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Webposting Clinical Trial Results Synopsis Study Sponsor: BSP AG Germany/Bayer Healthcare Pharmaceuticals Study Number: 11566 NCT00492024 Study Phase: IIIb Study Title: Prospective, Multicenter, Randomized, Double-Blind, Placebo Controlled Trial to Evaluate the Efficacy and Safety of Moxifloxacin 400 mg QD for 5 days versus Placebo in the Treatment of Acute Bacterial Sinusitis Therapeutic Area: Primary care Name of Test Product: BAY 12-8039/moxifloxacin/Avelox Active Ingredient: Moxifloxacin Dosage: 400mg daily Reference Therapy: Not applicable. Dosage: Not applicable. Route of Administration: Oral Placebo: Matching placebo contained microcrystalline cellulose. Treatment Duration: 5 days Study Period: Date of first subjects first visit: 06 Jan 2005 Date of last subjects last visit 18 Mar 2008 Methodology: This was a prospective, multicenter, placebo-controlled, randomized, double-blind, Phase IIIb clinical trial designed to evaluate the efficacy and safety of moxifloxacin as compared with placebo in subjects with ABS. After giving written informed consent, subjects who satisfied all inclusion and exclusion criteria were randomized in a 2:1 ratio to treatment with either moxifloxacin 400 mg QD or matching placebo for 5 days. Subjects were evaluated for efficacy and safety at scheduled visits as follows: During Therapy (Day 3 or Day 4); TOC (Day +1 to +3); Premature Discontinuation; Follow-Up (Days +17 to +21); and Post- Alternative Antibiotic (Days +2 to +4 post-alternative antibiotic). Study Site: The study was conducted at 37 centers in the United States (US). Main Inclusion Criteria: The primary diagnosis for inclusion in the study was ABS. Subjects included in the study were men and nonpregnant women, 18 years of age or older, who had a clinical diagnosis of ABS with signs and symptoms present for 7 days but < 28 days as defined by radiographic and clinical criteria. Radiographic criteria included the presence of either or both of the following on a radiographic paranasal sinus film (Waters view): evidence of air-fluid levels and opacification. Eligible subjects also had the presence of 2 major symptoms (purulent anterior or posterior nasal discharge and unilateral facial pain or malar tenderness), or the presence of at least 1 major and 1 minor (frontal headache or fever [oral 38.0 C/100.4 F, tympanic 38.5 C/101.2 F, axillary 37.5 C/99.5 F]) symptom. Culture material was obtained by sinus puncture and the aspirated specimen sent to the central laboratory for Gram stain, quantitative culture, and susceptibility testing prior to initiation of antimicrobial therapy. Subjects with a history of chronic sinusitis, defined as greater than 4 weeks of continuous symptoms, were excluded.
Study Objectives: Overall: Evaluation Criteria: Statistical Methods: To evaluate the efficacy and safety of moxifloxacin 400 mg once daily (QD) for 5 days as compared with placebo in the treatment of acute bacterial sinusitis (ABS). Primary: The primary objective was the clinical response at the Test of Cure (TOC) visit in the Modified Intent-to- Treat (Modified ITT) population. Secondary: Secondary objectives included time to clinical improvement of sinusitis symptoms; subject-reported time to symptom improvement (Sino-Nasal Outcome Test-16 [SNOT-16] and Activity Impairment Assessment [AIA]); time to return to normal activities; clinical response during therapy and at long-term follow-up; microbiological response at the TOC visit and at long-term follow-up; and safety. Efficacy (Primary): The primary efficacy variable was clinical response at the TOC visit (Study Day +1 to +3, corresponding to 6 to 8 days after the start of therapy) in the Modified ITT population. Efficacy (Secondary): Secondary efficacy variables were time to clinical improvement of sinusitis symptoms; subject-reported time to symptom improvement (SNOT-16, AIA); time to return to normal activities; clinical response at the During Therapy visit and at long-term follow-up; and microbiological response at the TOC visit and at longterm follow-up. Safety Safety variables included the incidence of premature termination, adverse events, and clinical laboratory abnormalities. Pharmacokinetics Not applicable. All efficacy analyses were performed on data for the MITT, ITT, and per protocol populations. The primary efficacy population was the MITT population. Safety analyses were performed on data for the safety/itt population. A Cochran-Mantel-Haenszel test was performed to test the null hypothesis of no difference in the clinical cure rates between the moxifloxacin group and the placebo group. The test was to be 2 sided, using an level of 0.05. In order to include all centers in the Cochran-Mantel-Haenszel test for the primary efficacy variable, clinical response, some small centers were combined for the purposes of analysis. Descriptive statistics were used for the secondary efficacy variables clinical response during therapy and at long-term follow-up, and time to improvement of symptoms. An additional secondary analysis was performed to compare the proportion of subjects with clinical cure who improved to the proportion of clinically cured subjects who obtained complete resolution. A minimally important difference (MID) was calculated for the Sino-Nasal Outcome Test-16 (SNOT-16) and Activity Impairment Assessment (AIA) scales. Comparison of the incidence rates of adverse events was done in a descriptive manner. Events were tabulated by type (according to the Medical Dictionary for Regulatory Activities [MedDRA] glossary) and frequency for all events and for those considered by the investigator to be drug-related. Laboratory data were analyzed using descriptive statistics and identification of values outside the normal range. Subjects with indeterminate (or missing) clinical evaluations at the TOC visit were included as clinical failures in the ITT and MITT analyses. For time-to-event analyses, subjects for whom the event had not occurred were considered censored at the time of their last evaluation. Number of Subjects: A total of 374 subjects were enrolled and randomized (251 in the moxifloxacin group and 123 in the placebo group). Of these 374 subjects, 118 were included in the MITT population (the primary analysis population). MITT subjects were defined as those subjects who received at least 1 dose of study drug and whose initial quantitative culture, obtained by sinus puncture, was positive for at least 1 of the following organisms: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pyogenes, or Staphylococcus aureus (only if 10 4 colony forming units [CFU]/mL were present).
Results Summary Overall, most subjects in the MITT population were female (61.9%) and white (78.0%). The subjects ranged in age from 18 to 77 years, with a mean age of 38.4 years. The number of subjects included in each analysis population is summarized in Table 1. Table 1: Subjects Included in Each Analysis Population Analysis Population Moxifloxacin 400 mg Placebo Total Randomized 251 123 374 Valid for ITT/Safety 251 123 374 Valid for MITT 75 43 118 Valid Per Protocol 62 42 104 Abbreviations: ITT = intent-to-treat; MITT = modified intent-to-treat Subject Disposition and Baseline A total of 374 subjects enrolled at 37 study centers in the US received at least 1 dose of study medication and were included in the analysis of the safety/itt population. An additional subject was enrolled and randomized to study drug treatment at Center 75; however, midway through the study, the principal investigator developed a terminal illness. Numerous attempts to contact this site were unsuccessful, and this subject s data (including bacteriological, laboratory, and questionnaire data) were never entered in the CRF. Therefore, data for this subject are not in the clinical database and were not included in the analyses. Of the 251 subjects randomized to treatment with moxifloxacin, 222 (88.4%) subjects completed the study, and of the 123 subjects randomized to placebo, 101 (82.1%) subjects completed the study (P=0.0936). The leading cause of premature termination was insufficient therapeutic effect, with dropouts due to this reason occurring in the placebo group at nearly twice the rate as in the moxifloxacin group (16.3% versus 8.4%). Results Summary Efficacy Moxifloxacin 400 mg PO QD for 5 days failed to show statistically significant superiority over placebo in the treatment of subjects with ABS. Of the 73 MITT subjects treated with 400 mg moxifloxacin, 57 (78.1%) achieved clinical success (complete resolution, or improvement such that no further therapy with an antimicrobial agent, steroid, or irrigation was required) at the TOC visit compared with 30 of 45 (66.7%) MITT subjects who received placebo (P=0.189). The clinical success rate in the moxifloxacin group was close to the expected rate, while the clinical success rate in the placebo group exceeded the projection. The null hypothesis of treatment group equality could not be rejected, and the primary objective of the study was not achieved. Measuring clinical response at the Follow-up visit (Days +17 to +21) increased the difference in clinical success rate (combined clinical cure and continued clinical cure) to 16% (73.9% for moxifloxacin compared with 57.8% for placebo; P=0.067). Alleviation of symptoms was monitored using the SNOT 16 instrument, which showed that 5 days of treatment with moxifloxacin accelerated symptom relief as compared with placebo. The decrease in mean SNOT 16 scores reached a relative plateau between Day 3 and TOC for the placebo group, while mean scores in the moxifloxacin group continued to decrease. The proportion of subjects with signs and symptoms associated with ABS (cough, nasal congestion, postnasal drainage/discharge, purulent nasal drainage, anosmia, hyposmia, and ear pain/pressure/fullness) of moderate or severe intensity at TOC occurred at a rate at least 10% higher in the placebo group than in the moxifloxacin group. For all signs and symptoms, the proportion of subjects with intensity of none was higher in the moxifloxacin group. In general, concomitant medication use for symptomatic relief was lower in the moxifloxacin group as compared with the placebo group antibacterials for systemic use (used by 24.8% of moxifloxacin subjects and 36.1% of placebo subjects); nasal preparations (used by 11.4% of moxifloxacin subjects and 25.0% of placebo subjects); and corticosteroids for systemic use (used by 7.6% of moxifloxacin subjects and 17.9% of placebo subjects). Antibacterials and corticosteroids for systemic use were taken posttreatment by subjects who were treatment failures. The use of symptomatic relief medications decreased from baseline to TOC by 6.8% in the moxifloxacin group, while it increased by 15.6% in the placebo group. This difference was attributed to a higher rate of use in the placebo group of analgesics (P=0.023) and nasal preparations (P=0.062). The rate of premature discontinuation due to insufficient therapeutic effect was higher in the placebo group (22.2%) than in the moxifloxacin group (8.2%) (P=0.022). Although the 5-day moxifloxacin treatment did not meet the protocol-specified endpoint, there was substantial evidence of a positive treatment effect across a number of supportive analyses. Confounding factors, such as the nonstandardized use of concomitant medications for symptomatic relief, may have had an impact on its outcome and conclusions. Results Summary Pharmacokinetics Not applicable. Results Summary Safety The incidence of adverse events for the moxifloxacin and placebo groups is summarized in Table 2.
Table 2: Overview of Adverse Events (Subjects Valid for Safety) Moxifloxacin 400 mg (N=251) Placebo (N=123) n (%) n (%) At least 1 adverse event 96 (38.2%) 50 (40.7%) At least 1 drug-related adverse event 34 (13.5%) 6 (4.9%) At least 1 serious adverse event 1 (0.4%) 1 (0.8%) At least 1 drug-related serious adverse event 0 (0) 0 (0) Adverse event leading to discontinuation 3 (1.2%) 1 (0.8%) Death 0 (0) 0 (0) Note: The incidence rate is the number of subjects reporting any event with a start date during or after treatment / the number of subjects No deaths occurred during the study. Two subjects experienced nonfatal serious adverse events. Subject 11566-025-012 (moxifloxacin group) required hospitalization for severe pneumonia, and Subject 11566-052-001 (placebo group) required hospitalization for severe hypertension. Both serious adverse events occurred after study drug therapy was completed or stopped, and neither was considered by the investigator to be related to study drug therapy. Four subjects experienced adverse events leading to discontinuation of study drug treatment. Three of these subjects had events that were judged by the investigator to be related to study drug. Subject 11566-007-021 (placebo group) had drug-related abdominal pain, diarrhea, and a toxin-positive C difficile culture result. Subject 11566 030-012 (moxifloxacin group) experienced drug-related diarrhea. Subject 11566-030-073 (moxifloxacin group) experienced drug-related burning of the veins. Subject 11566 019 004 (moxifloxacin group) developed a tooth abscess that was unrelated to study drug. Among the clinical laboratory abnormalities, increases in liver transaminases and blood glucose were reported as treatment-emergent adverse events in both treatment groups. None of these laboratory adverse events led to discontinuation of study drug treatment. Moxifloxacin was well tolerated, and the observed safety profile was consistent with that seen in previous moxifloxacin studies evaluating the tablet formulation. Conclusion(s) In conclusion, the results of the present study did not demonstrate the statistically significant superiority of a 5-day regimen of moxifloxacin 400 mg QD compared with placebo in terms of the primary endpoint (clinical response at the TOC visit in the MITT population). Confounding factors, such as the nonstandardized use of concomitant medications for symptomatic relief, may have had an impact on its outcome and conclusions. There was, however, a clear trend in favor of moxifloxacin for most of the other efficacy variables, including accelerated symptom relief as evidenced by the SNOT-16 instrument, a better single symptom relief profile, lower usage of symptomatic relief medications, and a lower rate of premature discontinuation due to insufficient therapeutic effect. Moxifloxacin was well tolerated, and the observed safety profile was consistent with that seen in previous moxifloxacin studies evaluating the tablet formulation. Antimicrobial agents are recommended for certain patients with a diagnosis of ABS, and 7- and 10 day regimens of moxifloxacin are approved for the indication of ABS in Europe and the US, respectively. In addition, moxifloxacin has been shown to be clinically and bacteriologically efficacious in subjects who failed first-line treatment or who were at high risk for complications. Publication(s) Hadley JA, Mösges R, Desrosiers M, Haverstock D, van Veenhuyzen D, Herman-Gnjidic Z. Moxifloxacin five-day therapy versus placebo in acute bacterial rhinosinusitis. Laryngoscope. 2010 May;120(5):1057-62. Updated: 08 Nov 2012
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 BAY12-8039 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: 29 August 2012