Psychometric Evaluation of the Cushing’s Quality-of-Life Questionnaire
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Cushing’s disease (CD) is a rare disorder of chronic hypercortisolism due to an adrenocorticotropic hormone (ACTH)-secreting pituitary corticotroph adenoma. Because hypercortisolism symptoms are wide ranging, it is important to assess a variety of outcomes including both clinical factors, such as cortisol levels, and health-related quality of life (HR-QOL), to better understand the severity and impact of CD on patients and the potential efficacy of CD treatment. Pasireotide, a somatostatin analog that targets somatostatin receptors on the pituitary adenoma, is under development as a treatment for CD. A phase III clinical trial was conducted to investigate its safety and efficacy in patients with CD. In this trial, HR-QOL was assessed with the Cushing’s Quality-of-Life (CushingQOL) questionnaire, specifically developed and validated in patients with Cushing’s syndrome.
Reliability, validity, the ability to detect change, and a minimal important difference (MID) were evaluated for the CushingQOL questionnaire using data from patients diagnosed with CD who participated in the phase III clinical trial designed to assess the safety and efficacy of different doses of pasireotide.
Adult patients (n = 162) with CD participated in a randomized, double-blind, multinational, phase III clinical trial. Patients received subcutaneous pasireotide (600 μg or 900 μg) twice daily for 3 months (double blind). After 3 months, some patients were unblinded based on their mean urinary free cortisol (mUFC) levels and were given the chance to increase their dosage, while the other patients remained blinded. At month 6, an open-label 6-month period began. The CushingQOL questionnaire was self-administered four times (baseline [n = 160], and at months 3 [n = 134], 6 [n = 113], and 12 [n = 76]). A confirmatory factor analysis (CFA) was conducted. Reliability estimates were calculated for internal consistency (coefficient alpha) and test retest (intraclass correlation coefficients [ICCs]) for patients with stable hypercortisolism at month 3 and month 6. Construct validity hypotheses (correlations), mean differences in known groups (ANOVAs), and responsiveness effect sizes (Guyatt’s) were estimated based on measures of cortisol, body mass index (BMI), waist circumference, weight, facial rubor (redness), striae (stretch marks), bruising, supraclavicular fat pad, dorsal fat pad, and results of the Beck Depression Inventory II (BDI-II). The half-standard deviation distribution method was used to estimate MID.
CFA loadings supported a one-factor solution for the CushingQOL questionnaire items. Internal consistency reliability (0.87–0.88) and ICCs (0.87) were high. Construct validity hypotheses were in the anticipated direction. Changes in CushingQOL scores were moderately correlated with changes in mUFC levels, in BMI, and in weight. Mean scores for minimally depressed patients were significantly higher (indicating better HR-QOL) than for severely depressed patients. Moderate Guyatt’s responsiveness effect sizes were observed for patients who achieved reductions in weight, BMI, and waist circumference. Using the half-standard deviation method, an estimate of the MID was computed as 10.1.
This study provided evidence within the context of a longitudinal design that the CushingQOL questionnaire is a reliable, valid, and responsive instrument for the assessment of HR-QOL in adults with CD in accordance with recommendations set forth by regulatory agencies in the USA and Europe.
KeywordsWaist Circumference Minimal Important Difference Pasireotide Facial Rubor Bilateral Inferior Petrosal Sinus Sampling
This work was a collaboration between Novartis, IMS Health, and RTI Health Solutions (RTI-HS) with the financial support of Novartis. Novartis (USA or Switzerland) employees included Anna Forsythe, Sonia Pulgar (now employed by GlaxoSmithKline, Research Triangle Park, NC, USA), Mario Maldonado, and Yanqiong Zhang. Consultants, who were paid by Novartis, included Lori McLeod, Lauren M. Nelson, and Theresa Coles (RTI-HS employees); Susan M. Webb (Universitat Autònoma de Barcelona employee); and Xavier Badia (IMS Health employee). The authors thank the sites and patients included in the clinical study as well as the two anonymous reviewers who provided thoughtful comments and suggestions.
Lauren M. Nelson and Theresa Coles were involved in the development of the analysis plan, analyses, and interpretation of the data. Anna Forsythe was involved in the planning of the manuscript, including acquiring the data, critical review, and revision to the analysis plan, and interpretation of the data. Lori McLeod was involved in the development of the analysis plan as well as review of the analyses and interpretation. Sonia Pulgar and Mario Maldonado were involved in the planning of the study as well as critical review and revision of the analysis plan, and interpretation of the data. Yanqiong Zhang was involved in critical review of the analysis plan, acquiring data, critical review of the analyses, and interpretation of the data. Susan M. Webb and Xavier Badia were involved in the development of the CushingQOL questionnaire, critical review and revision of the analysis plan, and interpretation of the data. All authors were involved in the drafting of sections of the manuscript and approved the final version. Lauren M. Nelson is the corresponding author and guarantor of the overall content.
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