2 11 September 1.997 Page 9 of161 SYNOPSIS FUT 9403 INT : FUCIDIN VERSUS ERYTHROMYCIN IN SKIN AND SOFT TISSUE INFECTION. A comparison of sodium fusidate tablets 250mg bd (Fucidin tablets) and erythromycin tablets l.og bd (Erythroped A tablets) in skin and soft tissue infection. Objectives: To compare the overall clinical and bacteriological effect, symptomatic response, tolerability, acceptability and cost effectiveness of Fucidin tablets with Erythroped A tablets in treating skin and soft' tissue infection. The primary criterion of response was the investigators' assessment of overall clinical response 'cured' or 'improved' after five days of treatment. Study design: The study was a multicentre, prospective, randomised, doubleblind, parallel-group study. Eligible patients were randomly assigned to receive an initial five day course of Fucidin tablets 250mg bd or Erythroped A tablets 1.0g bd and were reviewed on day 6. Patients requiring a further five day course of antibiotic were seen again on day 11. A follow-up visit was conducted 14 days after co~pletion of trea't ment. Assessments were made at days 1, 6, 11 and at the follow-up visit (day 20 or 25). Duration of study phases: The study was divided into two phases: phase I, double blind comparative treatment and phase II, follow-up. Phase I started at visit 1 (day 1) and ended at visit 2 (day?) for patients who received five days of treatment and ended at visit 3 (day 11) for patients who received ten days treatment. Phase Il, follow-up was only for patients rated as 'cured' at visit 2 or 3. Phase II started at the end of treatment (visit 2 or 3) and ended at the follow-up visit, 14 days later. Source of patients: Patients enrolled into this study were general practice or domiciliary patients. This docwnent has been downloaded from \V\vw.leo-pharma.com subject to the terms of use state on the website. It contains data and results regarding approved and non-approved uses, formul ations or treatment regimens, and it is provided for transparency and informational purposes only. The content does not reflect the complete results from all studies related to a product. As a document of scientific nature 1t is not to be seen as a recommendation or advic-e regarding the use of any products and you must always consult the specific prescribing information approved for the product prior to any prescription or use.
Page 10 of 161 Patient group studied: Patients of either sex, aged 18 years or over, with skin and/ or soft tissue infection, for which oral antibacterial therapy was indicated, e.g. boil(s), carbuncle(s), superficial abscess(es), acute paronychia, impetigo, traumatic wound infection, or acute folliculitis, were included after they had given signed, informed consent. Excluded were hospitalised patients and patients who had cellulitis,. chronic/ recurrent furunculosis, post-operative wound infections, leg ulcers or deep tissue abscess(es). Also excluded were patients with known or suspected hypersensitivity to constituents of either treatment, diabetics or patients receiving immunosuppressives, digoxin, warfarin, carbamazepine, high dose theophylline or topical or systemic antibiotic therapy within the previous seven days. Study medication: Patients were randomised to either Fucidin tablets 250 mg bd or Erythroped A tablets l.og bd. Patients were instructed to take all tablets from a blister, morning and evening for five days. Tablets were to be taken with a glass of fluid either with or without food. Criteria for efficacy, safety, acceptability and cost t:ffectiveness: The two treatment groups were compared in respect of the primary efficacy criterion which was the investigators' assessment of overall clinical response 'cured' or 'improved' after five days of treatment. Secondary criteria of response included the investigators' assessment of overall clinical treatment response at end of treatment and assessment of relapse. The patients' assessment of symptomatic improvement and treatment acceptability was examined. The bacteriological response, cost effectiveness and safety were also assessed. Study procedures: Investigators' assessments at the first visit: diagnosis, duration, severity, location and signs/symptoms of the skin or soft tissue infection were recorded. At each on treatment visit the investigator recorded the overall clinical response to treatment as 'cured', 'improved' (visit 2 only), failed' or 'unevaluable'. The local signs/symptoms (overall severity of lesion, redness and oedema); spontaneous discharge (purulent and serous) were assessed. An assessment of relapse was determined at the follow-up visit.
Page 11 of 161 Patients' assessments: at the first visit and at each on treatment visit heat and pain were recorded. At each on treatment visit the patients' satisfaction with treatment was recorded.. Bacteriological assessments: lesion cultures were taken at baseline and at each subsequent visit where pathological material was present. Adverse events: were recorded at each post-randomisation visit. A tabulated schedule of study procedures is outlined below. Visit 1 (Day1) Informed consent Inclusion/ exclusion checklist Medical history Primary diagnosis Other concurrent diagnoses Concurrent medication Clinical assessment of lesion Stratify to 'open'/' closed' lesion group Randomisation Bacteriological assessment Dispense treabnent Overall clinical resp<>_nse Assessment of relapse Acce_p_tability of treabnent Recording of adverse events Collecting of \,~Sed/ unused trial medication I). Visit 2 (Day6± 1 day) Visit 31 (Day11±2 days) Follow-up visit' (Day 20 or 25, i.e. 14 days 2 to +6 days after treatment completed} x2 x2 x2 x. Visit 3 is only required for those patients who are not rated 'cured' at visit.2 and who therefore have a second course of treatment 2) 3) Only reqllired for those patients who have pathological material present. Follow-u.p visit only required for patients rated ' cured' at end of treatment (visit 2 or visit 3). Patient numbers: Four hundred and sixty-nine patients were recruited and 467 randomi.s ed (exclusion criteria became apparent in two patients). Two patients randomised to Erythroped A were excluded from the safety population (one took no medication the other was lost to follow-up). Therefore the safety population comprised 465 patients.
Page 12 of 161 Thirteen patients were excluded from the intention-to-treat efficacy analyses (in addition to the four patients mentioned previously who were excluded from the safety population, nine patients provided no efficacy data). The intentionto-treat population therefore comprised 456 patients. One patient in the Erythroped A group was unevaluable at visit 2. Therefore the analysis was performed on 455 patients in respect of the primary efficacy criterion. A further 19 patients were excluded from the per-protocol population (11 received forbidden medication prior to visit 2, seven had visit 2 efficacy assessments more than three days after their last dose of study medication and one had an incorrect type of infection). The per-protocol population therefore comprised of 437 patients. The bacteriologically evaluable population comprised patients in the perprotocol population in whom a pathogen (Staphylococcus aureus and/or ~ haemolytic streptococci) was isolated at visit 1. There were 137 patients in the bacteriologically evaluable population (70 randomised to Fucidin, 67 randomised to Erythroped A). Efficacy results: The primary criterion of efficacy was the uwestigators' assessment of overall clinical response 'cured' or 'improved' after five days of treatment (visit 2). There was a statistically significant difference between treatments in respect of the primary criterion of efficacy in both the intentionto-treat (p=o.olo, odds ratio 0.38: 95% CI 0.17, 0.80) and per-protocol (p=0.008, odds ratio 0.34: 95% CI 0.14, 0.76) populations in favour of Erythroped A tablets. There was no significant difference (p=0.598, odds ratio 0.73: 95% CI 0.20, 2.40) in the bacteriologically evaluable population. summarised in the table overleaf. Results are
Fucidin No. Page 13 of 161 Erythroped" A (\1 No. (\) Odds Ratio 1 (95\ CI) p- va lue No. of patients with overall clinical response at visit 2 of cured or improved INTENTION-TO-TREAT POPULATION (89. 4) 202 (n = 226) (95. 6) 219 (n = 2291 2 0. 38 (0.17. 0.80) p = 0.010 PER-PROTOCOL POPULATION 195 (90. 3) (n = 2161 213 (96.41 (n = 2211 0.34 (0.14. 0.76) p c 0.008 BACTERIOLOGICALLY EVALUABLE POPULATION 63 (n 62 (92. 51 (n = 671 0.73 (0.20. 2.401 p = 0.598 1 2 = 701 (90.01 Odds ratio for the comparison of Fucidin relative to Erythroped A. One patient in the intention-to-treat population was unevaluable at visi t 2. There was a statistically significant difference between treatments with regard to the presence or absence of oedema at visit 2 in the per-protocol population (p=0.038; odds ratio 0.64: 95% CI 0.42, 0.97) in favour of Erythroped A. There were no statistically significant differences between treatments with respect to lesion severity, redness, pain, heat, purulent or serous discharge at visit 2. At the end of treatment there was no statistically significant difference between treatments with respect of the investigators' overall assessment of clinical respons~ in the intention-to-treat (p=0.516, odds ratio 0.84: 95% CI 0.49 to 1.43), per-protocol (p=0.523, odds ratio 0.83: 95% CI 0.47 to 1.46) or ~acteriologlically evaluable (p = 0.560, odds ratio 0.75: 95% CI 0.30 to 1.91) populations. Maintenance of response was monitored 14 days after completion of treatment. Only patients rated as 'cured' at end of tr~atment were eligible to attend the follow-up visit. Of the 374 patients eligible for follow-up (183 Fucidin, 191 Erythroped A), 337 patients attended visit 4 (160 Fucidin of which one patient was. unevaluable, and 177 Erythroped A)~ A relapse was reported in 5.0% of patients in the Fucidin group and 2.8% of patients in the Erythroped A group in the per-protocol population. This represents a high percentage of patients in both treatments where cure was maintained post-treatment (95.0% Fucidin, 97.2% Erythroped A).
Page 14 of 161 Bacteriological assessments were performed for all patients at visit 1 and at all subsequent visits where pathological material was still present. Staphylococcus aureus and Only P-haemolytic streptococci were regarded as pathogens. A bacteriological response was assessed (as 'success' or 'failure') in patients who had pathogen(s) present at visit 1. In the bacteriologically evaluable population which comprised 137 patients (70 Fucidin, 67 Erythroped A), the bacteriological response at the end of the.treatment was rated successful in 97.1% of patients on Fucidin tablets and 94.0% of patients on Erythroped A tablets. There was no evidence that Staphylococcus aureus developed resistance to fusidic acid in patients treated with Fucidin tablets. After visit 1, Staphylococcus aureus was isolated from ten patients in the Fucidin group, in all cases the pathogen retained the same sensitivity to fusidic acid throughout the study at whichever visit the pathogen was isolated. There was no evidence that Staphylococcus aureus isolated from patients receiving Erythroped A tablets developed resistance to erythromycin. Safety results: Adverse events were recorded in 69 (30.0%) patients receiving Fucidin tablets and 74 (31.5%) patients receiving Erythroped A tablets. There were 16 withdrawals due to adverse events, ten (4.3%) from the Fucidin group and six (2.5%) from Erythroped A group. Conclusion: At the end of the first five days of treatment (visit 2) there was a statistically significant difference in the overall clinical efficacy between treatments in favour of Erythroped A tablets. Overall the clinical and bacteriological efficacy of Fucidin tablets and Erythroped A tablets was similar with both treatments being highly effective at the end of treatment. Both treatments also demonstrated a low relapse rate and there was no evidence of resistance to fusidic acid developing during or after treatment with Fucidin. Both treatni.ents were well tolerated.