Donohue et al.

BMC Pulmonary Medicine (2016) 16:65

DOI 10.1186/s12890-016-0223-3

RESEARCH ARTICLE Open Access

Efficacy and safety of ipratropium bromide/

albuterol compared with albuterol in
patients with moderate-to-severe asthma: a
randomized controlled trial
James F. Donohue1, Robert Wise2, William W. Busse3, Sandra Garfinkel4, Valentina B. Zubek4, Mo Ghafouri4,6,
Raymond C. Manuel4, Rozsa Schlenker-Herceg4 and Eugene R. Bleecker5*

Abstract
Background: Many patients with asthma require frequent rescue medication for acute symptoms despite
appropriate controller therapies. Thus, determining the most effective relief regimen is important in the
management of more severe asthma. This study’s objective was to evaluate whether ipratropium bromide/albuterol
metered-dose inhaler (CVT-MDI) provides more effective acute relief of bronchospasm in moderate-to-severe
asthma than albuterol hydrofluoroalkaline (ALB-HFA) alone after 4 weeks.
Methods: In this double-blind, crossover study, patients who had been diagnosed with asthma for ≥1 year were
randomized to two sequences of study medication “as needed” for symptom relief (1–7 day washout before
second 4-week treatment period): CVT-MDI/ALB-HFA or ALB-HFA/CVT-MDI. On days 1 and 29 of each sequence,
6-hour serial spirometry was performed after administration of the study drug. Co-primary endpoints were FEV1
area under the curve (AUC0–6) and peak (post-dose) forced expiratory volume in 1 s (FEV1) response (change
from test day baseline) after 4 weeks. The effects of “as needed” treatment with ALB-HFA/CVT-MDI were analyzed
using mixed effect model repeated measures (MMRM).
Results: A total of 226 patients, ≥18 years old, with inadequately controlled, moderate-to-severe asthma were
randomized. The study met both co-primary endpoints demonstrating a statistically significant treatment benefit
of CVT-MDI versus ALB-HFA. FEV1 AUC0-6h response was 167 ml for ALB-HFA, 252 ml for CVT-MDI (p <0.0001);
peak FEV1 response was 357 ml for ALB-HFA, 434 ml for CVT-MDI (p <0.0001). Adverse events were comparable
across groups.
Conclusions: CVT-MDI significantly improved acute bronchodilation over ALB-HFA alone after 4 weeks of
“as-needed” use for symptom relief, with a similar safety profile. This suggests additive bronchodilator effects
of β2-agonist and anticholinergic treatment in moderate-to-severe, symptomatic asthma.
Trial registration: ClinicalTrials.gov No.: NCT00818454; Registered November 16, 2009.
Keywords: Randomized controlled trial, Moderate-to-severe asthma, Ipratropium bromide, Albuterol
hydrofluoroalkaline, Ipratropium bromide/albuterol metered-dose inhaler, Anticholinergic/β2-agonist,
Bronchodilation, As-needed, Acute symptom relief

* Correspondence: [email protected]
5
Wake Forest School of Medicine, Center for Genomics and Personalized
Medicine, Winston-Salem, NC 27157, USA
Full list of author information is available at the end of the article

© 2016 Donohue et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Donohue et al. BMC Pulmonary Medicine (2016) 16:65 Page 2 of 15

Background week) despite medium- to high-dose inhaled corticosteroids

Despite the availability of effective asthma controller (ICS), with or without long-acting β2-agonist (LABA) [22].
therapies, a significant proportion of patients have sub- Patients demonstrated significant improvement in pulmon-
optimal asthma control, characterized by frequent symp- ary function after treatment with CVT-MDI versus ALB-
toms, lifestyle restrictions, and healthcare use [1–3]. In HFA alone. We designed a study based on these results,
addition to controller medications, acute reliever or res- and according to results from the Asthma Clinical Research
cue medications, e.g. short-acting β2-agonists (SABAs) Network studies [27], which indicated that inhaled long-
are used to treat acute symptoms and exacerbations [4]. acting muscarinic antagonists (LAMAs) might be an alter-
The frequency of SABA use as rescue medication reflects native to LABAs and other controllers in patients whose
the frequency and intensity of symptoms, and is an im- condition is inadequately controlled on an ICS alone [28].
portant component for classifying asthma severity and The objective of this study was to evaluate whether
level of disease control [4–6]. CVT-MDI provides more effective acute relief of broncho-
Short-acting anticholinergic agents have been used in spasm in moderate-to-severe asthma than ALB-HFA
asthma for decades; however, their exact role in asthma alone after 4 weeks, as add-on to stable doses of their con-
has not been well established [7, 8]. Studies directly troller medications (ICS, LABA, leukotriene modifier,
comparing short-acting anticholinergic agents with a theophylline, anti IgE, oral corticosteroids). Patients were
variety of SABAs have shown that SABAs provide required to be on stable doses of these medications for at
greater bronchodilation than short-acting anticholinergic least 4 weeks prior to screening to achieve a clear baseline
agents alone in stable asthma [9–11]; however, individual before study commencement. The efficacy of CVT-MDI
studies have demonstrated that specific asthma popula- or ALB-HFA was compared for acute improvement in
tions, e.g. older patients [12], and those whose asthma is lung function at the beginning and end of treatment, and
related to psychogenic factors [13, 14], cigarette smoke, other measures of asthma control (medication was with-
or β-blocking drugs [15, 16], might benefit from anti- held before measurement of acute response). Patients
cholinergic therapy. were instructed to use open-label ALB-HFA in addition to
Short-acting anticholinergic agents have also been the blinded study medication if required.
evaluated in combination with a SABA or sequentially
following SABA administration. The rationale for use Methods
of a combination of a short-acting anticholinergic agent Ethics, consent and permissions
and a SABA includes differences between the two clas- This randomized, double-blind, two-way crossover study
ses of medications regarding mechanisms of action, was conducted in accordance with the Declaration of
side-effect profiles, onset and duration of action, and Helsinki. The protocol and all amendments were approved
site of action [9]. Studies evaluating combination therapy by the institutional review board/ethics committee at each
with a short-acting anticholinergic and a SABA have participating site (Additional file 1: Table S1). All patients
shown variable results, mainly due to small numbers of provided written informed consent.
patients or inappropriate patient populations [8, 11, 17–
24]; however, many of these studies showed an additional Trial design
(although not significant) benefit [8]. Every effort was made to collect spirometry data for
Combivent® inhalation aerosol metered-dose inhaler each time-point at the clinic visit. To be able to include
(CVT-MDI) is a fixed-dose combination of the short- the same patients at each time-point in the spirometry
acting anticholinergic, ipratropium bromide, and the SABA, summaries, missing values were estimated using other
albuterol sulfate, using a chlorofluorocarbon (CFC) propel- values recorded for the patient on that test day. For patients
lant. It should be noted that the CFC-MDI formulation of with missing data on a given test-day because additional
Combivent (CVT-MDI) used in this study is no longer SABA medication was taken during testing, missing data
available, but Combivent is available in the Respimat® Soft were estimated by the least favorable observation on that
Mist™ inhaler (Combivent® Respimat®), which is considered test-day. Randomly missing data were estimated by either
therapeutically equivalent to the CFC-MDI formulation, linear interpolation of adjacent data or by the last observed
and studies in chronic obstructive pulmonary disease data if no subsequent data were available. The decision to
(COPD) have indicated that it has similar bronchodilator use estimates for missing data was made prior to unblind-
effects [25, 26]. ing of the treatment assignments.
A prior, single-dose, double-blind, crossover study
compared CVT-MDI to albuterol hydrofluoroalkaline Participants
(ALB-HFA) in patients with moderate-to-severe asthma Patients were male or female, ≥18 years of age, with
and persistent symptoms. These patients required regu- physician diagnosis of asthma for ≥1 year, baseline forced
lar use of albuterol as rescue medication (6–56 puffs per expiratory volume (FEV1) ≤80 % predicted normal and
Donohue et al. BMC Pulmonary Medicine (2016) 16:65 Page 3 of 15

post-bronchodilator reversibility of ≥12 % or ≥200 ml after Patients were instructed to use the asthma monitor
administration of four puffs of ALB-HFA. Spirometry was (AM3) throughout the study. Patients used the AM3 to
performed according to American Thoracic Society guide- record twice-daily peak expiratory flow (PEFs), as-needed
lines [29, 30], and National Health and Nutrition Examin- study medication use, additional open-label ALB-HFA
ation Survey reference equations were used to calculate use, daily symptom assessments, and background con-
predicted values [31]. Patients received treatment with troller medication use (such as ICS, LABA, leukotriene
ICS with or without LABA and other asthma controller modifier, theophylline, anti IgE, OCS) for the duration
medications for ≥6 weeks prior to screening, and used a of the study.
short-acting bronchodilator ≥3 times a week for symptom
relief in the 2 weeks prior to screening. Patients were en- Interventions
tered in the study only if they had an Asthma Control CVT-MDI (Combivent® Inhalation Aerosol CFC-MDI
Questionnaire (ACQ) score of ≥1.5 [32]. (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield
Patients were excluded from the study if they had been CT, USA) or ALB-HFA (IVAX Pharmaceuticals, Water-
diagnosed with COPD or other significant disease; how- ford, Ireland) was used during clinic visit days for pul-
ever, all patients who were non-smokers or ex-smokers monary function testing, and as needed between clinic
who stopped smoking for >1 year prior to study partici- visits for symptom relief. Each actuation of CVT-MDI
pation and had a smoking history <10 pack-years were delivered 18 μg ipratropium bromide and 103 μg albute-
eligible. Patients who had been hospitalized for cardiac rol sulfate (equivalent to 90 μg albuterol base) from the
failure in the past year or who had a recent history of mouthpiece. For the ALB-HFA MDI, each actuation de-
myocardial infarction were excluded. livered 120 μg albuterol sulfate from the canister valve
The study included a 2-week screening period to es- and 108 μg albuterol sulfate from the actuator mouth-
tablish patients’ baseline asthma measures and confirm piece (equivalent to 90 μg albuterol base). During each
eligibility using bronchodilator reversibility testing—12 % treatment period, patients recorded in their eDiary the
and 200 ml improvement in FEV1 post-bronchodilator number of puffs of study medication taken (AM and PM).
after four puffs of ALB-HFA MDI—at visit two. Patients If patients perceived that study medication was not
recorded symptoms, medication use (maintenance ICS ± adequately controlling their asthma symptoms, they were
LABA and “as needed”) and peak expiratory flow (PEF) instructed to use the open-label ALB-HFA (ProAir® HFA,
in an electronic diary (eDiary)/peak flow meter (Asthma IVAX Pharmaceuticals, Waterford, Ireland) in addition to
Monitor® [AM3]; ERT Products, Philadelphia) during the the study medication.
screening period. After the run-in period, eligible pa- For the study duration, patients were required to re-
tients were randomly assigned (1:1) to either CVT-MDI main on stable doses of their asthma controller medica-
or ALB-HFA. Patients used blinded study medication as tions and changes in background controller medications
needed (two puffs every 4–6 h, up to four times daily) were documented. Additions or increases in the dose of
between visits for symptom relief during the 4-week oral corticosteroids were allowed for the management of
treatment period. Additionally, patients received open- asthma exacerbations and were recorded.
label ALB-HFA for use if symptom relief could not be
achieved with the blinded study medication. Mainten- Study end points
ance therapy with high- or low-dose ICS had no impact Co-primary endpoints were FEV1 area-under-the-curve
on outcomes (Table 2) and, as this was a crossover (AUC0–6) above test-day baseline from 0 to 6 h, and
study, all patients served as their own control. peak FEV1 response. The study defined peak FEV1 re-
Following the first 4-week treatment period, patients sponse as the maximum change in FEV1 from test-day
had a 1–7 day washout period (a 6–8-hour wash-out baseline within the 6-hour post-treatment interval, after
period is generally considered adequate for short-acting 4 weeks of treatment.
antimuscarinics (SAMAs) before entering the second 4- The secondary endpoints were the mini Asthma Quality
week treatment period with crossover treatment using of Life Questionnaire (mini-AQLQ) responses, ACQ-7 re-
either CVT-MDI or ALB-HFA. All other (non-asthma) sponses, and the number of puffs of study medication and
concomitant therapies taken at screening and through- open-label ALB-HFA (AM and PM) patients used during
out the trial period were recorded. For washout, patients each treatment period. Other endpoints included forced
were instructed to refrain from using their study medica- vital capacity, peak expiratory flow (data not shown), night-
tion for at least 6 h prior to the scheduled clinic visit. time awakenings due to asthma symptoms (from eDiary),
On days 1 and 29, patients underwent lung function and duration of bronchodilator FEV1 response. Broncho-
testing with 6-hour serial spirometry. Baseline FEV1 was dilator response was achieved if an FEV1 value of ≥1.15
measured 10-minutes before, and at 5, 15, 30, 60 min, times the corresponding test-day baseline value was re-
and 2, 3, 4, 5, 6 h after study drug administration. corded at any time-point during the first 6 h after treatment
Donohue et al. BMC Pulmonary Medicine (2016) 16:65 Page 4 of 15

administration. Termination of bronchodilator response Statistical methods

was identified by the first fall of <1.15 times the corre- Co-primary efficacy endpoints of CVT-MDI and ALB-
sponding test-day FEV1 baseline value on two consecutive HFA were compared using mixed-effect model repeated
measurements following a bronchodilator response during measures (MMRM). The MMRM model has treatment,
the 6-hour observation period on the test day. Duration of period, day, and the interaction between treatment and
bronchodilator response was defined as the time interval day as fixed effects, test-day baseline value as a covariate,
between onset (bronchodilator response first achieved) and and patient as random effect. In the MMRM model, day
termination of bronchodilator response; duration was zero refers to the start (day 1) or end (day 29) of 4 weeks of
if there was no bronchodilator response. treatment. In the results section, only results for day 29
Safety endpoints included monitoring of adverse events will be presented. A hierarchical testing procedure was
(AEs), vital signs, screening laboratory values (hematology, used to address multiple comparisons. The null hypothesis
chemistry, and urinalysis), and electrocardiogram (ECG). for FEV1 AUC0–6 response was tested first (alpha = 0.025,

CONSORT Flow Diagram

Assessed for eligibility (n=548)
Enrollment

Excluded (n=322)
♦ Not meeting inclusion criteria (n=282)
♦ Consent withdrawn (n=6)
♦ Adverse event (n=3)
♦ Lost to follow-up (n=3)
♦ Other (n=28)

Randomized (n=226)

Allocation
Albuterol HFA Combivent

Allocated to albuterol HFA (n=115) Allocated to Combivent (n=111)

♦ Received allocated intervention (n=115) ♦ Received allocated intervention (n=111)
♦ Did not receive allocated intervention (n=0) ♦ Did not receive allocated intervention (n=0)
Treatment Phase 1

Follow-Up

Prematurely discontinued trial medication (n=3) Prematurely discontinued trial medication (n=1)
Reasons: Reasons:
Adverse event (n=0) Adverse event (n=1)
Worsening of asthma (n=0) Worsening of asthma (n=1)
Non compliance with protocol (n=0) Non compliance with protocol (n=0)
Lost to follow-up (n=0) Lost to follow-up (n=0)
Refused to continue study medication (n=0) Refused to continue study medication (n=0)
Other (n=3) Other (n=0)

Crossed-over to albuterol HFA (n=110) Crossed-over to Combivent (n=112)

Received allocated intervention (n=107) Received allocated intervention (n=108)
Did not receive allocated intervention (n=3) Did not receive allocated intervention (n=4)
Reasons: Reasons:
Treatment Phase 2

Adverse event (n=1) Adverse event (n=1)

Worsening of asthma (n=0) Worsening of asthma (n=1)
Adverse event other (n=1) Adverse event other (n=0)
Non compliance with protocol (n=0) Non compliance with protocol (n=2)
Other (n=2) Other (n=1)

Prematurely discontinued trial medication (n=1) Prematurely discontinued trial medication (n=2)
Reasons: Reasons:
Other (n=1) Other (n=2)

Analysis

Analyzed (n=107) Analyzed (n=112)

Excluded from analysis (n=4) Excluded from analysis (n=3)
Reasons: Reasons:
Blind broken early (n=4) Blind broken early (n=3)

Fig. 1 Consolidated Standards of Reporting Trials (CONSORT) flowchart of patient disposition

Donohue et al. BMC Pulmonary Medicine (2016) 16:65 Page 5 of 15

one-sided); if this null hypothesis was rejected, the null approximately 144 completed patients was calculated;
hypothesis for peak FEV1 response was tested next this was increased to 200 to adjust for patients who
(alpha = 0.025, one-sided). dropped out prior to completing both 4-week periods.
The primary efficacy analysis was performed on a With an estimated 15 % discontinuation rate, 170 pa-
modified full analysis set (FAS). The FAS consisted of tients were expected to complete the first and second
all patients receiving study medication, who were docu- periods of the crossover (phases I and II).
mented to have taken at least one dose of investigational
drug, and who had no missing test-day baseline values or
missing responses for FEV1 AUC0–6 and peak FEV1 after Results
4 weeks of treatment. Seven patients who reported that A total of 548 patients recruited from 41 study centers
their study medication devices were working improperly, in the United States from December 2008 to September
and whose treatment blind was broken prior to database 2009 were screened and 226 patients were randomized
lock, were excluded from all efficacy analyses. using a validated system and received at least one dose
A post-hoc analysis was also performed on endpoints of study medication; 222 randomized patients were treated
related to the co-primary endpoints. The MMRM model with ALB-HFA, and 219 with CVT-MDI (107 received
described above was used to analyze the ratio of FEV1 ALB-HFA, then CVT-MDI and 112 received CVT-MDI,
AUC0–6 response to test-day baseline FEV1, and the ratio then ALB-HFA). During the crossover period, 14 patients
of peak FEV1 response to test-day baseline FEV1. prematurely discontinued study medication; three patients
Subgroup analyses for the co-primary endpoints were had AEs leading to discontinuation (one taking ALB-HFA,
performed for: onset of asthma; type of asthma; percent two taking CVT-MDI), and only 3 % of patients had
predicted FEV1 categories; concomitant asthma medica-
tion usage; puff usage of medication at study baseline; Table 1 Summary of demographic and baseline characteristics
gender; race; age categories; smoking status; and FEV1/ of randomized patients
forced vital capacity (FVC) percentage categories based Total No. of randomized patients, no (%) 226 (100)
on pre-bronchodilator measurements at randomization. Female, no. (%) 130 (57.5)
Subgroup analyses were performed to test whether the Race, no. (%) White 174 (77)
treatment effect was uniform across subgroups, at the end Black African/Asian 44 (19.5)
of the 4-week treatment period.
Other 8 (3.5)
Secondary endpoints were analyzed using the MMRM
model described for the primary analysis. The analysis of Age, mean (SD) 47.1 (13.7)
the duration of bronchodilator response was pre-specified Body mass index (kg/m2), mean (SD) 31.1 (6.7)
as descriptive statistics; a post-hoc analysis of bronchodila- Smoking history, no. (%) Never smoked 163 (72.1)
tor response duration on day 29 was also performed using Ex-smoker 63 (27.9)
an MMRM model with treatment and period as fixed Characteristics
effects, and patient as random effect.
FEV1 (L), mean (SD) 2.075 (0.630)
A post-hoc responder analysis (McNemar’s sign test)
was performed to test for the difference in the proportion % predicted FEV1, mean (SD) 63.4 (11.3)
of responders (those who achieved bronchodilator FEV1 FEV1/FVC (%), mean (SD) 64.4 (10.3)
response) between treatment groups. FEV1 reversibility (%), mean (SD) 25.7 (15.6)
All safety data were displayed and analyzed using de- ACQ score, mean (SD) 2.46 (0.57)
scriptive statistical methods. Mini-AQLQ score, mean (SD) 4.52 (1.04)
Based on a recent, single-dose, crossover trial with
Open-label albuterol usea, mean (SD) 3.63 (1.62)
CVT-MDI and ALB-HFA, the standard deviation for the
difference between treatment groups (paired t-test) in Controller: ICS + LABA during the cross-over phase (%) 160 (70.8)
FEV1 AUC0–6 was expected to be 200–220 ml [22]. For Controller: ICS (low doseb) (%) 52 (23.0)
the peak FEV1 endpoint, the mean difference between b
Controller: ICS (medium dose ) (%) 157 (69.5)
treatments and the standard deviation of the mean treat- Controller: ICS (high doseb) (%) 17 (7.5)
ment difference were expected to be similar to that ob- ACQ asthma control questionnaire (7-point scale), AQLQ asthma quality of life
served for FEV1 AUC0–6 (usually AUC0–3 is similar to questionnaire, FEV1 forced expiratory volume in 1 s, ICS inhaled corticosteroid,
peak FEV1 – AUC0–6 also includes duration of effect of LABA long acting β2-agonist
a
Weekly mean puffs albuterol/day
these relatively short-acting bronchodilators). b
Dose either as ICS monotherapy (low-dose ICS, <320 μg: 9/52 patients [17 %];
To detect a 60 ml difference in mean values (based on medium-dose ICS, >320 – <800 μg: 63/157 patients [40 %]; high-dose ICS, >800 μg:
1/17 patients [6 %]), or ICS component of combination ICS/LABA therapy (low-dose
the single-dose crossover trial) using a 2.5 % level of sig- ICS component: 43/52 patients [83 %]; medium-dose ICS component: 94/157
nificance (one-tailed) and 90 % power, a sample of patients [60 %]; high-dose ICS component: 16/17 patients [94 %])
Donohue et al. BMC Pulmonary Medicine (2016) 16:65 Page 6 of 15

Fig. 2 Change from test-day baseline (SE) in FEV1 AUC0–6 and peak FEV1 after 4 weeks. Mean (adjusted) change and post-hoc analysis of mean
ratio of change from test-day baseline (SE) in FEV1 AUC0–6 and peak FEV1 after 4 weeks using the mixed-effect model repeated measures (MMRM).
a Mean (adjusted) change from test-day baseline in FEV1 AUC 0–6 (ml) (95 % CI of the difference: (0.058, 0.112) p <0.0001); b Mean ratio of
change from test-day baseline in FEV1 AUC0-6 (%) (95 % CI of the difference: (0.032, 0.061) p <0.0001); c Mean (adjusted) change from test-day
baseline in peak FEV1 (ml) (95 % CI of the difference: (0.047, 0.107) p <0.0001); d Mean ratio of change from test-day baseline in peak FEV1 (%)
(95 % CI of the difference: (0.027, 0.060) p <0.0001)

missing data. Patient disposition is presented in Fig. 1, and AUC0–6 response to test-day baseline FEV1 was 13 % for
demographics and baseline characteristics in Table 1. CVT-MDI and 8.3 % for ALB-HFA (p <0.0001) (Fig. 2b).
At day 29, mean change in FEV1 AUC0–6 from test- The mean test-day baseline at day 29 for FEV1 was
day baseline was 85 ml greater with CVT-MDI versus 219.3 ml for CVT-MDI and 212.6 ml for ALB-HFA.
ALB-HFA (252 ml vs. 167 ml, p <0.0001) (Fig. 2a). In a Mean change from test-day baseline in peak FEV1 for
post-hoc analysis, at day 29, the mean ratio of FEV1 CVT-MDI was 77 ml greater than ALB-HFA (434 ml vs.

Fig. 3 Changes from test-day baseline in FEV1. Estimated mean (adjusted) changes from test-day baseline in FEV1 at post-dose time-points after
4 weeks using the mixed-effect model repeated measures (MMRM) (day 29; range of difference 50 ml to 115 ml, p <0.006 for all comparisons)
Donohue et al. BMC Pulmonary Medicine (2016) 16:65 Page 7 of 15

Table 2 FEV1 AUC0−6 [L] treatment comparisons by subgroups – FAS

Subgroup Subgroup level Number of patients Subgroup by Difference (CVT-MDI 18/103 –
ALB-HFA 108/CVT-MDI treatment ALB-HFA 108)
18/103 interaction
p value* Mean (SE) 95 % CI P value
Onset of asthma 0.0463
Early 98/98 0.114 (0.024) (0.067, 0.161) <.0001
Late 117/114 0.063 (0.016) (0.031, 0.095) 0.0002
Type of asthma (based on patient history) 0.6444
Allergic 182/181 0.089 (0.015) (0.060, 0.119) <.0001
Non−allergic 33/31 0.079 (0.036) (0.005, 0.154) 0.0364
% Predicted FEV1 categories 0.3127
≤45 % 17/19 0.044 (0.046) (−0.056, 0.144) 0.3562
>45 % and ≤55 % 33/32 0.138 (0.037) (0.062, 0.214) 0.0011
>55 % and ≤65 % 55/54 0.094 (0.030) (0.034, 0.154) 0.0026
>65 % and ≤75 % 76/75 0.073 (0.020) (0.032, 0.113) 0.0006
>75 % 34/32 0.061 (0.033) (−0.005, 0.127) 0.0683
Concomitant asthma medication usage 0.7610
ICS, with LABA 153/149 0.090 (0.018) (0.055, 0.125) <.0001
ICS, without LABA 62/63 0.074 (0.018) (0.037, 0.110) 0.0001
Puff usage of medication (at baseline, daily 0.9938
average in week prior to visit 3)a
≤4 puffs per 143/141 0.080 (0.016) (0.048, 0.111) <.0001
24 h day
>4 and <8 puffs per 71/70 0.094 (0.027) (0.040, 0.148) 0.0010
24 h
≥8 puffs per 1/1
24 h day
Gender 0.2585
Female 125/127 0.2585 0.091 (0.015) (0.060, 0.121) <.0001
Male 90/85 0.082 (0.023) (0.036, 0.128) 0.0007
Raceb 0.1311
Amer.Ind./Alaska Nat 1/1
Asian 2/2
Black/African Amer. 42/40 0.164 (0.041) (0.082, 0.247) 0.0002
Hawaiian/Pacif. Isle 4/5
White 166/164 0.074 (0.014) (0.046, 0.102) <.0001
Age category 0.7044
<35 44/41 0.076 (0.051) (−0.028, 0.180) 0.1464
≥35, <50 68/69 0.082 (0.020) (0.042, 0.123) 0.0001
≥50, <60 62/60 0.115 (0.022) (0.071, 0.159) <.0001
≥60 41/42 0.074 (0.027) (0.019, 0.129) 0.0094
Smoking status 0.9982
Ex-smoker 59/59 0.077 (0.026) (0.026, 0.128) 0.0038
Never smoked 156/153 0.088 (0.016) (0.057, 0.119) <.0001
FEV1/FVC [%] pre−BD at Rand 0.1453
<60 59/60 0.132 (0.027) (0.079, 0.186) <.0001
Donohue et al. BMC Pulmonary Medicine (2016) 16:65 Page 8 of 15

Table 2 FEV1 AUC0−6 [L] treatment comparisons by subgroups – FAS (Continued)

≥60, <65 46/45 0.117 (0.026) (0.063, 0.170) <.0001
≥65, <70 43/44 0.074 (0.029) (0.015, 0.132) 0.0148
≥70 67/63 0.022 (0.024) (−0.025, 0.070) 0.3506
ALB-HFA albuterol hydrofluoroalkaline, CVT-MDI ipratropium bromide/albuterol sulfate metered-dose inhaler, FAS full analysis set, FEV1 forced expiratory volume in
1 s, FVC forced vital capacity, ICS inhaled corticosteroids, LABA long-acting β2-agonist, pre-BD at Rand pre-bronchodilator at randomization
a
Last category not included in modelling due to insufficient number of patients
b
Asian, Hawaiian/Pacific Islander and American Indian/Alaska National not included in modelling due to insufficient number of patients
*Unadjusted p values

357 ml, p <0.0001) (Fig. 2c). In a post-hoc analysis, at by subgroup interaction for the subgroup of onset of
day 29, the mean ratio of peak FEV1 response to test-day asthma for FEV1 AUC0–6 (p = 0.0463); however, this study
baseline FEV1 was 22 % for CVT-MDI and 17.6 % for was not powered to assess whether all subjects with more
ALB-HFA (p <0.0001) (Fig. 2d). The mean change from severe asthma and low lung function (FEV1 <45 % pre-
test-day baseline in FEV1 was greater at all post-dose dicted) would benefit from the regime.
time-points in those receiving CVT-MDI (Fig. 3). During each 4-week period of active treatment, there
Greater bronchodilation with CVT-MDI than with were no significant differences between CVT-MDI and
ALB-HFA was noted in all subgroups. The subgroup ALB-HFA in number of puffs of study medication used
analyses demonstrated that treatment differences were or in number of puffs of open-label (rescue) ALB-HFA
consistent across the subgroups, with no significant used (Table 4). No significant differences were observed
treatment by subgroup interactions (Table 2 and Fig. 4 in ACQ or mini-AQLQ questionnaire scores, or in the
[FEV1 AUC0–6] and Table 3 and Fig. 5 [peak FEV1]). The number of nighttime awakenings evaluated at the end of
single exception was a marginally significant treatment the treatment period (Table 5).

Fig. 4 Forest plot of all subgroups for FEV1 AUC0–6

Donohue et al. BMC Pulmonary Medicine (2016) 16:65 Page 9 of 15

Table 3 Peak FEV1 [L] treatment comparisons by subgroups − FAS

Subgroup Subgroup level Number of patients Subgroup by Difference (CVT-MDI 18/103 –
ALB-HFA 108/CVT-MDI treatment ALB-HFA 108)
18/103 interaction
p value* Mean (SE) 95 % CI P value
Onset of asthma 0.7890
Early 98/98 0.076 (0.024) (0.028, 0.124) 0.0023
Late 117/114 0.078 (0.021) (0.037, 0.118) 0.0003
Type of asthma (based on patient history) 0.3838
Allergic 182/181 0.082 (0.017) (0.049, 0.116) <.0001
Non−allergic 33/31 0.067 (0.035) (−0.005, 0.138) 0.0679
% Predicted FEV1 categories 0.1378
≤45 % 17/19 0.004 (0.046) (−0.094, 0.102) 0.9317
>45 % and ≤ 55 % 33/32 0.142 (0.040) (0.060, 0.225) 0.0013
>55 % and ≤ 65 % 55/54 0.081 (0.029) (0.022, 0.140) 0.0081
>65 % and ≤ 75 % 76/75 0.059 (0.020) (0.018, 0.100) 0.0052
> 75 % 34/32 0.090 (0.053) (−0.016, 0.196) 0.0949
Concomitant asthma medication usage 0.5364
ICS, with LABA 153/149 0.082 (0.018) (0.047, 0.117) <.0001
ICS, without LABA 62/63 0.071 (0.031) (0.009, 0.132) 0.0251
Puff usage of medication (at baseline, 0.8736
daily average in week prior to visit 3)a
≤4 puffs per 24 h day 143/141 0.074 (0.016) (0.042, 0.107) <.0001
>4 and <8 puffs per 24 h 71/70 0.094 (0.035) (0.025, 0.164) 0.0083
≥8 puffs per 24 h day 1/1
Gender 0.1187
Female 125/127 0.090 (0.019) (0.052, 0.127) <.0001
Male 90/85 0.067 (0.024) (0.018, 0.115) 0.0076
b
Race 0.0980
Amer.Ind./Alaska Nat 1/1
Asian 2/2
Black/African Amer. 42/40 0.188 (0.050) (0.089, 0.288) 0.0004
Hawaiian/Pacif. Isle 4/5
White 166/164 0.063 (0.015) (0.034, 0.092) <.0001
Age category 0.7860
<35 44/41 0.077 (0.050) (−0.023, 0.177) 0.1280
≥35,< 50 68/69 0.083 (0.031) (0.022, 0.144) 0.0079
≥50,< 60 62/60 0.097 (0.022) (0.053, 0.142) <.0001
≥ 60 41/42 0.061 (0.030) (0.001, 0.121) 0.0459
Smoking status 0.9106
Ex−smoker 59/59 0.075 (0.037) (0.002, 0.149) 0.0436
Never smoked 156/153 0.076 (0.016) (0.045, 0.107) <.0001
FEV1/FVC [%] pre−BD at Rand 0.1852
<60 59/60 0.145 (0.036) (0.074, 0.217) 0.0001
Donohue et al. BMC Pulmonary Medicine (2016) 16:65 Page 10 of 15

Table 3 Peak FEV1 [L] treatment comparisons by subgroups − FAS (Continued)

≥60,< 65 46/45 0.100 (0.029) (0.041, 0.159) 0.0013
≥65,< 70 43/44 0.056 (0.031) (−0.007, 0.119) 0.0785
≥ 70 67/63 0.013 (0.021) (−0.028, 0.054) 0.5431
ALB-HFA albuterol hydrofluoroalkaline, CVT-MDI ipratropium bromide/albuterol sulfate metered-dose inhaler, FAS full analysis set, FEV1 forced expiratory volume in
1 s, FVC forced vital capacity, ICS inhaled corticosteroids, LABA long-acting β2-agonist, pre-BD at Rand pre-bronchodilator at randomization
a
Last category not included in modelling due to insufficient number of patients
b
Asian, Hawaiian/Pacific Islander and American Indian/Alaska National not included in modelling due to insufficient number of patients
*Unadjusted p values

In a post-hoc analysis, the duration of bronchodilator (defined in the protocol as worsening of asthma requiring
response at the end of the treatment period was twice as treatment with IV or oral corticosteroids) were reported
long with CVT-MDI versus ALB-HFA (137.5 min vs. by seven CVT-MDI patients versus two ALB-HFA pa-
66.6 min, nominal p <0.0001). In another post-hoc ana- tients (none related to study drug). No severe asthma ex-
lysis, the proportion of responders (peak FEV1 response acerbations were classified as a serious AE or resulted in
at 4 weeks that was ≥1.15 times the test−day baseline) hospitalization, and no fatal events occurred (Table 6).
was significantly greater with CVT-MDI than ALB-HFA:
59.2 % versus 45.6 %, nominal p = 0.0014. Discussion
Among the 226 patients randomized, 68 (30.1 %) re- This study found a statistically significantly greater bron-
ported at least one AE, with 22.8 % of the CVT-MDI chodilator effect of CVT-MDI versus ALB-HFA after
group (mainly due to the higher frequency of cough with 4 weeks of “as needed” use of rescue medication, in patients
CVT-MDI) versus 14 % of patients in the ALB-HFA with moderate-to-severe asthma, confirming results from a
group reporting an AE. Severe asthma exacerbations previous single-dose study [22]. CVT-MDI demonstrated

Fig. 5 Forest plot of all subgroups for Peak FEV1

Donohue et al. BMC Pulmonary Medicine (2016) 16:65 Page 11 of 15

Table 4 Analysis of number of puffs of study medication and open-label albuterol used during day and separately at night (mean
changes from study baselinea) at the end of the 4-week treatment period
ALB-HFA CVT-MDI Difference (CVT-MDI – ALB-HFA)
Endpoint n Mean SE N Mean SE Mean 95 % CI p value
Weekly meanb number of AM puffs of study medication used 176 −0.49 0.07 178 −0.53 0.07 −0.04 (−0.17, 0.08) 0.510
Weekly meanb number of PM puffs of study medication used 178 −0.10 0.05 180 −0.12 0.05 −0.02 (−0.12, 0.08) 0.659
b
Weekly mean number of AM puffs of open label ALB-HFA used 176 −2.24 0.05 178 −2.28 0.05 −0.04 (−0.14, 0.05) 0.363
Weekly meanb number of PM puffs of open label ALB-HFA used 178 −0.92 0.02 180 −0.93 0.02 −0.01 (−0.06, 0.04) 0.679
SE standard error, 95 % CI 95 % confidence interval, ALB-HFA albuterol hydrofluoroalkaline, CVT-MDI ipratropium bromide/albuterol sulfate metered-dose inhaler
a
Mean observed in last week prior to administration of the first dose of the randomized treatment
b
Weekly mean number of puffs during the fourth week of treatment

significant improvement in efficacy over ALB-HFA for Peters et al. showed that the addition of tiotropium to
FEV1 AUC0–6 response, and peak FEV1 response on day low-dose ICS resulted in significant improvements in
29, indicating maintenance of effect without any evidence morning and evening PEF, and pre-bronchodilator FEV1.
of a loss of effect after 4 weeks of as-needed CVT-MDI use. The combination of tiotropium and low-dose ICS was
In a post-hoc analysis, the duration of bronchodilator re- comparable to a LABA/ICS combination and was signifi-
sponse at the end of the treatment period was twice as long cantly better than doubling the ICS dose [28]. In a separ-
with CVT-MDI compared with ALB-HFA (137.5 min vs. ate study of patients with severe uncontrolled asthma
66.6 min, nominal p <0.0001); CVT-MDI has shown con- despite treatment with at least high-dose ICS plus LABA,
sistent benefit in bronchodilation in all subgroups. the addition of tiotropium significantly improved lung
As anticipated for medications added for acute symptom function; however, no significant differences were ob-
relief to maintenance therapy, overall asthma control did served in asthma-related health status or rescue medica-
not significantly differ between the CVT-MDI and ALB- tion use in this crossover and short-term setting, the
HFA groups in this short-term, crossover study. The ACQ design of which may have impacted the clinical outcome
and mini-AQLQ were developed to measure effects of [33]. In a larger, 48-week study of a similar population of
long-term controller medications, while the investigational patients, the add-on therapy of tiotropium to high-dose
medications used in this study were designed for acute ICS/LABA led to significant increases in lung function
symptomatic relief during the 4-week active treatment and significantly increased the time to first severe asthma
period. Despite significant differences in lung function, no exacerbation [34]. Bateman et al. showed that adding tio-
differences in rescue medication use were observed be- tropium to medium-dose ICS was non-inferior to salme-
tween the CVT-MDI and ALB-HFA groups. This suggests terol and superior to placebo in patients with moderate
that the weekly mean number of rescue puffs used per day asthma with the B16-Arg/Arg genotype whose asthma
does not reflect potential differences in lung function im- was not well controlled with ICS alone [35]. Once-daily
provement during acute symptom relief. tiotropium Respimat® added on to ICS was shown to im-
Increasing evidence shows the benefit of anticholinergic prove lung function in symptomatic adult [36] and adoles-
agents in moderate-to-severe asthma, including recent cent [37] patients with moderate asthma. These studies
studies evaluating tiotropium as add-on therapy in uncon- support a potentially important therapeutic role for the
trolled asthma [28, 33–37]. In addition, a Cochrane review long-acting anticholinergic tiotropium as maintenance
of combined inhaled SAMAs and SABAs showed a lower therapy in the treatment of patients with asthma.
risk of hospital admission and a greater improvement In this study, the overall safety profile of CVT-MDI
in lung function versus SABAs alone in acute asthma was similar to ALB-HFA. As previously observed with
in children [38]. short-acting anticholinergics, patients receiving CVT-MDI

Table 5 Mean changes from study baseline for Mini-AQLQ, ACQ, and nighttime awakenings for the comparisons of CVT-MDI to
ALB-HFA, evaluated at 4 weeks
ALB-HFA CVT-MDI Difference (CVT-MDI – ALB-HFA)
Endpoint N Mean SE N Mean SE Mean (95 % CI) p value
Mini-AQLQ 191 0.15 0.05 193 0.22 0.05 0.06 (−0.03, 0.15) 0.159
ACQ 191 −0.25 0.04 193 −0.25 0.04 0.01 (−0.07, 0.08) 0.828
Nighttime awakenings 178 −0.15 0.02 180 −0.16 0.02 −0.01 (−0.05, 0.04) 0.764
ACQ asthma control questionnaire (7-point scale), ALB-HFA albuterol hydrofluoroalkaline, AQLQ asthma quality of life questionnaire, CVT-MDI ipratropium bromide/
albuterol sulfate metered-dose inhaler
 Donohue et al. BMC Pulmonary Medicine (2016) 16:65
Table 6 Characteristics of patients with severe asthma exacerbations
CVT-MDI ALB-HFA
Patient 10868 Patient 11356 Patient 11473 Patient 12410 Patient 12454 Patient 10853 Patient 11752 Patient 11803 Patient 12055
Age (years), gender, 52, Female, 69, Female, 64, Female, 36, Female, 59, Male, 45, Female, 35, Male, 49, Female, 74, Female,
race Caucasian Caucasian Hawaiian/PI Caucasian Caucasian Afr Amer Afr Amer Caucasian Caucasian
BMI (kg/m2) 33.2 32.5 22.5 48.2 28.6 41.4 N/A N/A 29.0
Exacerbation - start day, Day 3, Ph 1 Day 2, Ph 1 Day 29, Ph 1 Day 24, Ph 1 Day 15, Ph 1 Day 19, Ph 2 Day 29, Ph 2 Day 11, Ph 2 Day 22, Ph 2
phase
Exacerbation in prior year None Yes, None Yes, 6 months prior Yes, 2.5 months None N/A Yes, 6 months prior None
2 months prior
prior
Baseline FEV1 % predicted 56.3 % 36.4 % 41.4 % 71.3 % 64.9 % 52.3 % 46.8 % 63.7 % 72.5 %
Background and concomitant Advair 500/ Symbicort Advair 1000/ Advair 250/50 μg; Advair 1000/ Advair 1000/ Advair 1000/100 μg; Flovent 440 μg, Xopenex 2.5 mg,
asthma medications (daily dose) 100 μg; Alb 640/18 μg; 100 μg; Alb Singulair 10 mg; 100 μg; 100 μg Singulair 10 mg; Combivent 84/480 μg, Pulmicort 360 μg,
180 μg, d/c; 180 μg, d/c; Zyrtec; Flonase; Singulair 10 mg; Alb 180 μg, d/c; Alb 180 μg, d/c Flonase Alb, d/c
Zyrtec D; Nasonex;
Respiratory infection reported No No No No No Yes Yes No No
preceding exacerbation
Use of rescue medication −3 days: 2 −3 days: 2 −3 days: 4 −3 days: 0 −3 days: 5 −3 days: 2 −3 days: 6 −3 days: 6 −3 days: 4
(No. of puffs) 3 days before
−2 days: 4 −2 days: 3 −2 days: 8 −2 days: 2 −2 days: 4 −2 days: 0 −2 days: 8 −2 days:6 −2 days: 4
and day of exacerbation
−1 day: 2 −1 day: 3 −1 day: 4 −1 day: 2 −1 day: 5 −1 day: 6 −1 day: 6 −1 day: 6 −1 day: 4
0: 4 0: 6 0: 0 0: 2 0: 7 0: 4 0: N/A 0: 6 0: 6
PEF (L/min) 3 days before −3 days: 365 −3 days: 189 −3 days: 155 −3 days: 381 −3 dy: 371 −3 days: 254 −3 days: 388 −3 days: 392 −3 days: 339
and day of exacerbation
−2 days: 359 −2 days: 160 −2 days: 172 −2 dy: 392 −2 days: 399 −2 days: 227 −2 days: 298 −2 days: 395 −2 days: 334
(best of day)
−1 day: 353 −1 day: 180 −1 day: 129 −1 day: 426 −1 day: 337 −1 day: 180 −1 day: 307 −1 day: 406 −1 day: 305
0: 350 0: 181 0: 104 0: 368 0: 353 0: 194 0: 284 0: 374 0: 281
Duration of exacerbation 17 days 9 days 4 days 9 days 7 days 9 days 13 days 81 days 11 days
PEF (L/min) 3 days after end +1 day: 356 +1 day: 154 N/A +1 day: 368 +1 day: 492 +1 day: 310 N/A +1 day: 326 N/A
of exacerbation
+2 days: 311 +2 days: 155 +2 days: 402 +2 days: 486 +2 days: 347 +2 days: 344
+3 days: 361 +3 days: 153 +3 days: 384 +3 days: 536 +3 days: 271 +3 days: 314
Afr Am African American, ALB-HFA albuterol hydrofluoroalkaline, Alb albuterol, BMI body mass index, CVT-MDI ipratropium bromide/albuterol sulfate metered-dose inhaler, d/c discontinued, FEV1 forced expiratory
volume in 1 s, FVC forced vital capacity, ICS inhaled corticosteroids, LABA long-acting β2-agonist, PEF peak expiratory flow, ph phase, PI pacific islander

Page 12 of 15
Donohue et al. BMC Pulmonary Medicine (2016) 16:65 Page 13 of 15

reported more cough. The patient population chosen for clinicaltrial/com_EN/results/1012/1012.57_U10-3568-

this study had moderate-to-severe asthma, and was symp- 01-DS.pdf.
tomatic despite continuous treatment with ICS with or The redacted Clinical Study Reports and related clinical
without LABA and other asthma controller medications, documents are available on request, based on a “Docu-
and had ACQ scores ≥1.5. Therefore, in this population ment Sharing Agreement”, only for scientific purposes at
with poor asthma control, exacerbations are expected to http://trials.boehringer-ingelheim.com/trial_results/clinical_
be more frequent. Although there was a slight excess of submissiondocuments_new.html.
patients in the CVT-MDI group (seven CVT-MDI vs. two Researchers can use the following external platform to
ALB-HFA patients) who met the protocol-defined criteria request access to raw data from our clinical studies:
for severe asthma exacerbation, no patients were hospital- https://clinicalstudydatarequest.com/.
ized, and one patient discontinued on day 29 of the study
due to a severe asthma exacerbation. While differences in Additional file
the number of severe asthma exacerbations between the
groups were not significant, exacerbation data was exam- Additional file 1: Table S1. IRB Approval details from individual
ined in greater detail. An independent review of the severe centers. (DOC 88 kb)
asthma exacerbations revealed no specific pattern except
that five of the seven patients who had severe asthma ex- Abbreviations
ACQ: asthma control questionnaire; AE: adverse event; ALB-HFA: albuterol
acerbations in the CVT-MDI group had a body mass hydrofluoroalkaline; AQLQ: asthma quality of life questionnaire; AUC: area
index (BMI) of 32.5–48.2 kg/m2. In two of these patients, under the curve; BMI: body mass index; CFC: chlorofluorocarbon;
respiratory infection preceded the exacerbation. COPD: chronic obstructive pulmonary disease; CVT: ipratropium bromide/
albuterol sulfate; ECG: electrocardiogram; FAS: full analysis set; FEV1: forced
Based on an analysis of the individual eDiary data, expiratory volume in 1 second; FVC: forced vital capacity; ICS: inhaled
there was no increased use or misuse of open label ALB- corticosteroid; LABA: long-acting β2-agonist; MDI: metered-dose inhaler;
HFA and/or blinded study medication before the onset MMRM: mixed effect model repeated measures; PEF: peak expiratory flow;
SABA: short-acting β2-agonist.
of the severe exacerbation in four of the seven CVT-
MDI group patients. There was also no evidence of a de- Competing interests
crease in the PEF, indicating the onset of worsening of James Donohue reports grants from Boehringer Ingelheim to the Univ.
asthma, in four of the seven CVT-MDI group patients. North Carolina and personal fees from Boehringer Ingelheim.
Robert Wise reports personal fees from AstraZeneca, Genentech, Intermune,
Janssen, Medimmune, Mylan, Novartis, Pulmonx, Spiration, and Sunovion,
grants from Pearl, and grants and personal fees from Boehringer Ingelheim,
Conclusions GlaxoSmithKline, and Merck.
These findings are consistent with those from recent William Busse reports personal fees from Amgen, Boston Scientific,
studies that demonstrated the value of using the long- Genentech, GlaxoSmithKline, ICON, MedImmune, Merck, and Novartis, grants
from NIH-NIAID and NIH-NHLBI, and royalties from Elsevier.
acting anticholinergic, tiotropium, as add-on therapy to Sandra Garfinkel has no competing interests.
ICS [39], or as an add-on to ICS plus LABA [34, 40], Raymond Manuel, Rozsa Schlenker-Herceg, and Valentina Zubek are employees
or compared with doubling the ICS dose [28], in the of Boehringer Ingelheim Pharmaceuticals, Inc.
Mo Ghafouri was an employee of Boehringer Ingelheim at the time of
chronic management of moderate or severe asthma. The the study.
results of this study suggest that use of a short-acting anti- Eugene Bleecker reports personal fees from AstraZeneca, Boehringer
cholinergic bronchodilator in a fixed-dose combination Ingelheim, Forest, Genentech, GlaxoSmithKline, Johnson and Johnson,
Merck, Regeneron, and Sanofi-Aventis, and other support from AstraZeneca,
with a SABA has a greater effect on lung function in Boehringer Ingelheim, Cephalon, Forest, Genentech, GlaxoSmithKline, Kalabios,
moderate-to-severe asthma than SABA alone, and should MedImmune, Novartis, and Sanofi-Aventis.
therefore provide better symptomatic relief. In the future,
additional studies will be useful to investigate the additive Authors’ contributions
JD participated in the design of the trial, participated as an investigator,
effects of these drugs in patients with all spectra of asthma reviewed the data, assisted at all stages of manuscript development and
severity. writing, and approved the final draft. RW participated in the design of the
These results support the use of a short-acting anti- study, interpreted the results, assisted with drafting and editing the
manuscript, and approved the final draft. WB participated in the design of
cholinergic bronchodilator in a fixed-dose combination the study, was involved in all stages of manuscript development, and
with a SABA in asthma, and the need for further clinical approved the final draft. SG was the Trial Clinical Monitor/Project Manager
trials to determine the role of short- and long-acting an- and was responsible for all operational aspects of the trial from start up to
clinical trial report. She was involved in the manuscript at all stages of
ticholinergics (ipratropium and tiotropium, respectively) development, and approved the final draft. VZ participated in the design of
for managing asthma. the study, performed the statistical analysis, assisted at all stages of
manuscript development, and approved the final draft. MG reviewed the
clinical trial report, was involved in the manuscript at all stages of
Availability of data and materials development, and approved the final draft. RM contributed to the study
design, study conduct, and data analysis, was involved in all stages of
The synopsis for this study is available at http://trials. manuscript development, and approved the final draft. RSH led the
boehringer-ingelheim.com/content/dam/internet/opu/ conceptualization of the study design, provided medical input to the writing
Donohue et al. BMC Pulmonary Medicine (2016) 16:65 Page 14 of 15

of the protocol and the study conduct, contributed to interpretation of the 15. Storms WW, Bodman SF, Nathan RA, Busse WW, Bush RK, Falliers CJ, et al.
results, writing of the manuscript, and approved the final draft. ERB reviewed Use of ipratropium bromide in asthma. Results of a multi-clinic study. Am J
manuscript drafts, and read and approved the final version. Med. 1986;81(5A):61–6.
16. Gross NJ, Skorodin MS. Anticholinergic, antimuscarinic bronchodilators. Am
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Acknowledgements
17. Lightbody IM, Ingram CG, Legge JS, Johnston RN. Ipratropium bromide,
We thank all the Investigators who participated in the study (a list of all the
salbutamol and prednisolone in bronchial asthma and chronic bronchitis.
Investigators is provided in e-appendix 1) and Cixuang Zheng, who helped
Br J Dis Chest. 1978;72(3):181–6.
run the analysis on duration of bronchodilator response. The authors meet
18. Rebuck AS, Chapman KR, Abboud R, Pare PD, Kreisman H, Wolkove N, et al.
criteria for authorship as recommended by the International Committee of
Nebulized anticholinergic and sympathomimetic treatment of asthma and
Medical Journal Editors (ICMJE) and were fully responsible for all content and
chronic obstructive airways disease in the emergency room. Am J Med.
editorial decisions, and were involved at all stages of manuscript development.
1987;82(1):59–64.
The authors received no compensation related to the development of the
19. Garrett JE. Combined anticholinergic therapy in the management of acute
manuscript. This work was supported by Boehringer Ingelheim Pharmaceuticals,
asthma. Respirology. 1997;2 Suppl 1:S17–8.
Inc. (BIPI). Writing, editorial support, and/or formatting assistance was provided
by Gill Sperrin CBiol MRSB CMPP of Envision, which was contracted and 20. Lanes SF, Garrett JE, Wentworth 3rd CE, Fitzgerald JM, Karpel JP. The effect
compensated by BIPI for these services. of adding ipratropium bromide to salbutamol in the treatment of acute
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Funding children and adults with acute asthma: a systematic review with
This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). meta-analysis. Thorax. 2005;60(9):740–6.
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Author details Bronchodilator efficacy of the fixed combination of ipratropium and
1
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Hopkins University School of Medicine, Baltimore, MD, USA. 3Department of 23. Petrie GR, Palmer KN. Comparison of aerosol ipratropium bromide and
Medicine, University of Wisconsin, Wisconsin, WI, USA. 4Boehringer Ingelheim salbutamol in chronic bronchitis and asthma. Br Med J. 1975;1(5955):430–2.
Pharmaceuticals, Inc., Ridgefield, CT, USA. 5Wake Forest School of Medicine, 24. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, et al.
Center for Genomics and Personalized Medicine, Winston-Salem, NC 27157, Use of regularly scheduled albuterol treatment in asthma: genotype-
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