13 August Fucidin-H vs. Hydrocortisone in Atopic Dermatitis.

Transcription

1 FUH9401DK 13 August 2002 Page 11 of108 2 SYNOPSIS Study code number FUH9401 DKStudy Study title Fucidin-H vs. Hydrocortisone in Atopic Dermatitis. Study Subtitle A comparative study of Fucidin-H cream (fusidic acid 2% + hydrocortisone acetate 1%) and Hydrocortisone cream (hydrocortisone acetate 1%) in children (4-17 yrs) with a flare-up of atopic dermatitis. A study using non-invasive bioengineering techniques. Study objective To compare the effect of Fucidin-H cream with that of Hydrocortisone cream in patients with a flare-up of atopic dermatitis with special emphasis on a) the severity of disease measured by bioengineering teclmiques and b) the quantity of Staph. aur. on the diseased skin. Study design A single-centre, prospective, randomised, double-blind, controlled, right-left comparative study of Fucidin-H cream applied twice daily on one arm and Hydrocortisone cream applied twice daily on the opposite arm for 14 days. The patients were assessed at baseline (day 0), day 2, 4, 7, and 14. Sample size Twenty-four patients will be included in the study in order to be able to demonstrate a clinically important difference between the two treatments in respect of reduction in transepidermal water loss. This document has been do,vnloaded from ''>''Ww.leo-pharma.com subject to the terms of use state on the 'vebsite. It contains data and results regarding approved and non-approved uses, formulations or treatment regimens, and it is provided for transparency and informational purposes only. The content doe.s not reflect the complete results from all studies related to a product. As a document of scientific nature it 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.

2 --- -~ Page 12 of August 2002 FUH9401DK Eligibility criteria Outpatients, 4-17 years of age, either sex with a diagnosis of atopic dermatitis defined according to criteria proposed by Hanifin and Rajka. The disease must be present on both arms and be in a stage of flare-up, lesions must be synunetric with uniform eczema. Females of child bearing potential must have a negative pregnancy test at visit 1 and must use an adequate method of contraception throughout the study period. Excluded are patients with impetigo or cutaneous herpes infection or widespread pruritic excoriation of the target lesions, patients treated with: 1) systemic corticosteroid within 8 weeks prior to visit 1, 2) UV radiation within 1 week prior to visit 1, 3) topical corticorsteroids within 1 week prior to visit 1, and patients who concurrently are participating in any other clinical study or who have previously been randomised in the present study. Patients are not permitted to receive any other treatment (topically or systemic) that can affect the course of the disease. Treatment of pruritus with antihistamine is allowed. Parents/legal guardians and patients (when appropriate) will give their signed information consent to join the study. Study drugs Fucidin-H cream containing 20 mg/ g fusidic acid and 10 mg/ g of hydrocortisone acetate. Hydrocortisone cream containing 10 mg/ g hydrocortisone acetate. The drugs will be applied twice daily for 2 weeks without occlusion to affected skin. Primary response criterion The two treatments will be compared with respect to reduction in Trans Epidermal Water Loss (TEWL) from baseline (visit 1) to a) end of treatment and b) each post-randomisation visit.

3 FUH9401DK 13 August 2002 Page 13 of108 Assessments Non-invasive bioengineering measurements including TEWL, skin colour, skin surface hydration, skin surface contour and skin thickening and oedema will be done at baseline and at each post-randomisation visit. The severity of the atopic dermatitis in the patient's target lesions will be assessed by investigator at baseline (visit 1). Furthermore, the investigator will assess the overall response to therapy at each post-randomisation visit. At all visits a microbiological assessment will be done including quantitative bacteriology. Adverse events will be elicited at all post-randomisation visits. Schedule of study procedures: Double-blind treatment Visit Day Medical history Randomisation Transepidermal water loss Additional non-invasive bioengineering measurements: Skin colour Skin surface hydration Skin surface contour Skin thickening and oedema Bacteriology Investigator. Oinical Signs/ symptoms Investigator: Overall efficacy assessment Pregnancy test Adverse events Supply of trial medication Collection of trial medication In female patients of child-bearing potential.

4 Page 14 of August 2002 FUH9401DK Patient population A total of 25 patients were recruited from a single Danish centre. Of these 24 were randomised to treatment with Fucidin-H on one arm and Hydrocortisone on the other arm. All the 24 randomised patients were analysed for efficacy and safety. Sixteen females (66.7%) and 8 males (33.3%) were randomised in the study. The mean age was 9.0 years (range 3 to 17). The mean duration of the atopic dermatitis was 6.7 years (range 1 to 16). Table 1 gives the investigator's assessment of the severity of clinical signs for atopic dermatitis - for each arm separately. Table 1: Investi_gator's clinical assessment of randomised patients at baseline (visit 1) Cli nical s ign of atopic dermatitis Severity Fuci d i n- H <n=24l pat:ienta ~ Hydrocortisone (n=24) pat:ient:s ~ E:rythema score Absent: Slight i nvol vement: Moderat:e involvement Sever e involvement All pat:ients Excoriation score Absent: Sl igh~ i nvol vement Moderate involvement severe involvement: Lichenification score Slight involvement Moderate involvement Severe involvement All pat:ients Scaling score Absent Slight involvement Moderate involvemen t Severe i nvolvement Serious d i scharge Absent Slight involvement Moderace involvement Th i ckness score Absent: Slight i nvolvement Moderate invol vement Severe i nvolvement l s ~ l ~

5 FUH9401 DK 13 August 2002 Page 15 of108 Efficacy results Non-invasive bioengineering measurements (including TEWL). The two treatments were not statistically significantly different regarding any bioengineering measurements of response, including the primary response criterion, TEWL (Table 2). Table 2: Percentage change in non-invasive bioengineering parameters from baseline to end o treatment (Intention-To-Treat o ulation) Type of non- i nvasive bioengineering measurements Fucidi n- H (n 24) Mean percent age change Hydrocor t i sone (n 24 ) Mean percentage change Treatment comparison (paired t-test ) Difference (95% Cil P-val ue TEWL Skin col our Skin surface hydration Skin t hickening I nflammatory oedema Skin surface contour (R:zp 111 vertical) ( to 6.3) p ( to 3.2) p ( t o 37. 0) p : ( 2.o to 9.6) p = ( to 31.4) p 0.39 ~9.8 ( t o 11.4) p = Table 2 contains the primary skin surface contour roughness parameter, RzorN vertical. Twelve skin surface contour parameters were measured and analysed. The results of the analyses are given in the main text of this report (Section 12.8). A total of 48 hypothesis tests regarding skin surface contour were performed (change and percentage change, respectively, at visit 2 and at end of treatment). Five of these resulted in P-values less than 0.05, but larger than These results might be type 1 errors in the significance tests. With any reasonable adjustment for multiplicity no difference between the two treatments reached statistical significance. Bacteriology Fucidin-H was statistically significantly (P = 0.031) superior to Hydrocortisone with respect to eradication of pre-treatment pathog~ns. Eight (89%) out of the 9 patients with pre-treatment pathogens at both sides had their pre-treatment pathogens eradicated on the Fucidin-H side. Two (22%) out

6 Page 16 of August 2002 FUH9401DK of the 9 patients had their pre-treatment pathogens eradicated on the Hydrocortisone side. Investigator's overall assessment of efficacy Seventeen (71 %) patients obtained 'marked improvement' or 'clearance' on the Fucidin-H side according to the investigator's overall efficacy assessments. Sixteen ( 67%) patients obtained 'marked improvement' or 'clearance' on the Hydrocortisone side. The difference between the treatments was not statistically significant (P = 1.00). The distribution of the investigator's overall assessment of efficacy at each treatment arm are given for each post randomisation visit in Table 3. Table 3: Investigator's overall assessment of efficacy at control visits (Intention-To Treat population) Via it Investi gatoris overal l assessment Fucidin-H (n:24) pat:.ient s t Hydrocort:.iaone (n: 24) pat:.ients % VISIT 2 Wor se No change Minimal i mpr ovement. Moderate i mprove ment Marked improvement Complet ely cleared Total VISIT 3 Worse No change Minimal improvement Moderate i mprovement Marked i mprovement completely c leared Total VISIT 4 worse Minimal improvement Moderate i mprovement Marked i mprovement Compl etely cleared Tot:.al VISIT 5 (END OP T~TMENT) Worse No change Minimal i mprovement Mode rate improvement Marked improvement. Complet:.ely cl eared Total l ll l o

7 FUH9401 DK 13 August 2002 Page 17 of108 Safety evaluation A total of 5 patients reported mild adverse events. Table 4: Adverse events listed by system-organ class 1 System-organ clas~ 1 Pucidin-H Hydrocortisone Not arm- Treatment treated treat ed a.r m dependent (n=24) comparison arm only only adverse (n 24) (n 24 ) event (no24) (McNemar's patients patients patients patients test) Skin and appendages disorders l 5 adverse Total number of events Total number of pat.ien t s ( %) 1 (4. 2) 1 (4. 2) 3 (12. 5) 5 ( 20.8) p = ) Cl assification according to the WHO Advers e Reaction Dictionary, 31. December ) Differ ent adverse event s withi n t he same class and involving t he same patient have been counted as one. A single patient could appear in mul tiple classes. Conclusion There was no statistically significant difference between Fucidin-H cream and Hydrocortisone regarding the effect measured by bioengineering techniques. Fucidin-H was statistically significantly (P = 0.031) superior to Hydrocortisone with respect to eradication of pre-treatment pathogens. Fucidin-H was not statistically significantly superior to Hydrocortisone regarding the investigator's overall assessment of efficacyr