Period of study: 12 Nov 2002 to 08 Apr 2004 (first subject s first visit to last subject s last visit)

Transcription

1 Study Synopsis This file is posted on the Bayer HealthCare Clinical Trials Registry and Results website and 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 on this 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 BAY Study synopsis Title of the study: A study of Avelox (BAY ) for treatment of elderly patients with Community Acquired Pneumonia (the SAFE CAP study). (Study 10872) Investigator(s): Principal/Coordinating Investigator: Antonio Anzueto MD, South Texas Veterans Health Care System, Pulmonary Diseases (111E), 7400 Merton Minter Blvd, San Antonio, TX (For details see Section ) Study center(s): This study was conducted at 47 centers in the United States. Publications (references): None Period of study: 12 Nov 2002 to 08 Apr 2004 (first subject s first visit to last subject s last visit) Clinical phase: Phase IV Objectives: The primary objective of this study was to assess the safety of sequential intravenous (IV)/oral (PO) moxifloxacin compared with sequential IV/PO levofloxacin (Levaquin ) in the treatment of elderly subjects (aged 65 years) with community-acquired pneumonia (CAP) who required initial parenteral therapy. The secondary objectives included an assessment of the clinical and bacteriologic efficacy of both drugs. Methodology (design of study): This trial was a prospective, third party blinded, double-dummy, multi-center, comparative protocol to evaluate cardiac safety. Elderly subjects (aged 65 years) with CAP who required initial parenteral therapy and met the study eligibility criteria were stratified by disease severity using the revised American Thoracic Society (ATS) severity criteria and were randomized to receive study drug for 7 to 14 days. Subjects in both treatment groups were switched to oral therapy after at least 2 days of IV therapy if they were improving on IV therapy, afebrile for at least 8 hours, and had no vomiting or diarrhea. If necessary, subjects were switched back to IV therapy to complete the 7- to 14-day therapy course. Safety was assessed on the basis of digital Holter electrocardiogram (ECG) recordings, cardiac adverse events and serious adverse events, and all other adverse events and mortality. A critical events committee (CEC), consisting of 2 cardiologists,

3 BAY evaluated and adjudicated all cardiac events reported during the course of the study. Number of subjects: In total 401 elderly subjects were enrolled in this study. All subjects had CAP and required initial parenteral therapy. The mean age of all subjects valid for safety was 77.8 ± 7.6 years. The disposition of subjects is shown in Table 2-1. Table 2-1: Disposition of Subjects Subject population All subjects Premature discontinuation Valid for safety Valid for efficacy Moxifloxacin N (%) 197 (100) 47 (24) 195 (99) 141 (72) Levofloxacin N (%) 204 (100) 51 (25) 199 (98) 140 (69) Diagnosis and main criteria for inclusion: Test product, dose and mode of administration, batch number: Men and women 65 years or older with CAP who required initial parenteral therapy were eligible for enrollment. In addition to radiological evidence of a new or progressive infiltrate(s) consistent with bacterial pneumonia, subjects had to have at least 2 important symptoms of pneumonia. For Treatment Group 1, IV moxifloxacin 400 mg was administered once daily (QD) for a minimum of 2 doses, followed by oral moxifloxacin 400 mg QD for a total therapy duration of 7 to 14 days. The dosing regimens selected for this study are recommended for managing CAP in the moxifloxacin and levofloxacin package inserts and have been approved by the Food and Drug Administration (FDA). Batch numbers are presented in Section Duration of therapy: Reference therapy, dose and mode of administration, batch number: 7 to 14 days For Treatment Group 2, IV levofloxacin 500 mg was administered QD for a minimum of 2 doses, followed by oral levofloxacin 500 mg QD for a total therapy duration of 7 to 14 days. For subjects who had a documented or calculated creatinine clearance (CrCl) of 20 to 49 ml/min, the IV and oral dose of levofloxacin was a 500 mg loading dose followed by 250 mg QD for a total therapy duration of 7 to 14 days.

4 BAY Levofloxacin 500 mg for IV administration and 250 mg tablets were manufactured by Ortho-McNeil Pharmaceutical, Inc. The levofloxacin 250-mg tablets were overencapsulated into DB AA capsules for blinding purposes. Criteria of evaluation: Efficacy: Efficacy analyses were the secondary analyses in the study. Efficacy variables were the clinical and bacteriological response on therapy Days 3 to 5, clinical response at the TOC visit (Days 5 to 21 after therapy), bacteriological response at TOC, and overall cost of hospitalization. Safety: The primary safety variable was the primary safety composite variable, consisting of Holter monitor findings of (1) cardiac arrest fatal and non-fatal, (2) sustained monomorphic or polymorphic ventricular tachycardia (VT) without cardiac arrest, (3) non-sustained monomorphic VT, and non-sustained polymorphic VT, as defined in the protocol. The occurrence of at least 1 of these events resulted in a composite score of 1 for the subject. The secondary safety composite variable consisted of Holter monitor findings of (1) atrial fibrillation with rapid ventricular response, (2) new onset atrial fibrillation, (3) new onset sustained (>60 seconds) supraventricular tachycardia (SVT), (4) any nonsustained SVT with a rate >120 beats/minute, and (5) long RR pauses >3 seconds (interval between successive electrocardiogram R-waves), as defined in the protocol. Other secondary safety variables included overall adverse events, drug-related adverse events, predefined cardiac adverse events identified by the investigator, serious adverse events, overall mortality, clinical laboratory test results, vital signs measurements, and electrocardiogram (ECG) findings. Statistical methods: The primary analysis was performed on the safety population. The primary safety variable was a composite endpoint that consisted of events that were identified by Holter recording. A 95% confidence interval for the weighted difference between treatment groups in the rates of this primary safety endpoint was constructed. Other safety data summarized included cardiac related

5 BAY Summary and conclusions: Summary of efficacy: adverse events, adverse events, serious adverse events, death, and Holter and ECG findings. Clinical and bacteriological response at TOC were summarized for the subjects valid for efficacy and for safety. Subgroup analyses were also performed in the efficacy analyses. In all, 401 subjects were enrolled in 47 centers; 197 subjects received moxifloxacin, and 204 received levofloxacin. Forty-seven moxifloxacin and 51 levofloxacin subjects did not complete the study. Two moxifloxacin subjects and 5 levofloxacin subjects were randomized but did not receive study medication. These subjects were excluded from the analysis of safety. Therefore, 195 moxifloxacin and 199 levofloxacin subjects were included in the safety population. The valid for efficacy population included 141 moxifloxacin and 140 levofloxacin subjects. Of the 141 moxifloxacin subjects, 69 (49%) were men and 72 (51%) were women; 71 (51%) of the levofloxacin subjects were men and 69 (49%) were women. Caucasian accounted for 84% of the moxifloxacin group and 88% of the levofloxacin group; Blacks accounted for 9% of the moxifloxacin group and 5% of the levofloxacin group. The mean age of the moxifloxacin subjects was 77.9 ± 7.1 years; that of the levofloxacin subjects was 77.4 ± 7.7 years. For most subjects in both groups, Patient Outcomes Research Team (PORT) scores ranged between 3 and 5 (considered very sick). The severity of CAP based on the revised ATS criteria was mild to moderate for 87% of moxifloxacin and 81% of levofloxacin subjects and severe for 13% of moxifloxacin and 19% of levofloxacin subjects. Efficacy was assessed as a secondary objective. Table 2-2 summarizes treatment duration. Table 2-2 Treatment Duration in Days for Subjects Valid for Efficacy Moxifloxacin N = 141 Levofloxacin N = 140 Total duration, mean IV duration, mean Switched to PO (%) 132/141 (94%) 124/140 (89%) PO duration, mean Day of switch, mean The distributions of treatment duration were again similar in the 2 treatment groups. More subjects in the moxifloxacin group (94%) were switched to oral therapy than in the levofloxacin group (89%). Table 2-3 summarizes the clinical response at TOC.

6 BAY Table 2-3: Clinical Response at Test of Cure for Subjects Valid for Efficacy Moxifloxacin N = 141 Levofloxacin N = 140 Mild to Moderate CAP Cure 113/122 (92.6%) 101/114 (88.6%) Failure 9/122 (7.4%) 13/114 (11.4%) Severe CAP Cure 18/19 (94.7%) 22/26 (84.6%) Failure 1/19 (5.3%) 4/26 (15.4%) Overall cure rate 131/141 (92.9%) 123/140 (87.9%) 95% Confidence interval (-1.9%, 11.9%) Abbreviation: CAP = community acquired pneumonia Subjects in the moxifloxacin group had consistently higher clinical cure rates than the subjects in the levofloxacin group across the 2 strata of CAP severity. Since the lower limit of the confidence interval was greater than 10%, moxifloxacin was non-inferior to levofloxacin using a delta of 10%. The moxifloxacin group had fewer positive respiratory site cultures and blood cultures than the levofloxacin group (17 versus 22 subjects in the respiratory site and 5 versus 8 subjects in the blood). Twenty-one moxifloxacin subjects and 30 levofloxacin subjects had a causative respiratory site or blood organism. The bacteriologic response (eradication/presumed eradication) at the TOC visits for the subjects valid for efficacy was 17/21 (81%) for moxifloxacin treated and 21/28 (75%) for levofloxacin treated subjects. Subjects in the moxifloxacin group had a higher clinical cure rate than those in the levofloxacin group both in the efficacy and safety populations. In addition, among subjects in the efficacy population with causative organisms, the moxifloxacin group had higher bacteriological success rates than the levofloxacin group. Summary of safety: Primary Safety Variable The primary safety composite variable was a score based on the occurrence of 3 cardiac events: cardiac arrest; sustained monomorphic or polymorphic VT (>30 seconds); nonsustained monomorphic VT or nonsustained polymorphic VT ( 10 beats) as defined in the protocol. If at least 1 of these events occurred on Holter monitoring, the subject received a composite variable score of 1. A summary of the results is listed in Table 2-4.

7 BAY The CEC concluded that this study comparing moxifloxacin with levofloxacin failed to detect any proarrhythmic effect of moxifloxacin in this population at high risk for arrythmia of moxifloxacin even though the expected 5 msec to 6 msec QTc prolongation was observed. They suggest that the inability to demonstrate an increase in arrythmias during therapy supports the conclusion that moxifloxacin has a favorable benefit versus risk ratio. Table 2-4: Primary Safety Composite Variable Moxifloxacin Levofloxacin Any safety event 16/192 (8.3%) 10/195 (5.1%) Ventricular tachycardia >30 Seconds 1/192 (0.5%) 0/195 (0%) Ventricular tachycardia 10 Beats 15/192 (7.8%) 10/195 (5.1%) Cardiac arrest 1/192 (0.5%) 0/195 (0%) 95% Confidence interval (-1.8%, 8.2%) Note: Each subject counted once only The moxifloxacin group had a 3.2% higher rate in the primary safety variable than the levofloxacin group. The protocol stated that if the upper limit of the confidence interval for the difference in the primary safety variable was less than 10%, then non-inferiority would be concluded. Since the upper limit of the confidence interval was 8.2% and the lower limit was less than 0, the conclusion is that moxifloxacin is noninferior to levofloxacin. A logistic regression analysis was performed using predefined risk factors for arrhythmia. No significant correlation was identified between the incidence of the primary composite safety events and the treatment groups after adjusting for other risk factors. Secondary Safety Composite Variable The secondary safety composite variable was a score based on the occurrence of 5 secondary cardiac events: atrial fibrillation with rapid ventricular response, new-onset atrial fibrillation, supraventricular tachycardia >120 beats/minute, supraventricular tachycardia >60 seconds, and long RR pauses >3 seconds on Holter monitoring. The occurrence of at least 1 of these events resulted in a score of 1 for the subject. Table 2-5 summarizes the results for the secondary composite score. Table 2-5: Secondary Safety Composite Variable Moxifloxacin Levofloxacin Any safety event 141/192 (73.4%) 140/195 (71.8%) Atrial fibrillation with rapid ventricular response 20/192 (10.4%) 22/195 (11.3%) New onset atrial fibrillation 10/192 (5.2%) 9/195 (4.6%) Supraventricular tachycardia > 120 bpm 125/192 (65.1%) 125/195 (64.1%) Supraventricular tachycardia > 60 Seconds 6/192 (3.1%) 4/195 (2.1%) Long RR pauses >3 seconds 0/192 (0%) 0/195 (0%) Abbreviations: bpm = beats per minute; RR = interval between successive ECG R-waves

8 BAY There were 73.4% of the moxifloxacin subjects and 71.8% of the levofloxacin subjects who experienced at least 1 of the 5 secondary safety events. The rates of having a particular secondary safety event were very similar between the moxifloxacin and levofloxacin groups. Table 2-6 summarizes the occurrence of safety events. Table 2-6: Overview of Safety Events Moxifloxacin N = 197 Levofloxacin N = 204 Died 15 (7.7%) 11 (5.5%) Any adverse event 164 (84.1%) 146 (73.4%) Any drug-related adverse event 51 (26.2%) 45 (22.6%) Any serious adverse event 46 (23.6%) 45 (22.6%) Discontinuation due to adverse event 15 (7.7%) 20 (10.1%) Although the overall adverse event rate was somewhat higher in the moxifloxacin group, the frequency of severe adverse events was similar between the 2 treatment groups (14% for moxifloxacin versus 15% for levofloxacin). Adverse Events The rate of cardiac adverse events defined by the investigator for the moxifloxacin group (9.7 %) was lower than that for the levofloxacin group (14.6%). The drug-related event rates were similar in both groups (26% moxifloxacin versus 23% levofloxacin). The 3 most common adverse events were diarrhea (6% moxifloxacin versus 5% levofloxacin) and oral candidiasis (4% in each group). The death rate was 7.7% in the moxifloxacin group and 5.5% in the levofloxacin group. Nine of the 15 deaths with moxifloxacin and 4 of the 11 deaths with levofloxacin occurred more than 7 days after the last dose of study drug. None of the deaths were considered related to study drug.

9 BAY The incidence of serious adverse events was similar in the 2 groups (23.6% with moxifloxacin, 22.6% with levofloxacin). The most common serious adverse events were chronic obstructive airway disease, pneumonia, congestive heart failure, respiratory failure, renal insufficiency and atrial fibrillation. There were 7 serious drug-related serious events 5 subjects in the moxifloxacin group and 16 in 8 subjects in the levofloxacin group. The incidence of adverse events that resulted in premature discontinuation was low in both treatment groups (15 subjects, 7.7% with moxifloxacin, 20 subjects, 10.1% with levofloxacin). In ECG findings from subjects who had paired valid ECGs, there was a mean increase in QTcB of 5.3 (± 23.7) msec in the moxifloxacin group at maximum drug concentration (C max ) on Day 3 of IV therapy and no QTcB increase in the levofloxacin group. No subject in either treatment group had QTc values greater than 500 msec in Day 3 measurements. The incidence rate of QTc prolongation of 30 to 60 msec from baseline was 15.5% versus 6.8% for QTcB; 10.3% versus 6.8% for QTcF; and QTc prolongation of > 60 msec occurred in 1 subject from each group. Findings from clinical laboratory test results and vital signs determinations generally showed similar results for both treatment groups. Summary of pharmacokinetics: This section is not applicable to this report. Conclusions: The findings of this study support the following conclusions: In the primary analysis of the primary safety composite variable for Holter ECG, in elderly subjects with CAP, sequential IV/PO therapy with moxifloxacin was non-inferior to sequential IV/PO therapy with levofloxacin. In both groups, the rate of the cardiac events defining this variable was low. Similarly, consistent results between treatment groups were found for the secondary Holter ECG safety composite variable. The CEC concluded that this study comparing moxifloxacin with levofloxacin failed to detect any proarrhythmic effect of moxifloxacin in this population at high risk for arrythmia even though the expected 5 msec to 6 msec QTc prolongation was observed. They suggest that the inability to demonstrate an increase in arrythmias during therapy supports the conclusion that moxifloxacin has a favorable benefit versus risk ratio.

10 BAY Moxifloxacin produced an overall cure rate of 92.9% at TOC, compared with 87.9% for levofloxacin. In subgroup analyses according to baseline demographic variables, moxifloxacin consistently produced higher cure rates than levofloxacin in nearly all subgroups. High cure rates with both drugs were also seen in subjects with severe CAP.Both sequential IV/PO therapy with moxifloxacin and sequential IV/PO therapy with levofloxacin were well tolerated in elderly subjects ( 65 years old) with CAP who initially required parenteral therapy. Adverse event patterns with moxifloxacin were generally similar to those with levofloxacin and were typical of the events to be expected in the population of elderly subjects studied. The rate of cardiac events was low overall. There were no drug-related adverse events resulting in death in either treatment group. No clinically significant differences between treatment groups were seen for clinical laboratory test values, vital sign values. Subjects were monitored by 12-lead Holter ECG for 72 hours. A 12-lead ECG was extracted pre-therapy and at C max on Day 3 of IV therapy. There was a small increase in QTc prolongation in the moxifloxacin subjects (mean QTc increase of 5.3 msec), and in individual subjects only 1 in each group had an increase of > 60 msec. There was only 1 event in each group that may be possibly related to drug. (An episode of torsades de pointes in the levofloxacin group and a short polymorphic episode of VT in the moxifloxacin group.) There were no other events that may have been related to prolongation of the QT interval. In this study population of elderly subjects with CAP who initially required IV therapy, sequential IV/PO moxifloxacin was shown to be non-inferior to sequential IV/PO therapy with levofloxacin in cardiac safety, as indicated by a primary safety composite variable defined by 3 specific cardiac events. Secondary safety measures also showed that moxifloxacin was equivalent to levofloxacin and that both drugs were well tolerated in elderly subjects with severe CAP. Secondary efficacy analyses showed both drugs to be highly effective in producing clinical response in elderly subjects with CAP. Results with moxifloxacin were consistently better than those with levofloxacin in the principal efficacy analysis and in subgroup analyses. A high efficacy rate was also achieved in subjects with severe CAP.