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 supraphysiologic glucocorticoid doses are often needed to optimally suppress the ACTH-driven adrenal androgen overproduction.

Objective: To approximate physiologic cortisol secretion via continuous subcutaneous hydrocortisone 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 conventional 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 conventional 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-

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, compared 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 one or more glucocorticoid-related last visits, patients underwent dual-energy X-ray Absorptiom- comorbidities: obesity [body mass index (BMI) Ͼ 30.0 kg/m2], etry (DXA) to assess body composition and BMD, and radio-

Figure 1. Continuous Subcutaneous Hydrocortisone Infusion (CSHI) Study Design. Fasting labs were obtained on Day 2 of Visits1-4and included: biochemistry and safety panels. 24 hours (2300 – 2300) Serial sampling included: ACTH, cortisol, 17-hydroxyprogesterone, androstenedione, progesterone and testosterone.

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. 4 Hydrocortisone pump therapy in CAH J Clin Endocrinol Metab at half of the lower limit was used in calculations. Logarithmic 0920) vs. 0832hr (0759–0905)] and exposure to cortisol transformation was used as needed to achieve a normal distri- [24hr-AUC (hr*␮g/dL): 153.5 (127.3–179.8) vs. 160.2 bution. Two-tailed tests were performed and P-values Ͻ 0.05 (148.6–171.6)], but peak cortisol concentration (Cmax) were considered statistically significant. ␮ ␮ SF-36 score was calculated using the SF-36 OptumInsight was lower [13.2 g/dL (11.0–15.4) vs. 16 g/dL (14.6– ϭ software which provides norm-based scores and applies a linear 17.4), P .020]. Efforts to increase Cmax were under- T-score transformation (mean 50, SD 10) (22, 26). AddiQoL taken, but were limited by symptoms of early morning questionnaire scores range from 30 - 120, where higher scores awakening. Glucocorticoid dose in hydrocortisone equiv- indicate better HRQoL (21). MAF data was used to compute the alents at baseline (on oral glucocorticoid) and following 6 Global Fatigue Index (GFI) score, which ranged from 1 (no fatigue) to 50 (severe fatigue), as previously described (20). months of CSHI were similar (conventional vs. CSHI: 17.7 Ϯ 1.9 vs. 17.5 Ϯ 1.3 mg/m2/d).

Results Biomarkers of disease control At 6 months, the primary efficacy endpoint, the percent 28 patients were screened. Eight adult patients with classic of patients with early morning 0700hr 17-OHP Յ 1200 CAH participated in the study (Table 1). All patients com- ng/dL, was not different than baseline (only 3 patients pleted the study but, according to medication and supply achieved this goal); however, 0700hr 17-OHP (P ϭ .021), accountability, one patient was found to be partially non- ACTH (P ϭ .024), androstenedione (P ϭ .015), and pro- compliant with the pump being disconnected approxi- gesterone (P ϭ .007) significantly decreased (Table 2). mately 30% of the time. When this patient was excluded, Similarly, 6 months of CSHI resulted in lower 24-hour analysis yielded similar results. Of the 8 patients, 6 (75%) AUC of ACTH (P ϭ .031), 17-OHP (P ϭ .027), and an- expressed the desire to continue CSHI, 2 patients found drostenedione (P ϭ .009). This was mostly due to lower the pump incompatible with their lifestyle. daytime and midday (0700–2300hr) levels (Table 2, Fig- ure 2B-E). Testosterone and plasma renin activity concen- Pharmacokinetics tration remained unchanged. CSHI pharmacokinetic cortisol profile approximated physiologic secretion (Figure 2A). CSHI therapy at 6 Glucocorticoid-related comorbidities, metabolic months compared to a prior study of healthy volunteers indices and HRQoL assessment (6) resulted in similar time to peak cortisol concentration Although weight increased (107 Ϯ 9 vs. 112 Ϯ 9 kg, P ϭ [CSHI vs. healthy: Tmax (mean, 95% CI): 0845hr (0810– .004), no significant changes were observed in HOMA-

Table 1. Baseline characteristics and hormone levels of 8 adult patients with classic congenital adrenal hyperplasia

GC Equiv GI Adrenal Age/ Dose/ 17-OHP A4 BMI Fatty Low intolerance TART/ Mass or Pt Sex Phen Meda ng/dL ng/dL kg/m2 IRb Liverc BMDd to GC PCOSe* hypertrophy 1 43/M SV 26.5/P 5972 458 28.8 ϩ -- - ϩϩf 2 25/M SW 19.3/P 19 731 1003 34.8 ϩϩ - ϩϩϩg 3 19/F SW 16/P 2999 268 51.8 ϩϩ -- - - 4 38/F SW 24.4/P 11 438 1711 39.8 ϩϩ -- - ϩ g,h 5 32/F SW 12.7/HC,P 5661 676 54.1 ϩϩ ϩ ϩ ϩ - 6 41/F SW 8.8/HC,Pl 6092 182 43 ϩϩ -- - - 7 25/F SV 13/P 6158 498 40.3 ϩ - ϩϩ ϩ - 8 41/M SW 21.2/D 7198 425 27.7 - - ϩ - ϩϩg Abbreviations: Pt, patient; Phen, phenotype; GC Equiv Dose, glucocorticoid equivalent dose; Med, medication; 17-OHP, 17-hydroxyprogesterone;

A4, androstenedione; BMI, body mass index; IR, insulin resistance; BMD, bone mineral density; GI intolerance to GC, gastrointestinal intolerance to glucocorticoid; TART, testicular adrenal rest tissue; PCOS, polycystic ovary syndrome; M, Male; F, Female; SV, simple virilizing; SW: salt-wasting; P, prednisone; HC, hydrocortisone; Pl, prednisolone; D, dexamethasone; ϩ: present; -: not present. a Glucocorticoid equivalent dose (mg/m2/day): hydrocortisone ϫ 1, prednisone and prednisolone ϫ 5, and dexamethasone ϫ 80 (3) b HOMA-IR Ͼ 2.6 c AST/ALT Ͻ1 or steatosis by ultrasound d DEXA T-score Ͻ-1 e 12 or more follicles 2–9 mm in diameter and/or an increased ovarian volume Ͼ 10 ml by ultrasound (30) f Adrenal myelolipomas g Adrenal hyperplasia h Adrenal adenoma

IR, C-peptide, leptin, C-reactive protein (CRP), lipids and six month visit, a 5% or more increase in measurable liver waist/hip circumference. Only one patient had elevated fat was observed in 2 patients, one of which was also noted systolic BP at baseline, and this did not change during the to have the largest weight gain. Adrenal imaging demon- study. Osteocalcin (16.6 Ϯ 1.8 vs. 22.6 Ϯ 2.0 ng/mL; P ϭ strated multiple fatty tumors compatible with myelolipo- .004) and CTX (379.1 Ϯ 50.6 vs. 460.0 pg/mL Ϯ 69.8, P ϭ mas in one patient and minimal bilateral hyperplasia in 3 .013) increased. patients. The patient with poor compliance had an in- Whole-body BMD and total fat mass by DXA did not crease in myelolipoma size (5 cm to 6.4 cm maximum Ϯ Ϯ change, but lean mass increased (60.7 3.7 vs. 64.3 4.4 dimension), whereas no other adrenal changes were ap- ϭ kg, P .016). AST/ALT ratio and visceral fat (as fraction preciated following 6 months of CSHI in the other 7 pa- of total fat) remained unchanged. At baseline, a moderate tients. All three men had TART, which decreased by ap- to large degree liver fat was noted in 5 of 8 patients. At the proximately 40% in the youngest (27 yo) male patient and remained stable in the other two. Three out of five women presented with secondary amenorrhea; one had resump- tion of menses during CSHI. Two women had sono- graphic findings compatible with polycystic ovaries (Ͼ25 follicles in one or both ovaries) with no observed changes over time. Compared to baseline, HRQoL (SF-36 Vitality Score: 32 Ϯ 5 vs. 64.8 Ϯ 6, P ϭ .001; AddiQoL: 72.4 Ϯ 4 vs. 86.8 Ϯ 4, P ϭ .004), and fatigue, (GFI: 25.8 Ϯ 2 vs. 12.3 Ϯ 2, P ϭ .001) improved at 6 months on CSHI (Figure 3). In addition, both symptoms of adrenal insufficiency (P ϭ .014) and symptoms of glucocorticoid overtreatment (P ϭ .003) also improved.

Adverse events CHSI was well tolerated. Serious adverse events did not occur (Table 3). No pump failure or hydrocortisone infusion set blockage was reported. All skin reactions were self-limited apart from one case, requiring oral antibiotics, and incision and drainage. Poor skin hygiene was reported or observed in all cases of local skin infection. Early morning symptoms resolved following dose adjustments. Two patients reported early morning awakening that resolved following rate adjustments aimed at producing a later cortisol rise. Symptoms of dizziness and lightheadedness resolved after increasing early morning dose. Two patients received stress dosing for minor procedures (molar extrac- tion, endoscopic carpal tunnel release) and 4 for illness.

Discussion

This is the first clinical trial to systematically evaluate CSHI in comparison to conventional oral glucocorticoid therapy in patients with classic CAH. We demonstrate

Figure 2. 24-hour serial measurement of (A) cortisol, (B) ACTH, (C) that CSHI can safely and easily achieve a cortisol profile 17-hydroxyprogesterone (17-OHP), (D) androstenedione, and (E) similar to physiologic cortisol secretion. We also show progesterone (mean Ϯ SEM) at baseline while receiving conventional that near physiologic cortisol replacement via CSHI con- oral glucocorticoid (open circles) and following 6 months of continuous subcutaneous hydrocortisone infusion (CSHI) (solid trols adrenal steroid production and improves HRQoL squares). and fatigue in difficult-to-treat classic CAH patients suf-

Table 2. Comparison of Early Morning and 24-hour Hormone Levels on Conventional Glucocorticoid Therapy at Baseline and Following 6-months of Continuous Subcutaneous Hydrocortisone Infusion (CSHI)

CSHI at 6 Baseline Months P-value 17OHP 0700 h (ng/dl) 8313 Ϯ 2748 2150 Ϯ 531 0.021 AUC-24 h (h*␮g/dl) 98.5 Ϯ 39.3 25.7 Ϯ 9.5 0.027 AUC 0700–1500 h (h*␮g/dl) 48.6 Ϯ 22.4 6.8 Ϯ 1.8 0.008 AUC 1500–2300 h (␮g*h/dl) 20.5 Ϯ 6.8 7.5 Ϯ 4.9 0.012 AUC 2300–0700 (h*␮g/dl) 29.5 Ϯ 11.1 11.4 Ϯ 3.0 0.157

A4 0700 h (ng/dl) 748 Ϯ 295 317 Ϯ 77 0.015 AUC-24 h (h*␮g/dl) 12.7 Ϯ 4.5 5.2 Ϯ 1.4 0.009 AUC 0700–1500 h (h*␮g/dl) 5.3 Ϯ 2.1 1.8 Ϯ 0.4 0.008 AUC 1500–2300 h (h*␮g/dl) 3.7 Ϯ 1.1 1.6 Ϯ 0.6 0.009 AUC 2300–0700 (h*␮g/dl) 3.7 Ϯ 1.3 1.8 Ϯ 0.4 0.043 ACTH 0700 h (pg/ml) 405 Ϯ 114 139 Ϯ 47 0.024 AUC-24 h (h*pg/ml) 2538 Ϯ 743 1087 Ϯ 359 0.031 AUC 0700–1500 h (h*pg/ml) 1239 Ϯ 402 340 Ϯ 107 0.005 AUC 1500–2300 h (h*pg/ml) 458 Ϯ 179 183 Ϯ 55 0.004 AUC 2300–0700 (h*pg/ml) 841 Ϯ 233 564 Ϯ 216 0.524 Progesterone 0700 h (ng/dl) 9.5 Ϯ 5.4 0.8 Ϯ 0.4 0.007 AUC-24 h (h*ng/dl) 101.1 Ϯ 48.8 13.7 Ϯ 4.6 0.084 AUC 0700–1500 h (h*ng/dl) 42.2 Ϯ 20.0 4.2 Ϯ 1.6 0.057 AUC 1500–2300 h (h*ng/dl) 30.7 Ϯ 17.7 5.5 Ϯ 3.2 0.103 AUC 2300–0700 (h*ng/dl) 28.2 Ϯ 12.5 4.0 Ϯ 0.5 0.070 Ϯ Abbreviations: 17OHP, 17-hydroxyprogesterone; A4, androstenedione; ACTH, adrenocorticotropic hormone; AUC, area under the curve. Means SEM P values Ͻ 0.05 are indicated with bold typeface. fering from hyperandrogenism and glucocorticoid-related ability. Despite this initial dose miscalculation, we safely comorbidities. and easily approximated a physiologic cortisol profile by Management of classic CAH with conventional oral using 24-hour sampling and multiple infusion rates glucocorticoids remains challenging since optimal sup- throughout the day. An alternative approach to using cor- pression of adrenal steroids is difficult to achieve without tisol clearance data to estimate starting rates might be to supraphysiologic glucocorticoid doses (5, 6). We chose to use an average starting dose of hydrocortisone of 15 mg/ treat an especially challenging subset of CAH patients m2/d, with subsequent dose adjustments based on 24-hour with CSHI, those with hyperandrogenism and other treat- sampling. This approach would have sufficed in half of ment-related comorbidities, because ultimately these our patients, who had a final rate within 20% of this es- types of patients might be the best candidates for pump timate. However, this approach might extend the time therapy. CSHI is expensive and complex, requiring much required to approximate a physiologic cortisol profile in patient commitment and might be best reserved for those some patients and would delay identification of patients who are not easily managed with oral therapy. who are fast metabolizers. Initially, we started patients on a basal infusion rate New ways of replacing glucocorticoid aim to improve using calculations provided by Bryan et al (10), but this the outcome of patients with adrenal insufficiency by overestimated the total daily hydrocortisone dose by ap- mimicking physiologic circadian rhythm. In our study, proximately 30%. This may be attributed to the nonlin- CSHI approximated the mean physiologic cortisol profile earity of cortisol clearance at higher hydrocortisone con- in all patients, but ACTH was not fully suppressed result- centrations due to the saturable binding of hydrocortisone ing in mildly elevated adrenal steroids in some patients. to plasma proteins. Using a lower dose of hydrocortisone Interestingly, the cortisol levels necessary to suppress the in the clearance study might have avoided this issue. In early morning ACTH rise were not tolerated by all patients addition, obesity coupled with weight fluctuations because of early or frequent awakening. Our inability to throughout the study (potentially altering the volume of fully suppress ACTH might also be due to CAH specific distribution and half-life of hydrocortisone), as well as alterations in the hypothalamic-pituitary-adrenal axis. In- patient differences in hydrocortisone metabolic rates trauterine glucocorticoid deficiency might affect postnatal likely contributed to the observed cortisol clearance vari- sensitivity to feedback inhibition, thus blunting the central

Table 3. Adverse events during Continuous Subcutaneous Hydrocortisone Infusion (CSHI) therapy.

# Adverse Event Patients Outcome (n) Skin erythema with pruritus at the 3 Self-limited (n ϭ 3). infusion set site Local skin infection at the infusion 5 Self-limited (n ϭ 4), resolved after oral antibiotics and incision and set site drainage (n ϭ 1). Dizziness 5 Resolved 2 months following CSHI (n ϭ 1), resolved after increasing early morning and decreasing 0900–1100 h dose (n ϭ 1), intermittent (n ϭ 2). Lightheadedness 5 Resolved 2 to 4 months following CSHI (n ϭ 2), resolved after increasing early morning and decreasing 0900–1100 h dose (n ϭ 1), intermittent (n ϭ 2). Weakness 3 Resolved 2 months following CSHI (n ϭ 2), intermittent (n ϭ 1). Fatigue 7 Resolved 2 months following CSHI (n ϭ 2), intermittent (n ϭ 5). Nausea 2 Resolved 2 months following CSHI (n ϭ 1), resolved after dose increase (n ϭ 1). Headache 7 Resolved by 4 months of CSHI (n ϭ 3), intermittent (n ϭ 4). Carpal Tunnel 1 Resolved after surgical procedure (n ϭ 1). Knee pain when walking 1 Intermittent (n ϭ 1). Tinnitus 1 Mild, prior diagnosis Meniere’s disease, resolved at 6 months (n ϭ 1). Decreased appetite 2 Resolved 2 months following CSHI (n ϭ 1), while on CSHI (n ϭ 1). Increased appetite 6 Resolved 2 months following CSHI (n ϭ 2), resolved spontaneously (n ϭ 2), intermittent (n ϭ 1). Difficulty Falling Asleep or Frequent 5 Resolved 2 months following CSHI (n ϭ 3), resolved after dose Wakening adjustments (n ϭ 1), intermittent (n ϭ 1). Early Morning Wakening 3 Resolved 2 months following CSHI (n ϭ 1), resolved after dose adjustments (n ϭ 2). Increased acne 2 Resolved spontaneously (n ϭ 2). Weight gain 5 Weight stable following dose reduction (n ϭ 4).

iologic cortisol exposure with nadir levels in the evening lish. However, local skin pruritus, erythema and infection may have been responsible for the above findings. De- occurred at rates similar to insulin pump users (30). It is creased fatigue may have resulted in increased physical unknown if Chronocort®, an oral modified-release hy- activity, contributing to the lean mass increase (28). Pro- drocortisone aimed at mimicking physiologic cortisol se- gestin-only oral contraceptives have been associated with cretion, is comparable to CSHI therapy. However, the a decrease in lean mass (29), suggesting that changes in the ability to fine tune the cortisol profile with a continuous adrenal hormone milieu may have contributed, but little is infusion allows for more individualized therapy, which known about the effect of progesterone or other adrenal might be beneficial in a subset of patients. In addition, steroids on lean mass. CSHI is the optimal route of hydrocortisone delivery for This exploratory study has several limitations derived patients with GI conditions that interfere with oral from its small sample size, lack of blinding and random- therapy. ization, lack of placebo-control design and heterogeneity In summary, CSHI was a well-tolerated and safe mo- of the study population (diverse comorbidities, small num- dality of hydrocortisone replacement. A physiologic cor- bers of men and women). We aimed to achieve cortisol tisol profile was achieved resulting in improved adrenal levels approximating the mean of a representative sample steroid control and positive effects on HRQoL and fatigue of healthy controls, which may not be ideal for the man- in CAH patients poorly controlled with oral glucocorti- agement of CAH patients. Additionally, although CSHI coid therapy. Longstanding morbidities such as fatty liver, was able to approximate a normal cortisol circadian se- insulin resistance, adrenal and testicular tumors, and poly- cretion profile, it was not able to mimic its ultradian cystic ovaries remained mostly unchanged following 6 rhythm. It is unknown if patients would have benefited months of CSHI, suggesting that earlier (childhood) in- from lower or higher cortisol concentrations during the tervention and preventative strategies are needed. The 24-hour period. As expected, management of CSHI was long-term effect of near physiologic cortisol replacement more time-consuming and intensive than clinical manage- has yet to be determined, but is also being studied with a ment with oral therapy. Extensive teaching was necessary novel modified-release oral preparation, Chronocort® (9). and proper hygiene with pump use took months to estab- Adverse outcomes in CAH are due to a combination of

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. doi: 10.1210/jc.2016-1916 press.endocrine.org/journal/jcem 9 disease-related and treatment-related side effects. Long- a cohort of 244 patients with congenital adrenal hyperplasia. J Clin term studies of physiologic cortisol replacement starting in Endocrinol Metab. 2012;97:4429–4438. 4. Merke DP. Approach to the adult with congenital adrenal hyper- childhood would help unravel the role glucocorticoids plasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. play in the development of comorbidities and advance 2008;93:653–660. preventative management strategies. 5. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005;365:2125–2136. 6. Debono M, Ghobadi C, Rostami-Hodjegan A, Huatan H, Campbell MJ, Newell-Price J, Darzy K, Merke DP, Arlt W, Ross RJ. Modified- Acknowledgments release hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol Metab. 2009;94:1548–1554. 7. Debono M, Mallappa A, Gounden V, Nella AA, Harrison RF, The authors are grateful to the patients for participation in this Crutchfield CA, Backlund PS, Soldin SJ, Ross RJ, Merke DP. Hor- study and the nursing staff of the 5SWN Metabolic Unit for their monal circadian rhythms in patients with congenital adrenal hyper- assistance in conducting the study. We thank Tara Kuhn for her plasia: identifying optimal monitoring times and novel disease bio- assistance with the pharmacokinetic analysis. markers. Eur J Endocrinol. 2015;173:727–737. This research was supported by the Intramural Research Pro- 8. Mah PM, Jenkins RC, Rostami-Hodjegan A, Newell-Price J, Doane A, Ibbotson V, Tucker GT, Ross RJ. Weight-related dosing, timing gram of the National Institutes of Health, and (in part) by and monitoring hydrocortisone replacement therapy in patients Medtronic Diabetes Company who generously provided the with adrenal insufficiency. Clin Endocrinol (Oxf). 2004;61:367– pump devices and supplies, and offered training and technical 375. support. 9. Mallappa A, Sinaii N, Kumar P, Whitaker MJ, Daley LA, Digweed D, Eckland DJ, Van Ryzin C, Nieman LK, Arlt W, Ross RJ, Merke Disclosure summary: DPM received unrelated research funds DP. A phase 2 study of Chronocort, a modified-release formulation from Diurnal Ltd and is a Commissioned Officer in the United of hydrocortisone, in the treatment of adults with classic congenital States Public Health Service. adrenal hyperplasia. J Clin Endocrinol Metab. 2015;100:1137– 1145. Address all correspondence and requests for reprints to: 10. Bryan SM, Honour JW, Hindmarsh PC. Management of altered *Corresponding Author and person to who reprint requests hydrocortisone pharmacokinetics in a boy with congenital adrenal hyperplasia using a continuous subcutaneous hydrocortisone infu- should be addressed: Aikaterini A. Nella, M.D., Department of sion. J Clin Endocrinol Metab. 2009;94:3477–3480. Pediatrics, Division of Pediatric Endocrinology, University of 11. Gagliardi L, Nenke MA, Thynne TR, von der Borch J, Rankin WA, Texas Medical Branch, Research Building 6, Suite 3.270C, 301 Henley DE, Sorbello J, Inder WJ, Torpy DJ. Continuous subcuta- University Blvd., Galveston TX, 77555–0373, Office: (409) neous hydrocortisone infusion therapy in Addison’s disease: a ran- 747–6661, Fax: (409) 747–2213, Email: [email protected]. domized, placebo-controlled clinical trial. J Clin Endocrinol Metab. This work was supported by This work was supported by the 2014;99:4149–4157. Intramural programs of the National Institutes of Health Clin- 12. 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