Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Schmith GD

PROVIDER: S-EPMC4429579 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Schmith G D GD Singh R R Gomeni R R Graff O O Hamedani A G AG Troughton J S JS Learned S M SM

CPT: pharmacometrics & systems pharmacology 20150417 4

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 ...[more]

PMID: 26225249

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Project description:BACKGROUND:The Hand Eczema Severity Index (HECSI) is used to measure the severity of hand eczema. It is unclear what HECSI scores mean and what is the minimally important change (MIC). Furthermore, its responsiveness has not been studied. OBJECTIVES:To study the responsiveness and interpretability of the HECSI. METHODS:This was a prospective study covering two time points: baseline and after 4-12 weeks. Responsiveness was assessed using a criterion approach, with at least one-step improvement on the 'Photographic guide for severity of hand eczema' as the anchor for important improvement. Interpretability of single scores was determined by defining severity bands based on agreement with the anchor. For change scores, the smallest detectable change (SDC) was calculated in patients indicating no change and the MIC was obtained in patients indicating that they had changed using three methods: mean cutoff, receiver operating characteristic (ROC) curve and 95% limit. RESULTS:In total, 294 patients participated (160 male, mean age 44·9 years). HECSI scores improved or deteriorated in parallel with the anchor. The area under the ROC curve was 0·86 (95% confidence interval 0·81-0·91). The final severity band for single scores had a ?-coefficient of agreement of 0·694: clear, 0; almost clear, 1-16; moderate, 17-37; severe, 38-116; very severe, ? 117. The SDC in 93 unchanged patients was 40·3 points. The obtained MIC values were all smaller than the SDC. CONCLUSIONS:The HECSI has good responsiveness. This study gives meaning to HECSI scores, which can be applied to clinical decision making and the design of clinical trials. We recommend that an improvement of 41 points on the HECSI is regarded as the minimally measurable true change. What's already known about this topic? The Hand Eczema Severity Index (HECSI) is one of the most widely used measurement instruments to measure the severity of hand eczema. The HECSI has good reliability, but its responsiveness and interpretability have not been studied. What does this study add? This study shows good responsiveness of the HECSI. A severity grading for single scores is proposed. The smallest detectable change and minimally important change for improvement are determined. What are the clinical implications of this work? The obtained values help to interpret HECSI scores in daily practice and clinical studies, and may facilitate researchers in the calculation of sample sizes for clinical trials.

Dataset Information

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

Publications

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

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