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Contents
Protocol for the administration of oral corticosteroids .................................................................... 2
Key inclusion criteria.......................................................................................................................3
Full list of exclusion criteria.............................................................................................................4
Susceptibility testing .......................................................................................................................6
Statistical analysis plan ..................................................................................................................7
Efficacy populations ...................................................................................................................7
Definitions of clinical and bacteriological response................................................................... 7
Statistics .....................................................................................................................................9
Sample size calculation .............................................................................................................9
Primary analysis.........................................................................................................................9
Secondary endpoints ....................................................................................................................12
Inclusion and exclusion criteria violations ....................................................................................13
Most frequent (≥5%) co-morbid conditions (PP population) ........................................................ 14
Characteristics at enrolment of patients with and without systemic corticosteroids for their current
exacerbation .................................................................................................................................15
Clinical failure rates at 8 weeks post-therapy by patient subgroups (Intent-to-treat population) 18
Baseline susceptibility of commonly isolated pathogens ............................................................. 19
Lung function outcomes ...............................................................................................................20
Patient-reported outcomes ...........................................................................................................24
MAESTRAL Investigators .............................................................................................................25
Page 1 of 27
Protocol for the administration of oral corticosteroids
Patients were stratified according to oral corticosteroid use.
Stratum 1 patients – co-administration of systemic corticosteroids for the current AECOPD:
1.
were not on long-term low-dose systemic corticosteroid treatment and
2.
had received treatment with systemic corticosteroids (≥50 mg over 10 days) for the
current AECOPD.
Stratum 2 patients – no co-administration of systemic corticosteroids for the current AECOPD:
•
were on long-term low-dose systemic corticosteroid treatment which remained stable or
increased minimally during the study treatment (cumulative dose <100 mg over 10 days)
for the current AECOPD or
•
had received systemic corticosteroids for the current AECOPD but at a cumulative dose
of <50 mg over 10 days.
Page 2 of 27
Key inclusion criteria
1. Outpatients with moderate-to-severe COPD and chronic bronchitis
2. ≥60 years old
3. Documented history of ≥2 exacerbations within the previous year requiring a course of
systemic antibiotics and/or systemic corticosteroids
4. Post-bronchodilator FEV1 ≤60% predicted
5. FEV1 /FVC <70%
6. Current or past cigarette smokers with a ≥20 pack-year smoking history
7. Experiencing an Anthonisen type I exacerbation [Anthonisen et al. 1987] (the presence of all
three of purulent sputum, increased sputum volume and increased dyspnoea as confirmed by
the investigator)
8. Be suitable for treatment with oral antibiotics
9. Exacerbation-free for at least 30 days prior to enrollment
Page 3 of 27
Full list of exclusion criteria
1. Known hypersensitivity to quinolones, beta-lactams, or to any of the excipients of the study
drugs
2. Pregnant or breastfeeding women (women of childbearing potential, based on investigator
assessment, must have negative urinary pregnancy test)
3. Congenital or acquired QT prolongation
4. Clinically relevant bradycardia
5. Clinically relevant heart failure with reduced left ventricular ejection fraction
6. Previous history of symptomatic arrhythmias
7. Taking QT prolonging drugs, for example Class Ia or III anti-arrhythmic agents (e.g. quinidine,
procainamide, amiodarone, sotalol), neuroleptics (e.g. phenothiazines, pimozide, sertindole,
haloperidol, sultopride), tricyclic antidepressants, certain antihistaminics (e.g. terfenadine,
astemizole, mizolastine), certain antimicrobials (sparfloxacin, erythromycin IV, pentamidine,
antimalarials particularly halofantrine) or other QT prolonging drugs (e.g. cisapride,
intravenous vincamine, bepridil, and diphemanil)
8. Uncontrolled electrolyte disturbances, particularly uncorrected hypokalaemia
9. History of hereditary problems of galactose intolerance, the Lapp lactase deficiency, or
glucose-galactose malabsorption
10. History of a tendon disease/disorder
11. History of liver dysfunction (Child-Pugh C), including elevated transaminase levels (alanine
aminotransferase and/or aspartate aminotransferase >5 times the upper limit of normal)
12. Severe renal impairment with glomerular filtration rate of <30 mL/minute
13. Neutropenia (neutrophil count < 1000/mm 3) caused by immunosuppressive therapy or
malignancy
14. AIDS (CD4 count of <200/mm 3), or HIV positive and receiving highly active anti-retroviral
therapy (testing for HIV is not mandatory)
15. Chronic asthma (>15% reversibility or at least 200 mL), bronchial carcinoma, active
pulmonary tuberculosis, known diffuse bronchiectasis, cystic fibrosis, or pneumonia (a chest
X-ray is not mandatory)
16. History of chronic colonisation of pathogenic organisms resistant to moxifloxacin and/or
amoxicillin/clavulanic acid (e.g. P. aeruginosa, meticillin-resistant S. aureus)
17. Receiving long-term (>4 consecutive weeks) systemic corticosteroid treatment (>10 mg/day
of prednisolone or equivalent)
18. Received short course of systemic corticosteroid treatment within 30 days prior to enrollment
19. Unable to take oral medication
20. Life expectancy of less than 6 months
Page 4 of 27
21. Receiving systemic antibacterial therapy within 30 days prior to study enrollment
22. Requiring concomitant systemic antibacterial agents
23. Use of any investigational drug or device within 30 days of screening, or previously enrolled
in this study
24. Requiring home ventilatory support (patients requiring home/portable oxygen therapy or
continuous positive airway pressure for sleep apnoea are not excluded) and/or those who
have a tracheotomy in situ
25. History of liver function disorders following previous treatment with amoxicillin/clavulanic acid
26. Receiving disulfiram therapy
Page 5 of 27
Susceptibility testing
Pure subcultures of all potentially pathogen bacteria were frozen and subsequently forwarded to
a central microbiology laboratory where they were re-identified and minimum inhibitory
concentrations (MICs) determined for moxifloxacin and amoxicillin/clavulanic acid and a range of
other antibiotics by the reference Clinical Laboratory Standards Institute broth microdilution
method [CLSI 2009]. MICs for penicillin were determined for Streptococcus pneumoniae and
meticillin resistance was determined in Staphylococcus aureus.
Page 6 of 27
Statistical analysis plan
Efficacy populations
The primary population for assessment of clinical outcomes was the per protocol (PP) population.
These patients all had an acute exacerbation at enrollment and received the study drug for a
minimum of 48 hours (cases of clinical failure) or received ≥80% of study medication (cases of
clinical cure). All had data for clinical evaluation at 8 weeks post-therapy (except for clinical
failures prior to the 8 weeks post-therapy visit) and had no protocol violations. The intent-to-treat
(ITT)/safety population included all patients randomised who received at least one dose of study
drug and with one observation after initiation of study treatment. The PP with pathogens
population was drawn from the PP population and comprised all patients with at least one
potentially pathogenic organism cultured from sputum provided prior to start of therapy and
where a bacteriological evaluation was available during the study. The ITT with pathogens
population included patients valid for ITT with at least one pre-therapy potentially pathogenic
organism.
Definitions of clinical and bacteriological response
Assessment of clinical response to therapy is based on determination of the effect of therapy on
auscultatory findings, chest pain/discomfort, cough frequency, dyspnea, sputum purulence,
sputum consistency, and sputum volume.
Clinical response is assessed as:
•
clinical improvement: signs and symptoms are improving and treatment continues (this
category is only available during antibiotic therapy)
•
clinical failure: exacerbation symptoms have not improved or have worsened such that
additional or alternate systemic antimicrobial and/or systemic corticosteroid therapy is
required
•
indeterminate: clinical response cannot be determined
•
clinical cure: resolution or improvement in the signs and symptoms of the exacerbation such
that additional or alternate systemic antimicrobial and/or systemic corticosteroid therapy is not
required
•
continued clinical cure: continued absence of acute signs and symptoms related to the
infection such that additional or alternate therapy (systemic antimicrobial and/or systemic
corticosteroid) is not required
Page 7 of 27
•
clinical relapse: reappearance of the signs and symptoms of infection such that re-institution
of therapy (systemic antimicrobial and/or systemic corticosteroid) is required; for the analysis,
this will be considered clinical failure at the 4 weeks post-therapy and 8 weeks post-therapy
visits.
Clinical failure rates were assessed during non-protocol-defined visits as well as during therapy,
at end of therapy and at 4 weeks post-therapy. Premature discontinuations due to study drug
failure were treated as failures. For patients who discontinued study drug for reasons other than
efficacy, the assessment at 8 weeks was used where completed. For those patients who did not
return for the week 8 visit, the response was considered missing. Those patients were excluded
from the per protocol population as were those with an indeterminate clinical outcome at the last
available assessment.
Bacteriological response rates were assessed during therapy, at end of therapy and at 4 and 8
weeks post-therapy. The categories of bacteriological response to therapy were:
•
bacteriological eradication without superinfection or reinfection: initial causative
pathogen(s) absent, no new pathogen isolated after start of study
•
presumed eradication: absence of appropriate culture material for evaluation because
subject has clinically improved on therapy
•
persistence: initial causative pathogen(s) still present
•
presumed persistence: absence of appropriate culture material for evaluation, in a subject
who has not clinically improved on therapy
•
bacteriological eradication with superinfection: initial causative pathogen(s) absent, a
new pathogen isolated during treatment
•
bacteriological eradication with reinfection: initial causative pathogen(s) absent, a new
pathogen isolated after end of treatment
•
eradication with recurrence: original causative organism absent at end of therapy, but
reappearance of the same organism at or before 8 weeks post-therapy
•
continued eradication: the causative organism(s) is absent at this time point
•
continued presumed eradication: the absence of appropriate culture material for evaluation
because the patients have clinically improved
•
Indeterminate: bacterial response to the study drug not evaluable
Page 8 of 27
Statistics
Sample size calculation
To power MAESTRAL for superiority the objective was to enroll 540 valid PP patients in each
treatment arm, therefore at least 1350 COPD patients with an Anthonisen type I exacerbation
were required to be randomised. Patients were drawn from across 30 countries. This requirement
for a high number of patients is driven by a 6% margin – a more rigorous definition of failure rates
than the standard 10% normally used in non-inferiority trials.
Primary analysis
The primary aim of the study was to show non-inferiority (defined as a difference in failure rates
of ≤6% using a one-sided test at a level of 2.5%) of moxifloxacin vs amoxicillin/clavulanic acid in
the PP population. If non-inferiority was statistically proven, the possibility that moxifloxacin is
superior to amoxicillin/clavulanic acid would be tested in the ITT population, using a one-sided
test at the 2.5% level. The primary ITT analysis will be clinical failure vs all other evaluations
(clinical cure, indeterminate and missing).
Two sensitivity analyses were planned:
1.
missing responses to be combined with indeterminates and clinical failures in an overall nonsuccess category
2.
missing and indeterminate responses to be excluded and only cures or failures to be
considered.
The 95% two-sided confidence interval (CI) of the difference of two clinical failure rates
(treatment group ‘moxifloxacin’ minus treatment group ‘amoxicillin/clavulanic acid’) was
calculated using Mantel–Haenszel weights for the strata steroid use (see Supplementary
Materials section ‘Protocol for the administration of oral corticosteroids’) and geographical
region. The following were included as separate strata: Asia Pacific (Australia, China, Hong
Kong, Indonesia, Pakistan, the Philippines, Thailand), Europe and South Africa (Andorra,
Belgium, Croatia, Czech Republic, Germany, Greece, Ireland, Italy, Latvia, Lithuania, The
Netherlands, Portugal, South Africa, Switzerland, Spain, UK) and Latin America and Canada
(Argentina, Mexico, Peru, Brazil, Colombia, Chile, Canada). The ratio of the sample size of the
largest region compared to the smallest region should not be greater than 2:1.
An upper limit of the CI of <6%, will prove that treatment with moxifloxacin is clinically no less
effective than treatment with amoxicillin/clavulanic acid. If the upper limit of this CI is <0,
superiority of treatment with moxifloxacin will be proven. To check the appropriateness of the
calculation of the Mantel–Haenszel weighted CIs, the Breslow–Day test, or Zelen’s test, was
Page 9 of 27
performed to test for homogeneity of odds ratios across strata. If the test indicated a treatment by
stratum interaction, exploratory analyses were performed to find the source of this interaction. If
such a source was found, the Mantel–Haenszel weighted CI was calculated using weighting
based on variables explaining the interaction.
Demographic and baseline characteristics were summarised by treatment group for the PP and
ITT populations and compared using the Cochran–Mantel–Haenszel test adjusted for strata and
region.
Secondary clinical and bacteriological endpoints were analysed as for the primary analysis, but
using appropriate patient populations and time points. Clinical and bacteriological outcomes at a
variety of time points (during therapy, end of therapy, 4 weeks and 8 weeks post-therapy) were
investigated in subpopulations of special interest as follows.
•
Males vs females
•
<65 years of age vs elderly patients (≥65 years old)
•
2, 3, and ≥4 previous exacerbations in the last 12 months
•
Active smokers at the study start
•
Cardiopulmonary disease (as defined by the MedDRA terms)
•
Previous respiratory failure
•
Patients receiving (stratum 1) or not receiving (stratum 2) co-administration of systemic
steroid administration
•
Patients receiving co-administration of systemic steroid administration, irrespective of stratum
allocation
•
FEV1 at enrollment according to the following categories: FEV1 <30% of predicted, 30%
≤FEV1 <60% of predicted, and FEV1 ≥60% of predicted
•
Previous systemic antimicrobial use in the last 90 days before study start (for any reason)
• Patients whose last exacerbation was ≥63 days before study start
• Patients whose last exacerbation was <6 months before study start
• Patients with bacteria isolated from sputum at baseline.
Page 10 of 27
AECB-SS and SGRQ scores were determined and analysed separately. The main analysis for
the SGRQ data compared the mean change from baseline in the total SGRQ score between
treatment groups at 8 weeks after the end of therapy. For AECB-SS, means, standard deviations,
medians, minimums and maximums were provided for the total score and change from baseline
in total score at each visit, by treatment group. For healthcare resource use, if the homogeneity
of between-country resource consumption was found to be satisfactory, data were to be pooled,
summarised and 95% CIs estimated.
For the safety analysis, a Cochran–Mantel–Haenszel test was used to assess the difference in
incidence rates between treatment groups for the overall rate of premature discontinuations,
discontinuations due to adverse events, and discontinuations due to insufficient therapeutic
effect. Other safety data were tabulated; vital signs were analysed descriptively.
Page 11 of 27
Secondary endpoints
Category
Endpoint
Clinical failure
• Clinical failure rates
measures
o
for all patients during therapy, at end of therapy and at 4
weeks post-therapy
o
for patients with positive sputum culture at enrollment at
all timepoints
o
for patients with and without co-administration of
systemic corticosteroids
Bacteriological
• Bacteriological eradication rates at all timepoints
outcomes
Symptom
burden and
quality of life
• Acute Exacerbation of Chronic Bronchitis Symptom Scale
(AECB-SS) for all acute symptom changes
• Health-related quality of life measured by the St George’s
Respiratory Questionnaire (SGRQ)
• Lung function (spirometry): between-group comparisons at each
assessment visit
Co-
• Need for any change in dosage or additional respiratory
medications
medication such as bronchodilators and inhaled
and healthcare
corticosteroids
resource use
• Healthcare resource use/consumption related to COPD/chronic
bronchitis
Safety
• Safety and tolerability of antibiotics, with particular attention to
rates of diarrhoea
Page 12 of 27
Inclusion and exclusion criteria violations
Total
Moxifloxacin
N=57 (100%)
Co-amoxiclav
N=73 (100%)
N=130
(100%)
n (%)
n (%)
n (%)
11 (19.2)
18 (24.6)
29 (22.3)
Documented history of ≥ AECB episodes,
within 12 months of study enrolment,
requiring a course of systemic antibiotics
and/or systemic corticosteroids
2 (3.5)
2 (2.7)
4 (3.1)
All symptoms/signs must be present and
confirmed by the Investigator (Anthonisen
type 1)
25 (43.8)
32 (43.8)
57 (43.8)
10 (17.5)
15 (20.5)
25 (19.2)
Known chronic asthma (>15% reversibility
or at least 200 mL), bronchial carcinoma,
active pulmonary tuberculosis, known
diffuse bronchiectasis, cystic fibrosis, or
pneumonia.
3 (5.2)
1 (1.3)
4 (3.1)
Receiving long term (>4 consecutive
weeks) systemic corticosteroid treatment
(>10 mg/day of prednisolone or equivalent)
3 (5.2)
2 (2.7)
5 (3.8)
Initial steroid treatment violation§
3 (5.2)
2 (2.7)
5 (3.8)
Criteria†
FEV1 ≤60% predicted and FEV1 / FVC <70%
at enrolment
Current or past cigarette smoker with 20
pack-year‡ smoking history
†
>1 Inclusion/exclusion criteria violation per subject are possible. Only the primary reason for
Inclusion/exclusion criteria violations are shown
‡
Calculated by dividing the number of cigarettes smoked/day by 20 (number of cigarettes/pack) and
multiplying by the number of years a person has smoked
§
This group includes subjects who were either under-dosed or treated with prolonged steroid treatment
FEV 1 : forced expiratory volume in 1 second; FVC: forced vital capacity; AECB: Acute Exacerbation of
Chronic Bronchitis
Page 13 of 27
Most frequent (≥5%) co-morbid conditions (PP population)
Moxifloxacin
Co-amoxiclav
Total
N=538 (100%)
N=518 (100%)
N=1056 (100%)
n (%)
n (%)
n (%)
Patients with ≥1 co-morbid condition
417 (77.5)
419 (80.9)
836 (79.2)
Cardiac disorders
101 (18.8)
80 (15.4)
181 (17.1)
Coronary artery disorders
29 ( 5.4)
18 (3.5)
47 (4.5)
Ischaemic coronary artery
34 (6.3)
25 (4.8)
59 (5.6)
Gastrointestinal disorders
84 (15.6)
77 (14.9)
161 (15.2)
Infections and infestations
57 (10.6)
59 (11.4)
116 (11.0)
Metabolism and nutrition
115 (21.4)
121 (23.4)
236 (22.3)
50 (9.3)
53 (10.2)
103 (9.8)
Diabetes mellitus
22 (4.1)
40 (7.7)
62 (5.9)
Type 2 diabetes mellitus
27 (5.0)
13 (2.5)
40 (3.8)
73 (13.6)
84 (16.2)
157 (14.9)
28 (5.2)
28 (5.4)
56 (5.3)
Nervous system disorders
41 (7.6)
46 (8.9)
87 (8.2)
Psychiatric disorders
50 (9.3)
44 (8.5)
94 (8.9)
Reproductive system and breast
40 (7.4)
47 (9.1)
87 (8.2)
34 (6.3)
39 (7.5)
73 (6.9)
34 (6.3)
39 (7.5)
73 (6.9)
Surgical and medical procedures
86 (16.0)
82 (15.8)
168 (15.9)
Vascular disorders
225 (41.8)
225 (43.4)
450 (42.6)
Vascular hypertensive disorders
214 (39.8)
219 (42.3)
433 (41.0)
Hypertension
203 (37.7)
203 (39.2)
406 (38.4)
Event
disorders
disorders
Diabetes mellitus (including
subtypes)
Musculoskeletal and connective
tissue disorders
Neoplasms benign, malignant and
unspecified (including cysts and
polyps)
disorders
Prostatic neoplasms and
hypertrophy
Benign prostatic hyperplasia
PP: per protocol
Page 14 of 27
Characteristics at enrolment of patients (for which comparisons led to p-values < 0.10)
with and without systemic corticosteroids for their current exacerbation (ITT population)
Characteristic
Regions
Asia, Pacific
Europe, Canada, South Africa
Latin America
Race 1
White
Black
Asian
Am. Indian/Alaskan
Hispanic
History of respiratory disorders
Yes
No
Corticosteroid use
No
Yes
301 (34.3)
362 (37.2)
214 (24.4)
116 (24.4)
211 (44.4)
148 (31.2)
503 (57.9)
3 (0.3)
294 (33.9)
2 (0.2)
66 (7.6)
313 (65.9)
10 (2.1)
128 (26.9)
3 (0.6)
21 (4.4)
0.0066
176 (20.1)
701 (79.9)
126 (26.5)
349 (73.5)
92 (10.5)
785 (89.5)
65 (13.7)
410 (86.3)
Duration of chronic bronchitis, yrs
<10
≥10, <20
≥20
531 (60.5)
255 (29.1)
91 (10.4)
307 (64.6)
137 (28.8)
31 (6.5)
0.0809
0.0136
0.0767
279
169
301
128
(31.8)
(19.3)
(34.3)
(14.6)
155 (32.6)
99 (20.8)
159 (33.5)
62 (13.1)
Wheeze at baseline 2
Absent
Present
544 (62.5)
327 (37.5)
327 (69.1)
146 (30.9)
Cough frequency at exacerbation3
None
Mild
Moderate
Severe
119 (13.6)
573 (65.6)
161 (18.4)
20 (2.3)
82 (17.3)
294 (62.2)
88 (18.6)
9 (1.9)
Dyspnea at exacerbation4
Same as baseline
0.0004
0.0007
Cardiopulmonary disease
Yes
No
Time since last exacerbation, months
<2
>2, ≤3
>3, ≤6
>6
P-value †
0.0145
0.0496
0.0001
3 (0.3)
Page 15 of 27
0
Slightly increased
Greatly increased
Heart rate at exacerbation, beats per
minute 5
≤90
>90
Respiration rate at exacerbation,
breaths per minute 3
≤20
>20
280 (32.0)
592 (67.7)
87 (18.3)
388 (81.7)
0.0001
712 (81.3)
164 (18.7)
299 (62.9)
176 (37.1)
0.0005
589 (67.5)
283 (32.5)
252 (53.2)
222 (46.8)
Temperature at exacerbation, °C1
≤36
>37, <37
≥37
90 (10.3)
558 (64.1)
223 (25.6)
41 (8.7)
324 (68.6)
107 (22.7)
FEV1 at exacerbation, % predicted6
<30
≥30 <60
≥60
198 (22.6)
665 (75.9)
13 (1.5)
141 (29.9)
328 (69.6)
2 (0.4)
AECB-SS at exacerbation: Cough
frequency7
Never - Occasionally
Often
Very often – All the time
AECB-SS at exacerbation: Phlegm
description7
No phlegm - Liquid
Quite thick
Thick – Very thick
AECB-SS at exacerbation: Phlegm
colour8
Clear/White/Grey
Yellow
Green/Brown
AECB-SS at exacerbation: Difficulties
in breathing7
Not at all/Slightly
Moderately
A lot/Extremely
AECB-SS at exacerbation: Sleep
disturbances7
Not at all/Slightly
0.0609
0.0001
0.0036
187 (23.9)
340 (43.4)
257 (32.8)
90 (20.9)
158 (27.6)
183 (62.6)
0.0876
18 (4.2)
154 (35.7)
259 (60.1)
53 (6.8)
300 (38.3)
431 (55.0)
0.0883
40 (9.3)
253 (58.8)
137 (31.9)
106 (13.6)
447 (57.2)
229 (29.3)
0.0001
105 (24.4)
148 (34.3)
178 (41.3)
250 (31.9)
316 (40.3)
218 (27.8)
0.0036
176 (40.8)
Page 16 of 27
344 (43.9)
Moderately
A lot/Extremely
AECB-SS at exacerbation:
Disturbances in daily activities7
Not at all/Slightly
Moderately
A lot/Extremely
106 (24.6)
149 (34.6)
238 (30.4)
202 (25.8)
0.0081
123 (28.5)
134 (31.1)
174 (40.4)
279 (35.6)
253 (32.3)
252 (32.1)
†
p-values are from the Wald chi-square statistic
2
3
4
n = 1343 patients; n = 1344 patients; n = 1346 patients ; n = 1350 patients ;
7
8
1347 patients ; n = 1215 patients ; n = 1215 patients
1
Page 17 of 27
5
6
n = 1351 patients ; n =
Clinical failure rates at 8 weeks post-therapy by patient subgroups (Intent-to-treat
population)
Group
Moxifloxacin
n/N (%)
Amoxicillin/
clavulanic acid
n/N (%)
Gender
Male
Female
114/534 (21.3)
24/143 (16.8)
123/545 (22.6)
23/130 (17.7)
Age
≥65 years
<65 years
90/486 (18.5)
48/191 (25.1)
106/492 (21.5)
40/183 (21.9)
FEV1 predicted
<30%
≥30%
52/174 (29.9)
86/501 (17.2)
40/165 (24.2)
104/507 (20.5)
Previous antibiotic†
Yes
No
53/235 (22.6)
85/442 (19.2)
53/227 (23.3)
93/448 (20.8)
Previous exacerbations
2
3
≥4
77/448 (17.2)
37/159 (23.3)
24/68 (35.3)
92/462 (19.9)
28/138 (20.3)
26/73 (35.6)
Exacerbation in preceding 9 weeks
Yes
No
48/206 (23.3)
90/471 (19.1)
50/228 (21.9)
96/447 (21.5)
Exacerbation in preceding 6 months
Yes
No
117/578 (20.2)
21/99 (21.2)
125/597 (20.9)
21/78 (26.9)
Previous respiratory failure
Yes
No
24/68 (35.3)
114/609 (18.8)
18/77 (23.4)
127/597 (21.3)
Cardiopulmonary disease
Yes
No
20/77 (26.0)
118/600 (19.6)
18/80 (22.6)
128/595 (21.5)
Active smoker
Yes
No
28/149 (18.8)
110/528 (20.8)
26/144 (18.1)
120/531 (22.6)
†
Antibiotic received for any indication within prior 3 months
Clinical failure = clinical failure + continued clinical relapse
n/N: number with clinical failure/number in category
FEV 1 : forced expiratory volume in 1 second
All P values >0.05
Page 18 of 27
Baseline susceptibility of commonly isolated pathogens
Organism
Moxifloxacin
Amoxicillin/clavulanic acid
mg/L
mg/L
Median
MIC 90
Range
Median
MIC 90
Range
H. influenzae (N=122)
0.015
0.03
0.002−1.0
1.0
2.0
1.0−4.0
P. aeruginosa (N=103)
2.0
8.0
0.06−8.0
64.0
64.0
2.0−64.0
S. pneumoniae† (N=80)
0.12
0.12
0.015−2.0
0.03
1.0
0.015−4.0
M. catarrhalis (N=69)
0.03
0.06
0.002−0.12
0.12
0.25
0.06−1.0
S. aureus (N=38)
0.06
2.0
0.03−2.0
0.75
4.0
0.06−4.0
†
MIC for S. pneumoniae vs penicillin 1.0 mg/L; range 0.015−2.0 mg/L
Page 19 of 27
Lung function outcomes
Spirometry outcomes (FEV 1 ) in the intent-to-treat population
a: FEV1 : percent predicted value by visit (EOT: end of therapy)
Page 20 of 27
b: FEV1 : changes in percent predicted value from pre-therapy by visit (EOT: end of
therapy)
Page 21 of 27
c: FEV1 : absolute value by visit (EOT: end of therapy)
Page 22 of 27
d: FEV1 : changes in absolute value from pre-therapy by visit (EOT: end of therapy)
Page 23 of 27
Patient-reported outcomes
SGRQ
During therapy, a greater change from baseline occurred in the total SGRQ score of moxifloxacin
(–4.27 ± 11.74) vs amoxicillin/clavulanic acid (–3.54 ± 13.03) in ITT patients, however, this was
not sustained to 8 weeks post-therapy (moxifloxacin –20.45 ± 20.97; amoxicillin/clavulanic acid –
20.40 ± 21.74).
AECB-SS
In ITT patients, similar improvements were seen in AECB-SS scores for both treatment groups
during treatment (data not shown) and from baseline to 8 weeks post-therapy (moxifloxacin –1.36
± 0.97, amoxicillin/clavulanic acid –1.42 ± 0.99, 95% CI –0.13, 0.05; P=0.405).
Page 24 of 27
MAESTRAL Investigators
ANDORRA: Jordi Roig Cutillas, Hospital Ntra. Sra. de Meritxell, Escaldes – Engordany;
ARGENTINA: Eduardo Abbate, Instituto Médico de Asistencia e Investigación, Buenos Aires;
Oscar Caberlotto, Hospital Zonal de Agudos; Dr. Antonio Cetrángolo, Vicente López Ramón
Ferreyra, Hospital Militar Central "CIR. MY. C. Argerich", Buenos Aires; Héctor Hugo Altieri,
Hospital Centro de Salud Zenon Santillan, Tucumán; Andrea Medina, Centro de Investigaciones
Médicas, Buenos Aires; Héctor Defranchi, Clínica del Sol, Buenos Aires; Marcelo Fernández,
Centro Respiratorio Quilmes, Buenos Aires; Ana María Stok, Investigaciones en Patologías
Respiratorias, Tucumán; Carlos Luna, Inst. de Dermatología y Neumonología, Buenos Aires;
María De Salvo, Centro Médico Dra. De Salvo - Clinical Research Center, Buenos Aires; Luisa
Rey, Centro de Enfermedades Respiratorias, Buenos Aires; AUSTRALIA: Anne-Marie
Southcott, Queen Elizabeth Hospital, Woodville; Martin Phillips, Sir Charles Gairdner Hospital,
Nedlands; Peter Frith, Repatriation General Hospital, Adelaide; David Serisier, Brisbane Mater
Misericordiae Hospital, Brisbane; BELGIUM: Bart Rombaut, Algemeen Stedelijk Ziekenhuis
Campus Aalst, Aalst; Jean-Benoît Martinot, Namur; Guy Vereecken, Halen; BRAZIL: Carlos
Fritscher, Pontificia Universidade Católica - Centro Clínico, Porte Alegre; José de Brito Jardim,
Lar Escola São Francisco, São Paulo; Julio Abreu de Oliveira, Universidade Federal de Juiz de
Fora- Hospital Universitario, Minas Gerais; Alberto Cukier, Hospital das Clínicas da Faculdade
de Medicina da USP Laboratório de Função Pulmonar, São Paulo; CANADA: William Arkinstall,
SciMed Research Inc., British Columbia; William Booth, Antigonish Clinical Trials, Antigonish;
Tharwat Fera, Vancouver, Canada; Michel Gagnon, CHUM - Hopital Notre-Dame, Montreal;
Lawrence Homik, Winnipeg Clinic, Winnipeg; Richard Leigh, University of Calgary, Calgary; Dale
Lien, University of Alberta, Edmonton; Michel McKeough, Medical Clinic, Sydney Mines; Lyle
Melenka, Grey Nun's Community Hospital, Edmonton; Robert Luton, London; Joseph Berlingieri,
JBN Medical Diagnostic Services, Inc., Burlington; CHILE: Manuel Barros, Hospital Carlos van
Buren, Valparaíso; Patricia Fernández, Hospital Nacional del Tórax, Santiago; Mónica Gutiérrez,
Clínica Ciudad del Mar, Viña del Mar; Werner Jensen, Hospital Gustavo Fricke, Viña del Mar;
María Parada, Clinica Avansalud, Santiago; CHINA: Nanshan Zhong, First Affiliated Hospital Of
Guangzhou Medical College, Guangzhou; Chuntao Liu, West China Hospital of Sichuan
University, Chengdu; Ce Shen, The 6th People's Hospital of Shanghai, Shanghai; Qingyu Xiu,
Shanghai Changzheng Hospital, Shanghai; Jieming Qu, Shanghai Huadong Hospital, Shanghai;
Baoyuan Chen, General Hospital, Tianjin Medical University, Tianjin; Bin Cao, Respiratory
Diseases Institute, Beijing Chaoyang Hospital; Beijing; Zhengyi He, Beijing Friendship Hospital
Affiliate of Capital University, Beijing; Jian Kang, The First hospital of China Medical University,
Shenyang; Li Zhao, Shengjing Hospital of China Medical University, Shengyang; Xiaohong Liu,
First Affiliated Hospital of Guangzhou University of TCM, Guangzhou; Shenghua Sun, Third
Xiangya Hospital of Central South University, Changsha; COLOMBIA: Gustavo Hincapie,
Hospital Militar Central, Bogotá; Guido Cardona, NeumoInvestigaciones, Bogotá; Julio Forero,
Hospital San Vicente de Paul, Medellin; Carlos Salgado, Centro Médico Imbanaco, Cali;
Bernardo Muñoz, Clínica Medellín, Medellín;Fernando Londoño, Clínica Soma, Mendellin;
Alberto Reyes, Centro de Investigación Clínica FOQUS, Bogota; CROATIA: Fadila Pavicic,
Klinika za plucne bolesti Jordanovac, Zagreb; Ljiljana Bulat-Kardum, KBC Rijeka, Rijeka;
Gordana Stjepanovic, OB dr. Ivo Pedisic, Petrinja; Neven Tudoric, Klinicka bolnica Dubrava,
Zagreb; CZECH REPUBLIC: Martina Cmakalova, Praha - Malesice, Praha – Malesice; Jan
Dindos, Clinic of Pulmonary Diseases, Neratovice; Viktor Jensovsky, Clinic Of Pulmonary
Diseases And Internal Medicine, Lovosice; Jan Krepelka, SPIiN, Praha; Miluse Zitkova, Clinic Of
Page 25 of 27
Pulmonary Diseases, Pardubice – Trnova; GERMANY: Anneliese Linnhoff, Praxis fü Lungenund Bronchialheilkunde, Berlin; Andreas Colberg, Praxis Hr. Dr. A. Colberg, Schleswig-Holstein;
Frank Käßner, Ambulantes Zentrum für Lungenkrankheiten und Schlafmedizin Cottbus,
Brandenburg; Thomas Schultz, Praxis Hr. Dr. Th. Schultz, Berlin; Reiner Laumen, Praxis Drs.
Laumen/Wiederhold, Hessen; Markus Huntemann, Praxis Hr. Dr. M. Huntemann Lüdenscheid,
Nordrhein-Westfalen; Karin Todoroff, Praxis Fr. Dr. K. Todoroff, Baden-Württemberg; Manfred
Raffenberg, Praxis Hr. Dr. M. Raffenberg, Brandenburg; Jens Becker, Praxis Hr. Dr. J. C.
Becker, Lübeck; Ulrike Westerhausen, Praxis Drs, Berlin; Hartmut Timmermann,
Gemeinschaftspraxis Drs. Hartjen, Sostmann, Timmermann für Allergologie, Lungen und
Bronchialheilkunde, Hamburg; Jörg Reinhardt, Medizinisches AllergoPneumologisches, Dresden;
Christian Geßner, Praxis Hr. Dr. C. Geßner, Leipzig; Andrés de Roux, Praxis Hr. Dr. A. de Roux,
Berlin; Regina Deckelmann, Praxis Drs.Deckelmann/Eckhardt, Leipzig; Gerald Eckhardt,
Medizinsches Versorgungszentrum Delitzsch, Delitzsch; Andreas Schwittay, Praxis Hr. Dr. A.
Schwittay, Böhlen; GREECE: Harry Bassaris, University General Hospital of Patras, Patras;
Michail Toubis, Sotiria General State Hospital of Chest Diseases, Athens; Fredericos Vlastos,
Sotiria General State Hospital of Chest Diseases, Athens; Stavros Constantopoulos, General
University Hospital of Ioannina, Ioannina; Constantinos Gourgoulianis, University General
Hospital of Larissa, Mezourlo; Georgios Tatsis, Evangelismos General Hospital of Athens,
Athens; HONG KONG: Kit Man Sin, Tuen Mun Hospital, Tuen Mun; Wai-Cho Yu, Princess
Margaret Hospital, Lai Chi Kok; INDONSESIA: Prijanti Z. Soepandi, Department of Respiratory
Medicine, Jakarta; Benjamin P Margono, Dr Soetomo Hospital, Surubaya; Jahja Teguh Widjaja,
Immanuel Hospital, Bandung; IRELAND Derek Forde, Slaney Medical Centre, Enniscorthy;
Eamonn Shanahan; Farranfore Medical Centre, Killarney; ITALY: Fernando De Benedetto,
AUSL 2 Lanciano-Vasto-Chieti, Chieti; Riccardo Pela, ASUR Marche ZT13 Ascoli Piceno
Pneumologia, Ascoli Pineco; Pietro Zanon, A.O. Ospedale Circolo Busto Ar Broncopneumologia,
Busto Arsizio; Mario Polverino, ASL SA/1 Nocera Inf - Campania Fisiopatologia Respiratoria
Centro Medico Italo-Australiano, Salerno; LITHUNANIA: Edvardas Danila, Vilnius Region
Outpatient Department, Vilnius; Audrone Urboniene, Saules Family Medicine Center, Kaunas;
Indre Reisaite, Silainiu Family Health Center, Kaunas; Ruta Radzeviciene, UAB "Mano Seimos
Gydytojas", Klaipeda; Stanislovas Naudziunas, Siauliai County Hospital, Siauliai; LATVIA:
Ludmila Borsa, Ltd "BINI" (SIA "BINI"), Ventspils; Ilze Aizsilniece, Gimenes Arstu Prakse, Riga;
Aiva Petersone, SIA Talsi Veselibas Centrer, Talsu; Zinaida Lapkovska, Kraslavas Hospital,
Kraslava; MEXICO: Roberto Perea Sánchez, Hospital Central Universitario, Chihuahua; Jorge
Rosas Cacho, Antiguo Hospital Civil de Guadalajara, Guadalajara; Francisco Chan Mérida,
Hospital General O'Horán SS, Mérida; Agustín López de Lara Díaz, Hospital San Agustín
Zacatecas, Zacatecas; Alicia Ramírez Rivera, Unidad de Investigación Clínica en Medicina,
Monterrey; THE NETHERLANDS: E.J. Haren, Atrium Medisch Centrum, Heerlen; J.A. Noord,
Atrium Medisch Centrum, Heerlen; P.L.M.L. Wielders, Catharina Afd. Longgeneeskunde en
Tuberculose, Eindhoven; PAKISTAN: Padeem Rizvi, Jinnah Postgraduate Medical Centre,
Karachi; PERU: Alberto Matsuno, Clínica San Pablo, Lima; Pablo Tokumoto Kishaba, Hospital
Central de la Fuerza Aerea del Perú, Lima; Alfredo Guerreros Benavides, Clínica Internacional,
Lima; Andrés Piñeiro García Calderón, Clínica El Golf, Lima; Oscar Gayoso, Hospital Nacional
Cayetano Heredia, Lima; THE PHILIPPINES: Mario Juco, Manila Doctors Hospital, Manila;
Dennis Teo, Lung Center of the Philippines, Quezon City; PORTUGAL: Fátima Teixeira, Centro
Hospitalar Coimbra, S. Martinho do Bispo; Jorge Pires, Centro Hospitalar Coimbra, S. Martinho
do Bispo; SOUTH AFRICA: Ismail Mitha, Worthwhile Clinical trials, Benoni; Salim Ahmed,
Worthwhile Clinical Trials, Benoni; Sue Blignaut, Paarl Research Centre, Paarl; Thomas
Page 26 of 27
Coetzer, Clinresco Kempton Park, Kepton Park; Ingrid Engelbrecht, I. . Engelbrecht Reseach
(Pty) Ltd, Centurion; Elvis Irusen, University of Stellenbosch Tygerberg Hospital, Cape Town;
Jaco Jansen, Vergelegen Medi-Clinic, Somerset West; J Lombaard,Josha Research,
Bloemfontein; Elane van Nieuwenhuizen, Emmed Research, Pertoria; Johan van Onselen,
Intercare Medical & Dental Centre Glenfair, Pertoria; Uttam Govind, Randles Road Medical
Centre, Durban; Dirkie Jansen van Rensburg, Park Medical Centre, Witbank; Leon Fouche,
Tambotie Medical Centre, Thabazimbi; Mashra Gani Gani, Mercantile Hospital Centre, Port
Elizabeth; Padaruth Ramlachan, Newkwa Medical Centre, Durban; SPAIN: Eduard Monsó,
Hospital Universitari Germans Trias i Pujol, Barcelona; Miguel Carrera Lamarca, Hospital
Universitari Son Espases, Palma de Mallorca,Juan José Soler, Hospital General de Requena,
Valencia; Luis Lores, Hospital Sant Boi, Barcelona; Manel Borrell, CAP Sarrià, Barcelona;
Francisco Pont, Consorci d’Atenció Primària de Salut de l’Eixample, Barcelona; SWITZERLAND:
Michael Tamm, Universitätsspital Basel, Basel; THAILAND: Charoen Chuchottaworn, Dept of
COPD Clinic, Nonthaburi;Chaicharn Pothirat, Maharaj Nakorn Chiang Mai Hospital, Chang Mai;
Chanchai Sittipunt, King Chulalongkorn Memorial Hospital, Bangkok; UK: John Langan,
Baillieston Health Centre, Glasgow; Iain McColl, Thornliebank Health Centre, Glasgow; C
McKinnon, Castlemilk Health Centre, Glasgow.
Page 27 of 27