A Phase 2 Study of Continuous Subcutaneous Hydrocortisone ...A Phase 2 Study of Continuous...

A Phase 2 Study of Continuous SubcutaneousHydrocortisone Infusion in Adults with CongenitalAdrenal 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, NationalInstitutes 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-IIstudy comparing CSHI to conventional oral glucocorticoid treatment. All patients had elevatedadrenal 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 fatiguequestionnaires.

Main Outcome Measure(s): The ability of CSHI to approximate physiologic cortisol secretion andthe percent of patients with 0700hr 17-hydroxyprogesterone (17-OHP) � 1,200 ng/dL.

Results: CSHI approximated physiologic cortisol secretion. Compared to baseline, 6 months of CSHIresulted 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-36Vitality Score) and fatigue. One of 3 amenorrheic women resumed menses. One man had reductionof testicular adrenal rest tissue.

Conclusions: CSHI is a safe and well tolerated modality of cortisol replacement that effectivelyapproximates physiologic cortisol secretion in patients with classic CAH poorly controlled on con-ventional therapy. Improved adrenal steroid control and positive effects on HRQoL suggest thatCSHI should be considered a treatment option for classic CAH. The long-term effect on establishedcomorbidities requires further study.

Congenital adrenal hyperplasia (CAH) refers to a groupof autosomal recessive disorders of adrenal steroid-

ogenesis with 21-hydroxylase deficiency accounting for95% of cases (1). In the classic form, 21-hydroxylase en-zyme function is lacking and deficient cortisol and aldo-

sterone biosynthesis results in excess adrenocorticotropichormone (ACTH)-driven adrenal steroid production.Conventional cortisol replacement with oral glucocorti-coids once, twice or thrice daily remains suboptimal, andoften fails to effectively suppress adrenal steroid produc-

ISSN Print 0021-972X ISSN Online 1945-7197Printed in USACopyright © 2016 by the Endocrine SocietyReceived April 18, 2016. Accepted September 22, 2016.

Abbreviations:

O R I G I N A L A R T I C L E

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.

tion without supraphysiologic doses (2–5). Difficult-to-treat CAH patients typically present with a combinationof CAH-related (hyper-androgenemia, testicular adrenalrest tissue, amenorrhea and adrenal tumors) and gluco-corticoid overtreatment-related [iatrogenic Cushing syn-drome, obesity, visceral adiposity, insulin resistance andlow bone mineral density (BMD)] complications (2, 3).

Physiologic cortisol secretion demonstrates a distinctcircadian rhythm, characterized by nadir cortisol levelshortly after midnight, peak secretion early in the morning(6) and variable, although declining levels during the day.Exogenous glucocorticoid replacement is unable to repli-cate this pattern since postdose peaks are typically fol-lowed by troughs before the next dose (7, 8). New oralhydrocortisone formulations (9) and alternative hydro-cortisone delivery systems (continuous subcutaneous hy-drocortisone infusion (CSHI)) (10–15) are being studiedwith the aim of mimicking the cortisol circadian rhythmand suppressing the overnight ACTH-driven steroid pro-duction. Two recent randomized multicenter clinical trialsof CSHI in Addison’s disease demonstrated morningACTH and cortisol levels similar to the normal circadiansecretion, unlike conventional oral hydrocortisone (11,13). Case reports of CSHI in CAH have shown improvedadrenal steroid control at doses similar or lower than con-ventional glucocorticoid therapy (10, 14, 15); however noclinical trials have been performed to systematically in-vestigate this hypothesis.

The aim of this study was to evaluate cortisol replace-ment via CSHI as compared to conventional oral gluco-corticoid therapy in difficult-to-treat classic CAH pa-tients. We aimed to mimic the normal diurnal cortisolrhythm and hypothesized that near-physiologic cortisolreplacement via CSHI would improve CAH control andrelated comorbidities in difficult-to-treat patients as com-pared to conventional oral glucocorticoid therapy.

Materials and Methods

PatientsEight adult patients (5 females, 19 - 42 years, and 3 males, 25

- 43 years) with classic CAH due to 21-hydroxylase deficiencyparticipated in this open label phase I-II study. Four patients wererecruited from a pool of 147 adult CAH patients enrolled in theNIH Natural History Study (NCT00250159). The remaining 4patients were recruited through advertisements.

The diagnosis of classic CAH due to 21-hydroxylase defi-ciency was confirmed by hormonal and genetic testing. All pa-tients had difficult-to-treat CAH, defined as the coexistence ofelevated adrenal biomarkers (17-OHP � 1200 ng/dL or/and an-drostenedione above the normal range at approximately 0700hrand prior to medication), and one or more glucocorticoid-relatedcomorbidities: obesity [body mass index (BMI) � 30.0 kg/m2],

fatty liver disease [AST to ALT ratio � 1 (16) and/or steatosis perliver ultrasound (17)], low insulin sensitivity [HomeostasisModel Assessment Insulin Resistance (HOMA-IR) � 2.6, whereHOMA-IR � [insulin (�U/ml) x glucose (mmol/L)]/ 22.5 (18,19)], osteopenia or osteoporosis (BMD T-score � –1), or glu-cocorticoid-related gastrointestinal (GI) side effects. Exclusioncriteria included: pregnancy, lactation or use of an estrogen-containing medication (women), use of medications that inducehepatic enzymes or interfere with glucocorticoid metabolism,use of glucocorticoids for reasons other than CAH, history ofbilateral adrenalectomy, or comorbid conditions that could in-terfere with protocol compliance. All patients were on un-changed fludrocortisone and glucocorticoid (5 prednisone, 1dexamethasone, 2 combination) therapy for at least 3 monthsprior to study entry.

The study was approved by the Eunice Kennedy Shriver Na-tional Institute of Child Health & Human Development Insti-tutional Review Board. All patients provided written informedconsent.

Study DesignOur objective was to safely achieve near-physiologic cortisol

replacement with CSHI and describe the efficacy of CSHI, com-pared to conventional oral glucocorticoid therapy, based onchanges in adrenal steroid production and comorbidity statusfollowing 6 months of therapy.

The primary efficacy endpoint was the percent of patientswith early morning 0700hr 17-OHP � 1200 ng/dL. Secondaryendpoints included changes in: a) 17-OHP, androstenedione,ACTH, progesterone [0700hr, AUC-24 hrs, AUC daytime(0700–1500), AUC midday (1500–2300), AUC nighttime(2300–0700)]; b) fasting insulin; c) HOMA-IR; d) weight andBMI; e) body composition and BMD; f) bone turnover markers[cross-linked telopeptide (CTX) and osteocalcin]; g) waist andhip circumference; h) percent of patients with hypertensive bloodpressure (BP); j) liver steatosis and AST/ALT ratio; i) adrenalgland size and morphology; k) fatigue and health-related quality-of-life (HRQoL); l) daily glucocorticoid dose based on gluco-corticoid equivalencies; and m) signs and symptoms of adrenalinsufficiency.

All patients underwent a screening visit for eligibility. Patientswere evaluated every two months over a 6-month period (Figure1). All patients underwent a history and physical (by A.A.N orA. M.), and fasting laboratory evaluation of electrolytes, liverand renal function, complete blood count (CBC), lipids, insulin,bone turnover markers, and pregnancy test (women only), alongwith 24-hour sampling. Questionnaires to evaluate fatigue (Mul-tidimensional Assessment of Fatigue (MAF) Scale) (20), HRQoL[adrenal insufficiency-specific HRQoL (AddiQoL) (21), SF-36v2® Health Survey/Four-Week Recall (22)], and symptoms ofadrenal insufficiency or glucocorticoid overtreatment were ad-ministered. A hydrocortisone clearance study was performed atbaseline. An intravenous (IV) bolus injection of 100 mg Hydro-cortisone (Solucortef®) was given followed by cortisol measure-ments every 10-minutes for a total of 150 minutes (23). After awashout period (12 hours for hydrocortisone and prednisone, 36hours for dexamethasone), CSHI was initiated. Pump infusionwas adjusted prior to discharge based on sampling approxi-mately 24 and 36 hours after pump initiation. On the first andlast visits, patients underwent dual-energy X-ray Absorptiom-etry (DXA) to assess body composition and BMD, and radio-

2 Hydrocortisone pump therapy in CAH J Clin Endocrinol Metab


logical studies (pelvic or testicular ultrasound, abdominal MRIwith liver proton magnetic resonance spectroscopy) to evaluatefor adrenal rest, visceral fat, hepatic steatosis, and adrenal hy-perplasia or tumors. All patients continued to receive dailyfludrocortisone throughout the study. At 6 months, patientswere offered the option to continue CSHI or transition to theiroriginal glucocorticoid regimen.

CSHI interventionTotal daily hydrocortisone dose was calculated based on the

patient’s estimated cortisol clearance (10). Rates were estab-lished to achieve peak and trough concentrations within the nor-mal circadian cortisol range based on an estimate of the mean inhealthy controls (6) and by using the formula [Infusion Rate(mg/24hrs) � clearance (mL/24hr) x target cortisol concentra-tion (mg/mL)]. Target cortisol levels used were: 0000–0259hr:4 mcg/dL; 0300–0459hr: 5 mcg/dL; 0500–0859hr: 14 mcg/dL;0900–1159hr: 10 mcg/dL; 1200–1759hr: 7 mcg/dL; 1800–2359hr: 4 mcg/dL. Infusion rates were selected and programmedan hour prior to the desired concentration peak, as previouslydescribed by Bryan et al (10); however our calculations overes-timated the desired daily hydrocortisone dose by approximately30% and all patients subsequently required hydrocortisone dosereduction by 2 months.

Overall, hydrocortisone dosing was primarily aimed atachieving a near physiologic cortisol profile (6), with consider-ation of adrenal steroid suppression and the clinical symptoms ofhyperandrogenism, glucocorticoid excess, or adrenal insuffi-ciency. In the case of conflicting data, dose adjustments werebased on clinical symptomatology (for details see Supplementaldata-Appendix 1).

The IV/ intramuscular (IM) powder preparation of hydro-cortisone sodium succinate (100 mg/2 mL Solu-Cortef® ACT-O-VIAL, Pfizer Inc, New York USA) was reconstituted to a 50mg/mL solution, resulting in 0.5 mg of hydrocortisone per pump-administered unit. The Paradigm REAL-Time (MMT-722) in-sulin pump, MMT-332A reservoir and Mio 9 mm/32�’ infusionset were used. Patients were asked to replace the hydrocortisonesolution with every insert/tubing set change, every third day.Patients received on-site training and had technical assistance

available upon request. All patients maintained a supply of oralhydrocortisone and IM hydrocortisone for stress dosing andemergency use.

Hormonal AssaysHormonal assays were performed at the NIH Clinical Center

(Bethesda, Maryland). Serum cortisol was analyzed by HPLC-tandem mass spectrometry (LC-MS/MS). Cortisol assay limit ofquantitation was 0.6 �g/dL, interassay coefficient of variation(CV) ranged from 3.1–3.2% and intra-assay CV from 5.0–7.7%. Plasma ACTH was analyzed by chemiluminescent immu-noassay on Siemens Immulite 2000 XPi analyzer; analytical sen-sitivity was 5 pg/mL, intra-assay CV 2.5% and interassay CV3.6%. Androstenedione, 17-OHP, progesterone and testoster-one were analyzed by LC-MS/MS (24, 25). Intra-assay CVranged from 2.5–9.5% and interassay CV from 2.9–11.1%.

Statistical AnalysisSample size calculation was based on the hypothesis that

CSHI therapy would achieve early morning 17-OHP � 1200ng/dL in 80% of patients at 6 months. Taking into account a10% drop-out rate, the power analysis yielded a sample size of8 subjects with an 80% statistical power and at a significancelevel of 0.05.

Results were expressed as mean � SEM, unless otherwisenoted. Data were analyzed by SPSS Statistics 21® and SAS v9.4(SAS Institute, Inc., Cary, NC). Comparisons of CSHI with con-ventional glucocorticoid therapy (at baseline) were made. Con-tinuous data between baseline and 6 months were compared bypaired t-tests, and categorical data were compared by McNe-mar’s test. Two-sample t-tests were carried out for comparisonsof data between independent groups (ie, normative data fromhealthy controls). Noncompartmental analysis (Phoenix Win-Nonlin software) was used to calculate the pharmacokinetic val-ues. The linear-up log-down trapezoidal rule was used to calcu-late AUC for the entire 24-hour and three 8-hour time periods.Actual collection times were used to define peak plasma concen-tration (Cmax) and time to peak plasma concentration (Tmax).For all values less than the detection limit of the assay, the value

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

doi: 10.1210/jc.2016-1916 press.endocrine.org/journal/jcem 3


at half of the lower limit was used in calculations. Logarithmictransformation was used as needed to achieve a normal distri-bution. Two-tailed tests were performed and P-values � 0.05were considered statistically significant.

SF-36 score was calculated using the SF-36 OptumInsightsoftware which provides norm-based scores and applies a linearT-score transformation (mean 50, SD 10) (22, 26). AddiQoLquestionnaire scores range from 30 - 120, where higher scoresindicate better HRQoL (21). MAF data was used to compute theGlobal Fatigue Index (GFI) score, which ranged from 1 (no fa-tigue) to 50 (severe fatigue), as previously described (20).

Results

28 patients were screened. Eight adult patients with classicCAH participated in the study (Table 1). All patients com-pleted the study but, according to medication and supplyaccountability, one patient was found to be partially non-compliant with the pump being disconnected approxi-mately 30% of the time. When this patient was excluded,analysis yielded similar results. Of the 8 patients, 6 (75%)expressed the desire to continue CSHI, 2 patients foundthe pump incompatible with their lifestyle.

PharmacokineticsCSHI pharmacokinetic cortisol profile approximated

physiologic secretion (Figure 2A). CSHI therapy at 6months compared to a prior study of healthy volunteers(6) resulted in similar time to peak cortisol concentration[CSHI vs. healthy: Tmax (mean, 95% CI): 0845hr (0810–

0920) vs. 0832hr (0759–0905)] and exposure to cortisol[24hr-AUC (hr*�g/dL): 153.5 (127.3–179.8) vs. 160.2(148.6–171.6)], but peak cortisol concentration (Cmax)was lower [13.2 �g/dL (11.0–15.4) vs. 16 �g/dL (14.6–17.4), P � .020]. Efforts to increase Cmax were under-taken, but were limited by symptoms of early morningawakening. Glucocorticoid dose in hydrocortisone equiv-alents at baseline (on oral glucocorticoid) and following 6months of CSHI were similar (conventional vs. CSHI:17.7 � 1.9 vs. 17.5 � 1.3 mg/m2/d).

Biomarkers of disease controlAt 6 months, the primary efficacy endpoint, the percent

of patients with early morning 0700hr 17-OHP � 1200ng/dL, was not different than baseline (only 3 patientsachieved this goal); however, 0700hr 17-OHP (P � .021),ACTH (P � .024), androstenedione (P � .015), and pro-gesterone (P � .007) significantly decreased (Table 2).Similarly, 6 months of CSHI resulted in lower 24-hourAUC of ACTH (P � .031), 17-OHP (P � .027), and an-drostenedione (P � .009). This was mostly due to lowerdaytime and midday (0700–2300hr) levels (Table 2, Fig-ure 2B-E). Testosterone and plasma renin activity concen-tration remained unchanged.

Glucocorticoid-related comorbidities, metabolicindices and HRQoL assessment

Although weight increased (107 � 9 vs. 112 � 9 kg, P� .004), no significant changes were observed in HOMA-

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

PtAge/Sex Phen

GC EquivDose/Meda

17-OHPng/dL

A4ng/dL

BMIkg/m2 IRb

FattyLiverc

LowBMDd

GIintolerance

to GCTART/

PCOSe*

AdrenalMass or

hypertrophy

1 43/M SV 26.5/P 5972 458 28.8 � - - - � � f

2 25/M SW 19.3/P 19 731 1003 34.8 � � - � � � g

3 19/F SW 16/P 2999 268 51.8 � � - - - -4 38/F SW 24.4/P 11 438 1711 39.8 � � - - - � g,h

5 32/F SW 12.7/HC,P 5661 676 54.1 � � � � � -6 41/F SW 8.8/HC,Pl 6092 182 43 � � - - - -7 25/F SV 13/P 6158 498 40.3 � - � � � -8 41/M SW 21.2/D 7198 425 27.7 - - � - � � g

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 toglucocorticoid; 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; �: present; -: not present.a Glucocorticoid equivalent dose (mg/m2/day): hydrocortisone � 1, prednisone and prednisolone � 5, and dexamethasone � 80 (3)b HOMA-IR � 2.6c AST/ALT �1 or steatosis by ultrasoundd DEXA T-score �-1e 12 or more follicles 2–9 mm in diameter and/or an increased ovarian volume � 10 ml by ultrasound (30)f Adrenal myelolipomasg Adrenal hyperplasiah Adrenal adenoma



IR, C-peptide, leptin, C-reactive protein (CRP), lipids andwaist/hip circumference. Only one patient had elevatedsystolic BP at baseline, and this did not change during thestudy. Osteocalcin (16.6 � 1.8 vs. 22.6 � 2.0 ng/mL; P �.004) and CTX (379.1 � 50.6 vs. 460.0 pg/mL � 69.8, P �.013) increased.

Whole-body BMD and total fat mass by DXA did notchange, but lean mass increased (60.7 � 3.7 vs. 64.3 � 4.4kg, P � .016). AST/ALT ratio and visceral fat (as fractionof total fat) remained unchanged. At baseline, a moderateto large degree liver fat was noted in 5 of 8 patients. At the

six month visit, a 5% or more increase in measurable liverfat was observed in 2 patients, one of which was also notedto have the largest weight gain. Adrenal imaging demon-strated multiple fatty tumors compatible with myelolipo-mas in one patient and minimal bilateral hyperplasia in 3patients. The patient with poor compliance had an in-crease in myelolipoma size (5 cm to 6.4 cm maximumdimension), whereas no other adrenal changes were ap-preciated following 6 months of CSHI in the other 7 pa-tients. All three men had TART, which decreased by ap-proximately 40% in the youngest (27 yo) male patient andremained stable in the other two. Three out of five womenpresented with secondary amenorrhea; one had resump-tion of menses during CSHI. Two women had sono-graphic findings compatible with polycystic ovaries (�25follicles in one or both ovaries) with no observed changesover time.

Compared to baseline, HRQoL (SF-36 Vitality Score:32 � 5 vs. 64.8 � 6, P � .001; AddiQoL: 72.4 � 4 vs.86.8 � 4, P � .004), and fatigue, (GFI: 25.8 � 2 vs. 12.3 �

2, P � .001) improved at 6 months on CSHI (Figure 3). Inaddition, both symptoms of adrenal insufficiency (P �

.014) and symptoms of glucocorticoid overtreatment (P �

.003) also improved.

Adverse eventsCHSI was well tolerated. Serious adverse events did not

occur (Table 3). No pump failure or hydrocortisone infu-sion set blockage was reported. All skin reactions wereself-limited apart from one case, requiring oral antibiotics,and incision and drainage. Poor skin hygiene was reportedor observed in all cases of local skin infection. Early morn-ing symptoms resolved following dose adjustments. Twopatients reported early morning awakening that resolvedfollowing rate adjustments aimed at producing a later cor-tisol rise. Symptoms of dizziness and lightheadedness re-solved after increasing early morning dose. Two patientsreceived 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 evaluateCSHI in comparison to conventional oral glucocorticoidtherapy in patients with classic CAH. We demonstratethat CSHI can safely and easily achieve a cortisol profilesimilar to physiologic cortisol secretion. We also showthat near physiologic cortisol replacement via CSHI con-trols adrenal steroid production and improves HRQoLand fatigue in difficult-to-treat classic CAH patients suf-

Figure 2. 24-hour serial measurement of (A) cortisol, (B) ACTH, (C)17-hydroxyprogesterone (17-OHP), (D) androstenedione, and (E)progesterone (mean � SEM) at baseline while receiving conventionaloral glucocorticoid (open circles) and following 6 months ofcontinuous subcutaneous hydrocortisone infusion (CSHI) (solidsquares).



fering from hyperandrogenism and glucocorticoid-relatedcomorbidities.

Management of classic CAH with conventional oralglucocorticoids remains challenging since optimal sup-pression of adrenal steroids is difficult to achieve withoutsupraphysiologic glucocorticoid doses (5, 6). We chose totreat an especially challenging subset of CAH patientswith CSHI, those with hyperandrogenism and other treat-ment-related comorbidities, because ultimately thesetypes of patients might be the best candidates for pumptherapy. CSHI is expensive and complex, requiring muchpatient commitment and might be best reserved for thosewho are not easily managed with oral therapy.

Initially, we started patients on a basal infusion rateusing calculations provided by Bryan et al (10), but thisoverestimated the total daily hydrocortisone dose by ap-proximately 30%. This may be attributed to the nonlin-earity of cortisol clearance at higher hydrocortisone con-centrations due to the saturable binding of hydrocortisoneto plasma proteins. Using a lower dose of hydrocortisonein the clearance study might have avoided this issue. Inaddition, obesity coupled with weight fluctuationsthroughout the study (potentially altering the volume ofdistribution and half-life of hydrocortisone), as well aspatient differences in hydrocortisone metabolic rateslikely contributed to the observed cortisol clearance vari-

ability. Despite this initial dose miscalculation, we safelyand easily approximated a physiologic cortisol profile byusing 24-hour sampling and multiple infusion ratesthroughout the day. An alternative approach to using cor-tisol clearance data to estimate starting rates might be touse an average starting dose of hydrocortisone of 15 mg/m2/d, with subsequent dose adjustments based on 24-hoursampling. This approach would have sufficed in half ofour patients, who had a final rate within 20% of this es-timate. However, this approach might extend the timerequired to approximate a physiologic cortisol profile insome patients and would delay identification of patientswho are fast metabolizers.

New ways of replacing glucocorticoid aim to improvethe outcome of patients with adrenal insufficiency bymimicking physiologic circadian rhythm. In our study,CSHI approximated the mean physiologic cortisol profilein all patients, but ACTH was not fully suppressed result-ing in mildly elevated adrenal steroids in some patients.Interestingly, the cortisol levels necessary to suppress theearly morning ACTH rise were not tolerated by all patientsbecause of early or frequent awakening. Our inability tofully suppress ACTH might also be due to CAH specificalterations in the hypothalamic-pituitary-adrenal axis. In-trauterine glucocorticoid deficiency might affect postnatalsensitivity to feedback inhibition, thus blunting the central

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

BaselineCSHI at 6Months P-value

17OHP0700 h (ng/dl) 8313 � 2748 2150 � 531 0.021AUC-24 h (h*�g/dl) 98.5 � 39.3 25.7 � 9.5 0.027AUC 0700–1500 h (h*�g/dl) 48.6 � 22.4 6.8 � 1.8 0.008AUC 1500–2300 h (�g*h/dl) 20.5 � 6.8 7.5 � 4.9 0.012AUC 2300–0700 (h*�g/dl) 29.5 � 11.1 11.4 � 3.0 0.157

A4

0700 h (ng/dl) 748 � 295 317 � 77 0.015AUC-24 h (h*�g/dl) 12.7 � 4.5 5.2 � 1.4 0.009AUC 0700–1500 h (h*�g/dl) 5.3 � 2.1 1.8 � 0.4 0.008AUC 1500–2300 h (h*�g/dl) 3.7 � 1.1 1.6 � 0.6 0.009AUC 2300–0700 (h*�g/dl) 3.7 � 1.3 1.8 � 0.4 0.043

ACTH0700 h (pg/ml) 405 � 114 139 � 47 0.024AUC-24 h (h*pg/ml) 2538 � 743 1087 � 359 0.031AUC 0700–1500 h (h*pg/ml) 1239 � 402 340 � 107 0.005AUC 1500–2300 h (h*pg/ml) 458 � 179 183 � 55 0.004AUC 2300–0700 (h*pg/ml) 841 � 233 564 � 216 0.524

Progesterone0700 h (ng/dl) 9.5 � 5.4 0.8 � 0.4 0.007AUC-24 h (h*ng/dl) 101.1 � 48.8 13.7 � 4.6 0.084AUC 0700–1500 h (h*ng/dl) 42.2 � 20.0 4.2 � 1.6 0.057AUC 1500–2300 h (h*ng/dl) 30.7 � 17.7 5.5 � 3.2 0.103AUC 2300–0700 (h*ng/dl) 28.2 � 12.5 4.0 � 0.5 0.070

Abbreviations: 17OHP, 17-hydroxyprogesterone; A4, androstenedione; ACTH, adrenocorticotropic hormone; AUC, area under the curve. Means �SEM P values � 0.05 are indicated with bold typeface.



effect of treatment. Other factors known to affect ACTHsecretion, such as CRH, neurotransmitters, arginine va-sopressin and angiotensin II may have played a role. Thisrequires further study.

Prior case reports of CSHI suggested that patientsachieved a 17-OHP in the target range within 3 months ofintervention (10, 12, 15). Thus, we hypothesized thatCSHI intervention would result in a 17-OHP � 1200ng/dL in 80% of the subjects within 6 months. However,this was only achieved in 3 of 8 patients (38%). Our failureto achieve target range 17-OHP in most patients could berelated to the population studied (difficult-to-treat pa-tients with established comorbidities including PCOS witha possible gonadal contribution), and to the way in whichwe adjusted pump settings. Our inability to fully suppressearly morning ACTH peak also probably contributed. Al-though an earlier rise in cortisol effectively suppressedmorning ACTH and 17-OHP in two patients, this was nottolerated and led to early morning awakenings. When theprofile was adjusted to prevent early awakening, adrenalsteroids were not as well controlled. Despite that short-coming, and although total daily glucocorticoid dose re-mained similar to baseline, all patients demonstrated sig-

nificantly improved adrenal steroid control and 6 of the 8patients achieved decreases of 17-OHP levels to 10%–50% of their baseline levels. Of those 6 patients, all re-ported improved sleep, 4 had improved fatigue, 3 hadimproved acne, hirsutism and anorexia, and 2 had de-creased skin pigmentation.

Our patients reported remarkable improvements inHRQoL and fatigue and this was the primary reason whymost patients wished to continue CSHI at the conclusionof the trial. Similarly, a three month CSHI multicentercrossover randomized trial of 33 patients with Addison’sdisease reported improved HRQoL (13). This is in con-trast to the Chronocort® study (9) and a double blindplacebo-controlled trial of CSHI vs. oral glucocorticoidtherapy in 10 patients with Addison’s disease (11), butboth of these studies had participants with relatively goodHRQoL at study entry. Our patients were all sufferingfrom multiple comorbidities with poor HRQoL at base-line, making improvement more likely to be achieved.

Longstanding morbidities such as fatty liver, insulinresistance, adrenal hypertrophy, and polycystic ovariesdid not change in this 6 month study. Similarly, TART didnot change in our older males, possibly because longstand-ing late-stage TART may become fibrotic and irreversibledespite improved disease control (27). However, a de-crease in TART size in one male patient and resumption ofmenses in one previously amenorrheic female patient didoccur.

Overall, decreased cortisol exposure was suggested bythe observed increase in osteocalcin (marker of bone for-mation) after 6 months of CSHI. An increase in CTX(marker of bone resorption) was also observed, possiblyrelated to decreased androgens. The significance and po-tential benefit of this is unclear. Whole-body BMDchanges were not observed, although lumbar BMD wasnot assessed. Weight gain (in the order of 2–9 kg) occurredin all but one patient, and it was more pronounced duringthe first 2 months of the study (2–6 kg); interestinglyweight gain was also noted prior to study enrollment (1–6kg between the screening and first study visits), implicat-ing an influence of dietary/lifestyle habits. Increased cor-tisol exposure during the first 2 months of CSHI treatmentand postintervention improvement of adrenal insuffi-ciency symptoms may have promoted food intake; the in-crease in lean mass may have also accounted for a portionof the weight gain. A tendency for weight gain was simi-larly reported in a CSHI study of Addison’s patients (13),although it was not as pronounced as in our study. Nev-ertheless, and despite the weight changes, insulin resis-tance (HOMA-IR) remained stable. In addition, whilelean mass increased, fat mass remained unchanged, find-ings in agreement with the Chronocort® study (9). Phys-

Figure 3. Measurements of subjective health status and fatigue atbaseline and following 6 months of continuous subcutaneoushydrocortisone infusion. Abbreviations: SF-36, 36-Item Short FormHealth Survey (36); AddiQoL, adrenal insufficiency-specific health-related quality-of-life (20–22, 26); GFI, General Fatigue Index. patient1 and patient 4 had the same SF-36 Vitality score.



iologic cortisol exposure with nadir levels in the eveningmay have been responsible for the above findings. De-creased fatigue may have resulted in increased physicalactivity, contributing to the lean mass increase (28). Pro-gestin-only oral contraceptives have been associated witha decrease in lean mass (29), suggesting that changes in theadrenal hormone milieu may have contributed, but little isknown about the effect of progesterone or other adrenalsteroids on lean mass.

This exploratory study has several limitations derivedfrom its small sample size, lack of blinding and random-ization, lack of placebo-control design and heterogeneityof the study population (diverse comorbidities, small num-bers of men and women). We aimed to achieve cortisollevels approximating the mean of a representative sampleof healthy controls, which may not be ideal for the man-agement of CAH patients. Additionally, although CSHIwas able to approximate a normal cortisol circadian se-cretion profile, it was not able to mimic its ultradianrhythm. It is unknown if patients would have benefitedfrom lower or higher cortisol concentrations during the24-hour period. As expected, management of CSHI wasmore time-consuming and intensive than clinical manage-ment with oral therapy. Extensive teaching was necessaryand proper hygiene with pump use took months to estab-

lish. However, local skin pruritus, erythema and infectionoccurred at rates similar to insulin pump users (30). It isunknown if Chronocort®, an oral modified-release hy-drocortisone aimed at mimicking physiologic cortisol se-cretion, is comparable to CSHI therapy. However, theability to fine tune the cortisol profile with a continuousinfusion allows for more individualized therapy, whichmight be beneficial in a subset of patients. In addition,CSHI is the optimal route of hydrocortisone delivery forpatients with GI conditions that interfere with oraltherapy.

In summary, CSHI was a well-tolerated and safe mo-dality of hydrocortisone replacement. A physiologic cor-tisol profile was achieved resulting in improved adrenalsteroid control and positive effects on HRQoL and fatiguein CAH patients poorly controlled with oral glucocorti-coid therapy. Longstanding morbidities such as fatty liver,insulin resistance, adrenal and testicular tumors, and poly-cystic ovaries remained mostly unchanged following 6months of CSHI, suggesting that earlier (childhood) in-tervention and preventative strategies are needed. Thelong-term effect of near physiologic cortisol replacementhas yet to be determined, but is also being studied with anovel modified-release oral preparation, Chronocort® (9).Adverse outcomes in CAH are due to a combination of

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

Adverse Event#

Patients Outcome (n)

Skin erythema with pruritus at theinfusion set site

3 Self-limited (n � 3).

Local skin infection at the infusionset site

5 Self-limited (n � 4), resolved after oral antibiotics and incision anddrainage (n � 1).

Dizziness 5 Resolved 2 months following CSHI (n � 1), resolved after increasingearly morning and decreasing 0900–1100 h dose (n � 1),intermittent (n � 2).

Lightheadedness 5 Resolved 2 to 4 months following CSHI (n � 2), resolved afterincreasing early morning and decreasing 0900–1100 h dose (n �1), intermittent (n � 2).

Weakness 3 Resolved 2 months following CSHI (n � 2), intermittent (n � 1).Fatigue 7 Resolved 2 months following CSHI (n � 2), intermittent (n � 5).Nausea 2 Resolved 2 months following CSHI (n � 1), resolved after dose

increase (n � 1).Headache 7 Resolved by 4 months of CSHI (n � 3), intermittent (n � 4).Carpal Tunnel 1 Resolved after surgical procedure (n � 1).Knee pain when walking 1 Intermittent (n � 1).Tinnitus 1 Mild, prior diagnosis Meniere’s disease, resolved at 6 months (n � 1).Decreased appetite 2 Resolved 2 months following CSHI (n � 1), while on CSHI (n � 1).Increased appetite 6 Resolved 2 months following CSHI (n � 2), resolved spontaneously (n

� 2), intermittent (n � 1).Difficulty Falling Asleep or Frequent

Wakening5 Resolved 2 months following CSHI (n � 3), resolved after dose

adjustments (n � 1), intermittent (n � 1).Early Morning Wakening 3 Resolved 2 months following CSHI (n � 1), resolved after dose

adjustments (n � 2).Increased acne 2 Resolved spontaneously (n � 2).Weight gain 5 Weight stable following dose reduction (n � 4).



disease-related and treatment-related side effects. Long-term studies of physiologic cortisol replacement starting inchildhood would help unravel the role glucocorticoidsplay in the development of comorbidities and advancepreventative management strategies.

Acknowledgments

The authors are grateful to the patients for participation in thisstudy and the nursing staff of the 5SWN Metabolic Unit for theirassistance in conducting the study. We thank Tara Kuhn for herassistance with the pharmacokinetic analysis.

This research was supported by the Intramural Research Pro-gram of the National Institutes of Health, and (in part) byMedtronic Diabetes Company who generously provided thepump devices and supplies, and offered training and technicalsupport.

Disclosure summary: DPM received unrelated research fundsfrom Diurnal Ltd and is a Commissioned Officer in the UnitedStates Public Health Service.

Address all correspondence and requests for reprints to:*Corresponding Author and person to who reprint requestsshould be addressed: Aikaterini A. Nella, M.D., Department ofPediatrics, Division of Pediatric Endocrinology, University ofTexas Medical Branch, Research Building 6, Suite 3.270C, 301University Blvd., Galveston TX, 77555–0373, Office: (409)747–6661, Fax: (409) 747–2213, Email: [email protected].

This work was supported by This work was supported by theIntramural programs of the National Institutes of Health Clin-ical Center and the Eunice Kennedy Shriver National Institute ofChild Health & Human Development.

Disclosure Statement: Medtronic Diabetes Company pro-vided the insulin pumps and supplies (reservoirs, infusion sets),and also training and technical support without charge, uponapproval of the study by the Institutional Review Board Com-mittee. No NIH investigator involved in this study received anypayment or other benefits from the Medtronic Diabetes Com-pany. DP Merke received unrelated research funds from DiurnalLimited, Ltd. through an NIH Cooperative Research and De-velopment Agreement.

Clinical Trial Registration Number: NCT01859312

References

1. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP,Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, RitzenM, White PC, Society E. Congenital adrenal hyperplasia due to ste-roid 21-hydroxylase deficiency: an Endocrine Society clinical prac-tice guideline. J Clin Endocrinol Metab. 2010;95:4133–4160.

2. Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, HanTS, Carroll PV, Conway GS, Rees DA, Stimson RH, Walker BR,Connell JM, Ross RJ. Health status of adults with congenital adrenalhyperplasia: a cohort study of 203 patients. J Clin EndocrinolMetab. 2010;95:5110–5121.

3. Finkielstain GP, Kim MS, Sinaii N, Nishitani M, Van Ryzin C, HillSC, Reynolds JC, Hanna RM, Merke DP. Clinical characteristics of

a cohort of 244 patients with congenital adrenal hyperplasia. J ClinEndocrinol Metab. 2012;97:4429–4438.

4. Merke DP. Approach to the adult with congenital adrenal hyper-plasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab.2008;93:653–660.

5. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet.2005;365:2125–2136.

6. Debono M, Ghobadi C, Rostami-Hodjegan A, Huatan H, CampbellMJ, Newell-Price J, Darzy K, Merke DP, Arlt W, Ross RJ. Modified-release hydrocortisone to provide circadian cortisol profiles. J ClinEndocrinol Metab. 2009;94:1548–1554.

7. Debono M, Mallappa A, Gounden V, Nella AA, Harrison RF,Crutchfield CA, Backlund PS, Soldin SJ, Ross RJ, Merke DP. Hor-monal circadian rhythms in patients with congenital adrenal hyper-plasia: identifying optimal monitoring times and novel disease bio-markers. Eur J Endocrinol. 2015;173:727–737.

8. Mah PM, Jenkins RC, Rostami-Hodjegan A, Newell-Price J, DoaneA, Ibbotson V, Tucker GT, Ross RJ. Weight-related dosing, timingand monitoring hydrocortisone replacement therapy in patientswith adrenal insufficiency. Clin Endocrinol (Oxf). 2004;61:367–375.

9. Mallappa A, Sinaii N, Kumar P, Whitaker MJ, Daley LA, DigweedD, Eckland DJ, Van Ryzin C, Nieman LK, Arlt W, Ross RJ, MerkeDP. A phase 2 study of Chronocort, a modified-release formulationof hydrocortisone, in the treatment of adults with classic congenitaladrenal hyperplasia. J Clin Endocrinol Metab. 2015;100:1137–1145.

10. Bryan SM, Honour JW, Hindmarsh PC. Management of alteredhydrocortisone pharmacokinetics in a boy with congenital adrenalhyperplasia using a continuous subcutaneous hydrocortisone infu-sion. J Clin Endocrinol Metab. 2009;94:3477–3480.

11. Gagliardi L, Nenke MA, Thynne TR, von der Borch J, Rankin WA,Henley DE, Sorbello J, Inder WJ, Torpy DJ. Continuous subcuta-neous hydrocortisone infusion therapy in Addison’s disease: a ran-domized, placebo-controlled clinical trial. J Clin Endocrinol Metab.2014;99:4149–4157.

12. Merza Z, Rostami-Hodjegan A, Memmott A, Doane A, Ibbotson V,Newell-Price J, Tucker GT, Ross RJ. Circadian hydrocortisone in-fusions in patients with adrenal insufficiency and congenital adrenalhyperplasia. Clin Endocrinol (Oxf). 2006;65:45–50.

13. Oksnes M, Bjornsdottir S, Isaksson M, Methlie P, Carlsen S, NilsenRM, Broman JE, Triebner K, Kampe O, Hulting AL, Bensing S,Husebye ES, Lovas K. Continuous subcutaneous hydrocortisoneinfusion versus oral hydrocortisone replacement for treatment ofaddison’s disease: a randomized clinical trial. J Clin EndocrinolMetab. 2014;99:1665–1674.

14. Sonnet E, Roudaut N, Kerlan V. Results of the prolonged use ofsubcutaneous continuous infusion of hydrocortisone in a man withcongenital adrenal hyperplasia. ISRN Endocrinol. 2011;2011:219494.

15. Tuli G, Rabbone I, Einaudi S, di Gianni V, Tessaris D, Gioia E, LalaR, Cerutti F. Continuous subcutaneous hydrocortisone infusion(CSHI) in a young adolescent with congenital adrenal hyperplasia(CAH). J Pediatr Endocrinol Metab. 2011;24:561–563.

16. Sorbi D, Boynton J, Lindor KD. The ratio of aspartate aminotrans-ferase to alanine aminotransferase: potential value in differentiatingnonalcoholic steatohepatitis from alcoholic liver disease. The Amer-ican journal of gastroenterology. 1999;94:1018–1022.

17. Saverymuttu SH, Joseph AE, Maxwell JD. Ultrasound scanning inthe detection of hepatic fibrosis and steatosis. Br Med J (Clin ResEd). 1986;292:13–15.

18. Ascaso JF, Pardo S, Real JT, Lorente RI, Priego A, Carmena R.Diagnosing insulin resistance by simple quantitative methods in sub-jects with normal glucose metabolism. Diabetes care. 2003;26:3320–3325.

19. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained fromoral glucose tolerance testing: comparison with the euglycemic in-sulin clamp. Diabetes Care. 1999;22:1462–1470.



mailto:[email protected]

20. Belza BL. Comparison of self-reported fatigue in rheumatoid ar-thritis and controls. J Rheumatol. 1995;22:639–643.

21. Oksnes M, Bensing S, Hulting AL, Kampe O, Hackemann A, MeyerG, Badenhoop K, Betterle C, Parolo A, Giordano R, Falorni A,Papierska L, Jeske W, Kasperlik-Zaluska AA, Chatterjee VK, Huse-bye ES, Lovas K. Quality of life in European patients with Addison’sdisease: validity of the disease-specific questionnaire AddiQoL.J Clin Endocrinol Metab. 2012;97:568–576.

22. <sf98norms.pdf>.23. Charmandari E, Hindmarsh PC, Johnston A, Brook CG. Congenital

adrenal hyperplasia due to 21-hydroxylase deficiency: alterations incortisol pharmacokinetics at puberty. The Journal of clinical endo-crinology and metabolism. 2001;86:2701–2708.

24. Guo T, Taylor RL, Singh RJ, Soldin SJ. Simultaneous determinationof 12 steroids by isotope dilution liquid chromatography-photo-spray ionization tandem mass spectrometry. Clin Chim Acta. 2006;372:76–82.

25. Stolze BR, Gounden V, Gu J, Elliott EA, Masika LS, Abel BS, Merke

DP, Skarulis MC, Soldin SJ. An improved micro-method for themeasurement of steroid profiles by APPI-LC-MS/MS and its use inassessing diurnal effects on steroid concentrations and optimizingthe diagnosis and treatment of adrenal insufficiency and CAH. JSteroid Biochem Mol Biol. 2016;162:110–116.

26. Ware JE, Gandek B. Overview of the SF-36 Health Survey and theInternational Quality of Life Assessment (IQOLA) Project. J ClinEpidemiol. 1998;51:903–912.

27. Claahsen-van der Grinten HL, Hermus AR, Otten BJ. Testicularadrenal rest tumours in congenital adrenal hyperplasia. Interna-tional journal of pediatric endocrinology. 2009;2009:624823.

28. Evans WJ, Cyr-Campbell D. Nutrition, exercise, and healthy aging.J Am Diet Assoc. 1997;97:632–638.

29. Lopez LM, Ramesh S, Chen M, Edelman A, Otterness C, Trussell J,Helmerhorst FM. Progestin-only contraceptives: effects on weight.Cochrane Database Syst Rev 2016; 8:CD008815.

30. Heinemann L, Krinelke L. Insulin infusion set: the Achilles heel ofcontinuous subcutaneous insulin infusion. J Diabetes Sci Technol.2012;6:954–964.



A Phase 2 Study of Continuous Subcutaneous Hydrocortisone ...A Phase 2 Study of Continuous...

Documents

Transcript of A Phase 2 Study of Continuous Subcutaneous Hydrocortisone ...A Phase 2 Study of Continuous...