by The Execare Working Group
Disclosure: The 15 investigators who conducted the study report no relevant conflicts of interest. Contributors to the article, Drs. Latha, Shantala, and Dhawan, and Mr. Krishnanand and Mr. Thangasaravanan are currently employees of Dr. Reddy’s Laboratories Ltd., India. Dr. Binny Krishnankutty is a former employee of Dr. Reddy’s Laboratories Ltd. and currently has no conflicts of interest. Dr. Reddy’s Laboratories Ltd., India, provided support for this study.
Abstract
Objective: The authors aimed to document the real-life performance of halometasone 0.05% w/w cream in day-to-day practice through this multicenter, open-label, Phase 4 study in India. Methods: The authors enrolled 302 eligible patients either with acute or chronic eczema and treated them with halometasone 0.05% cream daily. Efficacy variables (i.e., investigator’s global assessment and pruritis severity score) were assessed at baseline and end of study. Physician’s global evaluation of efficacy was assessed at the end of treatment. Treatment response was assessed as either a success or failure based on improvement in investigator’s global assessment. Results: Study population included 61.26 percent male and 38.74 percent female participants, with the average age being 30.79±14.52 (mean±SD) years. Contact dermatitis was seen in 22.52 percent of the study population. The mean (±SD) duration of primary diagnosis was 461.45 days (±854.67). The most common type observed was “chronic” (60.49%), followed by “acute” (24.83%) conditions. Levocetirizine was the most commonly prescribed concomitant medication (31.39%), followed by emollients (15.33%). The mean and median duration of therapy was 18.50 and 25 days, respectively. Post therapy, there was a significant (p<0.0001) reduction in the severity of eczema and pruritus. Therapeutic success defined as cure (85.43%) and improvement (11.26%) was seen in 96.69 percent of patients. Physician’s global evaluation of efficacy showed that in 96.67 percent of patients, treatment produced either an “excellent” (31.67%) or “good” (65.00%) response. Adverse events were reported in only 0.99 percent (3/302), with erythema being most common (0.66%). Conclusion: Halometasone is efficacious with a good safety and tolerability profile in patients with noninfected corticosteroid-responsive eczematous dermatoses. (J Clin Aesthet Dermatol. 2013;6(11):39–44.)
Treatment of eczema poses a great challenge to physicians. Currently available therapeutic agents only have the ability to alleviate symptoms. Treating eczema is difficult as the exact cause cannot be determined clinically because two or more varied forms of eczema can present in the same patient at a time. With many treatment options available, pharmacological and nonpharmacological approaches are routinely followed in clinical practice. Most forms of eczema require emollients, proper use of topical corticosteroids, immunosuppressive agents, and phototherapy along with diet and lifestyle modifications.
Topical corticosteroids have remained the mainstay in the treatment of eczema for more than three decades and are still the preferred agents in the symptomatic management of this clinical entity. Topical corticosteroids have been classified as mild (hydrocortisone acetate 1%, dexamethasone 0.01–0.1%), moderate (clobetasone 0.05%, triamcinolone 0.02%, fluocinolone 0.005%), potent (betamethasone diproprionate 0.05%, hydrocortisone 17-butyrate 0.1%, halometasone 0.05%), and very potent (halcinonide 0.1%, clobetasol proprionate 0.05%) agents according to British National Formulary.1 Halometasone is a potent (Group III) corticosteroid for topical application.
Halometasone cream 0.05% is indicated for the symptomatic relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. It exerts its actions through anti-inflammatory, anti-exudative, anti-epidermoplastic, anti-allergic, and anti-pruritic properties.[3] Clinical studies of halometasone have targeted all types of dermatitis (atopic dermatitis, contact dermatitis, seborrheic dermatitis), including acute or chronic eczematous dermatitis and psoriasis. Halometasone has been found to be equally effective in comparison to other moderately potent steroids. It was well tolerated, with a good safety profile, and without any local or systemic adverse events. Early onset of therapeutic effects was noted in patients treated with halometasone cream compared to those receiving treatment with comparative preparations.[4]
This study was conducted to document the actual in-practice usage and performance of halometasone 0.05% w/w cream in day-to-day clinical practice in India.
Methods
Study design. This study was an open-label, prospective, multicenter, post-marketing surveillance study.
Study population. Patients with noninfected eczematous dermatoses who were eligible for treatment with halometasone 0.05% w/w cream were enrolled in the study. Halometasone 0.05% cream is indicated for the relief of inflammatory and pruritic manifestations of noninfected corticosteroid-responsive dermatoses, such as eczema.
A total of 300 patients were planned to be observed from all over India, but two patients were lost to follow up, so 302 patients were included in this study. Each participating doctor reported his or her clinical experience after treating the patients with halometasone 0.05%.
Halometasone 0.05% cream was applied topically as a thin layer over the affected area of skin once or twice daily as required, depending on the clinical condition; rubbing gently over the site of application was advised. The duration of treatment was calculated, and concomitant medications were continued unless they were to be avoided as per the protocol or contraindicated in the prescribing information.
All patients were followed up until the treatment goals were achieved. During each follow-up visit, efficacy parameters were evaluated to ensure the achievement of the therapeutic goals.
Patients were advised to apply halometasone 0.05% cream daily in the prescribed dose. Eczema severity (investigator’s global assessment [IGA] scale) and pruritus severity were assessed for efficacy evaluation. These efficacy assessments were initially done at the time of inclusion (baseline) of patients in the study and subsequently at the end of the study. Dermatologists did a global evaluation of the efficacy at the end of treatment, and the treatment response was assessed by considering the improvement in IGA scale.
Efficacy variables were IGA, severity of pruritis score, and physician’s global evaluation of efficacy. Efficacy was analyzed based on the improvement in severity of pruritis, which was assessed by a four-point (0–3) scale, reduction in eczema severity grades assessed by the IGA scale compared to that at baseline.
The IGA improvement at the end of the study was further dichotomized into “success” and “failure.” Success included two classes: “cure” and “improvement.” Cure was defined as either attainment of either Grade 0 or Grade 1 at the end of the study or reductions by two or more grades in IGA scale at the end of the study compared to the grades in IGA scale at baseline. Improvement was defined as reduction of one grade in IGA scale at the end of the study compared to baseline. Failure was defined as either an increase in IGA grade or no change in the IGA grade at the end of the study compared to baseline.
Safety analysis. All subjects receiving at least one application of the drug were evaluated for safety. Medical conditions/diseases present before starting the study drug were considered adverse events (AEs) only if they worsened after starting the study drug.
The occurrence of AEs was sought by nondirective questioning of the patient at each visit during the study. Adverse events were also detected through history, physical examination, or when the patient volunteered to report during or between visits.
Significant findings or illnesses that were present prior to the study were considered co-existing illnesses, and significant findings or illnesses that occurred after the study drug administration that met the definition of AEs were recorded as the AEs. All AEs, whether previously known or not, were recorded with their description, intensity, action taken, duration, outcome, and opinion about causal relationship to halometasone.
Statistical analysis. The data from all participating doctors were pooled for analysis. After accounting for dropouts and exclusions, all evaluable patients were analyzed for demographic features, co-existing conditions, concomitant treatments if any, and the duration of current diagnosis. Severity of pruritis score and IGA were analyzed using Wilcoxon signed-rank test. Investigator’s global assessment of efficacy was analyzed descriptively and data was reported in frequency counts. Cure, improvement, and failure were assessed as per the criteria defined in the protocol, and results were presented in frequency counts.
All enrolled patients were analyzed for safety parameters. Adverse events were analyzed with respect to incidence, nature, intensity, action, relation to study drug, and outcome. Analyses were done using the licensed Statistics/Data Analysis software StataTM version 10 (Stata Corp, College Station, Texas, ©1984–2008).
Results
The study included 302 patients from 15 centers, 61.26% (n=185) and 38.74% (n=117) of whom were male and female participants, respectively. Of the 302 patients, 300 (99.34%) completed the study and two (0.66%) were lost to follow up. Primary diagnosis is shown in Table 1.
Age of the patients ranged from 1 to 90 years. The average age was 30.79±14.52 (mean±SD) years. The median age was 30 years with a 95-percent confidence interval of 29.15 to 32.44.
Of the 302 cases, 68 (22.52%) had contact dermatitis. The mean (±SD) duration of primary diagnosis was 461.45 (±854.67) days with the median duration of six months (180 days). The most common type observed was “chronic” (60.49%), followed by “acute” (24.83%).
Overall, there were 49 co-existing illnesses seen in 45 patients (14.90%), 20 (44.44%) of whom had diabetes mellitus and 15 (33.33%) of whom had hypertension at baseline. Concomitant medications were administered to 45.36 percent (n=137) of patients along with the study drug. Levocetirizine was the most commonly used concomitant medication (n=43, 31.39%), followed by emollients (n=21, 15.33%). Eight patients (5.84%) received methyl prednisolone, six of whom received it for 5.3 days. Two patients received methyl prednisolone for a period of one month, one of whom had a history of nummular dermatitis and the other had stasis dermatitis. Data regarding the treatment duration was available from 264 patients. The duration could not be calculated in 38 patients; among these, 36 patients continued to apply halometasone at the end of the study and two patients were lost to follow up. The mean and median duration of therapy was 25 days and 18.50 days, respectively.
Efficacy. There was a significant (p<0.0001) reduction in the severity of eczema and pruritus after therapy. Pre- and post-treatment changes are shown in Table 2.
Very severe eczematous dermatitis was present in 29 patients (9.60%) at baseline. However, with treatment, eczema severity in these patients was noted to be “normal” in five patients, “almost clear” in 12 patients, “mild” in 11 patients, and “moderate” in one patient. Similarly, among the 83 patients (27.48%) with “severe eczematous dermatitis,” eczema severity became “normal” in 25 patients, “almost clear” in 38 patients, “mild” in 10 patients, and “moderate” in 10 patients. There were 150 (49.67%) patients with “moderate” eczema. At the end of treatment, four patients remained with “moderate” eczema, 30 became “normal,” 91 became “almost clear,” 24 had “mild,” and one patient was lost to follow up. Eczema severity worsened in only one patient with treatment. This patient had “mild” eczema at the beginning of treatment, but developed “moderate” at the end of treatment.
“Severe” pruritus was present in 137 patients (45.36%) at baseline. Of these patients, 72 had no itching, 57 had mild itching, six had moderate itching, and one continued to have severe itching at the end of treatment. One patient was lost to follow up. Similarly, moderate itching was present in 116 patients (38.41%) at baseline, which remained unchanged in eight patients at end of therapy. However, at the end of therapy, there was no itching in 81 patients, mild itching in 26 patients, and one patient was lost to follow up.
The improvement in IGA severity of eczema was recorded as means of assessing the treatment response. Therapeutic success was noted in 96.69 percent of patients, 85.43 (n=258) percent in whom cure was observed, and 11.26 percent (n=34) in whom improvement was observed. The treatment was found to be a failure in only 2.65 percent of patients. IGA improvement could not be ascertained in two patients, as they were lost to follow up.
The physician’s global evaluation of efficacy was recorded at the end of treatment to reflect the dermatologists’ perception of efficacy, which revealed that in 96.67 percent of patients, treatment produced either an “excellent” or “good” response (Figure 1).
Safety. Halometasone 0.05% was well tolerated in this study. Four AEs were reported in three patients, indicating that the incidence of reported AEs in the present study was only 0.99 percent (3/302 patients). Two patients were male and one was female.
Erythema was the most common AE reported (0.66%). Stinging and burning sensations were the other AEs reported. Causality assessment, done by the dermatologists, showed that in one patient, the erythema was unlikely due to halometasone. The other three AEs reported were possibly related to the halometasone. Table 3 provides details of AEs according to the relation to study medication.
Discussion
Corticosteroids have proven successful in the symptomatic management of both acute and chronic eczema, though not as curative agents. Halometasone, a moderately potent corticosteroid in clinical use in Western countries is relatively new in India. It is formulated such that the molecules are suspended in a microcrystalline form, in a slightly acidic hydrophilic oil-water emulsion, which accords well with the physiological acidity of the skin. Halometasone has proven to be safe and efficacious, inclusive of Indian populations,3 and this has been attributed to its structure (i.e., chlorine and fluorine atoms, the C1,2 double bond, and the free OH moiety in C11 increases the affinity and potency of the steroid).
Earlier studies have shown that it is effective, safe, and well tolerated among Indian patients with eczema.[3] Its efficacy in Chinese populations with eczema was studied by Huang et al5 and was found to be effective with few AEs.[5]
Yawalkar et al4 obtained satisfactory results with halometasone in 717 patients with noninfected acute eczematous dermatoses. Therapeutic effect was good to very good in 89.7 percent of these patients; these trials also showed that halometasone exhibited early onset therapeutic response than other comparators under study. Halometasone was well tolerated by these patients without any systemic effect and there were no reports of skin atrophy, which is usually associated with the topical use of corticosterioids.[4]
Clinical studies with halometasone compared to other topical corticosteroids have shown results in favor of the former. In a multicenter controlled study of 208 patients with acute eczematous dermatoses in Austria and Switzerland, halometasone 0.05% cream showed significantly superior clinical efficacy than betamethasone dipropionate 0.05% cream with an equal tolerability.[6] In comparison with prednicarbate 0.25% cream, halometasone 0.05% cream was found to be more efficacious. Tolerability was equal with both therapies and no undesired AEs were reported for both.7 In another study, efficacy rate was significantly greater with halometasone (991.3%) compared to mometasone furoate (71.7%), with a statistically significant difference in therapeutic index (86.79% vs. 74.37%).[5]
Long-term use of halometasone was studied in patients with chronic eczema, which exhibited a very satisfactory therapeutic efficacy and very good tolerability with halometasone therapy. AEs were reported in only two patients who had transient itching at the site of application. Neither skin atrophy nor any systemic effect due to the transcutaneous systemic absorption of halometasone was observed in this study, nor were any instances of contact skin allergy reported.[8]
Previous studies have shown a therapeutic success rate of 90 percent or more with halometasone.[3,6,9] A study by Jerajani et al[3] in 200 Indian patients showed that treatment with halometasone, on average, caused a reduction in eczema area and severity index (EASI) score of 60 percent and two grades in IGA eczema severity. Pruritus severity score was reduced on an average by two grades with rapid symptomatic relief. A more than 75-percent reduction in severity score was observed within one month of starting treatment. A similar reduction in IGA score by two grades was seen in the study described herein, but reduction in severity of pruritus was less (1.87).
Efficacy and safety of halometasone in the pediatric population was also evaluated in various clinical trials. Herz et al10 have obtained a very good efficacy response in the majority of the children treated in the study with an early onset of therapeutic effect (within 6 days of starting the treatment) in 77.1 percent of patients. All children (including 18 infants) tolerated halometasone well without any AEs, either due to local skin intolerability or systemic absorption. Cosmetic acceptability and ease of application were considered “good” by 98 percent of patients.[10] Effect of halometasone in noninfected eczematous dermatoses in 60 children was studied by Blum et al.[11] In this study, overall cure rate was 74.3 percent; 90 percent showed good or very good results. Early cure within 20 days was seen in 62 percent with 78.3 percent showing early onset of effect within three days of receiving halometasone. Halometasone was well tolerated by this study population with a good safety profile.
In our study, 302 male and female patients were enrolled, with a predominance of male subjects (61.26%). Although the age of patients ranged from 1 to 90 years, there were only two geriatric patients. Contact dermatitis (22.52%) was the most common condition for which halometsone 0.05% cream was prescribed. Among patients with co-existing illnesses, 44.44 percent (n=20) of patients had diabetes mellitus and 33.33 percent had essential hypertension (n=15). Of these 302 patients, 257 (85.10%) had no co-illnesses, 41 (13.58%) had one co-illness, four (1.32%) had two co-illnesses, and no patients had three co-illnesses at the time of starting treatment with halometasone cream. It is interesting to note that 45.36 percent (137/302) of the study population was getting at least one concomitant medication. Only 10.60 percent (32/302) of patients were getting more than one concomitant medication. Among concomitant medications, levocetirizine was the most commonly prescribed.
The mean duration of therapy was 25 days. Efficacy analysis showed a significant reduction in eczema and pruritus severity with treatment. Additionally, overall success rate was more than 96 percent. This indicates that halometasone performed well in the clinical scenario and achieved the desired beneficial effects.
The authors observed erythema and stinging and burning sensations in the current study. Most of the AEs were of mild intensity and did not warrant discontinuation of the drug during the treatment period. The AEs that occurred subsided consecutively after patients were given symptomatic treatment or without any treatment. Symptomatic treatment was provided to the patient with stinging and burning sensations.
There is a paucity of data on halometasone use in the Indian population. These are the only studies available on the safety and efficacy of halometasone. Jerajani et al3 reported no serious adverse events (SAE) during the entire study period. Perilesional hypopigmentation was the most common AE (6%) in this study, and 94.59 percent of all AEs were either mild or moderate in severity. Of these AEs, 69.24 percent resolved or improved in due course. Similarly, the authors of the current study did not encounter any SAEs in their study.
Halometasone is relatively new in India and has been shown to be safe and effective in the Indian population. The authors recommend larger, comparative studies in this patient population to establish its place in actual clinical practice.
Conclusion
The results of this study indicate that halometasone is efficacious and has a good safety and tolerability profile in patients with noninfected corticosteroid-responsive dermatoses. Additionally, no SAEs were observed in the study.
Acknowledgment
The authors would like to acknowledge the Execare Working Group, which includes the following investigators who conducted the study: Dr. Sanjay Jadhav, Mumbai, Maharashtra, India; Dr. Satish Srivastava, Bangalore, Karnataka, India; Dr. Guru Prasad P. Visakhapatnam, Andhra Pradesh, India; Dr. Uday Kumar, Bhilai, Chhattisgarh, India; Dr. Sampriti Nanda, Kolkata, West Bengal, India; Dr. Sudip Das, Kolkata, West Bengal, India; Dr. Vijayakumar K. Chalakudy, Kerala, India; Dr. Tiken Singh A. Churachandpur, Manipur, India; Dr. Kharangate V N, Margao-Panaji, Goa, India; Dr. Abdul Gafoor K M, Kerala, India; Dr. Nitin Verma, Delhi, India; Dr. Amit Luthra, Delhi, India; Dr. Prasad C K, Kerala, India; Dr. Padmaja M. Hyderabad, Andhra Pradesh, India; Dr. Jindal V K Karnal, Haryana, India.
For their contribution to this study, the authors would also like to acknowledge Dr. M.S. Latha, Deputy Manager, Global Medical Affairs, Dr. Reddy’s Laboratories Pvt Ltd., Hyderabad, India; Dr. Binny Krishnankutty, Former Manager, Global Medical Affairs, Dr. Reddy’s Laboratories Pvt Ltd., Hyderabad, India; Dr. Shantala Bellary, Assistant Manager, Global Medical Affairs, Dr. Reddy’s Laboratories Pvt Ltd., Hyderabad, India; Mr. P. Krishnanand, Junior Manager, Global Medical Affairs, Dr. Reddy’s Laboratories Pvt Ltd., Hyderabad, India; Mr. P. Thangasaravananan, Group Product Manager, Dr. Reddy’s Laboratories Pvt Ltd., Hyderabad, India; and Dr. Shilpi Dhawan, Manager, Global Medical Affairs, Dr. Reddy’s Laboratories Pvt Ltd., Hyderabad, India.
The authors acknowledge the support of their marketing team who coordinated the study. They thank Drs. Julius Vaz and Akhilesh Sharma for their guidance, Mr. Mallavarapu Mohan for his assistance in data entry, and Mr. Prabhakar Rao for his assistance in the literature search.
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