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Webposting Clinical Trial Results Synopsis Study Sponsor: Bayer HealthCare AG Study Number: 11981 NCT00453349 Study Phase: IIIB Study Title: A prospective, randomized, double dummy, double blind, multi-center multinational trial comparing the efficacy and safety of moxifloxacin 400 mg PO QD 24 hours for 14 days to that of levofloxacin 500 mg PO QD 24 hours plus metronidazole 500 mg BID for 14 days in subjects with an uncomplicated pelvic inflammatory disease. Moxifloxacin, Metronidazole, and Levofloxacin in Asia (MONALISA Study) Therapeutic Area: Anti-Infective Name of Test Product: BAY 12-8039 / moxifloxacin HCl / Avelox Active Ingredient: Moxifloxacin, oral 400mg tablets Dosage: Moxifloxacin was administered orally 400 mg once daily (od) for 14 days. Ceftriaxone 250 mg was administered intramuscularly once at the During Therapy visit in subjects with a documented gonococcal infection. Reference Therapy: Oral levofloxacin 500 mg once daily (od) combined with oral metronidazole 500 mg twice daily (bid) Dosage: Levofloxacin 500 mg was administered as 2 x 250 mg tablets once daily (od) and metronidazole 500 mg was administered as one tablet twice daily (bid) for 14 days. Ceftriaxone 250 mg was administered intramuscularly once at the During Therapy visit in subjects with a documented gonococcal infection. Placebo: Not applicable Route of Administration: Oral ( moxifloxacin, levofloxacin and metronidazole); intramuscularly (ceftriaxone) Treatment Duration: The planned duration of the study was 6 to 8 weeks, including a 14 day treatment period and a 4- to 6-week (untreated) follow up period. Study Period: Date of first subjects first visit: 09 January 2007 Date of last subjects last visit 12 May 2008 Methodology: This was a multinational, multi-center, prospective, randomized, double-blind, phase IIIb study conducted using a parallel group design. Subjects matching eligibility criteria were assigned randomly to receive 14 days of treatment with either oral moxifloxacin 400 mg once daily or oral levofloxacin 500 mg once daily plus oral metronidazole 500 mg bid. One visit was planned during the treatment period (Day 4 to 7) to assess clinical progress. A single intramuscular injection of ceftriaxone 250 mg was administered at the During Therapy visit in all subjects with a documented gonococcal infection. Subjects were then followed until Day 28 to 42 after therapy with study medication was completed. Clinical, bacteriological, and laboratory examinations were performed pretreatment and at the test of cure (TOC) visit (7 to 14 days after last administration of study medication). In addition, all successfully treated subjects and subjects evaluated as indeterminate at TOC who did not receive additional antibiotic therapy had a follow-up evaluation 28 to 42 days after completion of study medication. Study Site: The study was conducted at 13 centers in 7 countries, including 6 centers in mainland China, 1 center in Indonesia, 1 center in South Korea, 1 center in the Philippines, 1 center in Pakistan, 1 center in Thailand, and 2 centers in Taiwan. Altogether, 463 subjects were enrolled.
Main Inclusion Criteria: Females aged 18 years or above Diagnosis of pelvic inflammatory disease (PID) based on all of the following symptoms Pelvic discomfort Direct lower abdominal tenderness with or without rebound tenderness Adnexal tenderness on bimanual vaginal examination Cervical motion tenderness on bimanual vaginal examination And one or more of the following signs: Rectal/tympanic/oral temperature value > 38.0 C or axillary temperature value > 37.5 C Elevated C-reactive protein (CRP) value (above the upper limit of normal [ULN] for the respective laboratory) White blood cell count (WBC) 10,500/mm3 Laparoscopic evidence of PID Signs suggestive of cervical infection, including mucopurulent cervical discharge or positive Gram stain for Gram-negative intracellular diplococci from the endocervix Untreated, recent (less than 14 days) documented gonococcal or chlamydial cervicitis Endocervical cultures and polymerase chain reaction (PCR) tests performed within 48 hours prior to start of therapy Willing to use condoms as barrier contraception until the completion of the TOC (or alternative antibiotic) visit Willing to have a physical examination at the different assessment visits Subjects who signed an informed consent form prior to study entry Study Objectives: Evaluation Criteria: Overall: The objectives of this study were to compare the efficacy and safety of oral moxifloxacin 400 mg administered once daily with those of oral levofloxacin 500 mg once daily plus oral metronidazole 500 mg twice daily in adult subjects with an uncomplicated PID. Efficacy (Primary): The primary efficacy variable was clinical response 7 to 14 days after the completion of study drug therapy (TOC visit). Efficacy (Secondary): Secondary efficacy parameters included the following: Clinical response on Treatment Day 4 to 7. Bacteriological response at the TOC visit. Clinical response at the TOC visit in subjects with a bacteriologically documented infection. Clinical and bacteriological responses at the Follow-up visit (28 to 42 days after the end of therapy). Necessity for modifying the antibiotic therapy for PID up to the TOC visit or for instituting an antibiotic therapy (for PID recurrence) from TOC up to the end of follow-up. Safety Evaluation of safety was based on adverse events, physical examinations including vital signs determination, and clinical laboratory tests
Statistical Methods: Efficacy (Primary): All statistical tests were 2-sided and performed at the 0.05 significance level. The primary efficacy variable was clinical response at the TOC visit, where failures from the During Therapy visit (Day 4 to 7) were carried forward (ie, successes were defined as subjects with clinical cure at TOC; failures were subjects with failure at the During Therapy visit or improvement or failure at TOC). For success rates, a 95% confidence interval (CI) of the difference between the two clinical success rates (moxifloxacin minus comparator group) was calculated using Mantel-Haenszel weights based on centers. If the lower limit of this 95% CI was greater than 15%, it was proven that treatment with moxifloxacin is clinically not less effective than the comparator treatment regimen. If the lower limit of this 95% CI was greater than 0, superiority of treatment with moxifloxacin was proven. Efficacy (Secondary): As secondary efficacy analyses, clinical response during treatment (4 to 7 days after start of treatment) and at the Follow-up visit (28 to 42 days post-therapy), and clinical response at the TOC visit in subjects with bacteriologically documented infection, were analyzed exploratively in the same way as the primary efficacy variable. In addition, bacteriological responses at the TOC and Follow-up visits were analyzed exploratively in the same way as the primary efficacy variable based on the subgroup of microbiologically valid subjects. At the TOC visit, persistence, presumed persistence, and superinfection were considered bacteriological failures. At the Follow-up visit, recurrence and reinfection were treated as bacteriological failures. A bacteriological success was defined as a subject with a bacteriological response classified as eradication or presumed eradication without occurrence of a superinfection. The correlation between clinical and bacteriological response was to be explored. Safety All analyses of safety endpoints were to be descriptive only; no formal testing was to be performed. All safety tabulations were to be produced for the ITT population (which is equivalent to the valid for safety population). Number of Subjects: A total of 460 randomized subjects (230 subjects/treatment arm) were planned (Revised per Amendment 2, dated 21 Dec 2007), with at least 200 subjects from mainland China. A total of 463 subjects were actually enrolled; 228 subjects were randomized into the moxifloxacin group and 232 into the levofloxacin/metronidazole group. Three subjects from mainland China were not randomized. Results Summary Subject Disposition and Baseline Figure 1 Subject Enrollment and Disposition 463 enrolled 460 randomized 412 completed treatment 399 completed study* Moxifloxacin 400 mg OD Levofloxacin 500 mg OD plus Metronidazole 500 mg BID 228 randomized 203 completed treatment 201 completed study* 232 randomized 209 completed treatment 198 completed study* 1 Subjects who had Follow-up assessment or alternative antibiotic assessment visit. Abbreviations: BID = twice daily; OD = once daily Source: Tables 14.1.1/1.1 and 14.1.1/2.1
Results Summary Efficacy The study demonstrated that a 14-day treatment with moxifloxacin 400 mg od is no less effective than a 14-day treatment with the comparator, levofloxacin 500 mg od plus metronidazole 500 mg bid, in adults with uncomplicated PID. Indeed, the lower limit of the 95% CI of the difference between the two clinical success rates (moxifloxacin minus comparator group) at the TOC visit was greater than 15%, see Table 2. Clinical Response Table 2 presents an overview of efficacy results (ie, success rates) for clinical response at TOC in the PP, ITT, and MBV populations. The success rate for clinical response at TOC in the PP population, the primary efficacy variable, was almost identical in the two treatment groups and the statistical hypothesis of inferiority of moxifloxacin to the comparator regimen could be rejected at the 2.5% level. Except for mainland China, sample sizes are too small to draw conclusion based on data from a single country. The results in mainland China were very much similar to those in subjects from all countries. The ITT clinical response results support the results from the per protocol analysis. Overall conclusions on the clinical response rates at the TOC visit in the microbiologically valid and ITT with causative organisms populations should be made with caution, since the number of subjects in this subgroup is small. The microbiologically valid population represents only 12.1% of the entire population. This subgroup is too small to allow for meaningful overall conclusions. Concerning the subgroup of subjects with microbiologically documented infection, the apparent difference in clinical cure rates between the two treatment groups is driven by an imbalance in subjects assessed as clinical improvements (scored as non-successes), ie, 9 in the moxifloxacin group versus 0 in the levofloxacin plus metronidazole group. The combined cure plus clinical improvement totals were 28/30 for moxifloxacin compared to 26/26 for levofloxacin plus metronidazole. Table 3 shows clinical resolution rates between the treatment groups in selected subject subgroups. No major differences between treatment groups in the clinical cure rates were observed. Results of the clinical efficacy analyses based on data for the ITT population generally were consistent with those in the PP population. Bacteriological Response The bacteriological success rates were high in both the moxifloxacin group (27/30=90%) and the comparator group (22/26=85%, 95% CI: -12.7% to 20.3%). The bacteriological success rates demonstrate that the apparent differences in clinical outcome between moxifloxacin and comparator in the microbiologically valid subjects are likely to be an artifact. Several factors may have contributed to the divergent clinical and bacteriological outcomes in this study. First, the small number of microbiologically evaluable subjects with pathogens at study entry (30 moxifloxacin subjects and 26 comparator subjects) limits the conclusions that can be drawn regarding bacteriological outcome. In addition, the difference between clinical and bacteriological success rates was driven mainly by high proportion of subjects with clinical improvement. In many cases, clinical improvement was associated with eradication, thus minimizing difference between the groups. Table 4 presents bacteriological successes at TOC by most frequently diagnosed organisms. In the MBV population, N. gonorrhoeae was diagnosed in 4 moxifloxacin subjects and 2 comparator subjects, and C. trachomatis was diagnosed in 8 moxifloxacin subjects and 12 comparator subjects. All 4 moxifloxacin subjects (100%) with N. gonorrhoeae and all 8 moxifloxacin subjects with C. trachomatis present at pre-therapy had an outcome of eradication at TOC. In the comparator group, 1 (50%) of the 2 subjects with N. gonorrhoeae and 10 of the 12 (83.3%) subjects with C. trachomatis present at pre-therapy had an outcome of eradication at TOC; the outcome in the other 3 subjects (1 [50%] with N. gonorrhoeae and 2 [16.7%] with C. trachomatis) was persistence. Overall, the number of individuals with diagnosed N. gonorrhoeae or C. trachomatis, was too low for meaningful comparisons or conclusions. Table 2: Overview of Efficacy Results (ie, Success Rates a ) for Clinical Response at TOC in the PP, microbiologically valid, ITT and ITT with causative organisms Populations Per Protocol Moxifloxacin Comparator 95% CI b n/n (%) n/n (%) Lower (%) Upper (%) Overall efficacy population 152/194 (78) 155/190 (82) -10.7 4.9 Microbiologically valid China Mainland 110/138 (80) 102/128 (80) -9.4 9.2 Indonesia 6/7 (86) 9/9 (100) Korea 8/11 (73) 7/11 (64) Philippines 10/13 (77) 13/15 (87) Pakistan 2/5 (40) 4/4 (100) Thailand 8/9 (89) 11/12 (92) China Taiwan 8/11 (73) 9/11 (82) Overall 19/30 (63) 26/26 (100) China Mainland 13/19 (68) 16/16 (100)
Table 2: Overview of Efficacy Results (ie, Success Rates a ) for Clinical Response at TOC in the PP, microbiologically valid, ITT and ITT with causative organisms Populations Valid for safety/intent to treat Moxifloxacin Comparator 95% CI b n/n (%) n/n (%) Lower (%) Upper (%) Indonesia 0/0 (0) 3/3 (100) Korea 0/1 (0) 0/0 (0) Philippines 3/6 (50) 5/5 (100) Thailand 2/3 (67) 2/2 (100) China Taiwan 1/1 (100) 0/0 (0) Overall 163/225 (72) 171/230 (74) -9.9 6.0 China Mainland 113/151 (75) 111/155 (72) -6.4 12.7 Indonesia 10/14 (71) 14/16 (88) Korea 8/12 (67) 8/13 (62) Philippines 10/15 (67) 13/15 (87) Pakistan 4/7 (57) 5/7 (71) Thailand 10/13 (77) 11/12 (92) China Taiwan 8/13 (62) 9/12 (75) Valid for safety/intent to treat with causative organisms Overall 23/36 (64) 30/34 (88) China Mainland 17/24 (71) 20/24 (83) Indonesia 0/1 (0) 3/3 (100) Korea 0/1 (0) 0/0 (0) Philippines 3/6 (50) 5/5 (100) Thailand 2/3 (67) 2/2 (100) China Taiwan 1/1 (100) 0/0 (0) a Success rate at TOC: No. of subjects with clinical response clinical cure / No. of subjects in population. b Hypothesis of inferiority of moxifloxacin rejected at the 2.5% level (ie, lower limit of CI > -15%) Source: Table 14.2.1/3.1, Table 14.2.1/3.2, Table 14.2.1/3.3, and Table 14.2.1/3.4 Table 3: Clinical Cure Rates at TOC in Selected Subject Subgroups (Per Protocol Population) Moxifloxacin Comparator (n = 194) (n=190) n/n a % n/n a % Overall resolution rate 152/194 (78%) 155/190 (82%) Age < 40 yrs 98/132 (74%) 111/135 (82%) > 40 yrs 54/62 (87%) 44/55 (80%) PID severity score 5-14 128/164 (78%) 125/155 (81%) 15-29 24/30 (80%) 30/35 (86%) Previous PID in the last 12 months None 102/133 (77%) 95/118 (81%) At least one episode 50/61 (82%) 60/72 (83%) Duration of symptoms Unknown 2/2 (100%) 3/3 (100%) before start of treatment 3 days 27/34 (79%) 36/40 (90%) > 3 days 123/158 (78%) 116/147 (79%) Condom use Sexual abstinence 38/48 (79%) 47/64 (73%) Only protected intercourse 113/140 (81%) 105/119 (88%) Unprotected intercourse 1/3 (33%) 3/6 (50%) Unknown 0/3 (0%) 0/1 (0%)
a No. of subjects with resolution in subgroup / total No. of subjects in subgroup Abbreviation: PID = pelvic inflammatory disease Source: Table 14.2.1/1.1.1, Table 14.2.1/1.2.1, Table 14.2.1/1.4.1, Table 14.2.1/1.5.1, and Table 14.2.1/1.7.1 Table 4: Bacteriological Success at TOC by Most Frequently Diagnosed Organisms (MBV Population) Overall Gram-positive aerobic Organism Moxifloxacin (n = 30) n/n a (%) Levofloxacin plus metronidazole (n = 26) n/n a (%) Staphylococcus aureus spp 3/3 (100) 3/4 (75) Gram-negative aerobic Neisseria gonorrhoeae 4/4 (100) 1/2 (50) Escherichia coli 6/7 (86) 2/2 (100) Proteus mirabilis 3/5 (60) 1/1 (100) Anaerobic organisms Peptostreptococcus spp 4/4 (100) 3/3 (100) Intracellular organisms Chlamydia trachomatis 8/8 (100) 10/12 (83) a No. of subjects with bacteriological success / No. of subjects with diagnosed organism Abbreviation: spp = species Source: Table 14.2.2/4.1 Results Summary Safety In the valid for safety population (moxifloxacin, 225 subjects; levofloxacin plus metronidazole, 230 subjects), treatment-emergent adverse events, and treatment-emergent drug-related adverse events were similar in the moxifloxacin and comparator groups (57% versus 57%, and 46% versus 49%, respectively). The 3 system organ classes in which the highest rates of adverse event occurred were gastrointestinal disorders (36% moxifloxacin versus 40% comparator); nervous system disorders (24% moxifloxacin versus 21% comparator); and general disorders and administration site conditions (8% moxifloxacin versus 6% comparator). The largest differences between treatment groups ( 2%) can be found in the SOC gastrointestinal disorders (36% moxifloxacin versus 40% comparator), nervous system disorders (24% moxifloxacin versus 21% comparator), general disorders and administration site conditions (8% moxifloxacin versus 6% comparator), psychiatric disorders (4% moxifloxacin versus 6% comparator), and cardiac disorders (1% moxifloxacin versus 3% comparator). The most commonly reported treatment-emergent adverse event in both the moxifloxacin (19% of subjects) and comparator (23% of subjects) treatment group was nausea. The only other adverse events reported in more than 5% of subjects in either treatment group were dizziness (reported in 17% and 16% of the moxifloxacin and comparator subjects), insomnia (reported in 3% and 6% of the moxifloxacin and comparator subjects), abdominal pain (reported in 4% and 6% of the moxifloxacin and comparator subjects) and vomiting (reported in 3% and 7% of the moxifloxacin and comparator subjects). No deaths were reported during the study. Four subjects experienced treatment-emergent serious adverse events, 3 moxifloxacin subjects and 1 comparator subject. Only one of the events, Stevens-Johnson syndrome, was considered drug related. This event occurred in a moxifloxacin-treated subject. Most adverse events reported in both treatment groups were mild or moderate in severity. Four subjects in the moxifloxacin group experienced adverse events of severe intensity, three in the comparator group. Of these, 3 events in each treatment group were considered drug related. Most adverse events resolved or had an improved outcome irrespective of whether they were assessed as drug related or not. Only 9 subjects in the moxifloxacin group reported an adverse event with outcome unchanged and none had an outcome of worsened. In the comparator group, 5 subjects experienced an adverse event that was unchanged and 2 had worsening as an outcome. The evaluation of significant changes of laboratory parameters did not reveal any relevant difference between treatments. No relevant treatment-related differences were detected in the analysis of vital signs. Conclusion(s) The results of the study provide evidence that moxifloxacin 400 mg PO od for 14 days is not clinically inferior in terms of clinical response rate to levofloxacin plus metronidazole for the treatment of uncomplicated PID. In addition, the safety profiles of moxifloxacin and of levofloxacin plus metronidazole regimens are similar.
Publication(s) Judlin P, Liao Q, Liu Z, Reimnitz P, Hampel B, Arvis P. Efficacy and safety of moxifloxacin in uncomplicated pelvic inflammatory disease: the MONALISA study. BJOG. 2010 Nov;117(12):1475-84. doi: 10.1111/j.1471-0528.2010.02687.x. Epub 2010 Aug 18. Updated: 8 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 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: 11 September 2013