Successful retreatment with alitretinoin in patients with relapsed chronic hand eczema

Summary Background Patients with severe chronic hand eczema (CHE) often respond to therapy with oral alitretinoin (9‐cis retinoic acid). However, the efficacy of alitretinoin after disease relapse has not been demonstrated. Objectives To assess the efficacy and safety of a second course of oral alitretinoin in patients with severe CHE who relapsed after achieving ‘clear’ or ‘almost clear’ hands following a previous course of alitretinoin. Methods The double‐blind study included 117 patients with CHE who had responded to therapy in an earlier clinical trial and subsequently relapsed. Patients were randomized to receive their previous treatment or placebo. Treatment was alitretinoin 30 mg or 10 mg or placebo given once daily for 12–24 weeks. Response was defined as an overall Physician’s Global Assessment rating of ‘clear’ or ‘almost clear’ hands at the end of therapy. Results Response rates were 80% in patients retreated with 30 mg alitretinoin compared with 8% for placebo (P < 0·001). In patients retreated with 10 mg alitretinoin response rates were 48%, compared with 10% in the placebo group. Alitretinoin was well tolerated. Adverse reactions comprised typical retinoid class effects, and no late‐arising side‐effects were observed during this second course of treatment. Conclusions The majority of patients with CHE who previously achieved ‘clear’ or ‘almost clear’ hands following treatment with alitretinoin 30 mg per day also responded to a second course of treatment. Retreatment was well tolerated. Intermittent treatment with alitretinoin is suitable for the long‐term management of CHE.     

Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial

BACKGROUND: Patients with severe chronic hand eczema (CHE) refractory to topical corticosteroids currently have limited treatment options suited for chronic use, and few controlled clinical studies have investigated new therapies in this setting. OBJECTIVES: To assess the efficacy and safety of oral alitretinoin (9-cis retinoic acid) taken at 10 mg or 30 mg once daily for up to 24 weeks, compared with placebo control, in the treatment of severe CHE refractory to topical corticosteroids. METHODS: A randomized, double-blind, placebo-controlled, prospective, multicentre trial was conducted in 111 dermatology outpatient clinics in Europe and Canada. A total of 1032 patients with severe refractory CHE were randomized in a 1 : 2 : 2 ratio to placebo, or 10 mg or 30 mg of oral alitretinoin once daily for up to 24 weeks. Safety was assessed for all patients during a follow-up period of 4 weeks, and responders were observed for relapse for 24 weeks after the end of therapy. The primary efficacy parameter was Physician Global Assessment of overall CHE severity, with response defined as clear or almost clear hands. RESULTS: Responses, defined as clear or almost clear hands, were achieved in up to 48% of patients treated with alitretinoin, compared with 17% for placebo (P < 0.001), with up to 75% median reduction in disease signs and symptoms. Treatment was well tolerated, with dose-dependent adverse effects comprising headache, mucocutaneous events, hyperlipidaemia, and decreased free thyroxine and thyroid-stimulating hormone. The median time to relapse, defined as recurrence of 75% of initial signs and symptoms, was 5.5-6.2 months in the absence of anti-eczema medication. CONCLUSIONS: Alitretinoin given at well-tolerated doses induced clearing of CHE in a substantial proportion of patients with severe disease refractory to standard therapy.     

Extended treatment with oral alitretinoin for patients with chronic hand eczema not fully responding to initial treatment

Background. In a previous large trial (Benefit of Alitretinoin in Chronic Hand Eczema; BACH), 47.7% of patients with severe chronic hand eczema (CHE) who received alitretinoin 30 mg achieved ‘clear’ or ‘almost clear’ hands during the initial 24‐week treatment course. Objectives. The current open‐label trial was designed to study extended treatment with a further 12‐ to 24‐week course of oral alitretinoin 30 mg in patients who did not fully respond to initial treatment in the BACH study. Methods. At the end of the BACH study, patients whose eczema was rated ‘mild’, ‘moderate’ or ‘severe’ according to the Physician’s Global Assessment (PGA) were eligible for a 24‐week, open‐label, multicentre study. Patients (n = 243) received 30 mg of alitretinoin once daily, irrespective of previous treatment in BACH; either alitretinoin 30 mg, alitretinoin 10 mg or placebo. Results. By the end of the follow‐on study, the PGA response rate to the subsequent course of alitretinoin 30 mg was 50% and 39% in patients treated previously in BACH with 10 or 30 mg per day, respectively, and 51% in patients who previously received placebo in BACH. Alitretinoin was well tolerated, and no significant late‐arising toxicities were seen. Conclusions. For a considerable number of patients with CHE who did not fully respond after an initial 24‐week treatment period, a switch from either placebo to the active compound at 30 mg or from the lower to the higher dose, or treatment prolongation at the higher dose could be beneficial. Alitretinoin remains well tolerated for overall treatment durations of up to 48 weeks.     

An open-label study assessing the safety and efficacy of alitretinoin in patients with severe chronic hand eczema unresponsive to topical corticosteroids

Background. Blinded, controlled studies have found that oral alitretinoin is well tolerated and effective in the treatment of severe chronic hand eczema (CHE). Aim. To assess the safety and efficacy of oral alitretinoin in patients with severe CHE in an open‐label study using flexible dosing and a new measurement of patient‐relevant benefits. Methods. In total, 249 patients aged 18–75 years with severe CHE unresponsive to treatment with topical corticosteroids received alitretinoin 30 mg once daily for up to 24 weeks. Safety assessments included adverse events (AEs) and laboratory tests. Efficacy assessments included Physician’s Global Assessment (PGA), the Modified Total Lesion Symptom Score, Patient’s Global Assessment and extent of disease, as well as intensity of pain and pruritus as determined by visual analogue scale (VAS) and a categorical scale for pruritus. Results. Alitretinoin was well tolerated when given for up to 24 weeks. Dose reduction occurred in 16.5% of patients. Dose interruption was required for 15.7% of patients, most commonly for headache. AEs and laboratory changes comprised effects typical of the retinoid class. A PGA response of ‘clear’ or ‘almost clear’ hands was reported for 46.6% of patients, similar to the response rate seen in blinded trials. Results of VAS and categorical assessments of pruritus provided supporting evidence of efficacy, and treatment was assessed as providing meaningful benefits to patients. Conclusions. Oral alitretinoin 30 mg was well tolerated and effective, and provided distinct therapeutic benefits in severe CHE, as assessed by patients.     

Efficacy and Safety of Alitretinoin Therapy in Korean Elderly Patients with Chronic Hand Eczema: A Retrospective Single Center Study

BackgroundChronic hand eczema (CHE) tends to be refractory to conventional therapy. Previous clinical trials have found that alitretinoin is an effective and well-tolerated treatment for CHE. However, there is a relative lack of data on the effectiveness of alitretinoin in elderly patients.ObjectiveThe aim of this study was to investigate the efficacy and safety of oral alitretinoin in elderly patients with moderate to severe CHE in Korea.MethodsWe retrospectively investigated 46 CHE patients who were treated with either 10 mg or 30 mg of alitretinoin between June of 2016 and July of 2018. The physician''s global assessment (PGA) was used to evaluate treatment efficacy. All adverse events were retrospectively evaluated with respect to laboratory testing, including complete blood cell count, fasting blood chemistry, lipid profile, and liver and thyroid function tests.ResultsThe mean patient age in this study was 71.0±5.1 years. The treatment period was over eight weeks. A total of 38 of 46 patients (82.6%) exhibited clinical improvement with PGA ratings of ‘clear’ or ‘almost clear.’ There were 13 patients (28.3%) who experienced an adverse effect, with the most common being headache (13.0%) and gastrointestinal symptoms (8.7%) followed by xerosis (6.5%). A total of 13 patients developed or exhibited worsening hypertriglyceridemia (28.3%).ConclusionAlitretinoin can be considered a safe and effective treatment option in elderly patients with moderate to severe CHE.     

Efficacy of alitretinoin depending on the concomitant use of topical corticosteroids in chronic hand eczema patients

Alitretinoin is the only systemic agent approved for the treatment of severe chronic hand eczema (CHE) unresponsive to potent topical corticosteroids. Clinical trials have shown the efficacy of oral alitretinoin with topical emollients for CHE treatment, but most studies have failed to reach a therapeutic success rate of 50%. Reasonably, we thought it would be more effective to combine topical corticosteroids with oral alitretinoin, but the concomitant use of topical corticosteroids has not been studied yet. One‐hundred and seven Korean patients diagnosed with CHE were recruited. The participants were divided into two groups depending on the concomitant use of topical corticosteroids. Comparative analysis was performed between the combined therapy (alitretinoin and topical corticosteroids) and monotherapy groups (alitretinoin only) by using physician global assessment (PGA), patient's global assessment (PaGA), modified total lesion symptom score (mTLSS), and recurrence rates. The combined therapy group showed a significantly higher treatment success rate than the alitretinoin monotherapy group for all efficacy parameters (PGA: P < 0.001, PaGA: P < 0.001, mTLSS changes: P < 0.001), but there was no significant difference in recurrence rates between the groups (P = 0.266). Combined use of topical corticosteroids is recommended for CHE patients being treated with oral alitretinoin due to clinically rapid and superior effectiveness.     

Efficacy and tolerability of alitretinoin for chronic hand eczema under daily practice conditions: results of the TOCCATA open study comprising 680 patients

This non-interventional observational open study (TOCCATA, sponsored by Basilea Pharmaceutica Germany) investigated the use of alitretinoin to treat chronic hand eczema under daily "real life" medical practice conditions in Germany. A total of 349 dermatologists through-out Germany enrolled 680 adult patients with chronic hand eczema. Patients were prescribed and treated with alitretinoin in accordance with the summary of product characteristics. The maximum observation duration was 24 weeks, with efficacy and safety parameters evaluated every 4 weeks. Efficacy was primarily evaluated by assessing disease severity according to the Physician Global Assessment. In total, 56.7% of patients achieved a Physician Global Assessment rating of "clear" or "almost clear" hands, with only small differences in patients with different morphological forms: hyperkeratotic-rhagadiform (59.2%), fingertip (52.2%) and vesicular (47.9%). This observational study demonstrates the effectiveness and tolerability of alitretinoin in everyday clinical practice in addition to the known efficacy and safety obtain-ed by randomized controlled clinical trials.     

Oral alitretinoin (9-cis-retinoic acid) therapy for chronic hand dermatitis in patients refractory to standard therapy: results of a randomized, double-blind, placebo-controlled, multicenter trial

OBJECTIVE: To assess the efficacy and safety of oral alitretinoin (9-cis-retinoic acid), 10 mg/d, 20 mg/d, and 40 mg/d, compared with placebo control, in the treatment of chronic hand dermatitis. DESIGN: Multicenter, randomized, double-blind, placebo-control, prospective trial. SETTING: A total of 43 outpatient clinics in 10 European countries. PATIENTS: Of 348 patients screened, 319 with moderate or severe refractory chronic hand dermatitis were randomized, in the ratio of 1:1:1:1, to 4 treatment groups and received allocated intervention. Of 75 patients who withdrew, 24 withdrew owing to adverse events. INTERVENTIONS: Placebo or 10 mg, 20 mg, or 40 mg of oral alitretinoin (9-cis-retinoic acid) taken once daily for 12 weeks. Safety was assessed for all patients during a follow-up period of 4 weeks, and responders were observed for a follow-up period of 3 months. MAIN OUTCOME MEASURE: Physician's global assessment of overall chronic hand dermatitis severity. RESULTS: Alitretinoin led to a significant and dose-dependent improvement in disease status, with responses in up to 53% of patients, and up to a 70% mean reduction in disease signs and symptoms. Treatment was generally well tolerated, with dose-dependent effects comprising headache, flushing, mucocutaneous events, hyperlipidemia, and decreased hemoglobin and decreased free thyroxin levels. Three months after discontinuation of treatment, the rate of relapse was 26%, independent of dose. CONCLUSION: Alitretinoin given at well-tolerated doses induced substantial clearing of chronic hand dermatitis in patients refractory to conventional therapy.     

Alitretinoin

About 10% of Germans have chronic hand eczema (CHE). Until recently only off-label use agents existed for the treatment of severe CHE cases refractory to topical steroids. In addition, data from controlled clinical trials confirming the efficacy of known treatment strategies was inadequate. With the availability of alitretinoin, 9-cis retinoic acid, this situation may change. In two large clinical trials alitretinoin showed high response rates and a favorable safety profile in the treatment of severe and refractory CHE. Alitretinoin has an anti-inflammatory and immunomodulatory mechanism of action. Acting as a panagonist it binds to retinoic acid receptors A (RAR) and X (RXR). It directly affects cytokine production in keratinocytes and down-regulates leukocyte activity. When used for CHE with detailed patient counseling and appropriate laboratory monitoring, alitretinoin is a promising new option for systemic treatment.     

Successful treatment of moderate to severe plaque psoriasis with the PEGylated Fab' certolizumab pegol: results of a phase II randomized, placebo-controlled trial with a re-treatment extension

Background Certolizumab pegol (CZP) is a PEGylated antitumour necrosis factor agent. Objectives To evaluate the efficacy and safety of CZP in patients with plaque psoriasis. Methods In a randomized, placebo‐controlled, double‐blind study, 176 patients with moderate to severe psoriasis received placebo or CZP 400 mg at week 0 followed by placebo or CZP (200 or 400 mg) every other week until week 10. Co‐primary endpoints were ≥ 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) and a Physician’s Global Assessment (PGA) of clear‐almost clear at week 12. A re‐treatment extension study was conducted in 71 CZP PASI 75 responders who relapsed during a 12‐ to 24‐week observation period without treatment. Results PASI 75 was achieved by 44/59 (75%), 48/58 (83%) and 4/59 (7%) patients in the CZP 200 mg, CZP 400 mg and placebo groups, respectively (P < 0·001 for both treatment arms vs. placebo). A PGA score of clear‐almost clear was achieved by 53%, 72% and 2%, respectively (P < 0·001 for both treatment arms vs. placebo). In the re‐treatment study median PASI scores were similar at week 12 in the first treatment and re‐treatment periods for both CZP groups. Serious adverse events occurred in 3%, 5% and 2% of CZP 200 mg, CZP 400 mg and placebo patients, respectively. Conclusions Treatment with CZP significantly improved psoriasis at week 12. Similar efficacy was observed at week 12 in patients receiving re‐treatment for loss of response after drug withdrawal.     

Alitretinoin abrogates innate inflammation in palmoplantar pustular psoriasis

Background Palmoplantar pustular psoriasis is often recalcitrant to therapy. Here we evaluated the therapeutic effect of alitretinoin in patients with recalcitrant palmoplantar pustular psoriasis and investigated subsequent immunopathological alterations. Methods Seven patients with palmoplantar pustular psoriasis were treated with oral alitretinoin 30 mg once daily for 12 weeks. Efficacy was assessed by palmoplantar pustular psoriasis area and severity index (PPPASI), visual analogue scales (VAS) on intensity of pain and pruritus and an overall patient assessment. Immunohistochemical staining for neutrophil elastase, CD3, CD4, CD8, CD1a CD11c, CD303,CD68, CD69, CD208 and HLA‐DR was on lesional skin biopsies obtained before and after 12 weeks of treatment. Results PPPASI and VAS for pruritus and pain decreased significantly after 12 weeks of treatment with alitretinoin. The overall patient assessment ranged from 60% to 90% clinical improvement. In correlation with clinical improvement a significant reduction, particularly of neutrophils, macrophages and dendritic cells, was also observed in the skin sections. Alitretinoin was well tolerated except for headache during the first month of treatment in two patients. Limitations of the study are a missing control group and the concomitant usage of topical therapy. Discussion Our findings suggest that alitretinoin may represent a new and promising therapy for recalcitrant palmo‐plantar psoriasis and warrants further controlled studies to confirm efficacy and safety of alitretinoin in this disease.     

Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension

Background In previous studies, etanercept 25 mg twice weekly (BIW) or 50 mg BIW significantly reduced disease severity in patients with plaque psoriasis and demonstrated a favourable safety profile. Objectives To assess the efficacy and safety of etanercept 50 mg administered once weekly (QW) compared with placebo in patients with moderate‐to‐severe plaque psoriasis over 24 weeks. Methods This study was conducted in two parts: (i) a 12‐week, double‐blind, placebo‐controlled phase, in which patients received etanercept 50 mg QW or placebo QW; and (ii) a 12‐week, open‐label extension phase, in which all patients received etanercept 50 mg QW. Primary endpoint was a 75% or greater improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at week 12. Secondary endpoints included percentage PASI improvement and Physician’s Global Assessment (PGA). Results One hundred and forty‐two patients were analysed in the double‐blind phase; 126 patients entered the open‐label phase. At week 12, significantly more patients receiving etanercept 50 mg QW (37·5%) achieved PASI 75 response than patients receiving placebo (2·2%; P < 0·0001). At week 24, 71·1% in the etanercept–etanercept group and 44·4% in the placebo–etanercept group achieved PASI 75. Mean percentage of PASI improvement from baseline was 55·4% with etanercept vs. 9·4% worsening with placebo at week 12 (P < 0·0001), with 77·4% and 57·7% improvement in the etanercept–etanercept and placebo–etanercept groups at week 24. A PGA score of 0–1 (clear–almost clear) was achieved by 64% and 42% in the etanercept–etanercept and placebo–etanercept groups at week 24, respectively. Etanercept 50 mg QW was well tolerated. No deaths, serious infections, opportunistic infections (including tuberculosis), demyelinating disorders, malignancies or new safety signals were reported. Conclusions Nearly three‐quarters of patients with moderate‐to‐severe psoriasis receiving etanercept 50 mg QW achieved significant improvement in disease severity over 24 weeks. This study also showed a favourable tolerability and safety profile with etanercept 50 mg QW.     

Oral pimecrolimus in the treatment of moderate to severe chronic plaque-type psoriasis: a double-blind, multicentre, randomized, dose-finding trial

BACKGROUND: There is a need for safe and effective alternative treatments for patients with moderate to severe psoriasis. OBJECTIVES: Pimecrolimus is a calcineurin inhibitor that is being investigated in oral form for the treatment of psoriasis. PATIENTS AND METHODS: A double-blind, randomized, parallel-group, dose-finding study was performed. Healthy adult outpatients with moderate to severe chronic plaque-type psoriasis (n = 143) were randomized to receive oral placebo or pimecrolimus 10 mg, 20 mg or 30 mg twice daily (b.d.) for 12 weeks. Main outcome measures: The Psoriasis Area and Severity Index (PASI) was used to assess clinical severity of psoriasis. Results were analysed at weeks 7 (primary endpoint) and 13. Safety was assessed by monitoring all adverse events, laboratory investigations (blood chemistry, urinalysis, haematology) and physical examinations. RESULTS: The change from baseline in PASI at week 7 showed a dose-dependent effect. The differences between each of the two higher doses of pimecrolimus and placebo were statistically significant (P < 0.001; ANOVA). The mean percentage decreases from baseline in PASI in the placebo group and pimecrolimus 10 mg, 20 mg and 30 mg b.d. groups at week 7 were 3.1%, 22.2%, 51.3% and 54.0%, respectively. Most adverse events were of mild or moderate severity. The only adverse event to show a dose-response relationship was a transient feeling of warmth. No clinically relevant effects on laboratory parameters were observed, and no increase in skin infection with pimecrolimus was seen. CONCLUSIONS: Oral pimecrolimus produces a dose-dependent reduction in psoriasis severity, with doses of 20 mg and 30 mg b.d. being the most effective and well tolerated.     

Changes in skin barrier during treatment with systemic alitretinoin: focus on skin susceptibility and stratum corneum ceramides

Alitretinoin is a new drug for systemic treatment of chronic hand eczema. Previous functional tests of skin topically treated with retinoids have indicated impaired skin barrier function, but no data are available on barrier parameters after systemic alitretinoin treatment. To investigate the effect of systemic alitretinoin on skin barrier function and response to irritants, a secondary objective was to determine if changes occur in the lipid profile of stratum corneum after treatment with systemic alitretinoin. We conducted an open clinical intervention study on eight people ascribed to systemic alitretinoin treatment. The criteria for being ascribed to alitretinoin were chronic hand eczema and insufficient therapeutic response to potent topical corticosteroids. Before initiation and after 2 months of systemic treatment with 30 mg alitretinoin, a challenge with sodium lauryl sulphate (SLS) was performed on the volar forearm and evaluated by trans-epidermal water loss (TEWL), erythema, and a cyanoacrylate skin sample was obtained for lipid analysis. We found no significant changes in response to SLS irritation as evaluated by TEWL and erythema, after treatment with alitretinoin for 2 months. No significant changes in stratum corneum lipids were found after 2 months of treatment. In conclusion, systemic alitretinoin does not influence skin susceptibility to irritants or the ceramide profile of stratum corneum.     

Nail improvement during alitretinoin treatment: three case reports and review of the literature

Alitretinoin is an endogenous vitamin A derivative, 9‐cis‐retinoic acid. Its anti‐inflammatory and immunomodulatory efficacy results from controlling leukocyte activity and cytokine production in keratinocytes. We describe three patients with severe chronic hand eczema accompanied by nail dystrophy, which was treated with alitretinoin 30 mg. Clinical evaluation at 6 months showed complete or almost complete clearing of the nail lesions. We also briefly review the literature reporting on nail dystrophy and alitretinoin treatment. There is some evidence of the clinical effect of retinoids on nail formation, owing to the presence of retinoid receptors on the nail matrix. Further studies are required to better understand the impact of alitretinoin in nail diseases. Our observation supports alitretinoin as a treatment option in retinoid‐responsive dermatoses associated with nail involvement.     

A phase III, randomized, controlled trial of the fully human IL-12/23 mAb briakinumab in moderate-to-severe psoriasis

A previous phase II trial demonstrated that the fully human anti-IL-12/23 mAb briakinumab was efficacious in moderate-to-severe psoriasis. A subsequent 52-week, double-blind, placebo-controlled phase III study evaluated induction and maintenance treatment. Patients were randomized 2:1 to briakinumab (200?mg at weeks 0 and 4 and 100?mg at week 8) or placebo; those with physician's global assessment "clear" or "minimal" (PGA "clear/minimal") at week 12 were then re-randomized 2:2:1 to briakinumab 100 mg every 4 weeks (q4-wk), every 12 weeks (q12-wk), or to matching placebo to week 52. Primary analyses conducted by nonresponder imputation compared proportions achieving PGA "clear/minimal" (weeks 12 and 52) and ≥75% improvement in psoriasis area and severity index (PASI 75; week 12). In all, 76.0% of briakinumab vs. 4.3% of placebo-treated patients achieved PGA "clear/minimal," and 80.7% vs. 4.5%, respectively, achieved PASI 75 at week 12 (P<0.001 each). At week 52, 79.2% of q4-wk-treated patients achieved PGA "clear/minimal" compared with 41.6% and 6.0% of q12-wk and placebo-treated patients, respectively (P<0.001 for all treatment comparisons). Higher numbers of the following adverse events (AEs) of interest were observed with briakinumab during the placebo-controlled period, suggesting the need for surveillance for these events: serious infections (five vs. one event with briakinumab vs. placebo, respectively), nonmelanoma skin cancers (NMSCs; four vs. zero squamous cell carcinomas (SCCs)), and major adverse cardiovascular events (MACEs; five vs. zero events).     

A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction

BACKGROUND: In previous studies, etanercept significantly improved plaque psoriasis and was well tolerated. OBJECTIVES: To examine further the efficacy and safety of etanercept and to assess maintenance of treatment effect after dose reduction of etanercept. METHODS: In this multicentre 24-week study in the U.S.A., Canada and Western Europe, patients were at least 18 years old; had active, clinically stable plaque psoriasis involving at least 10% of body surface area; had a minimum Psoriasis Area and Severity Index (PASI) of 10 at screening; and had received or were a candidate to receive systemic psoriasis therapy or phototherapy. During the first 12 weeks of the study, patients were randomly assigned to receive by subcutaneous injection etanercept twice weekly (BIW) at a dose of 50 mg or 25 mg, or placebo BIW in a double-blind fashion. During the second 12 weeks, all patients received etanercept 25 mg BIW. The primary endpoint was a 75% or greater improvement from baseline in PASI (PASI 75) at 12 weeks. RESULTS: Five hundred and eighty-three subjects were randomized and received at least one dose of study drug. At week 12, a PASI 75 was achieved by 49% of patients in the etanercept 50 mg BIW group, 34% in the 25 mg BIW group, and 3% in the placebo group (P < 0.0001 for each etanercept group compared with placebo). At week 24 (after 12 weeks of open-label 25 mg etanercept BIW), a PASI 75 was achieved by 54% of patients whose dose was reduced from 50 mg BIW to 25 mg BIW, by 45% of patients in the continuous 25 mg BIW group, and by 28% in the group that received placebo followed by etanercept 25 mg BIW. Etanercept was well tolerated throughout the study. CONCLUSIONS: Etanercept provided clinically meaningful benefit to patients with chronic plaque psoriasis, with no apparent decrease in efficacy after dose reduction.     

A phase I/II randomized, double-blind, placebo-controlled, dose-ranging study evaluating the efficacy, safety and pharmacokinetics of ravuconazole in the treatment of onychomycosis

OBJECTIVE: To determine the effectiveness and safety of ravuconazole in the treatment of toenail onychomycosis. DESIGN: A phase I/II randomized, double-blind, double-dummy, placebo-controlled, dose-ranging study. Four 12-week dosing regimens were used: 200 mg/day; 100 mg/week; 400 mg/week and placebo. Subjects returned at weeks 2, 4, 6, 8, 10, 12, 14, 16, 24, 36 and 48 for assessment. Subjects were enrolled at 10 dermatology practices (seven in the United States, one in Canada, two in France). SUBJECTS: Adults with distal subungual onychomycosis of one great (hallux) toenail (minimum area of 25%), and at least 2 mm of proximal nail clear of disease were selected. Onychomycosis was confirmed by direct microscopy and/or fungal culture. Subjects with conditions known to produce abnormal-appearing nails were excluded. One hundred and fifty-one subjects were randomized in a 2:2:2:1 ratio to the treatments above. MAIN OUTCOME MEASURES: Primary efficacy was the effective cure rate at week 48 (mycological cure, and clinical cure or > 30% improvement). RESULTS: Effective cure was found in 56% of subjects using 200 mg/day. Effective cure was 10% in subjects receiving 100 mg/week, 8% of subjects using 400 mg/week, and 15% of subjects using placebo. Mycological cure was seen in 59% of subjects in the 200-mg/day group, which was significantly higher than the rates found in the other groups. Drug-related adverse events were infrequent in all treatment arms. Headache was the most frequently reported event. Abnormal laboratory tests were infrequent over the 12 weeks of dosing. Abnormal laboratory findings with increases beyond normal of Grade 2, 3 or 4 were found in 8/148 subjects (5.4%). Only the 200 mg daily regimen had a mean plasma steady state concentration of ravuconazole exceeding the MIC(90) adjusted for 98% protein binding (3000 ng/mL). CONCLUSIONS: For the treatment of onychomycosis, ravuconazole 200 mg/day for 12 weeks is the most effective of the regimens investigated. The safety of all regimens was acceptable. The concentrations of ravuconazole in the plasma compared to the adjusted MIC(90) may be useful in predicting the clinical and mycologic response of therapy.     

Phase III Vehicle-Controlled, Multi-Centered Study of Topical Alitretinoin Gel 0.1% in Cutaneous AIDS-Related Kaposi’s Sarcoma

Objective

This randomized, double-blind and vehicle-controlled phase III study was conducted to evaluate the efficacy and safety of alitretinoin gel 0.1% for the topical treatment of the cutaneous lesions of AIDS-related Kaposi’s sarcoma (KS).

Methods

Patients received treatment with alitretinoin gel (n = 62) or vehicle gel (n = 72) twice daily for 12 weeks. The primary efficacy endpoint was the cutaneous KS tumor response rate according to AIDS Clinical Trials Group (ACTG) objective criteria applied to topical therapy, with the patient as the unit of analysis.

Results

Treatment of patients with alitretinoin gel resulted in a significant antitumor effect. The overall patient response rate (complete plus partial response) was 37% (23 of 62) for the alitretinoin-treated patients and 7% (5 of 72) for the vehicle-treated patients (p = 0.00003). The difference in response rates for the 2 treatment groups remained significant even after taking into consideration numerous variables, including age (p = 0.00001), Eastern Cooperative Oncology Group (ECOG) status (p = 0.00002), CD4+ cell count (p = 0.00002), history of opportunistic infection (p = 0.00002), aggregate area of indicator lesions (p = 0.00005), number of raised indicator lesions (p = 0.00002), prior therapy for KS (p = 0.00003), and number of drugs (p = 0.00002) used in concomitant antiretroviral therapy. Generally, treatment with alitretinoin gel was well tolerated. The overall incidence of adverse events was similar for the 2 treatment groups. Adverse events related to treatment with alitretinoin gel tended to be mild to moderate in severity and limited to the site of application. The most frequent adverse event occurring at the application site following alitretinoin gel treatment was irritation coded as rash (32%).

Conclusions

The results of this study provide convincing evidence of the superiority of alitretinoin gel over vehicle gel for the treatment of the cutaneous lesions of AIDS-related KS.