SKIN January 2019 Volume 3 Issue 1 Copyright 2018 The National Society for Cutaneous Medicine 7 ORIGINAL RESEARCH A Novel Hydrocortisone-Ethanol Gel Ointment for Treating Atopic Dermatitis in Children: A double blind, randomized, controlled clinical trial Dale L Pearlman, MD1 1Orliderm Inc., Menlo Park, CA Atopic dermatitis (AD) affects 17% of children1 and 7% of adults in the USA2. Moderate to severe AD disrupts the lives of children and their families3. Current therapies’ success is limited by low efficacy (40-60%), long duration of treatment (3-12 weeks4,5) and parental concerns about treatment safety. They worry antibiotics may cause antibiotic resistant bacteria6. More than 50% of patients (or their caregivers) turn to alternative (complementary) therapies because of these concerns7. A key component of AD therapy is directed at suppressing bacteria. Staphylococcus aureus is a primary trigger of the inflammatory changes in AD. Patients with atopic dermatitis are colonized by extremely high levels of Staphylococcus aureus8. The patients have elevated levels of IgE directed INTRODUCTION Importance: Current treatments for moderate to severe atopic dermatitis (AD) in children are limited by incomplete efficacy, long time to benefit, and parental concerns about safety. This study evaluated a novel ointment for treating AD containing 1% hydrocortisone and 17% dispersed ethanol gel micro bubbles. Observations: 20 children with moderate to severe AD participated in a one-week double blind, randomized, and controlled clinical trial. They were randomly assigned to apply BID either an ointment with 1% hydrocortisone ointment (HC) or a novel ointment containing 1% hydrocortisone and dispersed ethanol gel droplets (HC-EG). The primary endpoint was superiority of HC-EG over HC ointment in SCORAD score improvement during therapy. A secondary endpoint was improvement in pruritus score during therapy. Both the primary and secondary endpoints were reached in this study. SCORAD score improved 74% on average with HC-EG ointment vs 41% with HC ointment (p=.02). Pruritus score improved 68% on average with HC-EG ointment vs 37% with HC ointment (p=.009). No toxicity requiring stopping therapy was observed in either treatment group. Conclusions and Relevance: In this small controlled study HC-EG ointment was superior to HC ointment both in improving visible rash and pruritus of AD. Parents felt HC-EG ointment was safe because it contains no prescription corticosteroids, prescription immunosuppressants, or antibiotics. Independent, larger studies would be a next step in evaluating further this new way to treat AD. ABSTRACT SKIN January 2019 Volume 3 Issue 1 Copyright 2018 The National Society for Cutaneous Medicine 8 against staphylococcal cell surface proteins9. Oral antibiotics, topical antibiotics, and bleach baths are often used to treat AD10. A novel antibacterial strategy could be topical application of alcohol-based hand sanitizer gel (ABHSG). Such gels contain 62-70% ethanol and are reported to be 99.999% effective against staphylococci11. Children under the age of six years old may use ABHSG’s if an adult supervises the application12. One cannot directly apply ABHSG to eczematous skin because of stinging. While there is evidence that ethanol in solution with hydrocortisone does enhance delivery of the hydrocortisone across the skin13, we could find no report in the literature when the ethanol is in the form of gel microbubbles dispersed in an ointment. To use ABSHG in topical therapy of AD we needed to develop a new topical formulation which would prevent stinging, block possible absorption of ethanol and hydrocortisone across eczematous skin, and avoid exacerbating skin dryness. The novel ointment contains the ethanol in the form of dispersed ABHSG microbubbles. The dispersion minimizes stinging and absorption. Skin dryness is avoided by using an ointment vehicle and because ABHSG contains moisturizers. Trial design This is a double blind, randomized, controlled trial design in which neither the Principle Investigator (PI), patients, nor parents know whether HC or HC-EG ointment is used. Patients are randomly assigned to a treatment group. Patients have a pre-therapy visit and an end-therapy visit. At each visit the PI determines a modified SCORAD score based on surface area affected and the degree of redness, scaling, oozing/crusting, swelling, and excoriations. At each visit the parents score the pruritus in the preceding 24 hours on a 0 to 10 point scale. At the end- therapy visit parents are asked about local stinging with treatment, any change in skin color (blanching) where the ointment is applied, and signs of ethanol intoxication. Participants Written informed consent to participate and for photographs was obtained from the parents of the children participating. All photographs maintain the anonymity of the participant. No compensation was paid for participation. An independent IRB function was provided by a group of pediatricians at a local multispecialty clinic. They reviewed and approved the study design. The principles outlined in the Declaration of Helsinki were followed. Criteria for entry: 1) At the initial visit crusted and oozing lesions on some or all of these areas: trunk, limbs, and face. 2) History of inadequate response to prior used over-the counter ointments as well as to one or more of the following prescription medications: topical corticosteroids, topical calcineurin inhibitors, and topical and oral antibiotics. 3) Age 3 months and older. Intervention The test ointments were pre-formulated for dispensing. a) HC ointment: Aquaphor® and corticosteroid 2.5% ointment in a ratio to yield 1% concentration of hydrocortisone. b) HC-EG ointment: Aquaphor®, corticosteroid 2.5% ointment, and 70% METHODS SKIN January 2019 Volume 3 Issue 1 Copyright 2018 The National Society for Cutaneous Medicine 9 ethanol gel in a ratio to yield 1% hydrocortisone and 17% by volume ethanol gel. Treatment Patients applied at home a saturating dose of the assigned ointment to the affected areas BID for a week. A “saturating dose” meant apply ointment until no more will absorb and then wipe off the excess with a paper towel. During the clinical trial the only allowed topical treatment was the assigned ointment. The only oral therapy allowed was prn use of prior used oral antihistamines. Outcomes The primary endpoint was superiority in average SCORAD improvement in patients treated with HC-EG ointment vs HC ointment. Secondary endpoints were: 1. Pruritus: superiority of HC-EG ointment vs HC ointment in average reduction in pruritus score. 2. Enhanced corticosteroid absorption: lack of difference in skin blanching between the two treatment groups. 3. Adverse effects local: stinging at time of application 4. Adverse effects systemic: symptoms of ethanol intoxication: lack of difference in symptoms of mental confusion, slurred speech, and difficulty walking between the two groups. 5. Parental concern about the safety of the medication. Recruitment 20 patients were recruited from the local pediatricians who had reviewed and approved the study protocol. All 20 patients were available at the initial and end therapy visit. Age ranged from 3 months to 12 years. Primary endpoint: Average SCORAD improved 74% in the HC- EG ointment treated patients vs 41% in the HC ointment treated patients. This is a statistically significant difference with p=.02 (Table 1). These data are especially interesting in that they demonstrate that HC-EG ointment is better at treating more severe cases than HC ointment is at treating milder cases. By random assignment in this study, the patients Table 1: Change in SCORAD score in 20 patients with moderate to severe atopic dermatitis randomly assigned to apply for one week twice daily either 1% hydrocortisone (HC) ointment or 1% hydrocortisone ointment-ethanol gel (HC-EG). Average SCORAD score 10 Patients using HC ointment 10 Patients using HC-EG ointment Pre-Treatment 28.9 42.1 End-Treatment 17.1 10.9 Average change Pre to End Treatment -40.8%* -74.2%* *Statistically significant different between HC and HC- EG ointment group p=0.02. Table 2: Change in pruritus score in 20 patients with moderate to severe atopic dermatitis randomly assigned to apply either for one week twice daily 1% hydrocortisone (HC) ointment or 1% hydrocortisone ointment-ethanol gel (HC-EG) ointment. Average Pruritus Score (0-10) 10 patients used HC ointment twice daily 10 patients used HC-EG ointment twice daily Pre-treatment 6.1 6.1 End-treatment 4.1 1.95 % improvement 37%* 68%* *Statistically significant different between HC and HC- EG ointment group p=0.009. RESULTS SKIN January 2019 Volume 3 Issue 1 Copyright 2018 The National Society for Cutaneous Medicine 10 that used HC-EG ointment turned out to be a more severe group than the group who received HC ointment. At entry into the study the patients assigned to HC-EG ointment had a worse average SCORE than the HC ointment group (42.1 vs 28.9). Despite starting with a worse average SCORAD at entry, the HC-EG ointment cohort ended treatment with a better average SCORAD score at the end of therapy (SCORAD of 10.9 with HC-ED ointment vs 17.1 with HC ointment) For examples of the degree of improvement with the HC-EG vs HC ointment see Figure 1 and Figure 2. Secondary endpoints: Pruritus: Average score was 68% improved in the HC-EG ointment treated patients vs 37% in the HC ointment treated patients. This is a statistically significant difference with p=0.009 (Table 2). Stinging: One of ten of the HC-EG ointment treated patients experienced mild to moderate stinging when the ointment was applied. The remaining 9 patients and all the HC ointment patients reported no stinging. The stinging was relieved and the patient continued treatment by first applying a layer of Aquaphor® and then the ointment for the first two days of therapy. After day two of therapy no further pre-application of Aquaphor was needed. Local corticosteroid effects via percutaneous absorption on eczematous skin: No patient in either cohort exhibited local blanching at the post-therapy examination or parent reported seeing blanching during treatment at home. Evidence of systemic ethanol effect via percutaneous absorption on eczematous skin: None of the treated patients in the study Figure 1: A patient with atopic dermatitis behind the knee randomized to treatment with HC ointment. A) Before treatment. B) After 1 week of HC ointment. Figure 2: Another patient with more severe atopic dermatitis behind the knee randomized to treatment with HC-EG ointment. A) Before treatment. B) After 1 week of 1% HC-EG therapy. A B A B SKIN January 2019 Volume 3 Issue 1 Copyright 2018 The National Society for Cutaneous Medicine 11 evidenced at end-therapy exam or was reported by parents during home therapy to have mental confusion, impaired balance, unsteady walking, or other signs of inebriation. Concerns of patients about the safety of the study medications: All said they felt safe and comfortable about the ingredients in the study ointments and using them as directed to treat the AD. Limitations of this study include the small sample size and the potential bias by the Principle Investigator due to conflict of interest. In this study we hypothesized that the dispersed ethanol gel microbubbles in the hydrocortisone ointment would increase efficacy by suppressing the eczematous skin’s staphylococcal population. While this study showed the anticipated increased clinical efficacy, the antibacterial basis for the improvement was not investigated in this trial. We did not measure the change in the staphylococcal biofilm population before and after treatment. Thus further study will be needed to assess evaluate this hypothesized mechanism of action. In these patients with moderate to severe AD, 1% hydrocortisone-ethanol gel (HC-EG) ointment was superior to 1% hydrocortisone ointment (HC) in both objective improvement and reduction in pruritus. Local irritation was minimal and easily managed. No systemic signs of ethanol intoxication occurred. Parents reported their preference for HC-EG because of its rapid efficacy and being free of prescription corticosteroids and antibiotics. This is significant as parental noncompliance due to safety concerns can interfere with treatment.14,15 Conflict of Interest Disclosures: The principle investigator and article author is the inventor and holds patents on this new technology. Funding: None. Corresponding Author: Dale L. Pearlman, MD Orliderm Inc. Menlo Park, CA md@dpearlman.biz Acknowledgements: Jade Marcos provided principle administrative support for conducting this study. Other members of my staff who also provided administrative support during this study: Valerie Santos, Gianna Panlasigui, Linda Vien, and Elana Naderzad, Harry Morewitz Ph.D. provided extensive review of the literature as well as analysis of the physical chemistry aspects of the formulation. Myra Morewitz provided editorial guidance in this manuscript. References: 1. Carbone A, Siu A, and Patel R, “Pediatric Atopic Dermatitis: A Review of the Medical Management”, Ann Pharmacother 2010;44:1448-58. 2. Silverberg JI and Greenland P, “Eczema and cardiovascular risk factors in 2 US adult population studies “, Journal of Allergy and Clinical Immunology, 2015(135) 3, Pages 721-728. 3. National Institute for Health and Care Excellence, “Atopic eczema in children: Management of atopic eczema in children from birth up to the age of 12 years”, www.nice.org.uk/nicemedia/pdf/CG057F ullGuideline.pdf (accessed2009 March 15) 4. Vernon HJ, Lane AT, and Weston W, “ Comparison of mometasone furoate 0.1% cream and hydrocortisone 1.0% cream in the treatment of childhood atopic dermatitis”, JAAD 1991;24:603-7. 5. Huang JT, Abrams M, Tlougan B, et al, Treatment of Staphylococcus aureus DISCUSSION mailto:DalePearlmanMD@Orliderm.com SKIN January 2019 Volume 3 Issue 1 Copyright 2018 The National Society for Cutaneous Medicine 12 Colonization in Atopic Dermatitis Decreases Disease Severity, Pediatrics 2009;123;e808. 6. Kojima R1, Fujiwara T, Matsuda A, Narita M, Matsubara O, Nonoyama S, Ohya Y, Saito H, Matsumoto K, Factors associated with steroid phobia in caregivers of children with atopic dermatitis, Pediatr Dermatol. 2013 Jan-Feb;30(1):29-35. 7. Simpson EL, Basco M, Hanifin J, A cross- sectional survey of complementary and alternative medicine use in patients with atopic dermatitis, Am J Contact Dermat. 2003 Sep;14(3):144-7. 8. Cho S-H, Strickland I, Boguniewicz M, et al. Fibronectin and fibrinogen contributes to the enhanced binding of S. aureus to atopic skin. J Allergy Clin Immunol 2001;108:269–74. 9. Zollner TM, Wichelhaus TA, Hartung A, Von Mallinckrodt C, Wagner TO, Brade V, et al. Colonization with superantigen- producing Staphylococcus aureus is associated with increased severity of atopic dermatitis. Clin Exp Allergy 2000;30: 994-1000. 10. Jennifer TH, Melissa A, Brook T, Rademaker, and Paller AS, “Treatment of Staphylococcus aureus Colonization in Atopic Dermatitis Decreases Disease Severity” Pediatrics. 2009 May;123 (5):2008-2217. 11. Hall TS, Wren MW, Jeanes A, and Gant VA, “A comparison of the antibacterial efficacy and cytotoxicity to cultured human skin cells of 7 commercial hand rubs and Xgel, a new copper-based biocidal hand rub”, Am J Infect Control. 2009 May;37(4):322-6. doi: 10.1016/j.ajic.2008.09.011. Epub 2008 Dec 31. 12. US Department of health and Human Services, Household products database, http://householdproducts.nlm.nih.gov/cgi - bin/household/brands?tbl=brands&id=70 05062 accessed 09/05/2015. 13. Liu P, Kurihara-Bergstrom T, Good, Cotransport of estradiol and ethanol through human skin in vitro: understanding the permeant/enhancer flux relationship, WRPharm Res. 1991 Jul;8(7):938-44. 14. Hon KL1, Kam WY, Leung TF, Lam MC, Wong KY, Lee KC, Luk NM, Fok TF, Ng PC, Steroid fears in children with eczema. Acta Paediatr. 2006 Nov;95(11):1451-5. 15. Kojima R1, Fujiwara T, Matsuda A, Narita M, Matsubara O, Nonoyama S, Ohya Y, Saito H, Matsumoto K, Factors associated with steroid phobia in caregivers of children with atopic dermatitis, Pediatr Dermatol. 2013 Jan-Feb;30(1):29-35.