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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. 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