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Evaluation of Evidence of Adrenal Insufficiency in Trials of Normocortisolemic Patients Treated With Mifepristone.

ABSTRACT: Context:Adrenal insufficiency (AI) is an important medical concern for clinicians when normocortisolemia is achieved during treatment of endogenous Cushing syndrome (CS). Objective:To examine symptoms of potential AI in a large population of normocortisolemic patients without CS treated with mifepristone, a glucocorticoid receptor antagonist indicated for the treatment of patients with CS. Methods:We conducted a pooled safety analysis of five phase 3, placebo-controlled clinical trials of normocortisolemic adults without CS but diagnosed with psychotic depression (n = 1460). Patients were treated with once-daily mifepristone 300 mg (n = 110), 600 mg (n = 471), or 1200 mg (n = 252), or placebo (n = 627) administered for 7 consecutive days. All study investigators were trained and instructed to assess for the development of AI and to report all adverse events (AEs) at each clinic visit. The incidence of (1) AI or similar terminologies and that of (2) ?3 concurrent symptoms that could be associated with AI was evaluated. Results:Mean serum cortisol and adrenocorticotropic hormone levels increased dose dependently with mifepristone treatment. There were no reports of AI and no significant differences between the mifepristone-treated and placebo groups in the incidence of patients having ?3 AEs that could be associated with AI. Conclusions:This large pooled analysis of normocortisolemic patients without CS found no cases of AI and no differences between mifepristone therapy and placebo in the incidence of symptom combinations mimicking AI, even at the highest (1200 mg) dose. These findings further add clinically important insights to the safety and tolerability profile of mifepristone therapy.

SUBMITTER: Yuen KCJ

PROVIDER: S-EPMC5686650 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Evaluation of Evidence of Adrenal Insufficiency in Trials of Normocortisolemic Patients Treated With Mifepristone.

Yuen Kevin C J KCJ Moraitis Andreas A Nguyen Dat D

Journal of the Endocrine Society 20170221 4

<h4>Context</h4>Adrenal insufficiency (AI) is an important medical concern for clinicians when normocortisolemia is achieved during treatment of endogenous Cushing syndrome (CS).<h4>Objective</h4>To examine symptoms of potential AI in a large population of normocortisolemic patients without CS treated with mifepristone, a glucocorticoid receptor antagonist indicated for the treatment of patients with CS.<h4>Methods</h4>We conducted a pooled safety analysis of five phase 3, placebo-controlled cli ...[more]

PMID: 29264481

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Project description:ObjectiveThis study aimed at comparing precursors of endogenous corticosteroid production in patients with primary adrenal insufficiency and in secondary adrenal insufficiency.DesignTwenty patients with primary adrenal insufficiency and matched controls and 19 patients with secondary adrenal insufficiency participated in this ancillary analysis of two different studies.Patients and measurementsPatients with primary adrenal insufficiency were on stable hydrocortisone and fludrocortisone therapy. Patients with secondary adrenal insufficiency received two different doses of hydrocortisone in a randomized crossover study. Main outcome measures were concentrations of precursors of cortisol and aldosterone measured by LC-MS/MS RESULTS: Compared to controls, progressively lower concentrations of the glucocorticoid precursors 11-deoxycortisol, 11-deoxycorticosterone and corticosterone concentrations were found in patients with secondary adrenal insufficiency on lower hydrocortisone dose, secondary adrenal insufficiency on higher hydrocortisone dose and primary adrenal insufficiency, respectively. Half of the primary adrenal insufficient patients showed evidence of residual endogenous cortisol or aldosterone synthesis, as determined by quantifiable 11-deoxycortisol, 11-deoxycorticosterone and corticosterone conce ntrations. In secondary adrenal insufficient patients with higher endogenous cortisol production, as indicated by 11-deoxycortisol concentrations above the median, no increased cortisol exposure was observed both by plasma pharmacokinetic parameters and 24-hour free cortisol excretion in urine.ConclusionsAdrenal corticosteroid production is likely to continue during treatment in a considerable percentage of patients with both primary and secondary adrenal insufficiency. In patients with secondary adrenal insufficiency, this synthesis appears to be sensitive to the dose of hydrocortisone. However, the residual corticosteroid concentrations were quantitatively low and its clinical significance remains therefore to be determined.

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Evaluation of Evidence of Adrenal Insufficiency in Trials of Normocortisolemic Patients Treated With Mifepristone.

Publications

Evaluation of Evidence of Adrenal Insufficiency in Trials of Normocortisolemic Patients Treated With Mifepristone.

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