Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: Title: A Phase III open-label, non-comparative study of BRL25000 ES-600 in paediatric patients with otitis media Rationale: In Japan, as in the United States and other countries, separation of S. pneumoniae clinical isolates highly resistant to CVA/AMPC (e.g., MIC 4 µg/ml) from pediatric patients with infection has been reported. It is important to provide a treatment choice that is effective against current drug-resistant bacteria and against bacterial strains that are likely to increase in the future. Under the circumstances, we conducted a clinical study of BRL25000 ES-600 in pediatric patients with acute otitis media in Japan at the dosage of CVA 6.4 mg/kg/day and AMPC 90 mg/kg/day, which is the same as in the United States. Phase: III Study Period: 6-Jan Apr-2003 Study Design: Multicenter, open-label, non-comparative study Centres: 12 centres in Japan Indication: Paediatric patients with otitis media Treatment: After enrolled in the study, the subject orally received BRL25000 ES-600 (equivalent to CVA 6.4 mg/kg/day and AMPC 90 mg/kg/day) in two divided doses for 7 days (treatment phase), and then was observed for 7 days (post-therapy observation phase). The planned duration of participation in the study was 14 days in total. Objectives: To assess the efficacy and safety of BRL25000 ES-600 [clavulanic acid (CVA)/amoxicillin (AMPC) = 6.4/90mg/kg/day (in terms of potency)] administered to pediatric patients with otitis media in two divided doses for 7 days, and to verify the validity of the clinical dosage. Primary Outcome/Efficacy Variable: 1.Clinical response determined according to the Japanese criteria 2.Bacteriological response determined according to the Japanese criteria 3.Safety: subjective symptoms/objective signs, gastrointestinal symptoms (diarrhea/loose stools), laboratory test values. Secondary Outcome/Efficacy Variable(s): 1.Improvement 2.Clinical response determined according to the overseas criteria 3.Bacteriological response determined according to the overseas criteria 4.Pharmacokinetics: plasma drug concentration, MEF (otorrhea) drug concentration Statistical Methods: Efficacy analyses: The percentage of go od in a ssessment of clinical response according to the Japanese criteria, percentage of bac teriological in assessment of bacteriological response according to the Japanese criteria, percentage of improvem ent in a ssessment of improvement, and percentage of clinical/b acteriological success in assessment of clinical/bacteriological response according to the overseas criteria as well as 95% confidence intervals (CIs) were calculated. Direct approximation was used for CI calculation. Pharmacokinetic analyses: Summary statistics were calculated for plasma CVA and AMPC concentrations at 1.5 and 4 hours post dose. The mean, SD, median, minimum, maximum, and 90% CI for mean for descriptive statistics were calculated. Study Population: Patients meeting following key criteria were eligible for enrolment. There was no restriction as to sex or hospitalization (inpatient/outpatient) status. 1.Target disease: Patients with ac ute suppurative otitis media or ac ute exacerbation of chronic suppurative otitis media, di agnosed on the basis of the otoscopic findings described in 1) or 2) below: 1

2 1) Within 48 hours after the finding of purulent otorrhea 2) Middle ear effusion as evidenced by at least two of the following:decreased or absent tympanic mobility measured by pneumatic otoscopy; Yellow or white discoloration of the tympanic membrane; Opacification of the tympanic membrane; PLUS acute inflammation as evidenced by at least one of the following: Within 48 hours after the occurrence of ear pain (including the motions of unaccustomedly tugging or rubbing the ear); Redness of the tympanic membrane or mucosa; Bulging of the tympanic membrane. 2.Age: 3 months and <12 years As key exclusion criteria, patients who applied any of the following were not enrolled in the study. 1. Patient who has a severe infection and is not considered treatable with an oral preparation; 2. Patient who is undergoing or has undergone at least one or more doses of systemic antimicrobial therapy within the last 72 hours; 3. Patient who weighs 40 kg or more; 4. Patient who has a tympanostomy tube(s) in place in the infected ear(s) or who has anatomic abnormalities potentially having continuous effects on auditory tubal functions (e.g. cleft palate, high-arched palate, Down's syndrome); 5. Patient who has otitis media cholesteatoma. BRL25000 ES-600 Number of Subjects: Planned, N >60 Treated, N 107 Completed, n (%) 99 (93) Total Number Subjects Withdrawn, N (%) 8 (7) Withdrawn due to Adverse Events n (%) 3 Withdrawn due to Lack of Efficacy n (%) 0 Withdrawn for other reasons n (%) 5 (5) Demographics (C-FAS/SP) N (FAS) 107 Females: Males 51:56 Mean Age, years (SD) 4.55 (2.83) Oriental, n(%) 106 (99) Others, n(%) 1(<1%) Population Clinical response/fas (C-FAS) 107 Bacteriological response/fas (B-FAS) 81 Clinical response according to Japanese criteria/pps 77 (JC-PPS) Bacteriological response according to Japanese 60 criteria/pps (JB-PPS) Safety population (SP) 107 Pharmacokinetic analysis population (PKAP) 32 2

3 Primary & Secondary Efficacy Results: 3

4 Clinical and Bacteriologial Responses by Pathogen Isolated Clinical response (%) (JC PPS) Pathogen isolated Fair Poor (Clinical success rate) Bacteriological Bacteriological response (%) (End of therapy visit: JB PPS) Unchanged Unknown Bacteriological rate S. pneumoniae 11/16 (69) 5/16 (31) /16 16/ /16 PPSP 8/ /8 8/ /8 PISP 3/5 (60) 2/5 (40) 0 0 5/5 5/ /5 PRSP 0 3/ /3 3/ /3 H. influenzae 17/31 (55) 12/31 (39) 1/31 1/31 29/31 (94) 30/31 0 1/31 30/30 β lactamase non producing 17/30 (57) 11/30 (37) 1/30 1/30 28/30 (93) 29/30 0 1/30 29/29 β lactamase producing 0 1/ /1 1/ /1 M. (B.) catarrhalis 3/5 (60) 1/5 (20) 1/5 (20) 0 4/5 (80) 4/5 0 1/5 4/4 S. pyogenes 0 1/ /1 1/ /1 S. aureus 1/4 (25) 2/4 (50) 1/4 (25) 0 3/4 (75) 2/4 2/4 0 2/4 (50) Bacteriological rradication rate (%) = ( Bacteriological Eradication / (N Unknown )) 100 Bacteriological and Clinical Responses in Patients with Multiple Pathogens Bacteriological response (JB PPS) Pathogens isolated (β lactamase) On therapy visit End of therapy visit S. pneumoniae / P. aeruginosa (+) Unknown / Unknown / H. influenzae ( ) / S. aureus (+) Unchanged / Unchanged / H. influenzae ( ) / Staphylococcus sp ( ) / / H. influenzae ( ) / Staphylococcus sp (+) / / Unchanged M. catarrhalis (+) / P. aeruginosa (+) / / M. catarrhalis (+) / Staphylococcus sp (+) / Unknown / Unknown S. pneumoniae / H. influenzae ( ) / M. catarrhalis (+) / / / / S. pneumoniae / H. influenzae ( ) / Staphylococcus sp ( ) Unchanged / Bacteriological / / Bacteriological / S. aureus (+) / Streptococcus sp ( ) / Corynebacterium sp / / / / S.pyogenes / Staphylococcus sp ( ) / Corynebacterium sp / / / / Clinical response (JC PPS) Fair Improvement (S. pneumoniae; C-FAS) 4

5 Plasma AMPC and CVA concentrations 1.5hr (n=19) 4hr (n=18) Plasma AMPC concentrations, Mean µg/ml (SD) 16.8 (6.5) 6.9 (5.09) Plasma CVA concentrations, Mean µg/ml (SD) 2.1 (0.87) 0.5 (0.43) Safety Results: Most Frequent Adverse Events - On-Therapy n (%) Subjects with any AE(s), n(%) 49 (46%) diarrhea NOS 37 (35%) vomiting NOS 4 (4%) loose stools 2 (2%) eczema 2 (2%) dermatitis contact 2 (2%) pyrexia 2 (2%) nasopharyngitis 1 (<1%) influenza 1 (<1%) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, n (%) 0 Subjects with fatal SAEs, n (%) 0 Conclusion: The present study demonstrated excellent clinical and bacteriological efficacy of BRL25000 ES- 600 against the major pathogens of acute otitis media - S. pneumoniae, H. influenzae, and M. catarrhalis. The clinical and bacteriological responses were high even against penicillin-resistant and int ermediate S. pneumoniae (PRSP, PISP), as against penicillin-susceptible S. pneumoniae. BRL25000 ES-600 showed high clinical and bacteriological success rates in multiple (2 or 3 strains) infection, including β-lactamase producing strains. In safety evaluation, diarrhea/loose stools associated with changes in the nature of the stool occurred, but all the cases were considered clinically treatable or less severe than those of clinical concern. Publications: J. New Rem.&Clin. Vol.54 No : Updated: 24Nov08 5