Global clinical response in Cushing's syndrome patients treated with mifepristone

Abstract

Objective: Mifepristone, a glucocorticoid receptor antagonist, improves clinical status in patients with Cushing's syndrome (CS). We examined the pattern, reliability and correlates of global clinical response (GCR) assessments during a 6-month clinical trial of mifepristone in CS.

Design: Post hoc analysis of secondary end-point data from a 24-week multicentre, open-label trial of mifepristone (300-1200 mg daily) in CS. Intraclass correlation coefficient (ICC) was used to examine rater concordance, and drivers of clinical improvement were determined by multivariate regression analysis.

Patients: Forty-six adult patients with refractory CS along with diabetes mellitus type 2 or impaired glucose tolerance, and/or a diagnosis of hypertension.

Measurements: Global clinical assessment made by three independent reviewers using a three-point ordinal scale (+1 = improvement; 0 = no change; -1 = worsening) based on eight broad clinical categories including glucose control, lipids, blood pressure, body composition, clinical appearance, strength, psychiatric/cognitive symptoms and quality of life at Weeks 6, 10, 16, and 24.

Results: Positive GCR increased progressively over time with 88% of patients having improved at Week 24 (P < 0·001). The full concordance among reviewers occurred in 76·6% of evaluations resulting in an ICC of 0·652 (P < 0·001). Changes in body weight (P < 0·0001), diastolic blood pressure (P < 0·0001), two-hour postoral glucose challenge glucose concentration (P = 0·0003), and Cushingoid appearance (P = 0·022) were strong correlates of GCR.

Conclusions: Mifepristone treatment for CS results in progressive clinical improvement. Overall agreement among clinical reviewers was substantial and determinants of positive GCR included change in weight, blood pressure, glucose levels and appearance.

Figure 1

Global clinical response rate over time and by gender. (a) The prevalence of patients scored as responders increased over time (P<0·001). Week 24/ET represents all patients who completed the study or had an early termination visit. Final visit indicates the last visit evaluated (last observation carried forward). The a priori threshold responder rate for significance was set at ≥30%. Error bars represent the lower end of the one-sided 95% confidence interval. (b) The global clinical response (GCR) by gender through Week 24 differed by gender (P=0·02 for first GCR, and P=0·003 for effect over time). Week 24/ET represents all patients who completed or had an early termination visit. Final visit indicates the last visit evaluated (last observation carried forward).

Figure 2

Clinical improvement over time. Progressive improvement in Cushingoid appearance in the patient population as assessed by the clinical site investigators. P-values are compared to baseline.

Figure 3

Quality of life measures (SF-36). Clinical improvement over time based on evaluation of the SF-36 subdomains demonstrated improvement in 7 of 8 measures in the patient population. P-values are compared to baseline.