTD: 0.218; p < 0.001) versus MF at Week 12. Improvements in
all other secondary endpoints favoured low-dose IND/MF. Safety was comparable.
Conclusion: These results support the use of low-dose IND/MF 150/80 μg o.d. as a potential therapy for adult and
adolescent patients with inadequately controlled asthma.

(ICS) as the preferred initial controller option in patients with persistent

asthma [3]. ICS are considered as the cornerstone therapy for the
1. Introduction
treatment of inadequately controlled asthma in adult and adolescent
populations [4]. However, many patients remain symptomatic despite
Asthma affects approximately 350 million patients worldwide
receiving ICS monotherapy. Recent update in GINA 2019 recommends
causing a high burden of death and disability [1,2]. Global Initiative for
the addition of long-acting β2-agonist (LABA) to ICS monotherapy as the
Asthma (GINA) recommends short-acting β2-agonists (SABAs) as the
preferred controller and maintenance therapy in patients with
preferred initial reliever option and low-dose inhaled corticosteroids

* Corresponding author. IKF Pneumologie GmbH & Co. KG Institut für klinische Forschung Pneumologie, Clinical Research Centre Respiratory Diseases, Schau­
mainkai 101-103/ Stresemannallee 3, 60596, Frankfurt, Germany.
E-mail addresses: kornmann@ikf-pneumologie.de (O. Kornmann), mucsitrial@erzsebetgondozohaz.hu, mucsitrial@gmail.com (J. Mucsi), kolosa-nadezda@
hotmail.com (N. Kolosa), lorraine.bandelli@novartis.com (L. Bandelli), biswajit.sen@novartis.com (B. Sen), lisa.satlin@novartis.com (L.C. Satlin), peter.
dandrea@novartis.com (P. D’Andrea).

https://doi.org/10.1016/j.rmed.2019.105809
Received 9 September 2019; Received in revised form 31 October 2019; Accepted 1 November 2019
Available online 14 November 2019
0954-6111/© 2019 Published by Elsevier Ltd. This article is made available under the Elsevier license (http://www.elsevier.com/open-access/userlicense/1.0/).
O. Kornmann et al.
Abbreviations
ACQ Asthma Control Questionnaire
AEs adverse events
ANCOVA analysis of covariance
AQLQ asthma quality of life questionnaire
BMI body mass index
CI confidence interval
COPD chronic obstructive pulmonary disease
DAEs discontinuations due to adverse events
eDiary electronic diary
EU European Union
FAS full analysis set
FDC fixed dose combination
FEV1 forced expiratory volume in 1 s
inadequately controlled asthma [3]. The addition of LABA to ICS mon­
otherapy further helps in achieving asthma control by reducing symp­
toms and improving lung function [5–8]. Several twice-daily LABA/ICS
combinations are currently available along with one once-daily combi­
nation (fluticasone furoate/vilanterol) for GINA Step 3 to 5 treatment of
asthma [3].
The LABA indacaterol acetate (IND) is approved for chronic
obstructive pulmonary disease (COPD) at a dosing regimen of 150 μg
and 300 μg once daily (o.d.) in the EU and 75 μg o.d. in the US [9]. IND is
approved in many countries as dual combination with glycopyrronium
for treatment of COPD [10,11]. IND demonstrated sustained 24-h
bronchodilator efficacy, with a rapid onset of action in patients with
moderate-to-severe asthma when administered o.d. via a dry powder
inhaler [12]. Mometasone furoate (MF) is an ICS approved as a
once-daily dosing regimen for the treatment of asthma in patients aged
�12 years (220 μg–440 μg) and for children aged 4–11 years (110 μg) in
the US, which is administered as a dry powder via Twisthaler® in the
evening [13,14].
IND/MF 150/80 μg o.d. delivered via Breezhaler®, a single-dose dry
powder inhaler, is a fixed-dose combination (FDC) of IND and MF, and is
under development for treatment of symptomatic adult and adolescent
patients with inadequately controlled asthma. IND/MF is being devel­
oped for the treatment of asthma at three doses; high dose 150/320 μg;
medium dose 150/160 μg and low dose 150/80 μg o.d. as a lactose-
blended inhalation powder, hard capsule, delivered via the
Breezhaler® device. Previous studies demonstrated that 80, 160 and
320 μg doses of MF administered via the Breezhaler® device were
comparable to the 200, 400 and 2 � 400 μg doses of MF administered via
the Twisthaler® device, respectively, based on the pharmacokinetic
data, in vitro fine particle mass adjustments and subsequent pharmaco­
dynamic confirmation in an efficacy and safety study in asthma patients
[15,16].
The Phase III QUARTZ study was conducted to evaluate efficacy and
safety of low-dose IND/MF 150/80 μg o.d. delivered via Breezhaler®
compared with MF 200 μg o.d. delivered via Twisthaler® in terms of
lung function (trough forced expiratory volume in 1 s [FEV1]) and
asthma control (Asthma Control Questionnaire [ACQ-7] score) in
patients with inadequately controlled asthma.
2. Methods
2.1. Study design
The QUARTZ study was a Phase III, multicentre, randomised,
double-blind, double-dummy and parallel-group study that included a
12-week treatment period (Clinical trials identifier: NCT02892344). A
2-week screening period was followed by a 3-week run-in period, during
2
Respiratory Medicine 161 (2020) 105809
GINA The Global Initiative for Asthma
ICS inhaled corticosteroid
IND indacaterol acetate
LABA long-acting β2-agonist
LSM least squares mean
MF mometasone furoate
MMRM Mixed Model for Repeated Measure
o.d. once daily
OR odds ratio
RR rate ratio
PEF peak expiratory flow
SABA short-acting β2-agonist
SAEs serious adverse events
SE standard error
US United States
which all patients were administered open-label fluticasone propionate
100 μg twice daily delivered via Accuhaler®. After the run-in period, the
patients were randomised (1:1) to receive either IND/MF 150/80 μg o.d.
via Breezhaler® or MF 200 μg o.d. via Twisthaler® for 12 weeks; study
medication was administered to the patients as evening doses between 5
and 8 pm at approximately the same time each evening; patients entered
a follow-up period for 30 days after completion of the treatment period
(Fig. 1).
The study was approved by institutional review boards or ethics
committees at participating centres, and was conducted in accordance
with ICH Harmonized Tripartite Guidelines for Good Clinical Practice,
with local regulations applied, and the Declaration of Helsinki. All
patients provided written informed consent to participate in the
study.
2.2. Patients
The study population consisted of men and women aged �12
and � 75 years with a documented diagnosis of asthma for a period of at
least 3 months prior to screening, who were taking low-dose ICS (with or
without controller, e.g., LABA) for at least 1 month prior to screening
visit. Patients had FEV1 <90% predicted and were symptomatic (as
measured by ACQ-7 �1.5) prior to randomisation as per GINA 2016
[17]. Further information on inclusion and exclusion data is available in
the online Supplementary Appendix.
2.3. Study objectives
The primary objective of the study was to demonstrate superiority of
IND/MF 150/80 μg o.d. to MF 200 μg o.d. in terms of trough FEV1 after
12 weeks of treatment in adults and adolescents with inadequately
controlled asthma. The key secondary objective was to demonstrate
superiority of IND/MF 150/80 μg o.d. over MF 200 μg o.d. in terms of
improvements in asthma control (ACQ-7 score) after 12 weeks of
treatment.
Other secondary objectives included the assessment of IND/MF
versus MF with respect to – ACQ-7 responder analysis (a responder was
defined as a patient achieving an improvement of at least 0.5 units in
ACQ-7 score also known as minimal clinically important difference
[MCID]) [18] after 12 weeks of treatment, morning and evening peak
expiratory flow (PEF) over 4 and 12 weeks of treatment, Asthma Quality
of Life Questionnaire (AQLQ) total score, mean total daily symptom
score, nighttime awakenings, rescue medication use and rescue medi­
cation free days (collected via electronic diary [eDiary]) over 12 weeks
of treatment. Rate of exacerbations was evaluated in terms of exacer­
bation categories: all (mild, moderate, severe), and the combination of
moderate or severe for the 12-week treatment period.
O. Kornmann et al.
Fig. 1. QUARTZ study design.
In our study, mild exacerbation was defined as the occurrence of
deterioration of asthma symptoms, lung function and increased use of
“rescue” inhaled bronchodilators. Moderate exacerbation was defined as
progressive increase of asthma symptoms, deterioration of lung function
and increased use of “rescue” inhaled bronchodilators. Severe
exacerbation was defined as an aggravation of asthma symptoms (like
shortness of breath, cough, wheezing, or chest tightness) that requires
systemic corticosteroids for �3 consecutive days and/or a need for an
emergency hospitalisation due to asthma or death due to asthma.
Additional secondary endpoints for which the data are not reported
in this publication can be found at ClinicalTrials.gov (https://clinicaltr
ials.gov/ct2/show/NCT02892344). The safety and tolerability of
low-dose IND/MF and MF were also evaluated in terms of adverse
events, deaths, other serious or clinically significant AEs and serious
asthma outcomes (defined as asthma-related hospitalisation, or
asthma-related intubation, or asthma-related death).
2.4. Statistical analysis
All efficacy analyses were performed in the full analysis set (FAS),
which consisted of all patients in the randomised set who received at
least one dose of study medication. All safety evaluations were
performed in the safety set, which consisted of all patients who received
at least one dose of study medication including non-randomised patients
who received study medication in error. All safety evaluations were
based on the safety set. The primary endpoint: trough FEV1 and key
secondary endpoint: ACQ-7 treatment differences were analysed using a
Mixed Model for Repeated Measure (MMRM). For multiplicity
adjustment, a hierarchical testing procedure was applied to control the
type-I error rate for the primary and the key secondary endpoint. ACQ-7
responder analysis was analysed using a logistic regression model.
Percentage of nights with no nighttime awakenings was analysed using
linear mixed model. AQLQ total score, mean morning/evening PEF,
mean total daily symptom score and mean rescue medication use over a
12-week treatment period were analysed using an ANCOVA model. In
addition, mean morning/evening PEF over 4 weekly intervals were
analysed using a similar MMRM as for the primary analysis. The rate of
all and the combination of moderate or severe exacerbations was
analysed using a generalised linear model assuming the negative
binomial distribution.
3
Respiratory Medicine 161 (2020) 105809
3. Results
3.1. Study population
Of the 802 randomised patients, 768 (95.8%) completed the study
treatment (IND/MF, 386; MF, 382) (Fig. 2).
Overall, baseline demographic characteristics were balanced
between the two treatment groups (Table 1). The mean age was 45.6
years with 13.5% of randomised patients aged �65 years. This study
also included 64 (8.0%) adolescent patients (aged �12 to <18 years).
The majority of randomised patients were Caucasian (65.7%) and there
were more women (60.8%) than men (39.2%). The mean duration of
asthma in all patients was 14.0 years with >50% patients having asthma
for >10 years.
3.2. Lung function after 12 weeks of treatment
Low-dose IND/MF 150/80 μg o.d. showed statistically significant
improvements in trough FEV1 from baseline (0.234 L) compared with
MF 200 μg o.d. (0.051 L) after 12 weeks of treatment in symptomatic
adult and adolescent patients with inadequately controlled asthma with
a least squares mean (LSM) treatment difference of 0.182 L (95% CI:
0.148 to 0.217; p < 0.001) (Fig. 3, Table 2).
In sub-group analysis by age group, the LSM treatment difference for
trough FEV1 after 12 weeks of treatment was 0.251 L (95% CI: 0.130 to
0.371) for adolescent patients and 0.176 L (95% CI: 0.141 to 0.212) for
patients �18 years. With IND/MF treatment, the improvements in FEV1
were evident on Day 2 and treatment differences were maintained
throughout the study in favour of low-dose IND/MF (Fig. 4).
3.3. ACQ-7 treatment difference and proportion of patients achieving
MCID after 12 weeks of treatment
At Week 12, low-dose IND/MF 150/80 μg o.d. demonstrated statis­
tically significant decrease in ACQ-7 score from baseline compared with
MF 200 μg o.d. with a LSM treatment difference of 0.218 (95% CI:
0.293 to 0.143; p < 0.001) (Table 2).
A decrease in ACQ-7 score represents an improvement in asthma
control. A higher proportion of patients in the low-dose IND/MF 150/
80 μg o.d. group compared with the MF 200 μg o.d. group achieved
clinically meaningful improvement of at least 0.5 units from baseline in
the ACQ-7 score [18] after 12 weeks of treatment in symptomatic adults
and adolescents patients with inadequately controlled asthma (Fig. 5,
Table 2).
O. Kornmann et al.
Fig. 2. Patient disposition.
3.4. Mean morning and evening PEF (L/min)
Over Weeks 1–4, LSM treatment difference between low-dose IND/
MF 150/80 μg o.d. and MF 200 μg o.d. for both morning PEF 27.7 L/min
(95% CI: 22.7 to 32.8) and evening PEF 26.4 L/min (95% CI: 21.4 to
31.3) was in favour of IND/MF 150/80 μg o.d.
Over Weeks 1–12, LSM treatment difference between low-dose IND/
MF 150/80 μg o.d. and MF 200 μg o.d. for both morning PEF 27.2 L/min
(95% CI: 22.1 to 32.4) and evening PEF 26.1 L/min (95% CI: 21.0 to
4
Respiratory Medicine 161 (2020) 105809
31.2) was in favour of IND/MF 150/80 μg o.d (Table 2).
The improvements in mean morning and evening PEF were evident
from Week 1–4, after start of the treatment in favour of low-dose IND/
MF and were maintained throughout the study (Fig. 6A and B).
3.5. Rescue medication over 12 weeks of treatment
A greater reduction in the mean daily number of puffs of rescue
medication was observed in those patients treated with low-dose IND/
O. Kornmann et al. Respiratory Medicine 161 (2020) 105809

Table 1 Table 2
Baseline demographics and clinical characteristics of the patients (randomised Summary of results from the analyses of the primary (trough FEV1) and sec­
set). ondary endpoints (full analysis set).
Characteristic IND/MF 150/80 μg MF 200 μg o.d. Total Low-dose IND/MF 150/ MF 200 μg o.d.
o.d. (N ¼ 398) (N ¼ 404) (N ¼ 802) 80 μg o.d. (N ¼ 398) (N ¼ 404)

Age, years 46.1 � 16.26 45.1 � 16.27 45.6 � 16.26 Trough FEV1, L (Week 12)
Men, n (%) 151 (37.9) 163 (40.3) 314 (39.2) n 394 395
BMI, kg/m2 26.3 � 5.81 26.7 � 6.00 26.5 � 5.91 LS mean change from baseline 0.234 (0.0134) 0.051 (0.0134)
Duration of asthma, 14.4 � 13.18 13.6 � 12.48 14.0 � 12.83 (SE)
years Treatment difference vs MF 0.182 (0.148–0.217; p < 0.001)
Number of asthma exacerbations in the previous year, n (%) (95% CI; p-value)
0 324 (81.4) 319 (79.0) 643 (80.2) ACQ-7 (Week 12)
1 70 (17.6) 74 (18.3) 144 (18.0) n 387 384
>1 3 (0.8) 10 (2.5) 13 (1.6) LS mean change from baseline 0.947 (0.0411) 0.730 (0.0411)
Missing 1 (0.3) 1 (0.2) 2 (0.2) (SE)
Baseline ACQ-7 score 2.24 � 0.40 2.30 � 0.39 2.27 � 0.39 Treatment difference vs MF 0.218 ( 0.293 to 0.143; p < 0.001)
Prior asthma treatment, n (%) (95% CI; p-value)
Low-dose ICS 177 (44.5) 167 (41.3) 344 (42.9) ACQ-7 proportion of patients with improvements of � 0.5 (Week 12)
Medium- to high- 1 (0.3) 0 1 (0.1) n 395 399
dose ICS OR vs MF (95% CI) 1.69 (1.23–2.33)
Low-dose ICS/LABA 217 (54.5) 232 (57.4) 449 (56.0) Mean morning PEF, L/min (Weeks 1–4)
Medium- to high- 3 (0.8) 0 3 (0.4) n 385 384
dose ICS/LABA LS mean change from baseline 33.1 (1.91) 5.4 (1.90)
Missing 0 5 (1.2) 5 (0.6) (SE)
FEV1 pre- 2.23 � 0.64 2.22 � 0.58 2.23 � 0.61 Treatment difference vs MF 27.7 (22.7–32.8)
bronchodilator (L) (95% CI)
FEV1 pre- 73.3 � 7.57 72.2 � 7.63 72.7 � 7.61 Mean evening PEF, L/min (Weeks 1–4)
bronchodilator (% n 387 389
predicted) LS mean change from baseline 29.0 (1.78) 2.7 (1.78)
FEV1 reversibility (% 20.6 � 11.66 20.7 � 11.94 20.7 � 11.79 (SE)
increase) Treatment difference vs MF 26.4 (21.4–31.3)
(95% CI)
Data are presented as mean � SD unless otherwise specified. Mean morning PEF, L/min (Weeks 1–12)
ACQ-7, Asthma Control Questionnaire; BMI, body mass index; FEV1, forced n 382 382
expiratory volume in 1 s; ICS, inhaled corticosteroid; IND/MF, indacaterol ace­ LS mean change from baseline 31.0 (1.98) 3.8 (1.97)
tate/mometasone furoate; LABA, long-acting β2-agonist; MF, mometasone (SE)
furoate; o.d., once-daily. Treatment difference vs MF 27.2 (22.1–32.4)
(95% CI)
Mean evening PEF, L/min (Weeks 1–12)
n 386 386
LS mean change from baseline 26.8 (1.84) 0.7 (1.84)
(SE)
Treatment difference vs MF 26.1 (21.0–31.2)
(95% CI)
Rescue medication (number of puffs) over 12 weeks
n 393 392
Treatment difference vs MF 0.26 ( 0.37 to 0.14)
(95% CI)
% of Rescue medication free days
n 384 385
% treatment difference vs MF 8.1% (4.3–11.8)
(95% CI)
Quality of life (AQLQ total score) (Week 12)
n 381 379
Treatment difference vs MF 0.149 (0.064–0.234)
(95% CI)
Daily symptom score (Weeks 1–12)
n 373 380
Fig. 3. Treatment difference with IND/MF 150/80 μg o.d. versus MF Treatment difference vs MF 0.15 ( 0.26 to 0.05)
200 μg o.d. for trough FEV1 after 12 weeks of treatment (full analysis set). (95% CI)
% of nights with no nighttime awakenings
n 384 384
MF 150/80 μg o.d. compared with MF 200 μg o.d. with LSM treatment Treatment difference vs MF (95% 4.8% (1.8–7.7)
difference of 0.26 (95% CI: 0.37 to 0.14) that favoured IND/MF CI)
(Table 2). Rate of exacerbations
The percentage of rescue medication free days were greater with n 395 399
All (mild, moderate, severe), 20 (5.1) 60 (15.0)
low-dose IND/MF 150/80 μg o.d. compared with MF 200 μg o.d. with Number (%) of patients
treatment difference of 8.1% (95% CI: 4.3 to 11.8) (Table 2). Moderate to severe, Number 10 (2.5) 32 (8.0)
(%) of patients
3.6. Quality of life (AQLQ total score) over 12 weeks All (mild, moderate, severe), 0.30 (0.18–0.50)
RR vs MF (95% CI)
Moderate to severe, RR vs MF 0.25 (0.12–0.52)
Patients treated with low-dose IND/MF 150/80 μg o.d. showed (95% CI)
greater improvements in AQLQ overall score compared with the MF
n, number of patients included in the analysis.
200 μg o.d., with an LSM treatment difference from baseline of 0.149
ACQ-7, Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Ques­
(95% CI: 0.064 to 0.234) (Table 2).
tionnaire; CI, confidence interval; FEV1, forced expiratory volume in 1 s; IND/
MF, indacaterol acetate/mometasone furoate 150/80 μg o.d.; LS, least squares;

5
O. Kornmann et al. Respiratory Medicine 161 (2020) 105809

PEF, peak expiratory flow; MF, mometasone furoate 200 μg o.d.; o.d., once-
daily; OR, Odds ratio; RR, Rate ratio.

Fig. 6A. Change from baseline in mean morning PEF (L/min) at 4-weekly
intervals (full analysis set).

Fig. 4. Least squares means and associated 95% CI of trough and pre-dose
trough FEV1 (L) over post-baseline visits (full analysis set).

Fig. 6B. Change from baseline in mean evening PEF (L/min) at 4-weekly
Fig. 5. Proportion of patients with an improvement of ≥0.5 units in the
intervals (full analysis set).
ACQ-7 score after 12 weeks of treatment (full analysis set).

3.9. Safety assessments

3.7. Daily symptom score during weeks 1–12

Improvements from baseline in all asthma symptoms were collected
via eDiary. A greater reduction in total daily symptom scores were
achieved in patients treated with low-dose IND/MF 150/80 μg o.d.
compared with MF 200 μg o.d. [treatment difference: 0.15 (95% CI:
0.26 to 0.05)] (Table 2).
The percentage of nights with no nighttime awakenings were greater
with low-dose IND/MF 150/80 μg o.d. compared with MF 200 μg o.d.
with treatment difference 4.8% (95% CI: 1.8 to 7.7) (Table 2).
3.8. Rate of exacerbations over 12 weeks of treatment
Lower rates of moderate-to-severe [rate ratio (RR) 0.25, 95% CI: 0.12
to 0.52] and all exacerbations (RR: 0.30, 95% CI: 0.18 to 0.50) were
observed in patients treated with low-dose IND/MF 150/80 μg o.d.
versus MF 200 μg o.d (Fig. A1A and A1B; Table 2).
The overall incidence of AEs was lower in patients treated with low-
dose IND/MF compared with MF (32.3% vs 38.3%, respectively). The
majority of AEs (>90% AEs) in both treatment groups were mild-to-
moderate in severity, and were comparable between the treatment
groups. One serious asthma outcome (asthma-related hospitalisation)
was reported in the MF group and none in the IND/MF group. No death
was reported in any treatment group throughout the study. Overall, the
incidence of serious AEs (SAEs) was comparable between the treatment
groups (1.3% in the low-dose IND/MF group and 1.8% in the MF group).
4. Discussion
This QUARTZ study demonstrates that treatment with low-dose IND/
MF 150/80 μg o.d. in symptomatic adult and adolescent patients with
inadequately controlled asthma significantly improves lung function
and asthma control after 12 weeks of treatment compared to MF alone.
Overall, the study met its primary endpoint, trough FEV1 at 12 weeks,

6
O. Kornmann et al.
with low-dose IND/MF treatment demonstrating statistically significant
superiority compared to MF alone [LSM treatment difference 0.182 L,
p < 0.001 (Fig. 3)]. Subgroup analyses of trough FEV1 in adolescents
were generally consistent with results from overall population in this
study and other published studies [10,11,13,17–19]. Lung function
benefits were supported by PEF, which demonstrated improvements in
both the morning and evening PEF (Fig. 6A and B). Although PEF was
not part of statistical hierarchy, it provides important supportive evi­
dence of lung function benefit, which was measured on a daily basis by
patients using an eDiary. The magnitude of improvement in PEF is in the
range considered perceivable by patients [20].
Treatment with low-dose IND/MF showed statistically significant
improvements in asthma control (p < 0.001) measured by ACQ-7 as
compared to MF. This was supported by responder analysis, which
demonstrated that a greater proportion of patients achieved MCID (�0.5
points improvement from baseline) in ACQ-7 overall score (Fig. 5). Of
note, the MF arm also demonstrated a 64.9% responder rate. This
finding is consistent with meta-analyses of asthma clinical studies,
which demonstrated that use of ICS is associated with ‘placebo’ effect in
comparator arms. This is likely attributable to improved adherence in a
clinical trial setting [21]. Despite this and the limited duration of
treatment (12 weeks), the results of the responder analysis demonstrated
that low-dose IND/MF provided greater benefits in asthma control as
compared to MF.
All other secondary efficacy variables such as rescue medication use,
rescue medication free days, nighttime awakenings and daily symptom
score collected via eDiary as well as AQLQ total score also showed
improvement in favour of low-dose IND/MF 150/80 μg o.d.
The results from this study are consistent with previous studies that
compared ICS/LABA combination therapies over ICS monotherapy in
terms of improvements in lung function and asthma control in patients
with asthma [4,7,19,22–26]. For instance, the 28-week Phase III SMART
study demonstrated the efficacy of ICS/LABA combination inhalers
when compared to the individual mono-components ICS and LABAs [5].
Furthermore, previous studies reported that ICS/LABA combinations
are safe, effective, well tolerated and not associated with increased risk
of death or cardiac-related SAEs or discontinuations due to adverse
events (DAEs), and asthma-related SAEs and DAEs [5,6,26–28]. Our
study with low-dose IND/MF combination also demonstrated efficacy,
safety and tolerability delivered via Breezhaler® [4].
All currently approved ICS/LABA combinations are twice-daily
dosing regimens except for fluticasone/vilanterol, which is a once-
daily dosing regimen; hence, there is a need to evaluate once-daily
dosing regimens for effective asthma treatment, which may provide
adherence benefits. It has been well established that once-daily regimens
lead to better compliance when compared with twice-daily regimens in
asthma patients [25,29–31]. This study also provides evidence of the
benefit of adding LABA to a lower dose ICS as per GINA guidelines and
provides an important treatment option prior to advancing to combi­
nation therapies that include higher ICS dose.
To our knowledge, this is the first study to compare a low-dose ICS/
LABA FDC o.d. to low-dose ICS monotherapy in adult and adolescent
patients with inadequately controlled asthma. Overall, this study was
conducted in a clinically appropriate cohort of asthma patients for the
IND/MF dose studied and was of adequate length to make clinically
meaningful conclusions from the efficacy data. A strength of this study is
the use of eDiary, which provided daily electronic recording and
transmission of PEF, symptoms and rescue medication data. In addition,
spirometry was assessed in a standardised manner using centralised
spirometry through an external vendor. Taken together, these helped
ensure a high level of rigour in the assessment of these endpoints [32]. A
potential limitation of the study is that the 12-week duration does not
allow for longer-term safety data to be evaluated. In addition, limited
conclusions can be drawn from the exacerbation results due to the short
duration of the study.
7
Respiratory Medicine 161 (2020) 105809
5. Conclusions
The QUARTZ study showed that IND/MF 150/80 μg o.d. delivered
via Breezhaler® significantly improved trough FEV1 and asthma control
versus MF 200 μg o.d. and provided benefits across a range of lung
function and symptomatic endpoints including morning and evening
PEF, rescue medication use, nighttime awakenings, AQLQ total score,
mean daily symptom scores and exacerbation rates. Once-daily, low-
dose IND/MF can be a potential option for treatment of adult and
adolescent patients with asthma who remain inadequately controlled on
ICS (with/without LABA). IND/MF 150/80 μg o.d. was well tolerated.
Data from this study add to the existing evidence supporting, the efficacy
of ICS/LABA over ICS alone and the efficacy of a once-daily combination
of low-dose IND/MF 150/80 μg o.d., in patients with inadequately
controlled asthma.
Support statement
This study was supported by Novartis Pharmaceuticals Corporation,
East Hanover, New Jersey, USA.
Author contributions
All the authors contributed in the conception and design of the study,
facilitated the writing and reviewed the manuscript. All the authors
contributed to the development of the manuscript and approved the
final version.
Declaration of competing interest
OK’s institution received fees for conducting the study as partici­
pating site; OK reports personal fees from Sanofi, Boehringer Ingelheim,
Novartis, AstraZeneca and GlaxoSmithKline outside the submitted work.
JM declares financial support from Novartis during the conduct of the
study; from AstraZeneca, Chiesi, Sanofi-Aventis, GlaxoSmithKline,
Boehringer-Ingelheim, MSD, TEVA, and ACTELION outside the sub­
mitted work. NK has nothing to disclose. LCS, BS, LB and PDA are
Novartis employees.
Acknowledgements
The authors would like to thank the investigators and patients at the
investigative sites for their support of this study. We acknowledge
Abhijit Pethe, Kiran Bapatla and Sheikh Vikarunnessa from Novartis. We
acknowledge Juergen Lilienthal, Anna-Marie Hamann and their team
for support from DATAMAP. Hasitha Shilpa Anantaraju, Ph.D., and
Rahul Lad, Ph.D., professional medical writers at Novartis (Hyderabad,
India) provided editorial and technical support in the preparation of the
manuscript.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.rmed.2019.105809.
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