Oral alitretinoin treatment in patients with palmoplantar pustulosis inadequately responding to standard topical treatment: a randomized phase II study.

BACKGROUND: Palmoplantar pustulosis (PPP) is an inflammatory, debilitating skin disease. Topical drugs and systemic immunosuppressive agents are often ineffective. Previous uncontrolled studies have suggested that alitretinoin could be a meaningful treatment option for PPP. OBJECTIVES: The primary objective was to determine response to alitretinoin for the treatment of PPP based on the Palmoplantar Pustulosis Area and Severity Index (PPPASI) after 24 weeks of treatment. METHODS: A phase II, randomized, double-blind, placebo-controlled, multicentre study. Adult patients with PPP (with or without psoriasis) refractory to topical therapy and standard skin care were randomized 2:1 to alitretinoin 30 mg once daily or placebo for up to 24 weeks. The primary end point was PPPASI at week 24 (or the last visit in case of early withdrawal). Secondary end points included: percentage change from baseline in the modified Psoriasis Area and Severity Index (mPASI); percentage of patients with ≥ 50% or 75% improvement in PPPASI or mPASI scores from baseline; change in pustule count on the palms and soles; change in the Nail Psoriasis Severity Index and safety and tolerability assessments. RESULTS: Thirty-three patients were randomized: 24 patients to alitretinoin 30 mg and nine to placebo. Overall, there were no significant differences between alitretinoin 30 mg and placebo for any end point. The safety profile was consistent with that seen in patients with chronic severe hand eczema refractory to potent topical corticosteroids. CONCLUSIONS: Although the results were unexpected based on previous studies of alitretinoin in the treatment of PPP, this study provided no evidence to support further exploration of alitretinoin in the treatment of severe PPP.

Use of Longitudinal Dose-Response Modeling to Support the Efficacy and Tolerability of Alitretinoin in Severe Refractory Chronic Hand Eczema (CHE).

Longitudinal dose-response analyses of alitretinoin (an investigational agent in the US) were conducted to supplement results from phase III studies in severe, refractory chronic hand eczema, with objectives to address several outstanding development issues (e.g., optimal dose, possible factors affecting efficacy and/or tolerability). Models were fitted to the physicians' global assessment score and triglycerides over time. Five hundred trials were simulated to evaluate the relevance of findings. Analyses clarified that the optimal dose of alitretinoin was 30 mg once daily, where response rates were ∼10% over placebo at 12 weeks and increased by 5-7% over placebo for every 4 weeks thereafter, for up to 24 weeks. Elderly subjects had higher magnitudes of efficacy and an increased probability of high triglycerides. Results from analyses sufficiently addressed the development issues, thereby adding to the weight of evidence supporting the efficacy and safety of alitretinoin in the treatment of severe, refractory chronic hand eczema.

Leukocyte counts in cerebrospinal fluid and blood following firategrast treatment in subjects with relapsing forms of multiple sclerosis.

BACKGROUND AND PURPOSE: Firategrast is an orally bioavailable alpha4 beta1/alpha4 beta7 integrin antagonist designed to reduce trafficking of lymphocytes into the central nervous system (CNS). This could decrease multiple sclerosis (MS) activity, but may compromise CNS immune surveillance. We aimed to quantitate the effect of firategrast treatment on cerebrospinal fluid (CSF) lymphocyte count and the extent/speed of recovery after its discontinuation. METHODS: Forty-six subjects with relapsing forms of MS were treated for up to 24 weeks with open-label firategrast, 900 (females) or 1200 (males) mg twice daily. CSF and blood cell counts, and lymphocyte composition were determined using flow cytometry. RESULTS: Median (n, range) CSF lymphocyte counts (cells/µl) at weeks 0, 24, 28 and 36 were: 5.3 (44, 0.3-70.2), 3.3 (31, 0.0-99.0), 3.0 (32, 0.0-58.2) and 3.5 (29, 0.0-274.8). CD4+, CD8+ T- and CD19+ B-lymphocyte counts followed a similar pattern. Minimal changes were observed for CD3-CD16+CD56+ natural killer cells. Median CD4 : CD8 ratios were: 2.9 (41, 1.1-10.9), 2.2 (29, 0.6-5.9), 3.8 (28, 1.6-9.0) and 3.8 (21, 2.1-9.4). Blood lymphocyte counts were elevated at weeks 4 and 24, consistent with the mechanism of firategrast, and returned to baseline when firategrast was discontinued. There were minimal changes in CD4 : CD8 ratios. CONCLUSIONS: Firategrast treatment was associated with modest decreases in median CSF total, CD4, CD8 and CD19 lymphocyte counts. The generally small magnitude of decreases suggests that sufficient numbers of lymphocytes can access the subarachnoid space, preserving CNS immune surveillance.

Efficacy and safety of dofetilide in the prevention of symptomatic episodes of paroxysmal supraventricular tachycardia: a 6-month double-blind comparison with propafenone and placebo.

BACKGROUND: Existing drug therapies for paroxysmal supraventricular tachycardia (PSVT) have potentially serious adverse effects. Dofetilide, a pure class III antiarrhythmic agent, may offer an effective and safe alternative for treating PSVT. This study compared the efficacy and safety of dofetilide with that of propafenone and placebo in the prevention of PSVT. METHODS: This multicenter, randomized, placebo-controlled, parallel-group study compared the effectiveness of oral dofetilide 500 microg given twice daily with that of propafenone 150 mg given 3 times a day and placebo in preventing the recurrence of PSVT in 122 symptomatic patients. Episodes of PSVT were documented by symptom diaries and Hertcard (Hertford Medical, Hertfordshire, UK) event recorders. RESULTS: After 6 months of treatment, patients taking dofetilide, propafenone, and placebo had a 50%, 54%, and 6% probability, respectively, of remaining free of episodes of PSVT (P <.001 for both dofetilide and propafenone vs placebo). Both dofetilide and propafenone also decreased the frequency of episodes of PSVT; the median numbers of episodes in the dofetilide- and propafenone-treated groups were 1 and 0.5, respectively, compared with 5 in the placebo-treated group. Dofetilide was well tolerated; no proarrhythmia occurred. Three patients taking propafenone had serious treatment-related adverse effects that required drug discontinuation. CONCLUSIONS: Dofetilide and propafenone were equally effective in preventing the recurrence of or decreasing the frequency of PSVT.

Efficacy and safety of intravenously administered dofetilide in acute termination of atrial fibrillation and flutter: a multicenter, randomized, double-blind, placebo-controlled trial. Danish Dofetilide in Atrial Fibrillation and Flutter Study Group.

BACKGROUND: This study was designed to assess the efficacy and safety of intravenous dofetilide in acute termination of atrial fibrillation (AF) and flutter (AFL). Dofetilide, an investigational class III antiarrhythmic agent, selectively inhibits the rapid component of the delayed rectifier potassium current, thus prolonging the effective refractory period and duration of the action potential. Dofetilide can be administered intravenously and has a rapid onset of electrophysiologic action. METHODS AND RESULTS: Ninety-six patients with AF (n = 79) or AFL (n = 17) with a median arrhythmia duration of 62 days (range 1 to 180) were randomized to placebo (n = 30) or 8 micrograms/kg IV dofetilide (n = 66) over 30 minutes. Conversion was defined as termination of the atrial arrhythmia within 3 hours from the start of infusion. The conversion rate was 30.3% after dofetilide and 3.3% after placebo (P <.006). Conversion rate was higher in AFL than in AF: 64% versus 24% (P =. 012). In nonconverters, there was no statistically significant difference between the change in heart rate among the dofetilide-treated compared with the placebo-treated patients (P =. 42). Torsade de pointes ventricular tachycardia developed in 2 patients (3%). In both patients, drug infusion was discontinued before the event because of prolongation of the QT interval. CONCLUSIONS: Intravenous dofetilide is effective in acute termination of AF and AFL of medium duration, with a particularly high efficacy rate in AFL. A small but serious risk of proarrhythmia must be anticipated.