Clinical Study Synopsis

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1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labeling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare AG. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare AG. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.

2 Study Sponsor: Study Number: Study Phase: III Clinical Trial Results Synopsis Bayer Pharma, France Study Design Description NCT Official Study Title: A multinational, prospective, randomized, double-blind study to investigate the efficacy and safety of sequential intravenous/oral moxifloxacin in comparison to intravenous levofloxacin plus intravenous ceftriaxone followed by oral levofloxacin, in the treatment of patients with severe community-acquired pneumonia (CAP). Therapeutic Area: Anti-Infectives Test Product Name of Test Product: Name of Active Ingredient: Dose and Mode of Administration: Moxifloxacin (Avelox, BAY ) Moxifloxacin Hydrochloride Sequential intravenous (IV)/per os; orally (PO) moxifloxacin 400/400 mg once daily (od). Reference Therapy/Placebo Reference Therapy: IV levofloxacin plus IV ceftriaxone followed by oral levofloxacin Dose and Mode of Administration: Duration of Treatment: 7 to 14 days IV levofloxacin 500 mg bid (twice a day) plus IV ceftriaxone 2 g od followed by oral levofloxacin 500 mg bid. Studied period: Date of first subjects first visit: 08 JAN 2004 Premature Study Suspension / Termination: Substantial Study Protocol Amendments: Date of last subjects last visit: 08 JUL 2005 No Amendment no. 1 (dated 05 SEP 2003) specified that some health authorities considered intravenous clarithromycin unsafe for the treatment of very ill/elderly subjects due to QT interval prolongation problems with intravenous macrolides. The health authorities strongly advised the use of a comparator regimen that does not have cardiac safety issues in order to allow a clear safety assessment of moxifloxacin. Based on this recommendation, reference therapy of "IV ceftriaxone 2 g od plus IV clarithromycin followed by oral levofloxacin 500 mg bid" was changed to "IV ceftriaxone 2 g od plus IV levofloxacin 500 mg bid followed by oral levofloxacin 500 mg bid". Amendment no. 2 (dated 12 NOV 2003) specified the incorporation of an additional exclusion criterion for subjects with psychosis and/or schizophrenia. Amendment no. 3 (dated 20 FEB 2004) specified the incorporation of updated information to the "Warning/Precautions" section of the protocol. This Amendment also specified the incorporation of an additional exclusion criterion for subjects with pre-terminal failure Page 1 of 14

3 (creatinine clearance < 10 ml/min and subjects undergoing hemodialysis. Amendment no. 3 also specified the implementation of an external (unblinding) monitoring for drug accountability. Amendment no. 4 (dated 22 APR 2004) specified changes to the title of the protocol because of change of comparators. Amendment no. 5 (dated 03 JUN 2004) specified that hematology analyses would be performed by local laboratories for all visits, to avoid the long turn-around time between the sites and the central laboratory. Amendment no. 6 (dated 10 JAN 2005) specified modification in inclusion criteria. Subjects with fever and/or increase in white blood cell count or leucopenia could be recruited provided they met all other inclusion criteria, including radiological evidence of an infiltrate consistent with pneumonia. Study Centre(s): This study was conducted at 71 centers in 18 countries. Methodology: Subjects eligible for this study were stratified according to the severity of their illness to either Pneumonia Severity Index (PSI) Class III (Stratum 1) or PSI Classes IV to V (Stratum 2) according to the point scoring system of the prediction rule for assignment to PSI Classes I V in subjects with CAP. The number of subjects enrolled in Stratum 1 was not to exceed 50% of the overall study population. Subjects were maintained on IV therapy for the entire duration of the study if clinically indicated or switched to PO therapy after at least 3 full days of IV therapy. Clinical assessments were performed before therapy, during therapy on Days 3 to 5, and on the day-of-switch from IV to PO, at premature discontinuation/end-of-treatment (EOT), at the test-of-cure (TOC) Visit (4 to 14 days post therapy), and at follow-up (21to 28 days post therapy). The following signs and symptoms of pneumonia had to be documented: cough, dyspnea, sputum production, and quality, dullness to percussion, rigors, chills, rales, and pleuritic chest pain. Pre-therapy chest X-rays were systematically reviewed by a blinded committee and findings on chest examination were assessed for confirmation of the primary diagnosis. In subjects who required additional antimicrobial therapy, a clinical assessment was performed 5 to 7 days after completion of this therapy. This constituted the last assessment visit for these subjects. Indication/ Main Inclusion Criteria: A Critical Event Committee was set up to review all adverse events of cardiac nature. An independent clinical response evaluation Committee was responsible for the blinded evaluation of clinical response to study drugs. Indication Community-acquired pneumonia Main Inclusion criteria Adult subjects with CAP of PSI Class III, IV or V requiring hospitalization and initial parenteral antibiotic therapy. Page 2 of 14

4 Study Objectives: Overall: To determine the efficacy and safety of sequential IV/PO moxifloxacin monotherapy in comparison to a combination therapy with IV levofloxacin plus IV ceftriaxone followed by oral levofloxacin in the treatment of subjects admitted to hospital with severe CAP. Primary: To demonstrate that monotherapy with moxifloxacin IV/PO 400/400 mg once daily is not less effective than the comparator therapy based on clinical cure rate at the TOC visit. Evaluation Criteria: Secondary: To evaluate the safety including cardiac safety of monotherapy with moxifloxacin IV/PO 400/400 mg once daily in the treatment of subjects admitted to hospital with severe CAP. To assess the implications of each treatment group on healthcare resource utilization and overall costs associated with the treatment of CAP. Efficacy (Primary): Clinical response 4 to 14 days after completion of study treatment (TOC visit). \ Efficacy (Secondary): Clinical and bacteriological response on the day-of-switch from IV to oral therapy Clinical and bacteriological response on days 3 to 5 (if the dayof-switch was different from days 3 to 5) Clinical and bacteriological response at the EOT, i.e., on days 7 to 14 Bacteriological response at the TOC visit Mortality attributable to pneumonia at the TOC visit Clinical and bacteriological response 21 to 28 days after the EOT CAP symptoms course (at the different assessment visits) Economic analysis of study drug treatment on healthcare resource utilization and overall costs associated with the treatment of CAP Safety: Each subject was carefully monitored for adverse events. The following aspects of an adverse event were assessed: seriousness, severity, and relationship to study drug. Adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA). Moreover, safety assessments included results of physical examinations, vital signs data, and abnormal laboratory tests. Pharmacokinetics: Blood samples for determination of plasma moxifloxacin levels were obtained on Day 1 and Day 3, after the end of the moxifloxacin or ceftriaxone infusion, between the first and second post-infusion ECG recording. Page 3 of 14

5 Statistical Methods: Efficacy (Primary): The primary objective of this study was to reject the following null hypothesis: A 7 to 14 day sequential IV/PO treatment with moxifloxacin 400/400 mg od was more than 10% less effective than a 7 to 14 day treatment with IV levofloxacin 500 mg bid plus IV ceftriaxone 2 g od followed by oral levofloxacin 500 mg bid based on clinical success (= clinical cure) at the TOC Visit (4 to 14 days after the end of study drug treatment). The primary efficacy parameter was clinical response at the TOC Visit which was systematically and blindly assessed by the independent review board (Clinical Committee), and this constituted the primary efficacy analysis. For success rates, (i.e., cure rates at TOC), a 95% confidence interval (CI) of the difference of the 2 clinical success rates (Treatment Group "moxifloxacin" minus Treatment Group "comparator") was calculated using Mantel-Haenszel weights reflecting regions and strata. Non-inferiority of treatment with moxifloxacin was to be concluded if the lower limit of this CI was greater than -10% and the CI included 0. If, and only if the lower limit of this CI was greater than 0, the superiority of treatment with moxifloxacin was proven. Since the subjects were stratified with respect to the severity of disease, i.e., PSI Risk Class III vs PSI Risk Classes IV to V, a descriptive investigation was undertaken to determine the number of clinical cure and failure subjects within each of these strata for both treatment groups. Efficacy (Secondary): As secondary efficacy analyses, the clinical response assessed on the day-of-switch from IV to oral therapy, on days 3 to 5 (only if the day of the IV/PO switch was not days 3 to 5), at the EOT, at the follow-up, 21 to 28 days after completion of therapy, and the clinical response at TOC and follow-up in subjects with bacteriologically proven infection, was analyzed exploratively in the same way as the primary efficacy parameter. In those subjects with microbiological documentation, the clinical response at TOC was analyzed according to in-vitro susceptibility. At follow-up, analyses were performed on subjects who were assessed as "clinical cure" at the TOC Visit, but also on subjects with clinical failures at the TOC visit carried forward to the follow-up. Additionally, the bacteriological responses on the day-of-switch, on days 3 to 5 (if the day-of-switch was different from days 3 to 5), at the EOT, at the TOC visit (4 to 14 days after EOT) and follow-up were analyzed exploratively in the same way as the primary efficacy parameter based on the subgroup of microbiologically valid subjects. All efficacy analyses and tabulations of efficacy data were performed for the valid-per-protocol population (primary efficacy population) as well as for the intent-to-treat (ITT) population (secondary efficacy Page 4 of 14

6 population). The ITT populations corresponding to the subgroup of microbiologically valid subjects were subjects valid for the ITT analysis with causative organism(s) at enrollment. In the per protocol (PP) analyses of clinical and bacteriological response, the treatment comparisons were performed as "cure" vs "failure" (missing and indeterminate outcomes excluded from analysis), in the ITT analyses additionally to the analysis "cure" vs "failure", a comparison of "cure" vs "non-cure" was performed. Number of Subjects: Safety: In the safety analysis, special attention was paid to the nature and incidence of cardiac adverse events, including critical cardiac adverse events as blindly assessed by the Critical Event Committee (CEC), and their relationship to study drugs. Pharmacokinetics Descriptive statistics of moxifloxacin plasma concentrations were pooled according to time after end of infusion (safety population) and correlated with ECG data. A total of 748 subjects were enrolled in this study, 738 were randomized (371 in the moxifloxacin-treated group and 367 in the comparator-treated group). A total of 116 subjects withdrew early from the study (68 [18.3%] in the moxifloxacin-treated group and 48 [13.1%] in the comparatortreated group). Table 1 summarizes the disposition of subjects in this study. Table 1: Subjects included in each analysis population Study Results Results Summary Subject Disposition and Baseline Among moxifloxacin-treated subjects of the ITT/Safety population (n=368), 154 (41.8%) had a PSI score of II or III, 171 (46.5%), a PSI score of IV, and 43 (11.7%), a PSI score of V. Respective numbers in the comparator group (n=365) were 150 (41.1%), 172 (47.1%) and 43 (11.8%). Men subjects were predominant in the overall ITT population, i.e., 61.7% men vs 38.3% women. Mean age was 65.6 ± 16.7 years (range: 19 to 100 years) in the moxifloxacin-treated group versus (vs) 65.0 ± 17.1 years (range: 18 to 101 years) in the comparator-treated group. Mean BMI was 25.9 ± 5.2 kg/m 2 (range: 14.2 to 48.8 kg/m 2 ) in the moxifloxacin-treated group vs 26.0 ± 5.1 kg/m 2 (range: 12.6 to 50.8 kg/m 2 ) in the comparator-treated group. At study entry, 9.5% of the subjects in the moxifloxacin-treated group vs 10.4% in the comparator-treated group were admitted in an intensive care unit (ICU). Respectively, 5.4% of subjects in the moxifloxacin-treated group vs 5.2% in the Page 5 of 14

7 comparator treated group were ventilated at baseline. Partial pressure of arterial oxygen at room air was 60.6 ±11.4 mmhg vs 60.3 ± 12.9 in the moxifloxacin-treated group vs comparator-treated group respectively. Results Summary Efficacy Primary Efficacy Variables 187/291 (64.3%) moxifloxacin-treated subjects vs 185/278 (66.5%) comparator-treated subjects received at least 5 days of IV therapy. Table 2 summarizes treatment duration in the valid-per-protocol population according to Clinical Committee evaluation (PP1). Table 2: Duration of treatment for subjects valid in PP1 population (all regions) The clinical success rate at the TOC visit in the PP1 population was 86.9% in the moxifloxacin-treated group vs 89.9% in the comparator-treated group. Since the lower limit of the 95% CI for the difference in clinical success rates (-8.1%; 2.2%) was greater than -10%, moxifloxacin was not inferior to comparator in treating subjects with CAP of PSI Class III, IV or V. Table 3 summarizes results of clinical responses at the TOC visit in per protocol and ITT populations, based on Clinical Committee assessment. Table 3: Clinical success at the Test-of-Cure (PP1/ITT populations)- Clinical Committee assessment all regions Results of the ITT population and of the per protocol analyses based on clinical investigators assessment (PP2-87.8% moxifloxacin-treated group, 90.9% comparator-treated group; CI 95% [-8.0% - 2.0%]) were consistent with the primary efficacy analysis. Page 6 of 14

8 Table 4 summarizes results of the clinical responses at the TOC visit in different microbiologically documented subgroups. Table 4: Clinical success at Test-of-Cure (PP1 population in different microbiologically documented subjects subgroups) all regions Secondary Efficacy Variable The bacteriological success rate at the TOC Visit was 83.3% in the moxifloxacin-treated group and 85.3% in the comparator treated group for microbiologically valid subjects. Table 5 summarizes the bacteriological success rate at the TOC Visit in PP1 and intent-to-treat (ITT) populations. Page 7 of 14

9 Table 5: Bacteriological success at the Test-of-Cure from respiratory and/or blood cultures (PP1/ITT populations) all regions The bacteriological success rates against the key pathogens were similar between the two treatment groups. Table 6 summarizes the bacteriological success rate by causative organisms at the TOC visit in the per protocol microbiologically valid population (PP1/MBV). Table 6: Bacteriological success by causative organisms at the Test-of-Cure in respiratory and/or blood cultures (PP1/MBV a population) Results Summary Safety Table 7 shows the incidence rates of the various types of adverse events, premature discontinuation, hospitalization due to adverse events and death. Page 8 of 14

10 Table 7: Overview of adverse events and survival combined IV/PO administration of study drug (Safety population) In the valid for safety population, 208 subjects (57%) in the moxifloxacin-treated group and 193 subjects (53%) in the comparator-treated group presented with at least one treatment emergent adverse event. The most commonly occurring single adverse event was diarrhea (8% in the moxifloxacin-treated group vs 4% in the comparator-treated group; note that all data presentations are in the sequence moxifloxacin-treated group first followed by the comparator-treated group) followed by alanine transaminase (ALT) increased (3% vs 6%) and aspartate transaminase (AST) increased (3% vs 5%). Cardiac disorders were reported with the same incidence in both treatment groups (7%). Table 8 presents the overview of adverse events occurring under the IV route of treatment administration. Table 8: Overview of adverse events and survival occurring under the IV route of administration of study drug (Safety population) In the valid for safety population, 86 subjects (23%) in the moxifloxacin-treated group and 76 subjects (21%) in the comparator treated group had at least one drug-related treatmentemergent adverse event (investigator assessment). The most commonly occurring single adverse event was diarrhea (6% vs 2%) followed by ALT increased (2% vs 3%) and AST Page 9 of 14

11 increased (1% vs 3%). Most events of diarrhea in both groups were not diagnosed as Clostridium difficile-associated diarrhea. Drug-related cardiac adverse events were reported in less than 1% in the moxifloxacin-treated group vs 1% in the comparatortreated group. Table 9 summarizes the incidences of the most frequent (occurring in at least 1% of subjects) treatment-emergent adverse events by MedDRA system organ class and MedDRA event within system organ class. Table 9: Treatment emergent adverse events by MedDRA and adverse events occurring in at least 1% of subjects in any treatment group (Safety population) Table 10 summarizes the incidences of the most frequent (occurring in at least 1% of subjects) drug-related treatment-emergent adverse events by MedDRA system organ class and MedDRA event within system organ class. Page 10 of 14

12 Table 10: Drug-related treatment-emergent adverse events by MedDRA system organ class and MedDRA event within system organ class with incidence rate 1% in either treatment group (ITT/safety population). There were 40 deaths reported in the study. The death rate was 7% in the moxifloxacintreated group and 4% in the comparator-treated group (P = 0.11). A total of 12 of the 25 deaths with moxifloxacin and 5 of the 15 deaths with comparator occurred more than 7 days after the last dose of study drug. According to the Clinical Committee evaluation, the mortality rates attributable to pneumonia were 3% (12/368) in moxifloxacin-treated subjects and 2% (8/365) in comparator-treated subjects (in one subject of each group, the evaluation was not possible). All deaths attributable to pneumonia except one (in the comparator group) were in subjects with PSI Class IV or V. None of the deaths were considered related to study drug by the investigators. However, in one moxifloxacin treated subject, the cardiac arrest leading to death was assessed as being possibly related to study drug by the Critical Event Committee (for this subject, the Clinical Committee considered pneumonia to be the cause of death). The incidences of serious adverse events were 21% with moxifloxacin and 15% with comparator. Drug-related serious adverse events were reported in 5% and 3% of moxifloxacin-treated and comparator-treated subjects respectively. The most common drug related serious adverse events were electrocardiogram QT (corrected interval) prolongation: 2% vs 1%. These QT intervals corrected for heart rate (QTc) prolongations were not associated with any adverse events that could be considered a clinical surrogate for QTcprolongation related arrhythmias. The incidence of adverse events that resulted in premature discontinuation was low in both treatment groups (29 subjects, 8% moxifloxacin-treated group; 17 subjects, 5% comparatortreated group). Table 11 presents mean changes in QT interval according to Bazett s Formula (QTcB) and Fridericia s Formula (QTcF) for subjects who had paired valid ECGs. Page 11 of 14

13 Table 11: Mean and standard deviation of QT interval prolongation according to Bazett s Formula and Fridericia s Formula Results Summary Pharmacokinetics Table 12 summarizes the descriptive statistics of plasma concentrations. Table 12: Descriptive statistics of moxifloxacin plasma concentrations pooled according to time after end of infusion (Safety population) Page 12 of 14

14 Figure 1: Plasma concentration vs QTc interval changes from Baseline to Day 1 Population: Subjects valid for PK with valid Baseline, Day 1 and Day 3 ECGs, all regions, Day 1 Figure 2: Plasma concentration vs QTc interval changes from Baseline to Day 3 Population: Subjects valid for PK with valid Baseline, Day 1 and Day 3 ECGs, all regions, Day 3 The pharmacokinetics in this subject population was comparable to those obtained previously in subjects with CAP and in healthy subjects. Peak concentrations were similar to those found in Phase I studies (based on historic comparison). Analysis of the peak concentrations with Page 13 of 14

15 respect to age and sex were also in line with previous findings indicating that there was no clinically relevant age and gender effect in this subject population. No correlation was seen between moxifloxacin concentrations and QTc absolute changes, with the exception of the valid baseline, day 1, and day 3 ECG when QTcB changes from baseline observed on day 3 were tested for correlation with plasma concentrations (P = 0.034) (Figure 1 and Figure 2). Conclusion(s) In this study, the study population was adequately selected with over 60% of subjects having a PSI risk Class of Class IV or V. The mean duration of IV therapy was 6 days. The sequential IV to oral moxifloxacin regimen was demonstrated to be non-inferior to a combination regimen of levofloxacin plus ceftriaxone in the management of subjects with severe CAP. The clinical cure rate at the TOC visit in the primary efficacy analysis was 86.9% for moxifloxacin monotherapy and 89.9% for the ceftriaxone plus levofloxacin combination (95% CI: -8.1% to 2.2%). The non-inferiority of moxifloxacin was also demonstrated in the subgroups of subjects in PSI Class IV or V. Secondary efficacy analyses were consistent with the results of the primary analysis. Both sequential IV/oral moxifloxacin and the comparator regimen were well tolerated. The adverse events in moxifloxacin treated and comparator-treated subjects were generally similar and were typical of the events to be expected in subjects with severe CAP. Although moxifloxacin produced an - expected - QTc prolongation, an analysis of cardiac events and events considered surrogates of arrhythmia did not detect a proarrhythmic effect of moxifloxacin in this high risk population. There was no evidence of a drug-related death in either treatment group (with the exception of one moxifloxacin-treated subject for whom the Critical Event Committee assessed the event with fatal outcome as possibly related to study drug). Although the mortality rate was slightly higher in the moxifloxacin-treated group, it was not associated with a drug-related toxicity. There were no clinically significant differences between the treatment groups for clinical laboratory test abnormalities. In summary, this study demonstrated that sequential therapy with once daily IV/oral moxifloxacin was not less effective than a twice daily application of the combination therapy of high dose of levofloxacin and ceftriaxone in the treatment of hospitalized subjects requiring initial IV therapy for community-acquired pneumonia. Moxifloxacin was effective in the most severe cases including bacteremic subjects and subjects with a Pneumonia Severity Index Class IV to V. It demonstrated to have an acceptable safety profile. Publication(s): Date Created or Date Last Updated: Torres A, Garau J, Arvis P, Carlet J, Choudhri S, Kureishi A, Le Berre MA, Lode H, Winter J, Read RC; MOTIV (MOxifloxacin Treatment IV) Study Group. Moxifloxacin monotherapy is effective in hospitalized patients with community-acquired pneumonia: the MOTIV study--a randomized clinical trial. Clin Infect Dis May 15;46(10): FEB 2012 Date of Clinical Study Report: 14 SEP 2006 Page 14 of 14

16 Appendix to Clinical Study Synopsis Product Identification Information Product Type Drug US Brand/Trade Name(s) Avelox [Oral formulation] Brand/Trade Name(s) ex-us Generic Name Main Product Company Code Other Company Code(s) Chemical Description Other Product Aliases Avelox Avalox Actira Octegra Izilox Havelox Megaxin Proflox Promira Moxifloxacin BAY n/a 1-Cyclopropyl-6-fluoro-8-methoxy-7-[(4aS,7aS)- octahydro-6h-pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-1,4- dihydroquinoline-3-carboxylic acid hydrochloride. n/a Date of last Update/Change: 19 August 2010