Efficacy of Secukinumab in the Treatment of Moderate to Severe Plaque Psoriasis in the North American Subgroup of Patients: Pooled Analysis of Four Phase 3 Studies.

INTRODUCTION: Demographic and disease characteristics may impact response to psoriasis therapies. The objective of this study is to explore the safety and efficacy profile of secukinumab in North American (NA) versus non-NA patients with moderate to severe psoriasis. METHODS: Data were pooled from four phase 3 studies of secukinumab. Secukinumab (300 and 150 mg) was administered at baseline, weeks 1, 2, and 3, then every 4 weeks from week 4 to 48. RESULTS: Peak efficacy was observed at week 16 in NA and non-NA patients with secukinumab 300 mg and secukinumab 150 mg, and disease clearance was maintained to week 52. At week 52 with secukinumab 300 mg, Psoriasis Area and Severity Index (PASI) 90/100 response was achieved by 62.9%/37.9% of NA patients, respectively, and 70.2%/42.0% of non-NA patients, respectively. At week 52 with secukinumab 150 mg, PASI 90/100 response was achieved by 30.9%/17.5% of NA patients, respectively, and 53.9%/26.9% of non-NA patients, respectively. Response to secukinumab was rapid, and 50% reduction in mean PASI was achieved in both groups after 2.9 weeks with secukinumab 300 mg and 3.7 weeks with secukinumab 150 mg. CONCLUSION: Despite differences in baseline characteristics, the efficacy and safety of secukinumab were similar among NA and non-NA patients. FUNDING: Novartis Pharma AG. Plain language summary available for this article.

The effect of secukinumab on moderate-to-severe scalp psoriasis: Results of a 24-week, randomized, double-blind, placebo-controlled phase 3b study.

BACKGROUND: Moderate-to-severe scalp psoriasis has not been evaluated in prospective trials of patients without moderate-to-severe body psoriasis. OBJECTIVE: Evaluate the efficacy and safety of secukinumab in moderate-to-severe scalp psoriasis. METHODS: In this 24-week, double-blind, phase 3b study, 102 patients were randomized 1:1 to subcutaneous secukinumab 300 mg or placebo at baseline, weeks 1, 2, and 3, and then every 4 weeks from week 4 to 20. The primary efficacy variable was 90% improvement of Psoriasis Scalp Severity Index (PSSI 90) score from baseline to week 12. RESULTS: At week 12, PSSI 90 (secukinumab 300 mg vs placebo, 52.9% vs 2.0%) and Investigator's Global Assessment modified 2011 scalp responses of 0 or 1 (secukinumab 300 mg vs placebo, 56.9% vs 5.9%) were significantly greater with secukinumab 300 mg than placebo (P < .001 for both). In addition, significantly more patients achieved complete clearance of scalp psoriasis at week 12 with secukinumab 300 mg than placebo (35.3% vs 0%; P < .001). The median time to 50% reduction in PSSI score was 3.29 weeks with secukinumab 300 mg. The safety profile of secukinumab was consistent with previous phase 3 studies. LIMITATIONS: There was no active comparator arm. CONCLUSION: Secukinumab is efficacious and well-tolerated for patients with extensive moderate-to-severe scalp psoriasis.

Secukinumab improves scalp pain, itching, scaling and quality of life in patients with moderate-to-severe scalp psoriasis.

INTRODUCTION: Scalp psoriasis adversely affects patients' lives and is often resistant to treatment; however, it has not been a major focus of a clinical study. This analysis assessed the effect of secukinumab on patient-reported outcomes (PRO) of scalp psoriasis. METHODS: A randomized, double-blind, placebo-controlled, multicenter study was conducted in 102 adult patients with moderate-to-severe scalp psoriasis. Patients were randomized 1:1 to secukinumab 300 mg or placebo. Patients rated their scalp-related pain, itching and scaling using a 0-10 numeric rating scale (higher scores indicate greater severity). Scalp dermatitis-related quality of life (QOL) was assessed at baseline and then every 4 weeks using the Scalpdex. Analysis of covariance models examined PRO effect up to 12 weeks. RESULTS: Baseline scalp pain, itching and scaling mean (SD) values were 3.1 (3.00), 6.7 (2.60) and 7.3 (2.02) and similar for both treatment groups. At week 12, patients treated with secukinumab reported greater reduction in scalp pain (-1.98 vs. 0.61), itching (-4.07 vs. -0.04) and scaling (-5.76 vs. -0.95) as well as greater improvements in Scalpdex total scores (-39.62 vs. -7.91) compared with placebo (all p < .001). DISCUSSION/CONCLUSIONS: Secukinumab in moderate-to-severe scalp psoriasis reduces scalp pain, itching, and scaling and improves patients' QOL.

Population Pharmacokinetic Modeling of Secukinumab in Patients With Moderate to Severe Psoriasis.

Secukinumab is a human monoclonal antibody with demonstrated efficacy for moderate to severe psoriasis; it binds to and neutralizes interleukin (IL)-17A. The pharmacokinetic (PK) parameters of secukinumab were best described by a 2-compartment model. Only weight was included in the final model, as other covariates did not affect clinical relevance. The estimated serum clearance of secukinumab was 0.19 L/day, with interindividual variability (IIV) of 32% coefficient of variation (CV), and low total volume of distribution (central compartment volume, 3.61 L with IIV of 30% CV; peripheral compartment volume, 2.87 L with IIV of 18% CV). The bioavailability of secukinumab after subcutaneous dosing was approximately 73%, with an absorption rate of 0.18/day with IIV of 35% CV. The PK profile of secukinumab was linear, with no evidence of a dose dependence of clearance. Clearance and volume of secukinumab varied with body weight in an allometric relationship. The time to maximum serum concentration at steady state occurred approximately 6 days after dosing for both secukinumab 300 mg and secukinumab 150 mg. Overall, the PK properties of secukinumab were typical of a 150-kDa human IgG1 antibody interacting with a soluble target.

Assessing the overall benefit of a medication: cumulative benefit of secukinumab over time in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Conventional measurements for assessing psoriasis treatment effects capture improvements at fixed, pre-specified timepoints, failing to account for cumulative clinical benefit over time. OBJECTIVE: Explore the innovative concept of "cumulative clinical benefit" by examining the effect of secukinumab over 52 weeks in moderate-to-severe psoriasis patients. METHODS: Cumulative clinical benefit was determined as the area-under-the-curve of the percentage of responders over 52 weeks (AUC0-52 wks), using pooled data from two phase III trials for patients receiving secukinumab (300 or 150 mg) or etanercept. RESULTS: Normalized cumulative benefit with secukinumab 300 mg, secukinumab 150 mg, and etanercept was 74.2%, 63.2%, and 50.5%, respectively, for PASI 75; 58.0%, 42.5%, and 29.5%, respectively, for PASI 90; 32.3%, 18.8%, and 8.7%, respectively, for PASI 100; and 58.3%, 47.9%, and 38.3%, respectively, for DLQI 0/1. 52-week PASI 75 clinical benefit ratios for secukinumab 300 and 150 mg versus etanercept were 1.47 and 1.25, respectively; the ratio of the two secukinumab doses was 1.17, favoring 300 mg. LIMITATIONS: Post hoc analysis. CONCLUSION: Cumulative clinical benefit estimated by AUC0-52 wks is a novel measure for comparing psoriasis treatments. Secukinumab 300 mg provides greater cumulative clinical benefit than secukinumab 150 mg; both provide greater cumulative benefit than etanercept.

Secukinumab provides better relief from the impact of psoriasis on daily activities and personal relationships than etanercept: results of two phase 3 placebo-controlled randomized clinical trials in moderate-to-severe psoriasis.

BACKGROUND: Psoriasis can greatly impact patients' lives, influencing what clothing they wear and impairing their sexual functioning. OBJECTIVE: To provide a detailed comparison of the impact of secukinumab vs. etanercept on enabling patients with psoriasis to have more normal lives with respect to daily activities (DA) (e.g. choosing clothing) and personal relationships (PR) (e.g. sexual functioning). METHODS: Baseline to Week 52 ERASURE and FIXTURE data for secukinumab 300 mg and etanercept were analyzed. Treatment differences in mean scores on the DA and PR subscales and items from the Dermatology Life Quality Index were compared. The proportions of subscale and item responders (score = 0) were compared. RESULTS: Subjects receiving secukinumab (n = 572) achieved greater mean improvement in DA and items (q3 and q4) than subjects receiving etanercept (n = 326; all p < .01 through Week 52). Subjects receiving secukinumab achieved greater mean improvement in PR and items (q8 and q9) than subjects receiving etanercept (subscale: p < .05 at Weeks 8 and 12). Response rates were significantly higher for secukinumab than for etanercept for DA (all p < .0001) and PR (all p < .05 except Weeks 4 and 36). CONCLUSIONS: Secukinumab 300 mg provides greater improvements and more effective relief from psoriasis impact on DA and PR than etanercept.

Secukinumab Self-Administration by Prefilled Syringe Maintains Reduction of Plaque Psoriasis Severity Over 52 Weeks: Results of the FEATURE Trial.

BACKGROUND: Secukinumab, a human monoclonal antibody that selectively targets interleukin-17A, is highly efficacious in the treatment of moderate-to-severe psoriasis, starting at early time points, with a sustained effect and a favorable safety profile. METHODS: Patients with moderate-to-severe plaque psoriasis were randomized to secukinumab 300 mg, secukinumab 150 mg, or placebo self-administered by prefilled syringe at baseline, weeks 1, 2, and 3, and then every four weeks from week 4 to 48. Efficacy responses (≥ 75/90/100% improvement in Psoriasis Area and Severity Index [PASI 75/90/100] and clear/almost clear skin by Investigator's Global Assessment 2011 modified version [IGA mod 2011 0/1]) were measured to week 52. Patient-reported usability of the prefilled syringe was evaluated by the Self-Injection Assessment Questionnaire to week 48. RESULTS: The efficacy of secukinumab increased to week 16 and was maintained to week 52. With secukinumab 300 mg at week 52, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 83.5%/68.0%/47.5% and 71.5% of patients when analyzed by multiple imputation, respectively, and by 75.9%/62.1%/43.1% and 63.8% of patients when analyzed by nonresponder imputation, respectively. With secukinumab 150 mg at week 52, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 63.5%/50.3%/31.1% and 43.6% of patients when analyzed by multiple imputation, respectively, and by 61.0%/49.2%/30.5% and 42.4% of patients when analyzed by nonresponder imputation, respectively. Self-reported acceptability of the prefilled syringe was high throughout the study. The incidence of adverse events (AE) was well balanced between groups, with AEs reported in 74.4% of patients receiving secukinumab 300 mg and 77.3% of patients receiving secukinumab 150 mg. Nasopharyngitis was the most common AE across both secukinumab groups. CONCLUSION: Self-administration of secukinumab by prefilled syringe was associated with robust and sustained efficacy and a favorable safety profile up to week 52.

J Drugs Dermatol. 2016;15(10):1226-1234.

Efficacy of Secukinumab on Moderate-to-severe Plaque Psoriasis Affecting Different Body Regions: a Pooled Analysis of Four Phase 3 Studies.

INTRODUCTION: The impact of psoriasis varies with the body region affected. In addition, patients have different perceptions of disease improvement and treatment satisfaction based on the location of skin clearance with treatment. The monoclonal antibody secukinumab selectively targets interleukin-17A-a central cytokine of psoriasis-and provides rapid and sustained clearance for moderate-to-severe psoriasis affecting all body regions. The objective of this study was to evaluate the efficacy of secukinumab on moderate-to-severe psoriasis affecting the trunk, upper limbs, and lower limbs. METHODS: Data were pooled from four phase 3 studies. To be included in the analysis for each body region, patients were required to have a Psoriasis Area and Severity Index (PASI) score ≥12 for that body region and psoriasis covering ≥10% of the surface area of that region. Secukinumab was administered at Baseline, Weeks 1, 2 and 3, and then every 4 weeks from Week 4 to 48. RESULTS: Across the trunk, upper limbs, and lower limbs, initial PASI subscore responses were sustained to Week 52. At Week 52, trunk (T) PASI 90/100 responses were achieved by 78.4%/71.1% of patients receiving secukinumab 300 mg, respectively, and by 66.3%/56.9% of patients receiving secukinumab 150 mg, respectively. At Week 52, upper limb (UL) PASI 90/100 responses were achieved by 67.3%/59.1% of patients receiving secukinumab 300 mg, respectively, and by 50.3%/43.3% of patients receiving secukinumab 150 mg, respectively. At Week 52, lower limb (LL) PASI 90/100 responses were achieved by 63.9%/55.3% of patients receiving secukinumab 300 mg, respectively, and by 45.1%/36.4% of patients receiving secukinumab 150 mg, respectively. A 50% reduction in mean PASI subscore occurred after 2.8, 2.9, and 3.4 weeks with secukinumab 300 mg on the trunk, upper limbs, and lower limbs, respectively. CONCLUSION: Secukinumab provided robust and sustained efficacy for moderate-to-severe psoriasis affecting the trunk, upper limbs, and lower limbs. FUNDING: Novartis Pharmaceuticals Corporation. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01365455, NCT01358578, NCT01555125, and NCT01636687.

Efficacy of Secukinumab for Moderate-to-Severe Head and Neck Psoriasis Over 52 Weeks: Pooled Analysis of Four Phase 3 Studies.

INTRODUCTION: Psoriasis affecting the head and neck can be difficult to treat, and the presence of extensive and highly visible lesions may result in substantial psychosocial burdens. Secukinumab, a monoclonal antibody that selectively targets interleukin-17A, provides rapid and sustained clearance of moderate-to-severe psoriasis. The objective of this study was to evaluate the efficacy of secukinumab on moderate-to-severe psoriasis affecting the head and neck. The safety and overall efficacy of secukinumab in patients with moderate-to-severe psoriasis will be described. METHODS: Data were pooled from four phase 3 studies. To be included in the head and neck analysis, patients were required to have Baseline head and neck Psoriasis Severity Area Index (PASI) scores ≥12 and psoriasis covering ≥10% of the head and neck. Secukinumab (300 or 150 mg) was administered at Baseline, Weeks 1, 2 and 3, and then every 4 weeks from Week 4 to 48. RESULTS: Secukinumab demonstrated high efficacy on the head and neck and the whole body. At Week 52, head and neck PASI 90/100 subscore responses were achieved by 76.0%/68.7% of patients receiving secukinumab 300 mg, respectively, and by 61.4%/53.1% of patients receiving secukinumab 150 mg, respectively. At Week 52, whole body composite PASI 90/100 responses were achieved by 68.1%/40.8% of patients receiving secukinumab 300 mg, respectively, and by 47.6%/24.3% of patients receiving secukinumab 150 mg, respectively. Secukinumab also improved Dermatology Life Quality Index scores. CONCLUSION: Secukinumab provided robust and sustained efficacy for head and neck, and whole body psoriasis, over 52 weeks, with a favorable safety profile. FUNDING: Novartis Pharmaceuticals Corporation. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT01365455, NCT01358578, NCT01555125, and NCT01636687.

Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy.

OBJECTIVE: To evaluate the risk of venous thromboembolism (VTE) and cardiovascular disease (CVD) complications, and assess healthcare costs in menopausal women using an estradiol transdermal system versus oral estrogen therapy (ET). METHODS: Health insurance claims from 60 self-insured US companies from 1999 to 2011 were analyzed. Women at least 50 years of age, newly initiated on transdermal or oral ET, were included. Cohorts were matched 1:1 based on exact factors and propensity score-matching methods. The incidence rate ratios (IRRs) of CVD complications, as well as VTE and other CVD events separately, were assessed through conditional Poisson models. Cohorts were also compared for healthcare costs using linear regression models to assess per-patient per-month cost differences. Confidence intervals (CIs) and P values were determined using a nonparametric method for cost outcomes. RESULTS: From each cohort, 2,551 users were matched to form the study population. A total of 274 transdermal ET users developed CVD complications compared with 316 women in the oral ET cohort (adjusted IRR 0.81; 95% CI, 0.67-0.99). Transdermal ET users also incurred lower adjusted all-cause and VTE/CVD-related healthcare costs relative to oral ET users (all-cause per-patient per-month cost difference [95% CI] = $41 [-34; 137], P = 0.342). CONCLUSIONS: This large matched-cohort study based on real-world data suggests that women receiving transdermal ET have significantly lower incidences of CVD events compared with those receiving oral ET, and that they also incur lower healthcare costs.

Secukinumab improves patient-reported psoriasis symptoms of itching, pain, and scaling: results of two phase 3, randomized, placebo-controlled clinical trials.

BACKGROUND: Secukinumab is a human interleukin-17A antagonist indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The objective of this analysis was to measure the treatment response on psoriasis-related itching, pain, and scaling via the Psoriasis Symptom Diary (PSD)(©). METHODS: ERASURE (n = 738) and FIXTURE (n = 1306) were double-blind, multicenter phase 3 studies in adults randomized to secukinumab (300, 150 mg, n = 1144) or placebo (n = 574) (administered at Weeks 0, 1, 2, 3, and 4, followed by dosing every 4 weeks) or a biologic active control (FIXTURE only). Patient-reported itching, pain, and scaling were assessed during the first 12 weeks of treatment using the PSD. The results reported here are limited to subjects in the secukinumab and placebo treatment groups who completed the PSD. The proportions of subjects achieving prespecified responses (improvement:reduction of at least 2.2 points for itching, 2.2 points for pain, or 2.3 points for scaling) were compared for secukinumab versus placebo. RESULTS: Overall, 39% of subjects completed the PSD at baseline and Week 12 (n = 453 secukinumab; 225 placebo). Subjects treated with secukinumab achieved significantly greater improvements in itching, pain, and scaling at Week 12 versus placebo (all P < 0.0001) and had significantly greater proportions of itching, pain, and scaling responders at Week 12 versus placebo (all P < 0.05). CONCLUSION: Secukinumab significantly improves patient-reported itching, pain, and scaling in adults with moderate to severe psoriasis compared with placebo.

Psychometric validation of the Psoriasis Symptom Diary using Phase III study data from patients with chronic plaque psoriasis.

OBJECTIVES: This analysis aimed to confirm the reliability, validity, and responsiveness of the Psoriasis Symptom Diary (PSD) using data from two Phase III studies in patients with moderate to severe chronic plaque psoriasis. METHODS: Data from two randomized, double-blind, double-dummy, placebo-controlled, multicenter Phase III studies (n = 820) assessing the efficacy and safety of secukinumab were used. The PSD (24-h recall; 0-10 numeric rating scale) was electronically administered each evening. Test-retest reliability was determined using intraclass correlations. Construct validity hypotheses were evaluated via correlations with the Psoriasis Area and Severity Index (PASI), Investigator's Global Assessment (IGA), Dermatology Life Quality Index (DLQI), EuroQoL 5-Dimension Health Status Questionnaire, and Patient Global Impression of Change (PGIC). Discriminating ability and responsiveness were evaluated by estimating mean differences and effect sizes between known groups (using the PASI and IGA). Phase II-derived, anchor-based PGIC thresholds and cumulative distribution function (CDF) plots described meaningful change. RESULTS: Items on the PSD yielded high intraclass coefficients (>0.90). Correlations were in the anticipated direction and by week 12 were moderate to strong (0.41-0.73) in magnitude, demonstrating construct validity. Average PSD item scores differed predictably and significantly between known groups. Responsiveness effect size estimates were moderate to large (0.6-1.5), and CDF plots showed the percentage of responders to be consistently higher in treatment than in placebo arms across the range of change in PSD scores. CONCLUSIONS: The PSD is reliable, valid, and responsive, and represents a valid tool to enhance treatment decisions in patients with moderate to severe plaque psoriasis.

The 5-point Investigator's Global Assessment (IGA) Scale: A modified tool for evaluating plaque psoriasis severity in clinical trials.

BACKGROUND: To evaluate new psoriasis treatments, clinicians, regulators and pharmaceutical developers require well-accepted, clinically meaningful measures of disease severity. The Psoriasis Area and Severity Index (PASI) score is most widely used as a primary endpoint in clinical trials, although it is not routinely used in clinical practice. OBJECTIVE: Characterize a 5-point Investigator's Global Assessment (IGA) tool and evaluate whether it meets the needs for a valid, clinically meaningful measure. METHODS: A 5-point IGA tool was developed with input from regulatory authorities and clinical trial investigators involved with psoriasis drug development and evaluation. Associations between IGA 0/1 responder rates and PASI scores were evaluated using data from two phase 2 studies with the anti-interleukin (IL)-17A monoclonal antibody secukinumab (AIN457) that utilized a similar 6-point IGA. RESULTS: The 5-point IGA has a more stringent definition for a score of 1 ("almost clear") compared with 6-point IGA/Physician's Global Assessment (PGA) tools used in previous trials of other biologics in moderate-to-severe psoriasis. Whereas IGA/PGA 0/1 responder rates for earlier scales are strongly associated with PASI 75, the IGA 0/1 rate for the secukinumab 6-point scale was more robust, demonstrating a strong association with PASI 90, and the results for the 5-point IGA are expected to show the same association. DISCUSSION: The 5-point IGA is a valid measure of disease severity and meets the need for a clinically meaningful measure of success for psoriasis treatment studies.

The Psoriasis Symptom Diary: development and content validity of a novel patient-reported outcome instrument.

BACKGROUND: Chronic plaque psoriasis has a profound impact on a patient's daily life. To understand the effects of psoriasis treatments, it is essential to assess the patient's experience of symptoms and how they impact their daily life. The goal of this study was to develop and establish the content validity of a new patient reported outcome (PRO) psoriasis measure. METHODS: The Psoriasis Symptom Diary was developed by (i) identifying key plaque psoriasis-related symptoms and impacts through qualitative patient interviews (n = 29); (ii) developing an initial set of items that captured the key patient experiences; and (iii) conducting cognitive interviews to test patient understanding of items selected for inclusion in the new psoriasis symptom measure (n = 16). RESULTS: Patients noted a variety of symptoms, with plaque-related pain (including related concepts of burning and stinging), changes in skin appearance, and itching reported by all patients. Patients also expressed notable embarrassment and avoidance of social situations, due to the appearance of plaques, and limited mobility. The Psoriasis Symptom Diary assesses the severity and impact of symptoms using a 24-hour recall period to reduce recall bias and error. CONCLUSIONS: The Psoriasis Symptom Diary was developed to assess important symptoms and disease-related impacts in a manner consistent with guidelines for establishing the content validity of new PRO instruments. Following quantitative psychometric testing, the Psoriasis Symptom Diary may support efficacy endpoints in clinical trials.

Item-level psychometric properties for a new patient-reported psoriasis symptom diary.

OBJECTIVES: This research evaluated the psychometric properties of a new Psoriasis Symptom Diary, identified diary responder definitions for use in determining whether a patient has experienced clinically meaningful change, and refined diary item content for use in future clinical trials. METHODS: The Psoriasis Symptom Diary was administered in a phase 2 clinical trial of AIN457 to US adult outpatients (N = 172) with physician-diagnosed moderate to severe chronic plaque-type psoriasis. Participant compliance with daily diary administration and item score variability, reliability, construct and discriminant validity, sensitivity to change, and interpretation were all evaluated. RESULTS: Participants completed 94% of scheduled diary assessments across 12 study weeks. Diary items were generally normally distributed, and no floor or ceiling effects were observed. Item reliability (reproducibility) was acceptable (intraclass correlation coefficients > 0.80), with an exception for one item (skin color). At week 12, items significantly related to criterion measures as predicted (Psoriasis Area and Severity Index r = 0.27-0.57; Investigator's Global Assessment r = 0.25-0.59), with the exception of items that measured skin color and difficulty using hands. Most items generated change scores that were synchronous to changes as measured by the Psoriasis Area and Severity Index, Investigator's Global Assessment, Dermatology Life Quality Index (r > 0.37), as well as the Patient Global Impression of Change. Responders experienced a 2- to 3-point and 3- to 5-point change in item scores for minimal and large improvements, respectively. Four items that did not perform well were dropped from the diary. CONCLUSIONS: The 16-item Psoriasis Symptom Diary demonstrated favorable psychometric properties and is a brief, useful tool for measuring patient-based symptoms and the impact of chronic plaque psoriasis.

Terbinafine hydrochloride oral granules versus oral griseofulvin suspension in children with tinea capitis: results of two randomized, investigator-blinded, multicenter, international, controlled trials.

BACKGROUND: Although griseofulvin is currently considered the primary antifungal agent used to treat tinea capitis in many countries, increasingly higher doses and longer durations of treatment are becoming necessary to achieve effective treatment. Alternative antifungal therapies with shorter/simpler treatment regimens may be important to develop for this indication. OBJECTIVE: To compare the efficacy and safety of a new pediatric formulation of terbinafine hydrochloride oral granules with griseofulvin oral suspension in the treatment of tinea capitis. METHOD: Children (4-12 years of age) with clinically diagnosed and potassium hydroxide microscopy-confirmed tinea capitis were randomized in two identical studies (trial 1, trial 2) to once-daily treatment with terbinafine (5-8 mg/kg; n = 1040) or griseofulvin administered per label (10-20 mg/kg; n = 509) for a period of 6 weeks followed by 4 weeks of follow-up. End-of-study complete cure (negative fungal culture and microscopy with Total Signs and Symptoms Score [TSSS] = 0), and mycologic (negative culture and microscopy) and clinical cure (TSSS = 0) were primary and secondary efficacy variables, respectively. Efficacy analysis was based on pooled data using modified intent-to-treat population (those who received at least one dose of study drug and had positive baseline fungal culture, N = 1286). Safety assessments included monitoring of the frequency and severity of adverse events (AEs). RESULTS: Rates of complete cure and mycologic cure were significantly higher for terbinafine than for griseofulvin (45.1% vs 39.2% and 61.5% vs 55.5%, respectively; P < .05). A majority (86.7%) of patients received griseofulvin, 10 to 19.9 mg/kg per day; complete cure rate was not found to be higher among patients who received griseofulvin more than 20 mg/kg per day compared with those who received less than 20 mg/kg per day. Complete cure rate was statistically significantly greater for terbinafine compared to griseofulvin in trial 1 (46.23% vs 34.01%) but not in trial 2 (43.99% vs 43.46%). On the basis of pooled data, clinical cure was higher for terbinafine than for griseofulvin, but the difference was not found to be statistically significant (P = .10). Subgroup analyses revealed that terbinafine was significantly better than griseofulvin for all cure rates--mycologic, clinical, and complete--among patients with Trichophyton tonsurans but not Microsporum canis (P < .001). For M. canis, mycologic and clinical cure rates were significantly better with griseofulvin than with terbinafine (P < .05). Approximately 50% of patients in each group reported an AE; almost all were mild or moderate in severity. Nasopharyngitis, headache, and pyrexia were most common in both groups. There were no drug-related serious AEs, no deaths, and no significant effects on weight or laboratory parameters, including liver transaminases. LIMITATIONS: In retrospect, a difference in the distribution of infecting microorganisms between the two trials was a limitation. Stringent adherence to griseofulvin doses recommended by prescribing information but smaller than those used in current clinical practice, and exclusion of adjuvant therapies such as shampoos or topical agents, which are routinely used in practice, are other limitations. CONCLUSIONS: Data from this largest pediatric trial of terbinafine to date indicate that terbinafine is efficacious and well tolerated in the treatment of tinea capitis. Terbinafine is an effective alternative to griseofulvin against T. tonsurans tinea capitis.

The effect of simulated solar UV irradiation on tretinoin in tretinoin gel microsphere 0.1% and tretinoin gel 0.025%.

Topical tretinoin is highly effective and widely used in the treatment of acne vulgaris. Tretinoin gel microsphere 0.1% (TGM)--alone or in combination with erythromycin-benzoyl peroxide (EBP) or clindamycin-benzoyl peroxide (CBP) topical gels-and tretinoin gel 0.025% (TG)--alone or, combined with EBP-were exposed to simulated solar UV irradiation to determine the degree of tretinoin photodegradation/isomerization. The investigation revealed that 94% and 84% of the initial tretinoin in the TGM formulation remained stable after 2 and 6 hours, respectively, of simulated solar UV irradiation. When combined with EBP topical gel, 89% and 81% of the initial tretinoin remained stable after 2 and 6 hours, respectively, of exposure to simulated solar UV irradiation; 86% and 80% of the tretinoin remained stable after 2 and 6 hours, respectively, when combined with CBP topical gel. In contrast, only 19% and 10% of the tretinoin remained unchanged after 2 and 6 hours, respectively, of simulated solar UV irradiation of TG. Combined with the EBP topical gel, undegraded tretinoin quantities were further reduced to 7% and 0% at 2 and 6 hours, respectively, with TG. These data suggest that the TGM formulation offers marked protection against tretinoin photodegradation compared with TG, even in the presence of a topical gel containing a potent antibiotic or a strong oxidizing agent. Although simulated solar UV irradiation is not entirely reflective of actual conditions, the results appear to be substantial.

Intermittent versus continuous terbinafine in the treatment of toenail onychomycosis: a randomized, double-blind comparison.

BACKGROUND: Terbinafine is an established drug for the treatment of toenail onychomycosis. Minimizing the total dose of terbinafine and giving it intermittently could improve tolerability as well as compliance, provided efficacy is not compromised. OBJECTIVE: Two identical trials were conducted to compare the efficacy, safety and tolerability of the current standard regimen of terbinafine 250 mg daily with a new formulation of terbinafine given intermittently for three cycles of 2 weeks of treatment (350 mg daily) followed by 2 weeks off treatment. METHODS: A total of 2005 patients with a clinical diagnosis of subungual onychomycosis of the large toenail confirmed by microscopy and culture for a dermatophyte were recruited into the two trials and treated for 12 weeks. RESULTS: Patients with onychomycosis of prolonged duration (mean 9 years) and a median nail involvement of 63% with or without spikes, lateral involvement and white superficial onychomycosis (WSO) were included in the trial. The studies found a significant difference (p<0.05) in favour of standard daily dosing with terbinafine. Response rates for the primary variable complete cure (mycological and clinical cure) were lower with the new formulation in both Trial I (-5.8%; 95% CI -11.8, 0.07) and Trial II (difference -5.9%; 95% CI -12, 0.1). Both treatments were equally well tolerated, with approximately 11% of patients in both groups reporting at least one treatment-related adverse event. CONCLUSIONS: Pulsed dosing with terbinafine did not provide any clear safety advantages and was significantly less effective. Consequently, continuous treatment with terbinafine tablets remains the optimal therapy for onychomycosis.

Long-term efficacy and safety of tretinoin emollient cream 0.05% in the treatment of photodamaged facial skin: a two-year, randomized, placebo-controlled trial.

BACKGROUND: Long-term (>1 year) placebo-controlled studies of tretinoin in the treatment of photodamaged skin have not been conducted. Recently, we conducted a 2-year placebo-controlled study of tretinoin emollient cream 0.05%, including histopathologic assessment of safety and analysis of markers of collagen deposition. OBJECTIVE: The objective of the study was to determine the long-term safety and efficacy of tretinoin emollient cream 0.05% in the treatment of moderate to severe facial photodamage. METHODS: A total of 204 subjects were treated with tretinoin or placebo (vehicle emollient cream) applied to the entire face once a day for up to 2 years. Clinical and histologic effects were assessed at regularly scheduled clinic visits. RESULTS: Treatment with tretinoin resulted in significantly greater improvement relative to placebo in clinical signs of photodamage (fine and coarse wrinkling, mottled hyperpigmentation, lentigines, and sallowness), overall photodamage severity, and investigator's global assessment of clinical response (p<0.05). Histologic evaluation showed no increase in keratinocytic or melanocytic atypia, dermal elastosis, or untoward effects on stratum corneum following treatment with tretinoin compared with placebo. Immunohistochemistry studies, conducted at three study centers, showed a significant increase relative to placebo in facial procollagen 1C terminal, a marker for procollagen synthesis, at month 12 (p=0.0074). CONCLUSION: Long-term treatment with tretinoin emollient cream 0.05% is safe and effective in subjects with moderate to severe facial photodamage.

The stability of tretinoin in tretinoin gel microsphere 0.1%.

Topical tretinoin is highly effective and widely used in the treatment of acne vulgaris. In studies to determine the degree of tretinoin photo degradation (isomerization), 2 tretinoin formulations, tretinoin gel microsphere 0.1% and tretinoin gel 0.025%, alone or in combination with erythromycin-benzoyl peroxide topical gel, were exposed to fluorescent light, incandescent light, or darkness for up to 24 hours. Results of the investigations revealed that after 24 hours of exposure to fluorescent light, 98% of the initial tretinoin in the tretinoin gel microsphere 0.1% formulation remained unchanged. When tretinoin gel microsphere 0.1% was combined with erythromycin-benzoyl peroxide topical gel and exposed to fluorescent light, 99% and 87% of the tretinoin was recovered after 4 and 24 hours, respectively, indicating only a limited amount of degradation. In contrast, exposure of tretinoin gel 0.025% to 24 hours of fluorescent light resulted in up to 69% tretinoin degradation and up to 89% degradation when the gel was combined with the erythromycin-benzoyl peroxide topical gel. The data suggest that the tretinoin gel microsphere 0.1% formulation offers marked protection against tretinoin photo degradation, even in the presence of a strong oxidizing agent such as benzoyl peroxide.