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Phase-2-Pump-Study.Pdf ORIGINAL ARTICLE A Phase 2 Study of Continuous Subcutaneous Hydrocortisone Infusion in Adults with Congenital Adrenal Hyperplasia Aikaterini A. Nella1,2, Ashwini Mallappa2, Ashley F. Perritt2, Verena Gounden2, Parag Kumar2, Ninet Sinaii2, Lori-Ann Daley2, Alexander Ling2, Chia-Ying Liu2, Steven J. Soldin2, Deborah P. Merke1,2 (1) Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA 20892; (2) National Institutes of Health Clinical Center, Bethesda MD, USA 20892 Context: Classic congenital adrenal hyperplasia (CAH) management remains challenging, as sup- raphysiologic glucocorticoid doses are often needed to optimally suppress the ACTH-driven ad- renal androgen overproduction. Objective: To approximate physiologic cortisol secretion via continuous subcutaneous hydrocor- tisone infusion (CSHI) and evaluate the safety and efficacy of CSHI in difficult-to-treat CAH patients. Design: Eight adult patients with classic CAH participated in a single-center open label phase I-II study comparing CSHI to conventional oral glucocorticoid treatment. All patients had elevated adrenal steroids and one or more comorbidities at study entry. Assessment while receiving con- ventional therapy at baseline and 6 months following CSHI included: 24-hr hormonal sampling, metabolic and radiologic evaluation, health-related quality-of-life (HRQoL) and fatigue questionnaires. Main Outcome Measure(s): The ability of CSHI to approximate physiologic cortisol secretion and the percent of patients with 0700hr 17-hydroxyprogesterone (17-OHP) Յ 1,200 ng/dL. Results: CSHI approximated physiologic cortisol secretion. Compared to baseline, 6 months of CSHI resulted in decreased 0700hr and 24-hr AUC 17-OHP, androstenedione, ACTH, and progesterone, increased osteocalcin, c-telopeptide and lean mass, and improved HRQoL (AddiQoL, and SF-36 Vitality Score) and fatigue. One of 3 amenorrheic women resumed menses. One man had reduction of testicular adrenal rest tissue. Conclusions: CSHI is a safe and well tolerated modality of cortisol replacement that effectively approximates physiologic cortisol secretion in patients with classic CAH poorly controlled on con- ventional therapy. Improved adrenal steroid control and positive effects on HRQoL suggest that CSHI should be considered a treatment option for classic CAH. The long-term effect on established comorbidities requires further study. ongenital adrenal hyperplasia (CAH) refers to a group sterone biosynthesis results in excess adrenocorticotropic C of autosomal recessive disorders of adrenal steroid- hormone (ACTH)-driven adrenal steroid production. ogenesis with 21-hydroxylase deficiency accounting for Conventional cortisol replacement with oral glucocorti- 95% of cases (1). In the classic form, 21-hydroxylase en- coids once, twice or thrice daily remains suboptimal, and zyme function is lacking and deficient cortisol and aldo- often fails to effectively suppress adrenal steroid produc- ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: Printed in USA Copyright © 2016 by the Endocrine Society Received April 18, 2016. Accepted September 22, 2016. doi: 10.1210/jc.2016-1916 J Clin Endocrinol Metab press.endocrine.org/journal/jcem 1 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 17 October 2016. at 07:57 For personal use only. No other uses without permission. All rights reserved. 2 Hydrocortisone pump therapy in CAH J Clin Endocrinol Metab tion without supraphysiologic doses (2–5). Difficult-to- fatty liver disease [AST to ALT ratio Ͻ 1 (16) and/or steatosis per treat CAH patients typically present with a combination liver ultrasound (17)], low insulin sensitivity [Homeostasis Ͼ of CAH-related (hyper-androgenemia, testicular adrenal Model Assessment Insulin Resistance (HOMA-IR) 2.6, where HOMA-IR ϭ [insulin (␮U/ml) x glucose (mmol/L)]/ 22.5 (18, rest tissue, amenorrhea and adrenal tumors) and gluco- 19)], osteopenia or osteoporosis (BMD T-score Ͻ –1), or glu- corticoid overtreatment-related [iatrogenic Cushing syn- cocorticoid-related gastrointestinal (GI) side effects. Exclusion drome, obesity, visceral adiposity, insulin resistance and criteria included: pregnancy, lactation or use of an estrogen- low bone mineral density (BMD)] complications (2, 3). containing medication (women), use of medications that induce Physiologic cortisol secretion demonstrates a distinct hepatic enzymes or interfere with glucocorticoid metabolism, use of glucocorticoids for reasons other than CAH, history of circadian rhythm, characterized by nadir cortisol level bilateral adrenalectomy, or comorbid conditions that could in- shortly after midnight, peak secretion early in the morning terfere with protocol compliance. All patients were on un- (6) and variable, although declining levels during the day. changed fludrocortisone and glucocorticoid (5 prednisone, 1 Exogenous glucocorticoid replacement is unable to repli- dexamethasone, 2 combination) therapy for at least 3 months cate this pattern since postdose peaks are typically fol- prior to study entry. The study was approved by the Eunice Kennedy Shriver Na- lowed by troughs before the next dose (7, 8). New oral tional Institute of Child Health & Human Development Insti- hydrocortisone formulations (9) and alternative hydro- tutional Review Board. All patients provided written informed cortisone delivery systems (continuous subcutaneous hy- consent. drocortisone infusion (CSHI)) (10–15) are being studied with the aim of mimicking the cortisol circadian rhythm Study Design and suppressing the overnight ACTH-driven steroid pro- Our objective was to safely achieve near-physiologic cortisol duction. Two recent randomized multicenter clinical trials replacement with CSHI and describe the efficacy of CSHI, com- pared to conventional oral glucocorticoid therapy, based on of CSHI in Addison’s disease demonstrated morning changes in adrenal steroid production and comorbidity status ACTH and cortisol levels similar to the normal circadian following 6 months of therapy. secretion, unlike conventional oral hydrocortisone (11, The primary efficacy endpoint was the percent of patients 13). Case reports of CSHI in CAH have shown improved with early morning 0700hr 17-OHP Յ 1200 ng/dL. Secondary adrenal steroid control at doses similar or lower than con- endpoints included changes in: a) 17-OHP, androstenedione, ventional glucocorticoid therapy (10, 14, 15); however no ACTH, progesterone [0700hr, AUC-24 hrs, AUC daytime (0700–1500), AUC midday (1500–2300), AUC nighttime clinical trials have been performed to systematically in- (2300–0700)]; b) fasting insulin; c) HOMA-IR; d) weight and vestigate this hypothesis. BMI; e) body composition and BMD; f) bone turnover markers The aim of this study was to evaluate cortisol replace- [cross-linked telopeptide (CTX) and osteocalcin]; g) waist and ment via CSHI as compared to conventional oral gluco- hip circumference; h) percent of patients with hypertensive blood corticoid therapy in difficult-to-treat classic CAH pa- pressure (BP); j) liver steatosis and AST/ALT ratio; i) adrenal gland size and morphology; k) fatigue and health-related quality- tients. We aimed to mimic the normal diurnal cortisol of-life (HRQoL); l) daily glucocorticoid dose based on gluco- rhythm and hypothesized that near-physiologic cortisol corticoid equivalencies; and m) signs and symptoms of adrenal replacement via CSHI would improve CAH control and insufficiency. related comorbidities in difficult-to-treat patients as com- All patients underwent a screening visit for eligibility. Patients pared to conventional oral glucocorticoid therapy. were evaluated every two months over a 6-month period (Figure 1). All patients underwent a history and physical (by A.A.N or A. M.), and fasting laboratory evaluation of electrolytes, liver and renal function, complete blood count (CBC), lipids, insulin, Materials and Methods bone turnover markers, and pregnancy test (women only), along with 24-hour sampling. Questionnaires to evaluate fatigue (Mul- Patients tidimensional Assessment of Fatigue (MAF) Scale) (20), HRQoL Eight adult patients (5 females, 19 - 42 years, and 3 males, 25 [adrenal insufficiency-specific HRQoL (AddiQoL) (21), SF- - 43 years) with classic CAH due to 21-hydroxylase deficiency 36v2® Health Survey/Four-Week Recall (22)], and symptoms of participated in this open label phase I-II study. Four patients were adrenal insufficiency or glucocorticoid overtreatment were ad- recruited from a pool of 147 adult CAH patients enrolled in the ministered. A hydrocortisone clearance study was performed at NIH Natural History Study (NCT00250159). The remaining 4 baseline. An intravenous (IV) bolus injection of 100 mg Hydro- patients were recruited through advertisements. cortisone (Solucortef®) was given followed by cortisol measure- The diagnosis of classic CAH due to 21-hydroxylase defi- ments every 10-minutes for a total of 150 minutes (23). After a ciency was confirmed by hormonal and genetic testing. All pa- washout period (12 hours for hydrocortisone and prednisone, 36 tients had difficult-to-treat CAH, defined as the coexistence of hours for dexamethasone), CSHI was initiated. Pump infusion elevated adrenal biomarkers (17-OHP Ͼ 1200 ng/dL or/and an- was adjusted prior to discharge based on sampling approxi- drostenedione above the normal range at approximately 0700hr mately 24 and 36 hours after pump initiation. On the first and and prior to medication), and
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