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CLINICAL STUDY REPORT

COMPARATIVE EFFICACY OF LOW DOSE SYSTEMIC FUCIDIN 250 mg bd AND CIPROXIN 250 mg bd IN SKIN AND SOFT TISSUE INFECTION

A multicentre, prospective, randomised, single-blind, parallel group study

The dinic.al study report has been redacted using the following principles: 'i\'here necessary ,information is anonyrnis.ed to protect the priv a cy of study subjects and named persons a:.sociated with the trial .as. well as to retain conunercial confidential information. Summary data are included but data on individual study subjects, including data listings, are removed. 1his may result in page numbers not being consecutiv ely numbered. Access to anonyrnised data onindi' 'idu.alstudy subject may be o bt aine d up on approval of a research proposal by the Patient and Scientific Review Board. Appendices to thed.i.nical &tudy report are omitted. Further details and principles for anon~ationis available in the docurnentLEOPHAR..l\11A PRINCIPLES FOR ANONYiv1ISATION OF CLINICAL TRIAL DATA

STUDY FU9204UK/GP98

Medical Department Leo Pharmaceuticals Longwick Road Princes Risborough Bucks HP27 9RR UNITED KINGDOM

00068313

FINAL 5 June 1997

Study FU 9204UKIGP98

I Clinical Study Report

Study FU9204UK/GP98 Page 3

ABSTRACT Objectives: To compare the clin ical and bacteriological effect and tolerance of Fucidin tablets and Ciproxin tablets in skin and soft tissue infection . Methods: The study was a multicentre, randomised, single-blind, parallel group comparison. Patients of either sex, aged ~ 18 years with skin and/or soft tissue infection, for which oral antibacterial therapy was indicated, were included after giving signed, informed consent; eligible patients received an initial 5-day course of Fucidin 250 mg bid or Ciproxin 250 mg bid and were seen on day 7. Patients requiring a further 5-day course of antibiotic were seen again on day 13. Assessments were made at baseline at 7 and/or at 13 days: Investigators assessments; severity of local signs/symptoms (overall severity of lesion, pain, redness, heat, oedema); spontaneous discharge (purulent and serous); overall clinical response 'cured', 'improved' or 'failed' at the end of treatment (day 7 or 13). Bacteriological assessments; lesion cultures at baseline and at the end of treatment. Adverse events were recorded throughout. Results: The Primary Efficacy Criterion was the proportion of patients with a 'cured', or 'improved' clinical response at the end of treatment (day 7 or 13). The results are shown in the Table.

POCI OIN" CIPROXIN" TABLETS ptH Difference (%) FOCI DIN TABI..E:TS NO p t t (%) CIPROXlN (95%

NO pt t ( t ) Conf i dence Interval)'

No . ptt with overal l c linical r esponse at end of t r QatrnQnt o f cured' or impr oved I NTENTION TO TREAT POPULATION 84 (86 . 6)' 86 ( 9 1. 5) ' 0 .28 - 4 . 9

l n=97) Cn=94) ( - 13. 8 t o + 4 .0 ) EFFICACY POPULATION

8 2 (87. 2) ' 84 ( 91 . 3) ' 0.37 -3.9 (n=94) (n=92) 1-12.8 t o + 5 . 0 )

(I) Bet ween o:roup probab1li t y ( l} \ o t ptt Ln whom eCCicacy data. obtai ned (3} lt k g lJ hood r ati o Ch1Square

There was no significant difference between treatments in respect of the Primary Efficacy Criterion. There was a significant difference between treatments in the mean change in scores from baseline to the end of treatment for overall lesion severity (p=0.01 ;95% Cl +0.04 to +0.50), which was in favour of Ciproxin.

Bacteriological efficacy of the two treatments was 86.5% for Fucidin tablets and 90.9% for Ciproxine tablets.

Adverse Events were recorded in 16 (16.5%) patients given Fucidin tablets and in 21 (22.3%) patients given Ciproxine tablets. Adverse events contributed to treatment withdrawal in only one (0.9%) patient, who was given Fucidin tablets.

Conclusion: Fucidine tablets 250 mg twice-daily and Ciproxin tablets 250 mg twice-daily for 5-10 days were similarly highly effective in treating patients with skin and soft tissue infections.

CLINICAL STUDY REPORT APPROVAL

This Clinical Study Report has been approved by:

Medical Department Leo Pharmaceuticals Longwick Road Princes Risborough Bucks HP27 9RR UNITED KINGDOM

, Clinical Biometrics

Leo Pharmaceuticals Longwick Road Princes Risborough Bucks HP27 9RR UNITED KINGDOM

Signature

Signature

Study FU 9204UK/GP98

Date \ v~ D .J..!~ l'lCf1-

Signa

Study FU9204UK/GP98

REPORT AUTHOR

M ica ment Leo Pharmaceuticals Longwick Road Princes Risborough Bucks HP27 9RR UNITED KINGDOM

B Sc Clinical Biometrics

Leo Pharmaceuticals Longwick Road Princes Risborough Bucks HP27 9RR UNITED KINGDOM

Page 5


TABLE OF CONTENTS Page

ABSTRACT.. ..... ...... .. . ... ..... .. ... ... . .... ..... .. 3

CLINICAL STUDY REPORT APPROVAL . . . . . . . . . . . . . . . . . . . . . . 4

REPORT AUTHORS 0 0 0 0 0 0 0 o 0 0 0 o o o 5

TABLE OF CONTENTS . . ..... . . . ... .. .. .. .. ...... o 6

INVESTIGATORS AND STUDY CENTRES . . . . . . . . . . . . . . . . . . . . . 8

COMPANY PERSONNEL ......... .... . ... . ...... . . .. .. ... 14

0 EXPANDED SUMrvlARY . ....... ... ............... .. .. .... 16

1 INTRODUCTION AND RATIONALE . . .................... .. . . 26

2 OBJECTIVES OF THE STUDY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

3 DESIGN OF STUDY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

4 STUDY SCHEDULE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

5 SAMPLE SIZE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

6 CRITERIA FOR SELECTION OF STUDY PATIENTS . . . . . . . . . . . . . . 29 6.1 INCLUSION CRITERIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 6.2 EXCLUSION CRITERIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

7 CRITERIA FOR EARLY WITHDRAWAL FROM THE STUDY . . . . . . . . 30

8 TREA1MENT ASSIGNMENT METHOD . . . . . . . . . . . . . . . . . . . . . . . . 30

9 BLINDING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

10 BREAKING OF THE TREATMENT CODE . . . . . . . . . . . . . . . . . . . . . . 31

11 STUDY MEDICATION ... ... .. o o o o o 31

12 CONCOMITANT THERAPY ............. .. .... 0 0 33

13 STUDY PROCEDURES .. ............ .. o 0 0 0 34

14 CRITERIA FOR EFFICACY AND SAFETY .... ... o 37

Study FU9204UKIGP98 Page7

15 COMPLIANCE V\IITH Ell-IICAL RESPONSIBILITIES .. . . .... .. ... . 39

16 RESULTS: RANDOMISED, COMPARATIVE TREAllv1Ef\IT 16.1 STUDY PERIOD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 16.2 STUDY POPULA.TION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 16.3 BASELINE COMPARABILilY OF TREATMENT GROUPS . . . . . 44 16.4 DURATION OF RANDOMISED, COMPARATIVE,

TREA TMEf\IT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 16.5 EFFECT OF STUDY DRUGS . . . . . . . . . . . . . . . . . . . . . . . . . 51 16.6 CONCOMITANT DRUG TREATMENT . . . . . . . . . . . . . . . . . . . . 71 16.7 SAFETY OF STUDY DRUGS . . . . . . .. . . .. .... ... . . ..... 72

17 COMPLIANCE V\IITH GOOD CLINICAL PRACTICE . . . . . . . . . . . . . . . 75

18 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

19 CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

20 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

APPENDIX 1: APPENDIX Ill: APPENDIX IV: APPENDIXV: APPENDIX II:

Statistical Report Study Protocol Case Record Fonn GCP Compliance ~rtificate Individual Subject Data

INVESTIGATORS AND STUDY CENTRES

All Study Centres were in the United Kingdom.

Co-ordinating Investigator:

Other Investigators:



I 1

l \

l I I

.I I I I I

I

Study FU 9204UKJGP98

Study FU9204UKIGP98 Page 11

Study FU9204UKJGP98 Page 13

COMPANY PERSONNEL

STUDY MONITORING AND DATA VALIDATION

Principal Clinical Project Co-ordinator

Medical Department Leo Pharmaceuticals Longwick Road Princes Risborough Bucks HP27 9RR

Trial Monitors

STATISTICAL ANAL VSIS

B Sc

Clinical Biometrics Medical Department Leo Pharmaceuticals Longwick Road Princes Risborough Bucks HP27 9RR


Study FU9204UK/GP98

SECRETARIAL FUNCTIONS AND DATA COMPUTERISATION

ometrics Medical Department Leo Pharmaceuticals Longwick Road Princes Risborough Bucks HP27 9RR

Page 15


0 EXPANDED SUMMARY

PROTOCOL SYNOPSIS

Protocol objectives:

The objectives of the study were to compare the clinical and bacteriological

effect and tolerability of Fucidin tablets and Ciproxin tablets in patients with

skin and soft tissue infection.

Study design:

The study was a multicentre, randomised, single-blind, parallel group

comparison of the following:

i) Fucidin tablets 250 mg. twice daily, and

ii) Ciproxin tablets 250 mg, twice daily

Randomised, single-blind treatment was given for 5 or 10 days.

Patients were seen at baseline (visit 1 ), after 7 days (visit 2) and if necessary

13 days (visit 3)

The diagram summarises the study procedures

Phase Single blind randomised comparative treatment

Visit (Day) 1 (1} 2(7} 3(13)

Sample size calculation:

The protocol required a total of 150 analyzable patients, 75 in each treatment

group to complete the study. This would enable detection of a difference in the

proportion of patients assessed as 'cured' or 'improved' by the investigators of


1 0% between the treatments.

Subject eligibility criteria:

Patients of either sex, aged 18 years and over, with a clinical diagnosis of skin

and/or soft tissue infection for which oral antibacterial therapy was indicated

were included after giving signed informed consent. Excluded were patients

with cellulitis with no localised site of infection, chronic/recurrent furunculosis ,

post-operative wound infections, leg ulcers, deep tissue abscess(es), impetigo,

diabetes or immunosuppression, history of liver disease, epilepsy or history of

CNS disorder, glucose-6-phosphate dehydrogenase deficiency, concurrent

therapy with theophylline, antacids, iron containing preparations or

anticoagulants, known or suspected hypersensitivity to the constituents of

Fucidin tablets or Ciproxin tablets or any other quinolone. Uncooperative

patients, patients who had previously participated in this trial or were currently

participating in any other trial, patients who had received systemic antibacterial

therapy in the previous 7 days and females who were pregnant, wished to

become pregnant or were breast feeding, were also excluded.

Treatment assignment method:

At visit 1 eligible patients were assigned treatment at random. Patients were

stratified into those with open lesions (spontaneous discharge, purulent or

serous or surgical incision at baseline) or closed lesions (no discharge and

surgical incision/drainage not required at baseline).


Assessments: The diagram summarises the study procedures

Visit (day) 1 (1) 2 (7) 3(13)3

Demographics; Inclusion/exclusion checklist X

Signed informed consent X

Primary diagnosis/concurrent diagnoses X

Duration of current episode X

Concurrent medication X X X

Clinical assessment of lesion :

location X

severity X X X

pain X X X

redness X X X

heat X X X

oedema X X X

discharge X X X

Lesion swab X x, x2

Stratify to 'open'/'closed' lesion group X

Dispense treatment X (x)3

Overall clinical response (cured, improved, failed) X X

Collect treatment pack X X

Adverse events X X

1'

2 Only for those patients with pathological material present (not 'cured') at 1 visit 2,

and/or 2 visit 3. 3 For patients not 'cured' at visit 2.

Study FU9204UK/G P98 Page 19

Medical history:

At visit 1 the patients suitability for the study was checked using the inclusion

and exclusion criteria. The patients medical history was taken and any

concurrent medication recorded.

Investigator's clinical assessments:

At each visit, the investigator assessed the overall severity of the lesion and

the pain associated with it as 0= absent, 1 = mild, 2= moderate or 3= severe.

Redness, heat and oedema were also assessed as 0= absent or 1 = present.

At visits 2 and 3, the investigator assessed the overall response to treatment

as cured, improved, failed or unevaluable

Bacteriological efficacy: based on the results of lesion swabs taken at visits 1,2

and/or 3 was assessed as success, failure or unevaluable.

Adverse events:

At visits 2 and 3 patients were asked a non-leading question about adverse

events. No specific symptoms were asked for. If any adverse event was

reported by the patient or noticed by the investigator, its nature, severity and

causal relationship to trial medication was recorded.

Criteria for efficacy and safety:

Primary Response Criterion: The proportion of patients who were defined as

'cured' or 'improved', according to the Investigators' assessment of the overall

clinical response, at the end of treatment. The end of treatment was defineci

as the last on-treatment visit attended.


Change in score from baseline (visit 1) to subsequent visits for overall severity

and signs and symptoms of infection.

Bacteriological efficacy

Any reported adverse events


RESULTS SYNOPSIS

The study commenced on 8 March 1993 and was completed on 29 December

1993. A total of 199 patients was recruited by 32 investigators. All 199

patients were randomised to single-blind comparative treatment. There were

91 (45.7%) males and 108 (54.3%) females, with a mean age of 43.4 years,

range 15-89 years. There were 59 patients with boils, 30 patients with acute

paronychia, 43 patients with superficial abscesses, 48 patients with wound

infections and 19 patients with other miscellaneous infections.

The two treatment groups were well matched at baseline in respect of numbers,

sex distribution , types of infection and the severity of the infection.

The Primary Efficacy Criterion, which was the proportion of patients assessed

as 'cured' or 'improved' according to the investigators overall assessment of the

treatment response is shown below for the Intention to Treat Population and the

Efficacy Population .

Intention to Treat Population:

PUCIOIN" TABLETS CIPROXIN" TABLETS p(U

(n=97) (n=94)

No. ptt( t )with overal l clinical 84 (86 . 6) 86 (91. 5) 0 . 28 r esponse a t end or t.r eat.mGnt ot cured' or 'lmpt'oved

(I) eot.voon group probabll i ty

The -4.9 percentage difference between the two treatments had 95%

confidence intervals (Fucidin - Ciproxin) of -13.8 to + 4.0.

The difference in response between the two treatments was not significant

(p=0.28).


Efficacy Population

FUCIDI~ TABLETS CIPROXI~ TABLETS pill

Study FU9204UKIGP98 P~ge 23

The overall clinical response, according to the Investigators assessment at

visits 2, 3 and at the end of treatment is shown below.

Patients included in Efficacy Population : Overall Clinical Response.

~patients

100

90

80

70

60

so

10

30

20

1 0

0 n= 1

Fucldln Clpro xl n VI s I t 2

n=36 Fuc ld ln Clpro x l n

V I s I t 3

n=91 Fuc l dln Clpro x ln

End of treatment

ID]Fal l ed

illiJ Improved !IIC ured


There was no statistically significant difference between the treatments in

respect of the overall clinical response.

Both treatments significantly reduced the scores for severity of lesion, severity

of local pain, presence of redness, heat and oedema and purulent and serous

discharge at follow-up visits and at the end of treatment,and with no significant

difference between treatments. There was a significant difference between

treatments in favour of Ciproxin in the mean change in score for lesion severity,

at the end of treatment.

There was no statistically significant difference in the bacteriological response

between Fucidin tablets (86.5%) and Ciproxin tablets (90.9%).

The proportions of patients experiencing adverse events in the Fucidin group

was 16.5% and in the Ciproxin group was 22.3%. The most frequently

reported side effect was gastro intestinal disturbance, such as diarrhoea and

nausea. Only 1 patient who was given Fucidin tablets ceased treatment due

to unacceptable adverse events.

CONCLUSION:

Fucidin tablets 250 mg twice-daily and Ciproxin tablets 250 mg twice-daily for

5-1 0 days were similarly highly effective in treating patients with skin and soft

tissue infections.


1.1 TREATMENT OF SKIN AND SOFT TISSUE INFECTIONS

Skin and soft tissue infections are a common cause of discomfort and distress

to patients. Whilst many are self limiting, or just require surgical incision and

drainage, antibacterial therapy is appropriate whenever there is evidence of the

infection spreading, when resolution is slow and in patients such as diabetics

whose host defences may be impaired.

The primary bacterial pathogens recognised in skin and soft tissue infections

are Staphylococcus au reus and beta haemolytic streptococci.(1)

1.2 FUCIDIN

1.2.1 Pharmacology

Fucidin (fusidic acid/sodium fusidate) is a steroid-like antibiotic isolated from

Fusidium coccineum, and is highly active against virtually all strains of

S.aureus, including those resistant to other antibiotics. It also has moderate

activity against streptococci (2,3).

1.2.2 Completed studies using Fucidin~ at 250 mg bid

A recent study has shown that a low dose of oral Fucidin, 250 mg twice daily,

is as effective as the standard dose of 500 mg, three times daily, in patients

with skin and soft tissue infections requiring oral antibacterial therapy (4) . In

that study, a 5 to 10 day course of Fucidin at 250 mg twice-daily gave a

satisfactory clinical response in 94.7% of the 207 patients assessed. Clinical

efficacy was observed in 87 out of 89 patients with infection due to fusidic acid

sensitive strains of S.aureus and/or beta haemolytic streptococci.


1.3 PRESENT STUDY RATIONALE

The standard dose of Fucidin given to patients with skin or soft tissue

infections is 250 mg twice daily (4) . Ciproxin (Ciprofloxacin, -},a recently

introduced synthetic 4-quinoline derivative with a broad spectrum of

antibacterial activity (5} is clinically and bacteriologically effective in patients

with skin and soft tissue infection.

The study was designed to directly compare the clinical and bacteriological

efficacy and tolerability of Fucidin tablets (250 mg, twice-daily} with Ciproxin

tablets (250 mg, twice-daily) in the treatment of skin and soft tissue infection .


The following description up to and including Section 12, COMPLIANCE WITH

ETHICAL RESPONSIBILITIES, represents a synopsis of the protocol. The

protocol itself is presented in Appendix Ill.

2 OBJECTIVES OF THE STUDY

To compare the clinical and bacteriological effect of Fucidin tablets with that

of Ciproxin tablets in patients with skin and soft tissue infection.

To compare the tolerability of Fucidin tablets and Ciproxin tablets in the

above group of patients.

3 DESIGN OF STUDY

A multicentre, prospective, randomised, single-blind, parallel-group comparison .

4 STUDY SCHEDULE

The Study Schedule is indicated below

Phase Single blind randomised comparative treatment

Visit (Day) 1 (1) 2(7) 3(13)

5 SAMPLE SIZE

The Primary Efficacy Criterion in the study was the proportion of patients

assessed as "cured" or "improved" according to the Investigators overall

response assessment at the end of treatment.


Based on previous experience with Fucidine tablets, it was anticipated about

95% of patients would achieve a "cured" or "improved" response. To

demonstrate equivalence of


6.2.8 Systemic antibacterial therapy with in the previous 7 days.

6.2.9 Pregnant or breast-feeding females, or those likely to become pregnant.

6.2.1 0 Earlier participation in this study, or current participation in any other clinical

trial.

6.2.11 Considered to be unable to comply with the study protocol (ie psychotics,

alcoholics, drug abusers etc.).

7 CRITERIA FOR EARLY WITHDRAWAL FROM THE STUDY

7.1 Patient's voluntary withdrawal.

7.2 Medical deterioration.

7.3 Any unacceptable adverse events.

7.4 Exclusion criteria emerging during the study.

7.5 Non-compliance or default.

7.6 Resistant infection (presence of any pre-treatment pathogen resistant in vitro

to fusidic acid or ciprofloxacin).

8 TREATMENT ASSIGNMENT METHOD

At visit 1, qualifying patients were randomly assigned treatment with either

Fucidin tablets or Ciproxin tablets.

Randomisation was according to a computer generated, random numbers table

in balanced blocks of 4 treatments.

Patients were stratified into two groups as follows:-

i) Open Lesions (spontaneous discharge, purulent or serous, or surgical

incision/drainage required at baseline)


ii) Closed lesions (no discharge and surgical incision/drainage not required

at baseline.)

To ensure similar distribution of patients with either "open" or "closed" lesions

in the two treatment groups, the investigator dispensed their highest numbered

treatment pack for "open" lesions (spontaneous discharge, purulent or serous,

or surgical incision/drainage performed) and their lowest for "closed" lesions (no

discharge or surgical incision/drainage) .

9 BLINDING

Trial medication was given single blind and in blister packs contained in a

sealed outer pack so that the investigator was unaware which antibiotic was

given to a patient.

10 BREAKING OF THE TREATMENT CODE

Individual randomisation code-breaking envelopes were supplied to

Investigators to identify the treatment in case of emergency.

11 STUDY MEDICATION

Fucidin tablets manufactured by Leo Pharmaceutical Products, containing 250

mg sodium fusidate. The other constituents included: microcrystall ine cellulose,

crospovidone, gelatine, hydroxypropyl methylcellulose, lactose, magnesium

stearate, polyvinyl pyrrolidine, silicon dioxide, talc, titanium dioxide.

Batch no: C28 Expiry date: 15/8/95

Ciproxin tablets manufactures by containing 291.5 mg

ciprofloxacin hydrochloride monohydrate, equivalent to 250 mg ciprofloxacin.

Batch no: - Expiry date: 15/1/96


11.1 STORAGE OF STUDY MEDICATION

Study medication was stored at room temperature (below 25C).

11.2 ADMINISTRATION OF STUDY MEDICATION

Test medication was supplied in blister packs of ten tablets, and patients were

instructed to take one tablet morning and night for 5 days. A second pack was

issued to patients whose lesion was not deemed to be 'cured' by the

Investigator at day 7, making a total of ten days' treatment.

11.3 DURATION OF THERAPY

Therapy was for five days in the first instance, but any patient with lesion(s) not

rated as 'cured' by the Investigator received a further five days' antibiotic

treatment.

11.4 DRUG ACCOUNTABILITY

Investigators and their staff were fully responsible for maintaining adequate

control of the study medication and for documenting all transactions with the

patient. An inventory was kept of all supplies issued to and returned by each

patient enrolled in the study on drug accountability forms supplied by Leo

Pharmaceutical products; also an inventory of all trial medication supplied by

and returned to Leo Laboratories was kept by the trial monitor using Drug

Accountability Form 1 (see protocol, Appendix Ill).


12 CONCOMITANT THERAPY

Concomitant medication for conditions other than skin and soft tissue infection

could be started or continued throughout the study, and drug name and

indication recorded on the Case Record Form (CRF). Systemic or topical

antibacterials, theophylline, antacids, iron-containing preparations or

anticoagulants were not permissible.


13 STUDY PROCEDURES

Visit (day) 1 (1) 2 (7) 3(13)3

Demographics; Inclusion/exclusion checklist X

Signed informed consent X

Primary diagnosis/concurrent diagnoses X

Duration of current episode X

Concurrent medication X X X

Clinical assessment of lesion:

location X

severity X X X

pain X X X

redness X X X

heat X X X

oed~ma X X X

discharge X X X

Lesion swab X x1 x2

Stratify to 'open'/'closed' lesion group X

Dispense treatment X (x)3

Overall clinical response (cured, improved, failed) X X

Collect treatment pack X X

Adverse events X X


1'

2 only for those patients with pathological material present (not 'cured') at 1 visit 2,

and/or 2 visit 3. 3 For patients not 'cured' at visit 2.

13.1 MEDICAL HISTORY

At visit 1, (baseline) all details pertinent to the inclusion and exclusion criteria

specified in the protocol were checked. Demographic data, concurrent illnesses

and treatments, and the location, type (open or closed), and severity of local

signs and symptoms of the lesion were recorded.

13.2 CLINICAL ASSESSMENT

The Investigators made the following clinical assessments:

13.2.1 Presence and severity of local signs/symptoms:

At each visit, the overall severity of the lesion and the pain associated with it

were graded and assessed according to the following scale (and scored as

indicated):

Absent= 0

Mild= 1

Moderate= 2

Severe= 3

Redness, heat and oedema were also assessed and recorded as present (1)

or absent (0).

The presence (1) or absence (0) of any spontaneous discharge, defined as

purulent or serous, was also recorded.


13.2.2 Surgical incision/drainage of the lesion.

The investigator recorded whether surgical incision/drainage of the lesion was

required at visits 1 ,2 or 3.

13.2.3 Overall clinical response

This was assessed at visit 2 (and visit 3 if applicable) as follows:

Cured: Lesion completely healed during therapy or lesion sufficiently

improved that no further antibiotic therapy was required.

Improved: Partial resolution of the lesion eg. inflammation still present but

reduced. Further antibiotic therapy indicated.

Failed: either a) no alleviation, or worsening of inflammation

or b)

or c)

and signs of infection

surgical drainage of pus necessary (or

repeated) after day 1 (visit 1)

treatment discontinued due to inadequate

response

Unevaluable: Patients who defaulted.

13.3 BACTERIOLOGICAL ASSESSMENT

At visit 1, and at the other visits if pathological material was still present, a

swab was taken of the lesion, and sent for culture to the central laboratory,

Bacteriological Department,

-) for culture. For "closed" lesions a dry swab of pus aspirated from the

lesion or a wet swab rubbed over the surface of the lesion was made; for

"open" lesions, a dry swab of pus discharging from the lesion was made.

Only Staphylococcus aureus and beta-haemolytic streptococci were to be

considered as pathogens for the purposes of this study.


The in vitro susceptibility of bacterial isolates was determined by a disc

diffusion technique. Any isolate found to be resistant to fusidic acid or

ciprofloxacin was to be indicated immediately to the Investigator who was to

decide whether to withdraw the patient and offer alternative therapy.

13.4 RECORDING OF ADVERSE EVENTS (all on-treatment visits)

At visit 2 (and visit 3 if applicable) the patient was asked a non-leading question

about adverse events. No specific symptoms were asked for. If no adverse

events were mentioned no further questions were asked. If any adverse event

was reported by the patient, or noticed by the investigator, its nature, severity

('mild', 'moderate' or 'severe') and causal relationship to trial medication

('unlikely', 'possible' or 'probable') were recorded.

Any serious and unexpected adverse events were to be reported to the

company immediately (ie within 24 hours).

14 CRITERIA FOR EFFICACY AND SAFETY

The two treatment groups were compared in respect of the following:

14.1 PRIMARY EFFICACY CRITERION

The proportion of patients who were defined as 'cured' or 'improved', according

to the Investigators' assessment of the overall clinical response, at the end of

treatment. The end of treatment was defined as the last on-treatment visit

attended.


14.2 SECONDARY RESPONSE CRITERIA

14.2.1 Bacteriological efficacy

This was assessed as follows:

Success: Eradication of pre-treatment pathogen at end of treatment (visit

2 or 3)

or

Failure:

No swab taken at last visit as there was no pathological material

evident.

The pathogen, present pre-treatment, persisted at end of

treatment.

Unevaluable: A pathogen present pre-treatment but the patient lost to followp

at end of treatment.

A pathogen was defined a Staphylococcus aureus or beta-haemolytic

streptococci.

Only patients with pathogen(s) isolated at baseline were to be evaluated in the

bacteriological analyses.

14.2.2 Symptomatic improvement

The changes from baseline to the end of treatment (visit 2 or 3) in both the

overall severity and the signs and symptoms of infection.

14.2.3 Adverse events

The incidence, severity and causal relationship of adverse events compared

between treatments.

14.2.4 Treatment withdrawal

The incidence and reasons for withdrawal compared between treatments.

Study FU9204UK!GP98 Page 39

15 COMPLIANCE WITH ETHICAL RESPONSIBILITIES

15.1 The study was conducted to conform with the Declaration of Helsinki II as

adopted by the 18th World Medical Assembly, 1964, and revised by the 29th

World Medical Assembly, Tokyo 1975, Venice, 1983, and Hong Kong, 1989.

15.2 Patients only participated after giving signed consent, having received verbal

and written information about the study. The information emphasized that

participation in the study was voluntary and that the patient could withdraw from

the study at any time and for any reason.

15.3 The clinical trial was approved by local Health Authorities and Ethics

Committees.

15.4 Patients were covered by the product liability insurance of Leo Pharmaceutical

Products.

16 RESULTS: RANDOMISED, COMPARATIVE TREATMENT

16.1 STUDY PERIOD

16.1.1 Commencement of study

The first patient was randomised on 8th March, 1993.

16.1.2 Completion of study

The last patient completed the trial on 29th December, 1993.

Study FU 9204UKJGP98

16.1.3 Duration of study

The comparative treatment phase of the study was completed over a period of

42 weeks.

For individual data on the dates patients attended each of the visits see Appendix /1,

Table IU

16.2 STUDY POPULATION

16.2.1 Disposition of study subjects

16.2.1.1 Recruitment of patients

Patients were recruited for the present study by 32 investigators.

A total of 199 patients were randomised at visit 1. One-hundred and two

patients were assigned to treatment with Fucidin tablets and 97 patients

assigned treatment with Ciproxin tablets.

16.2.1.2 Withdrawal of patients from comparative treatment

A total of 26 (13.1 %) out of the 199 patients randomised in the study were

withdrawn from comparative treatment.

The reasons for withdrawal from the study are given in Table 1.


Table 1 Reasons for study withdrawal

FUCI DI N" TABLETS CIPROXIN" TABLETS P" (n=102J (n=97l

Voluntary 1 0

1' reatrru:;m t f ai lure 10 6

Default 4 3

Exc l u.s i on crit.eria emerg ing 1 1

Protocol compl i a n ce 1 1

Adverse ~vQnt. 1 0

( No. o f reasons 18 11

Total (

(NO. of pa t ients ( % ) 16 (15 .7) 10 (10. 3 ) 0.26 t) Chi--s q uar ed test

The most frequent reason for withdrawal was treatment failure. A total of 16

patients, 1 0 assigned Fucidin tablets and 6 assigned Ciproxin tablets were

withdrawn due to treatment failure.

For individual patient reasons, see Appendix II, Table 11.2.

16.2.2 Protocol violators

The protocol listed a number of inclusion and exclusion criteria (see Section 4)

with which the patients had to comply to be eligible for randomisation .

There were two protocol violators, two patients were aged under 18 years,

patient IIIII (aged 15) and patient IIIII (aged 16). However, both patients were included in the analysis.

16.2.3 Number of patients considered and analysed for safety and efficacy of

study medications

16.2.3.1 Safety

The protocol required that all patients who were randomised in the study be

accounted for in respect of safety (ie adverse events) of the study medications.

Eight patients provided no safety data.

Study FU 9204UKIG P98

There were 5 patients given Fucidin, 4 of whom defaulted and 1 whose

treatment was withdrawn shortly after commencing treatment due to exclusion

criteria emerging.Three patients given Ciproxin defaulted.

Therefore safety assessment was based upon 191 patients, 97 patients in

the Fucidin tablets group and 94 patients in the Ciproxin tablets group.

16.2.3.2 Efficacy

Intention to Treat Population

The Intention to Treat Population is the same as the Safety Population

and comprised 97 patients in the Fucidin group and 94 patients in the

Ciproxin group.

Efficacy Population

The protocol stipulated that data obtained at any visit which took place more

than 3 days after the last treatment day should be excluded from the analysis

of efficacy.

Five patients, 3 given Fucidin and 2 given Ciproxin attended for only 1 follow

up visit (visit 2 in 4 cases visit 3 in 1 case) more than 3 days after the last

treatment day. These patients were excluded from the efficacy population.

The Efficacy Population, therefore, comprised 94 Fucidine-treated patients

and 92 Ciproxine-treated patients.

A further 13 patients attended their second follow up visit (visit 3) more than

3 days after the last treatment day. Data relating to visit 3 were, therefore,

excluded from the analysis and visit 2 data were used for the end of treatment

assessment.

Study FU9204UK/GP98

Disposition of study subjects is shown in the figure.

Otf.,ll

EJ


16.3 BASELINE COMPARABILITY OF TREATMENT GROUPS

16.3.1 Baseline comparability of the two treatment groups for all randomised

patients.

16.3.1 .1 Baseline Characteristics

The two treatment groups were well matched at baseline with respect to

baseline characteristics. (Table 2).

Table 2 Baseline Comparison of Patient Characteristics: Randomised Patients-

Demography

Age (yr$ )

Mean

Range

Sex

Ma l e

FQtnale

Race

Caucasian

Negro

Asian

Duration of Current Episode (days) Mean (range}

Base linQ diagnos is:

Boils


The two treatment groups were also well matched with respect to the baseline

severity of lesions, and associated signs/symptoms of infection (Table 3).

Table 3 Baseline Comparison of Patient Characteristics: Randomised Patients

Overall Severity and Signs and Symptoms of Infection

PUCIDIN rABLE:TS C IPROXI~ TABLETS

!n=102) (n= 97 )

SEVERITY OF LESION Mild 11 4 t 10.8 4. 1 Moderate 72 77 t 70.6 79.4 Severe 19 16 t 18.6 16.5

REDNESS None 0 5 t 0 5. 2 Present 102 92 t 100.0 94.8

HEAT None 17 21 t 16. 7 21 . 6 Presen t 85 76 t 83 . 3 78.4

OEDEMA None 28 30 t 27.5 30.9 Present 74 67 % 72.5 69. 1

SERI OUS DISCHARGE None 78 76 t 76.5 78 . 4 Pre sent 24 21

"' 23.5 21.6

PURULENT DISCHARGE None 56 50 t 54.9 51 . 5 Present. 46 47

"' 45 . 1 48. 5

LOCAL PA IN Absent 7 8 t 6. 9 8 . 2 Mild 30 21

"' 29. 4 21.6 ModeratQ 54 54 " 52.9 55 . 7 Severe 11 14 t 10 . 8 14. 4

LOCATION LESION Head 15 23

"' 14 . 7 23 . 7 Trunk 26 23 "'

2 5 . 5 23.7 Limbs 61 51 t 59.8 52.6

For data in individual patients, see Appendix II, Tables II. 7 to II. 14


16.3.1.2 Concurrent diagnoses

There were no important differences between the two groups with regard to

concurrent diagnoses at visit 1. (Table 4).

Table 4 Baseline Comparison of Patient Characteristics - Randomised

Patients - Concurrent Diagnosis

Diagnosis

Hear t disease/hyper tens i on

As thma/bronchi tis

Osteoarthritis

Contraception/hormone

therapy

Psychiatric condi tions

HQartburn/colic/ulcer

Pain ( non lgs ional )

Ml sc'il lanoous

Tota l

FUCIDIN TABL.E'I'S

tn~l02l

No. ptt

11

6

2

9"

so

11 I nsomn i a (2). breast cane~u. 1 i pidaemia, pilos. olau collla, t innitus . o-czas:M, mi nor operation.

CIPROXIN" TABL.ETS

(n97)

No. ptt

13

6

12

5

14"

61

21 Tonsll l i t1 $/Sore throat. f2), insomnia (2) , folic acid defieiency, ha.eaorrhoids, cne, hypotbyroldis~. irri t.abl e bowe l syndrome ,

p:O\It, dental absc ess. tinea cruris, vomiting, di arrhoea.

For data on individual patients see Appendix, Table 11.4

16.3.1.3 Concomitant drug treatment

There were no important differences between the two treatment groups with

regard to concomitant non-antibiotic drug treatment taken at visit 1. The

concomitant drug treatment classified according to the ATC system (WHO

Anatomical Therapeutic Chemical Classification Index 1991) is given for the two

treatment groups in Table 5.


Table 5 Baseline Comparison of Patient Characteristics: Randomised Patients

- Concomitant Drug Treatment

ATC Cl ass

Alimenta r y tract and metabolism

Anti-neoplast i c and immunosuppressants

Blood and blood forming organs

Cardiovascul ar system

Central nervolls system

Der matologicals

Ge neral ant i - infQc tivos -systgmic

Geni t o-urinary system and s ex hormones

Musculo- skel etal system

Respiratory systom

Systemic hormone prep excl sex hormone

Unc lasstf ied

Total med i cations

FUCIDIN" TAB~ETS


16.3.2 Baseline comparability of treatment groups in respect of patients included

in the efficacy analyses.

The patients included in the efficacy analyses in the two treatment groups

were well matched at baseline in respect of numbers, age, sex distribution

(Table 6), and the overall severity of the lesion, plus the presence or absence

of other signs and symptoms of the infection (Table 7).

Table 6 Baseline Comparison of Patient Characteristics: Efficacy Population -

Demography

Age (yrs l

Mean

Range

Sex Mal9

FQmale

Race

Caucasian

Negro

Asian

Durati on of c urront Episode (days)

Haa n (range)

Base l ine di agnosis : Bolls (ca r bunclea, turuncles)

Acute PG~onychia

Superficial absc ess(es) Wound infec tion

Othe r

SUrgica l lncision/draina9o at baselinG

I'UCIDIW TABLETS

(n94)

No . ptt.. ( 'I: )

44.8

18 - 8 4

47 ( 50. 0)

~7 (50 . 0)

88 (93 .6)

2 (2 .1)

4 (4 . 3)

6.9 (1 - SG)

3 3 ( 35.1)

14 (14. 9)

15 (16.0)

24 (25. 5 )

s (8. 5 ) 1 4 (14 . 9)

CIPROXIWTABLETS

(nn J

No. pt.e ( \ )

41.1

1 5 - 89

38 141 .3)

54 {58 .7)

88 ( 95.7)

1 ( 1. 1)

3 {3. 3)

6.2 (1 - 29 )

23 (25. 0 )

H (1 5 .2)

22 123.9 )

23 (25 . 0 )

10 (10.9)

13 ( 14 .1)



Overall Severity and Other Signs and Symptoms of Infection

FUCIDIN" TABLETS CIPROXI~ TABLETS (n=94) (n=92)

No. ptt No . ptt

SENERITY OF LESION Mild 11 3

' 11 . 7 3 . 3 Moder



Bacteriological Findings at Baseline

Number o f patients c ultu r ed

Numbe r o f pdtients with no pathogen iso l a tQd:

Number ot pa t ients with pathogens'

Staphyl ococcus aureus ,

Staphyl ococcus aureus beta haemo l yti c streptococci'

BQta haQmoly t ic str~ptococci:

FUCIDIN" TABLETS

(n;94)

9 4

56

3 8

29

CIPROXI N" TABLETS

( n=92 )

92

46

46

33

6

Baseline microbiological findings were similar for both treatment groups. All

isolates of S.aureus and beta haemolytic streptococci were tested for their in

vitro susceptibility. The percentage of S.aureus susceptible (defined as

sensitive and moderately sensitive) to the antibiotics tested were: Fusidic acid

98.6%, ciprofloxacin 98.6%; penicillin 19.1 %, cephradine 100%, erythromycin

93.4%, flucloxacillin 100% and mupirocin 100%. The percentage of beta

haemolytic streptococci isolates susceptible to the antibiotics tested were:

fusidic acid 100%, ciprofloxacin 77.3%; penicillin, cephradine, erythromycin ,

flu cloxacillin and mupirocin all 100%.


16.4 DURATION OF RANDOMISED, COMPARATIVE, TREATMENT

The mean duration of treatment in all randomised patients (patients who

completed the entire comparative treatment period, patients who defaulted after

randomisation and patients who were withdrawn) was 7.6 days for Fucidin

tablets and 7.4 days for Ciproxin tablets.

In randomised patients, a total of 112 patients, 56 given Fucidin tablets and

56 given Ciproxin tablets took only 1 course of 5 days treatment. 87 patients,

46 given Fucidin tablets and 41 given Ciproxin tablets took 2 courses (1 0

days) of treatment.

The mean duration of treatment among patients included in the efficacy

population was 7.6 days for Fucidin tablets and 7.4 days for Ciproxin tablets.

In the efficacy population, a total of 99 patients, 48 given Fucidin tablets and

51 given Ciproxin tablets took only 1 course of 5 days treatment. 87 patients,

46 given Fucidin tablets and 41 given Ciproxin tablets took 2 courses (1 0

days) of treatment.

For data in individual patients, see Appendix II, Table II. 1

16.5 EFFECT OF STUDY DRUGS

As stated previously (Section 13.2.3.2) a total of 8 patients were excluded from

the Intention to Treat Population as they provided no data.

A further 5 patients were excluded from the Efficacy Population as they

returned for follow-up outside the 'time-window' allowed by the protocol.

A further 13 patients attended for their second follow-up visit outside the 'time

window' allowed by the protocol. Data relating to this visit were excluded from

the analysis.


NOTE: All safety data (ie adverse events), irrespective of the time post-

randomisation they were recorded, have been included in the

presentation of adverse events.

16.5.1 Clinical Effect of study drugs in patients included in the Intention to Treat

Population

The Primary Efficacy Criterion was defined as:

The proportion of patients who achieved a clinical response of "cured" or

"improved" as judged by the investigator at the end of treatment.

The clin ical effect of the study drugs in respect of the Primary Efficacy

Criterion is shown in Table 9.

Table 9 Intention to Treat Population Primary Efficacy Criterion

FUCI DIN" TABLE'l'S CIPROXI N" TABLE'l'S pUl

(n.=97 ) cn=9 4 )

No. pt.e(~ ) with ovr"ll clin ical 84 (86 . 6 ) 86 (91. 5) 0. 28

response at end of trea cznent. of

cured ' or ' irnprovd '

Ill Bt"'~n o:roup probe.bl \Ltv

The -4.9 percentage difference between the two treatments had 95%

confidence intervals (Fucidin - Ciproxin~ of -1 3.8 to + 4.0.

The difference in response between the two treatments was not statistically

significant (p=0.28) .


16.5.2 Clinical effect of study drugs in patients included in the Efficacy

Population.

16.5.2.1 Primary Efficacy Criterion

The Primary Efficacy Criterion was defined as:

The proportion of patients who achieved a clinical response of "cured" or

"improved" as judged by the investigator at the end of treatment.

The clinical effect of the study drugs in respect of the Primary Efficacy

Criterion is shown in Table 10.

Table 10 Patients included in Efficacy Population: Primary Efficacy Criterion

FUCIDI~ TABL.Ii:'l'S CIPROXI~ TABLETS pUl

(n94) Cn=92)

No. pt t(%} wi th overall c l inical 82 (87 . 2} 84 (91 . 3} 0. 37 response at end of treatment of

cured ' or ' i mprowd'

(I ) eo t we en group probabi ll ty

The -3.9 percentage difference in response between the two treatments had

95% confidence intervals (Fucidin - Ciproxin~ of - 12.8 to + 5.0.

The difference in response between the two treatments was not statistically

significant (p= 0.37)

For data on individual patients, see Appendix /1, Table II. 15.


16.5.2.2 Investigators assessment of Overall Clinical Response

The overall clinical response at visits 2, 3 and at the end of treatment is shown

in Table 11 , and in Figure 1.

Table 11 Patients Included in Efficacy Population: Overall Clinical Response

FUCIDIN" 'l'ASLE'l'S CIPROXIN" 'I'ASLETS p ' (n=94) (n=92l

' VISIT 2

Cured 40 46 % 42 . 6 50.0

ImprovGd 41 37 % 43 . 6 40.2

Failed 1 3 21 9 t 13.8 9.8

VISIT 3

Cured 1 7 2 3 % 47 . 2 60 . 5

Improved 16 13 % 44.4 34.2

Fa iled 3 2 % 8 . 3 5.3 n 36 38

Ei'IO OF TREAT ME:N'I'

Cured 57 69

' 60 . 6 75 . 0 0. 11 Improved 25 1 5 t 2 6.6 16 . 3

Fa i l ed 12 8 t 12.8 8.7

fl ) Ch1-squarga cest 12) ln.vosttgo.cor recor d&d t reatroent fa ilure t n 1 patlent, al though paelent di


Figure 1. Patients included in Efficacy Population: Overall clinical response.

~patien ts

1 0 0

90

80

70

60

50

10

30

20

1 ()

""9 1 Fucldln Clpro x ln

VI s f t 2

n = 3 6 Fucldln Clprox l n

v f s f t 3

n=92 fu cl d ln Cl pro xln

End of treat ment

W:f:I F I I d ~ a e

!ijlm proved

. Cu red


16.5.2.3 Severity of individual signs of soft tissue infection.

i) Severity of lesion

The overall severity of the lesion at baseline (visit 1) and at visits 2 and 3, and

at the end of treatment, is shown in Table 12.

Table 12 Patients Included in Efficacy Population: Severity of Lesion at

Respective Control Visits

FUCIDIN' TABLETS CIPROXIN' TABLETS (n 9 4 ) !n=92)

VISIT 1 Mi l d 11 3

" ll. 7 3.3 Mode ra te 65 33 t 69. 1 7 9.3 Sevoare 18 16 t 19.1 17.4

VISIT 2 Absen t 23 35 t 2 4.7 38 . 0 Mi l d 47 41 t 50.5 44 .6 Moder at> 22 11

" 23.7 12.0 severe 1 5 t 1.1 5 . 4 n 93 11 92

VISIT 3 AbsQn t 12 15

" 3 3.3 39.5 mild 2 1 20 t 58 .3 52.6 Mode r a te 3 3 t 8. 3 7.9 n 36 38

END OF TREATMENT Abswnt. 3 5 50

"' 37 . 6 54 . 3 Mild 43 35 % 4 6.2 38.0 Mod,. rate 14 5

' 15. 1 5. 4 Severe 1 2 t 1.1 2 . 2 n 93 ' 1 92

" ln.ve stiO:ltOt" reco r ded trot.niOnt h .iluro in 1 addl d o n.:ll pa.t iont. although p.ationt did not. ro .. at.tond tor tollow- up


The change in score for severity of lesion from baseline (visit 1) to subsequent visits

is shown in Table 13.

Table 13 Patients Included in Efficacy Population: Change in Score2 l for

Severity of Lesion from Baseline to Subsequent Visits

FUCIDI N" TABLETS CI PROX I N" TABLETS OiffGrencs in moan changQ FUCIDI N- CIPROXIN p' (95% Confidence inte r va l )

(n94 ) (nc92)

VISIT 1

mean 2 . 08 2.12

VISIT 2

m&an - 1.05 -1.27

so 0 . 84 0 . 83

minimum -3.0 -3 . 0

maximum 1.0 1.0

n 93" 92

VISIT 3

mean - 1.39 -1.55

so 0.73 0.69

mi nimum - 3 . 0 - 3 .0

maximum 0 . 0 0.0

n 36 38

END OF 'l'REATMEN'l'

mean - 1.29 -1.56 +0.27

so 0.85 0.72 (+0 . 04 to 0 . 50) 0 . 01

minimum - 3.0 - 3 . 0

max i mum 1.0 1.0

n 93" 92

tl) Be1:.wen group proNb1lltY t~t#t. (2) Ab$entO .. Mlldal, Kodoret2, S-ovorol. (3) Investigator r9corded t.retMnt C'elluro ln 1 o.dditionl pat lnt. lthough pthmt did not re "-t.ten.d tor t ollow up

Both treatments reduced score for severity of lesion at visits 2 and 3 and at the

end of treatment.

There was a significant difference (p=0.01) between the two treatments in the

reduction in the score for lesion severity at the end of treatment in favour of

Ciproxin tablets.

For data in Individual patients, see Appendix II, Table II. 7.


ii) Local Pain

The severity of the local pain at baseline (visit 1) and at visits 2 and 3 and at the

end of treatment is shown in Table 14.

Table 14 Patients Included in Efficacy Population: Severity of Local Pain at


FUC I DIN" TABLETS CI PROXIN" TABLETS

(n:94) (n:92)

VISIT 1 Absent 7 s % 7. 4 8.7 Mild 29 20 % 30 . 9 2 1. 7 Moderate 49 so % 52 . 1 5~.3 Severe 9 14 % 9.6 15 . 2

VISIT 2 Absent 49 51 % 52 . 7 55.4 Mild 29 26 % 31.2 28 .3 Moder a t e 13 14 t 14.0 15 . 2 severe 2 1 t 2.2 1 . 1 n 93" 92

VISIT 3 Absen t 24 25 % 66 . 7 65.8 mild 10 10 t 27.S 26 . 3 Moder .ace 2 3 t 5.6 7.9 n 36 38

END OF TREATMENT Absent 62 68 % 66.7 73 . 9 MHd 22 17 % 23 .7 18.5 Moder ate 8 6 % 8 . 6 6.5 Severe 1 I t 1.1 1. 1 n 93" 92

" Investigator reco r


The change in score for local pain from baseline (visit 1) to subsequent visits is

shown in Table 15.

Table 15 Patients Included in Efficacy Population: Change in Score2> for

Severity of Local Pain from Baseline to Subsequent Visits.

rUCIDI~ CIPROXI~ Difterence in mean chan9G p' TABLETS TABLETS PUCIDIN-CIPROXIN (n=94l (n=92.) (95% Confidence interval)

VLSIT 1

mean 1 . 61 1. 77

VLSI'I' 2

me an - 0 . 97 -1.18

so 1 . 04 0 . 89

minimum -3.0 - 3 .0

maximum 2 . 0 1.0

n 93" 92

VLSI'I' 3

mean -1 .30 -1.47

so 1. 01 0. 86

minimum -3.0 - 3 .0

ma ximum 2. 0 0.0

n 36 38

ENO OP' TREATMENT

mean -1 . 19 -1. 40 +0.21

so 1.03 0 . 92 (-0 . 07 to + 0.49) 0.1!'.

minimum -3 . 0 - 3.0

maximum 2.0 1.0

n 93" 92

(I) B-otween grO'UP PYObabi 1 1 tY t-tost. (2) AbsentO. Hi ld.l, Modorate l, sovrl (3) Investigator r ocordod troaCJt:ont tailur in 1 dditlonal patlont , althoug h patient dld noc r attend Cor Collow .. up

Both treatments reduced score for severity of local pain at visits 2 and 3 and at the

end of treatment.

There was no significant difference between the two treatments in the reduction of

the score for the severity of local pain at the end of treatment (p=0.15).


iii) Redness

The presence or absence of redness at baseline (visit 1) and at visits 2 and 3, and


Table 16 Patients Included in Efficacy Population: Presence of Redness at


FUC J OIN" 'I'ABLE'I'S C I PROX!N" 'l'ABI,E'J'S (nz94) (n 92)

VISIT 1

Abscm t 0 5 % 0 5 . 4

Present- 94 67 % 100.00 94 .6

VISIT 2

Absent 36 4 3 'I; 36 .7 46 . 7

Present 57 49 % 61.3 53.3 n 93 11 9 2

VISIT 3

Absen t 1 6 16 t 44 .4 47 . 4

Presen t 20 20 \ 55 . 6 52 .3 n 36 38

END OF TREATMEN'l'

Absan t 43 58

' 4 6.2 63 .0 Present so 34 % 53.6 37 .o n 93" 92

" l nvo~t1gato:r record.od t r eQtrnont tailuro 1n 1 ~ddi tional patient. although pat i4nt d id r.ot rQ Olttond for foll ow- up


The change in score for presence or absence of redness from baseline (visit 1) to

subsequent visits, is shown in Table 17.

Table 17 Patients Included in Efficacy Population: Change in Score21 for

Redness from Baseline to Subsequent Visits.

PVC I DIN" CIPROXIN" DiffgrGnco i n mGan change TABLETS TABLETS PVC IDIN-CI PROXIN

(n94) (n=92l (95t Confidance interval)

VISIT 1

mean 1. 00 0.95

VISIT 2

mean - 0. 41 - 0.41

so o. 47 0.50

mi nimum -1.0 -1 . 0

maximum 0.0 0.0

n 93" 92

VISIT 3

mean - 0. 44 - 0.47

so 0. 50 0.51

minimum -1.0 -1.0

maximum 0.0 o.o

n 36 38

END Of' TREATMEN'l'

rna an -0 . 55 - 0.58 +0.03

so 0. 40 o. 50 (-0.10 to + 0.16 )

minimum -1 . 0 -1 . 0

maximum 0.0 0.0

n 93" 92

(II 9otwe on grO\ll) probo.bi11ty t .. te~t. (l} Abfnnte-0 , PTentl (3) lnvost.ioat.ol" reord.O. trat.D.nt faHur in 1 addlti. ona\ p,at1ent. although pati ent d\d not r attend t:o r follow-up.

p'

0.65

Both treatments reduced score for redness at visits 2 and 3 and at the end of

treatment.

There was no significant difference between the two treatments in the reduction of

the score for redness at the end of treatment (p=0.65) .


iv) Heat

The presence of local heat at the site of the infection at baseline (visit 1) and

at visits 2 and 3, and at the end of treatment is shown in Table 18.

Table 18 Patients Included in Efficacy Population: Presence of Local Heat

at Respective Control Visits

F'UCI DIN" 'l'ABLI!TS CIP ROXI N" 'l'ABLE'l'S

(n =94) (n=92)

VISIT 1

Absent 17 2l %- 18 . 1 22. 8

P resen t 77 7 1 % 81.9 77.2

VISIT 2

Absent 70 7 4 t 7 5.3 77. 1

Pr esent 23 18 % 24 . 7 18 . 8 n 9 3 11 92

VISIT 3

Absen t 3 1 33

' 86 . 1 86.8 Pr9sEimt 5 s \ 13 .9 13 . 2 n 36 38

END OF TREATMENT

Absent 79 82 t 84 . 9 89. 1

Present 14 1 0 % 15.1 1 0 .9 n 93 11 92

(I) Investigator recorded treatment lai/ure in 1 addlonal patient, anhough patient did nol re attend lor foiiOwup.


The change in score for local heat at the site of infection , from baseline

(visit 1) to subsequent visits is shown in Table 19.


Heat at the Site of Infection from Baseline to Subsequent Visits.

VISIT 1

mean

VISIT 2

mean

so mi nimum

maximum

n

VISIT 3

mean

so minimum

maximum

n

END OF TREATMENT

mean

so minimu.m

maximum

n

(1) Bo twoon gro\lp probability t-tost. (2) AJ:>senc O, Pro~,-.nt = l.

FUCIOI~ TABLETS

(n 94 )

0.83

- 0.58

0.56

- 1.0

1.0

93"

-0.66

0 . 54

-1.0

1. 0

36

-0.68

0.52

- 1.0

1. 0

9311

CI PROXI~ Dif f ere nce in mean TABLETS change FUCIOINC I PROXIN ln=92) (95% Confiden ce i n terval)

0. 78

-0.5~

0.50

-1.0

0 .0

92

- 0 . 77

0 . 49

- 1.0

1.0

38

- 0.66 - 0.02

0.49 ( .. 0.17 t.o + 0. 13)

- 1.0

1.0

92

(3) tnvesdgator recorded tnu,tment. f4l lure i n l additional pa.t.ient. although patient dld noc. re a.ttenQ Cor follow-\IJ)

Both treatments reduced the score fo r heat at visits 2 and 3 and at the

end of treatment.

There was no significant difference between the two treatments in the

reduction of the score for local heat at the end of treatment (p=0.79).

P'

0. 79


v) Oedema

The presence of oedema at baseline (visit 1) and at visits 2 and 3, and at the

end of treatment is shown in Table 20.

Table 20 Patients Included in Efficacy Population: Presence of Oedema at


F'UCIDI~ TABLETS ClPROXItr TABLE:TS

(n=94) (n =92)

VISIT 1

Absent. 26 29

"' 27.7 3 1 .5

Present 68 63 % 72 . 3 68 . 5

VISIT 2

Absent:. 62 66 % 66 .7 71 .7

Present: 31 26

"' 33.3 28 . 3 n 93 11 92

VISIT 3

Absent. 27 32 t 75.0 84.2

Present. 9 6 % 25.0 1 5. 8 n 36 38

END Of' TREA'l'MEN'l'

Absent. 72 79 % 77.4 85 .9

Present 21 1 0 % 22.6 1 4. 1 n 93, 92

(I) Investigator recorded treatment failure In 1 add"ional patient, a~hough patient did not re attend for follow-up.


The change in score, for oedema at the site of infection, from baseline (visit 1)

to subsequent visits is shown in Table 21.

Table 21 Patients Included in Efficacy Population: Mean Change in Score 2>

for Oedema at the Site of Infection from Baseline to Subsequent Visits

FUCIDI~ CIPROXI~ Differe nce i n mea n change p ' TABLETS 'l'ABLBTS FUC IDIN-CI PROXIN

( n 94) tn=92 ) t 95% Confidence interval)

VISIT 1

mean 0 . 72 0 . 69

VISIT 2

mean - 0. 4 3 - 0 .40

SD 0 . 56 0.54

min i mum -1. 0 - 1. 0

maximum 1 . 0 1.0

n 93" 92

VISIT 3

me an - 0 . 64 - 0 .66

SD 0 . 42 0. 42

min i mu m -1.0 - 1.0

max i mum 1 . 0 0 .0

n 36 38

END OF TREATMENT

mean - 0 . 58 - 0 . 54 0 . 04

so 0.47 0 .50 (- 0. 18 co + 0.10) 0 . 58

minimum - 1.0 - 1.0

maximum 1.0 0.0

n 93" 92

(1 ) Becwoan group probabi 11 ty t-t.es t. ( 2) Abs:ent=O, E'resent l . ()) Inv est i gat or recorded troat.JMnt tailuro l n 1 addi tiona l pa ti ent , al though patient did not ro ottond for tol l ow .. up.

Both treatments reduced the score for oedema at visits 2 and 3 and at the end of

treatment.

There was no significant difference between the two treatments in the reduction of the

score for oedema at the end of treatment (p=0.58).


vi) Purulent Discharge

The change in presence of purulent discharge from baseline (visit 1) to

subsequent visits is shown in Table 22.

Table 22 Patients Included in Efficacy Population: Presence of Purulent

Discharge at Respective control Visits

FUCIDIN" TABL!l'l'S CIPROXI N" TABLETS

( n 9 4 ) (n92 )

VISIT 1

Abs


The change in score, for purulent discharge, from baseline (visit 1) to subsequent

visits is shown in Table 23.

Table 23 Patients Included in Efficacy Population: Change in Score2l

for Purulent Discharge at Respective Control Visits.

FUC IDIN" TABLE:'I'S (n=9 4 )

VJ:SI'l' 1

mean 0. 46

VJ:S I'l' 2

mean -0.35

SD 0. 45

mi nimum -1. 0

maximum 1.0

n 93"

VJ:SI'l' 3

mean - 0.33

so 0. 40

minimurn - 1 .0

maximum 1.0

n 36

END OF TREATMEN'l'

mean - 0 . 34

so 0. 45

mini mum - 1 .0

rnaxirnum 1. 0

n 93!)

( 1 ) Bet.woon g roup probab1 L 1 t.Y t -tat. ( 2 Ab$e.nt O, Prosant a l ,

CIPROXIN" TABLETS Diffe r ence in mean (n=92J change FUC!OI N- CIPROXIN

(95t Confidence interval)

0 . 50

-0.35

0. 54

-1.0

1.0

92

- 0.43

0.5S

- 1. 0

1.0

38

- 0 . 41 +0.07

0.54 (- 0.07 to + 0 .21)

-1 . 0

1 . 0

92

p'

0.34

tl) tnvegt1g:.to r r-o.corded. t.ro;~otrttont. f all ul"'o Ln 1 a.ddi tional patlont , a.l t.hou.gh patient did not ro oetond for fo llow-!JP .

Both treatments reduced the score for purulent discharge at visits 2 and 3 and at the

end of treatment.


score for purulent discharge at the end of treatment (p:::0.34)


vii) Serous Discharge

The presence of serous discharge at baseline (visit 1) and at visits 2 and 3, and


Table 24 Patients Included in Efficacy Population: Presence of Serous Discharge

at Respective Control Visits

FUCIDIN" TABLE'I'S C!PROXIN TABLE'I'S

(n94 l (n=92)

ViSIT 1

Absent 72 72 t 76.6 78.3

Pr esent 22 20 % 23 . 4 21 . 7

ViSIT 2

Absen t 83 83 % 89.2 90 . 2

Prasen t 10 9 % 10.8 9 . 8 n 93 11 92

ViSIT 3

Absent 33 33 t 91.7 86.8

Present 3 5 t 8 . 3 13.2 n 36 38

END OF TREATMENT

Absent 85 84 % 91 . 4 91.3

Present 8 8 t 8 . 6 8.7 n 93 92

(I) Investigator recorded treatment failure In 1 additional patient, anhough patient did not re attend for followup.


The change in score for serous discharge from baseline (visit 1) to subsequent

visits is shown in Table 25.


Serous Discharge from Baseline to Subsequent Visits.

FUCIDI~ CIPROXI N" Diffe r enc e in mean c hange p ' TABLETS TABLETS FUC I DI N-CIPROXIN (n=9 4) (n=92) (95% ConfidencQ int.Grval)

VISIT 1

mean 0 . 2 4 0. 22

VISI T 2

mean - 0. 1 3 - 0. 12

SD 0. 49 0. 49

minimum -1.0 - 1. 0

maximum 1.0 1.0

n 93" 92

VISIT 3

mean -0. 14 - 0.11

so 0 . 42 o. 51

minimum -1 .0 - 1 .0

maximum 1. 0 1 . 0

n 36 38

END OF TREATMENT

mean - 0.18 - 0.13 - 0.05

SD 0.45 0. 50 ( -0.19 to + 0.09 ) 0 . 47

minimum -1.0 - 1.0

maximum 1.0 1.0

n 93u 92

(1 1 Between g roup probabill ty t tost . (21 Absent s O, Pres&nt:1. 131 lnvott i ga tor r oeordd trea tment failure l n t additional patient. al though patient did not re attend t or foll ow-up

Both treatments reduced the score for serous discharge at visits 2 and 3 and at the

end of treatment.


score for serous discharge at the end of treatment (p=0.47).


16.5.4 Bacteriological outcome

16.5.4.1 Bacteriological Findings at End of Treatment

The bacteriological findings at the end of treatment are shown in Table 26.

Table 26 Patients Included in Efficacy Population: Bacteriological Findings

at End of Treatment

Number or pat i ents cultured

Number o f pat i ents wi t h no pa thogen isolated:

Number O( patients with pa thogens:

Pathogens isol ated:

Staphy lococcus aureus:

Staphylococcus aureus + be t a haemolytic streptococci :

Be ta haemolyt ic strep t ococci:

FUC IDIN" TA!lLET S C IPROX I N" TABLETS

1 4 1 5

10 11

0

6


16.5.4.2 Bacteriological response

The bacteriological response was determined in 81 of the 84 patients with a

proven infection, 37 given Fucidin tablets and 44 given Ciproxin tablets.

The bacteriological response is shown in Table 27.

Table 27 Patients Included in Efficacy Population: Bacteriological Response

VISIT 2

Success

F'ailure

VISIT 3

Success

Pa i lu r e

n

END OF TREATMENT

Success

F'ailure

FUC I DIN TABLETS ( n= 38)

26 (70 .3%)

11 (29. 7t)

20 87.0%)

3 (13.0%)

23

32 (86 . 5%)

5 (13.5%)

CIPROXIN" TABLETS (n =46 )

33 (75 . 0%)

1l (25 . 0% )

16 (94.1% )

l (5 . 9%)

17

40 (90.9%)

4 (9 . 1%)

There was no statistically significant difference between the two treatment groups

in respect of the bacteriological response at end of treatment (p=O. 73, Fishers'

Exact Test).

For data on individual patients, see Appendix II, Table 11.16.

16.6 CONCOMITANT DRUG TREATMENT

Use of concomitant medication at study entry is accounted for in Table 5.

Change in use of concomitant medication during comparative treatment is

accounted for in individual patients in Appendix II, Table II 17.


16.7 SAFETY OF STUDY DRUGS

16.7.1 Adverse Events Recorded

Methodology: Adverse event reporting was elicited at each post-randomisation visit

by the investigator recording all adverse events observed by him/her or reported by the

patient.

For each adverse event, the following related details were recorded in the Case Record

Form.

1) The adverse event in the investigator's own terminology.

2) The investigator's opinion on the severity of the adverse event, classified as

"mild", "moderate" or "severe".

3) Whether the investigator considered the relationship of the adverse event to the

study drug to be "unlikely", "possible" or "probable".

In the analysis and presentation of adverse events, the following approach was used:

1) Adverse events as described by investigators were categorised by the Principle

Project Co-ordinator before the treatment identities were revealed (Leo code).

If a particular adverse event category appeared more than once for a particular

patient, the category was counted as one event.

2) Adverse event descriptions were also categorised according to the WHO System

Organ Classification.

For individual adverse event data, using the SOC code, see Appendix II, Table II 18.


16.7.1.1 Adverse events presented bv WHO System Organ Class

Adverse events were assessed in 191 (96.0%) patients, as 8(4.0%) patients were

lost to follow-up and provided no data.

The analysis of adverse events according to the WHO System Organ Class is

presented in Table 28 and according to Investigators Term/Leo category in Table

29.

Table 28 Adverse Events Reported/Observed after Randomisation by

System Organ Class

Body as a whol e disorders %

Cardiovascular disorders (general)

t

Cent ral & peripheral nervous system disorders

%

Cast r o - intestinal system disor ders

%

Psychiatric disor ders t

Re productive disorde rs (female )

t

Respiratory system disorde r s t

Skin and appendage d i sorders

" Speci al senses (other ) disorders

%

Unclass i fiabla a t pre son t '1:

Visual d isorders t

Tota l evQnt.s Total pat i e n ts t

PUCIDI N" TAB~ETS (n=97 1 No ptt

1 1.2

1 1 . 2

1 1 . 2

11 12 .8

1 1 . 2

1 1.2

1 1.2

2 2.3

1 1.2

0 0

0 0

20 16 (16. 51

CI PROXI N" TAB~ETS (n=941

No. ptt

0 0

0 0

1 1. 1

12 13.8

0 0

0 0

6 6.9

3 3. 4

4 4. 6

3 3 . 4

1 1. 1

30 2 1 (22.3 )

P Odds

0. 31

Ratio (95% Cl )

0.69 (0.33- 1. 42)


16.7.1 .3 Table 29 Adverse Events Reported/Observed after Randomisation by Investigator's Term/Leo Category

ADVERSE EVEN"!'S

Abdomina.! pa i n %

Angina %

Bad/bitter taste %

Chest cough %

Constipation %

Dental abscess %

Diarrhoea/i ncreased defaecation

% Oizzinesll

% Drowsy/lethargy

% Dyspepsia

% Gritty eyes

% Ha emorrhoids

% Headache

% Ingrowing toe na i l

% Itch/itchi ness

% L~hangitis/ce1lul1ti s

% Loss ot smel l

% Na~sea

% Road traffic accident

Runny nose

Sinusitis

Skin rash

Sore throat

%

%

%

% Thrush (vagi nal)

% Tonsillitis

% Tooth extraction e 1.,ctive

% Volldting

% Wind (flatus)

%

'l'ota1 !:vents 'l'ota1 Patients %

FUCIO~ TABLETS CIPROXI~ TABLETS (n97) (n .. u)

1 0 1.2 0

1 0 1.2 0

1 3 1.2 1.1

0 1 0 1 . 1 2 1

2.3 1.1 0 1 0 1. 1

' 5 '. 6 5 . 7 1 0

1.2 0 2 0

2.3 0 1 0

1.2 0 0 1 0 1. 1 0 1 0 1.1 0 1 0 1.1 1 0

1.2 0 1 1

1.2 1.1 0 1

0 .o 1.1 0 1 0 1.1 2 4

2 . 3 ' 6 0 1 0 1.1 0 1 0 1. 1 0 1 0 1.1 0 1 0 1. 1 0 2 0 2.3 1 0

1.2 0 1 1

1 .2 1.1

0 1 0 1. 1 1 0

1.2 0 0 1 0 1.1

20 30 1 6 (16.5) 21 (22.3)


The severity of the adverse events and relationship to treatment was

assessed as follows:

Overall, the severity of adverse events in the Fucidin tablets group was

13 "mild" and 7 "moderate", while in the Ciproxin tablets group severity

was 16 "mild", 11 "moderate" and 3 "severe". There was no statistically

significant difference in the severity of the adverse events between the two

treatment groups (p=0.45) .

In the Fucidin group, the relationship to treatment was assessed as

"unlikely" in 3, "possible" in 10 and "probable in 7 patients.

In the Ciproxin group, the relationship to treatment was assessed as

"unlikely" in 13, "possible" in 1 0 and "probable" in 7 patients.

For data in individual patients, see Appendix II, Tables II. 18 - 11.20.

16.7.1.4 Adverse events Causing/Contributing to Withdrawal from Study

Medication

One patient withdrew from active treatment because of an unacceptable

adverse event; patient- (Fucidin tablets) experienced nausea and

dizziness.

17 COMPLIANCE WITH GOOD CLINICAL PRACTICE

This study complied with the general principles of Good Clinical Practice,

as drawn up in the European Community Commission Guideline 3/3976/88

(as of July, 1991).


18 DISCUSSION

This study compared the efficacy and tolerability of up to 10 days

treatment with Fucidin tablets 250 mg bd and Ciproxine tablets 250 mg bd

in patients with skin and soft tissue infection. Overall, both treatments

were similarly highly effective clinically.

The study was conducted in the United Kingdom and involved 32 centres.

The protocol required 180 patients to be recruited and this was achieved

(1 02 Fucidin tablets, 97 Ciproxin tablets). Two patients were protocol

violators, as they were younger than the age specified in the protocol.

However, they were included in the analysis.

Baseline evaluation showed that overall both treatment groups were well

balanced in respect of age and sex distribution, type of lesion and the

severity of the signs and symptoms of the infection and in the proportions

of patients with infection due to S.aureus and/or beta haemolytic

streptococci.

Eight patients provided no data and were, therefore, excluded from the

efficacy analyses. An intention to treat analysis was performed on 191

patients in respect of the Primary Efficacy Criterion.

A further five patients who attended for follow-up outside the time window

specified in the protocol were excluded from the Efficacy Population, .

which comprised 94 patients given Fucidin tablets and 92 patients given

Ciproxine tablets.

Overall, both treatments were similarly effective clinically. At the end of

treatment, the proportion of patients 'cured' or 'improved' was 87.2% for

Fucidin tablets and 91.3% for Ciproxin tablets in the efficacy population

analysis (86.6% and 91 .5%, respectively in the 'intention to treat' analysis).


The clinical efficacy of Fucidin tablets 250 mg twice-daily recorded

in this study is similar to that observed previously. Carr et al reported

a cure rate (success plus improvement) of 75.5% (4) and Nordin and

Mobacken using similar response criteria found a cure rate of 68.9%

(6).

Despite the similar overall efficacy of Fucidin and Ciproxin, there

was a statistically significant difference between them in the reduction

in the score for severity of lesion (p=0.01) . The difference was in

favour of Ciproxin. No significant differences between treatments

were seen in the improvement in scores for lesion

pain,redness,heat,oedema or discharge.Therefore, it is unlikely that

this minor difference in the assessment of response is of any real

clinical relevance.

Both treatments proved to be of similar bacteriological efficacy.

Bacteriological success was recorded in 32 (86.5%) of 37 patients

with a proven infection given, Fucidin tablets and in 40 (90.9%) of 44

patients with a proven infection, given Ciproxin tablets.

Previous studies employing a similar Fucidin tablet dosage have

used different criteria when assessing efficacy in bacteriologically

proven infection so it is not possible to compare the results seen in

this study. However, the bacteriological efficacy observed in this

study is comparable to that reported previously with doses of 1 000 -

1500 mg daily in patients with skin and soft-tissue infections (7 ,8).

Adverse events were recorded in 16 (16.5%) patients given Fucidin

tablets and in 21 (22.3%) patients taking Ciprofloxin tablets. The

majority of adverse events were mild to moderate; there was one

withdrawal due to an adverse event, a patient taking Fucidin tablets,

who experienced nausea and dizziness. The frequency of adverse

events reported previously in similar patients given Fucidin tablets at


the identical daily dosage was 17.8% (4) and 12.4% (6). Therefore

it would appear that minor adverse events are likely in 1 0-20% of

patients with skin and soft tissue infection given Fucidin 250 mg

twice-dai ly for 5-1 0 days.

19 CONCLUSION

Fucidin tablets 250 mg twice-daily and Ciproxin tablets 250 mg

twice-daily for 5-10 days. were similarly highly effective in treating

patients with skin and soft tissue infections.


20 REFERENCES

1. Harding J W, Knudsen E T

Flucloxacillin in the treatment of skin and soft tissue infections.

Practitioner (1970); 205 : 801

2. Verbist L

The antimicrobial activity of fusidic acid.

Journal of Antimicrobial Chemotherapy (1990); 25 Suppl B : 1

3. Barry A L, Thornsberry c, Jones R N

Evaluation of teicoplanin and vancomycin disk susceptibil ity

tests.

Journal of Clinical Microbiology (1986); 23 : 100

4. Carr WD, WallAR, Georgala-Zervogiani S, et al

Fusidic acid tablets in patients with skin and soft tissue

infection: a dose finding study.

European Journal of Clinical Research (1994); 5: 87.

5. Licitra CM, Brooks RG, Sieger BE

Clinical efficacy and levels of ciprofloxacin in tissue in patients

with soft tissue infection.

Antimicrobial Agents and Chemotherapy (1987); 31 : 805

6. Nordin P, Mobacken H.

A comparison of fusidic acid and flucloxacill in in the treatment

of skin and soft - tissue infection.

European Journal of Clinical Research (1994); 5:97

7. Porter lA, Wilson JSP.

Staphylococcal infections treated with fusidic acid in nurses.

Lancet (1963); 658

8.


Schumer W, Abtahi H.

Sodium fusidate in surgical wound infections.

American Journal of Surgery (1968); 115: 527

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