Interval Bolus Delivery of Subcutaneous Hydrocortisone Via Infusion Pump in Children With Congenital Adrenal Hyperplasia
Phase: PHASE1
Conditions: Congenital Adrenal Hyperplasia, Hyperplasia, Adrenal Hyperplasia, Congenital Disorders, Adrenocortical Hyperfunction, Disorders of Sex Development, Urogenital Abnormalities, Genetic Diseases, Inborn, Steroid Metabolic Diseases, Inborn, Adrenal Gland Disease, Hydrocortisone
Sponsor: University of Minnesota

University of Minnesota 
Clinical Research Study Protocol 
 
 
 
Interval Bolus Delivery of  Subcutaneous Hydrocortisone via Infusion 
Pump in Children With Congenital Adrenal Hyperplasia (FDA 
IND#125640)  
 
 
 
 
Principal Investigator:  
Kyriakie M. Sarafoglou, M.D 
 
Department of Pediatrics 
 
University of Minnesota 
 
 
Co-Principal Investigator: Richard Brundage, Ph.D. 
 
Department of Experimental/Clinical Pharmacology 
 
University of Minnesota 
 
Co-Investigator: 
Zan Gao, Ph.D. 
 
School of Kinesiology 
 
University of Minnesota 
 
Co-Investigator: 
Megan Gunnar, Ph.D. 
 
Institute of Child Development 
 
University of Minnesota 
 
Co-Investigator: 
Eric Bomberg, MD 
 
Department of Pediatrics 
 
University of Minnesota 
 
Study Statistician: 
James Hodges, Ph.D. 
 
Division of Biostatistics 
 
University Of Minnesota 
 
 
Version Date:  
September 20, 2021 
 
 
Confidential 
 
 

Interval Bolus Delivery of Cortisol in Children with CAH 
 
 
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Revision History 
Version 
Date 
Summary of Changes 
Consent 
Change? 
Y/N 
Consent 
Version 
Date 
2/4/15 
Original to FDA 
N/A 
 
3/2/15 
• 7.1.3 Dosage adjustment section was added 
• 9.3 Methods to minimize risk section was expanded 
• 10.4 Stopping rules section expanded detail on adrenal crisis 
N/A 
 
12/29/15 
• 6.2 Treatment Period section was changed to reflect that 
subjects will be discharged after second admission and continue 
on their usual HC oral dosing schedule for 1 week prior to initiation 
of the SQHC pump.    
 
N/A 
 
6/30/16 
• 9.3 Methods to minimize risk changed to reflect weekly visits and 
blood draws while on pump. 
N/A 
 
3/1/17 
• In section 8 Study Device, we added that the Medtronic quick-
set will be the ONLY infusion set used in this study. 
• 7.1.3 Dosage adjustment was changed to reflect that in the 
event of pump failure, patients will be instructed to resume their 
usual oral HC dose and notify the investigators. 
• 5.2.2. Exclusion criteria section was changed to reflect that 
patients with body surface areas under 1m2 or over 2m2 will be 
excluded from the study. 
• 7.1.3 Dosage adjustment section was changed to reflect 
procedure if a pump malfunction results in delivery of the entire 
reservoir (worst case scenario 100 mg of hydrocortisone) and for 
missed doses due to occlusions. 
N/A 
 
9/15/17 
• 3.1 Moved Admission 3, that was part of Primary Objective 2, 
and combined it with Primary Objective 1.  There is no change to 
the specifications of Admission 3.   
• 3.2 Moved the nonlinear mixed-effects population analysis from 
Primary Objective 2 to the Secondary Objectives section.  There is 
no change to the approach of the analysis.  With the moving of 
both Admission 3 and the analysis, Primary Objective 2 was no 
longer needed as the approaches have been moved to other 
sections.    
• In Section 4 Study Design information was added to explain in 
more detail the criteria that will be used for dosing changes during 
the 6-week SQHC trial. Also, the number of home visits by the 
nurse have been increased from 7 to 8 home visits.    
• 7.1.2 Dosage and Administration section was expanded to 
provide more detail the criteria that will be used for dosing 
changes during the 6-week SQHC trial.   
• In Section 6, the Studies Procedure table was changed to reflect 
the additional home nursing visit and additional safety measure of 
daily blood pressure measurements while on 6-week SQHC trial.    
• Section 9.1 has been reorganized so that the potential risks of 
HC more specific to this study are listed before the listing of all of 
the potential risks of HC that can happen in any age group and 
population.  
• Section 9.3 has been changed to reflect that parents will be 
provided with an automatic upper arm blood pressure monitor with 
N/A 
 

Interval Bolus Delivery of Cortisol in Children with CAH 
 
 
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cuff as an additional safety measure for monitoring pump failure 
that does not trigger an alarm.   
•11.1 – 11.2 The statistical analysis of what was formerly Primary 
Objective 2 has been moved from Section 11.1 (Primary Outcome 
Measures) to Section 11.2 (Secondary Outcome Measures).  
6/14/18 
• Per request from the FDA and from University of Minnesota IRB, 
the title of protocol has been changed to remove reference to 
“pulsatile.”  The protocol has been renamed: “Interval Bolus 
Delivery of  Subcutaneous Hydrocortisone via Infusion Pump in 
Children With Congenital Adrenal Hyperplasia.” 
• Per request from the University of Minnesota IRB, when 
referencing the pump within the text of the protocol, “pulsatile 
delivery” has been replaced with “interval bolus delivery.”  
• Section 5.2: Added description/explanation of “Inclusion of 
Children,” “Rationale for Specific Age Range,” and “Expertise of 
the investigative team for working with the age group.”   
• Section 5.3: Added description/explanation of “Resources 
available,” “Provisions to Protect the Privacy Interests of 
Participants,” “Consent Process” and “Compensation for 
Research-Related Injury.”   
• Section 12.2: Added description/explanation of “Confidentiality – 
Data Security,” “Data Banking” and “Sharing of Results with 
Participants.” 
N/A 
 
3/12/19 
• Sec 6.0: Study procedures: addition of ACTH to the lab results 
during PKPD study blood samples 
• Sec 6.0: Study procedures: addition of 24 hour urine collection 
during admission 1, 2 and 3 
• Sec 6.0: Study procedures: addition of salvia samples during 
admission 1, 2 and 3 
• Section 10.5 medical monitoring by physician outside of trial 
• Section 10.2 will not use UMCC SAE form but will used 
MedWatch3500  
• Section 3.2 and  6.0 addition of sleep and mood surveys to be 
administered  
 
 
3/29/19 
• Sec 8: The CRONO P is designed to be used with any 
commercially available infusion sets so that the decision of which 
set to use could be made by the healthcare professionals 
following the patient. Based on the pediatric patient population we 
will ONLY use the following infusion sets in this protocol, both of 
which are cleared for use in the United States:  
a) Tandem Diabetes Care AutoSoft™ XC infusion set. 
b) Tandem Diabetes Care TruSteel™ infusion set. 
 
 
5/20/19 
• 
Add co-I, Bomberg 
• 
Sec 3.2 NIH took box includes Flanker assessment 
• 
Sec 5.1 confirmed 3 outpatient visits at Prism 
• 
Sec 6.0 add subject diary to study procedures, used 
through week 0-20 
• 
Sec 6.2.1.1 increased to 3mL blood draws for total 75mL 
over visit period 
• 
Sec 6.2.1.1 added that Quest samples will be saved for 
Quest future research, if approved by participant, through 
consent 
• 
Sec 6.2.1.3 Week 6 removed surveys and NIH testing, 
added RN assessment 
 
 

Interval Bolus Delivery of Cortisol in Children with CAH 
 
 
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• 
Sec 6.2.1.4 instruction on use of blood pressure cuff, 
started on week 7 through 13 
• 
Sec 6.2.1.4 Dilution will occur with 8 mL of 0.9% normal 
saline and NOT sterile water 
• 
Sec 6.2.1.4 added provision and instruction on blood 
pressure cuff 
• 
6.2.1.6 Week 8, phone call from RN for assessment 
• 
6.2.2.1 Week 9 outpatient visit includes physical exam 
and RN assessment. Addressed that after outpatient visit, 
RN will be making phone calls regarding pump, events, 
questions. Home visits Week 9-13 Add ACTH to home 
visits, RN assessments, actigraph provided 
• 
6.2.2.2 Week 13 removed 
• 
Sec 6.2.2.2 Week 14 increased to Week 14 + 5 days in 
order to ensure adequate time period of intervention. 
Physical exam performed. Surveys & NIH toolbox 
repeated.  
• 
Sec 6.2.3.1 to ensure adequate time period of 
intervention, adjusted 15 weeks to 15 week + 1 day 
• 
 Sec 6.2.3.2 week 19 is a home visit. Removed surveys, 
NIH toolbox tests 
• 
Sec 6.2.3.3 Week 20 separated out to include outpatient 
visit procedures (physical, surveys/NIH toolbox, 
assessments) 
• 
Removed study table, added new schedule of events 
table clarifying study procedure adjustments (on page 19) 
• 
Sec 7.1.2 updated sterile 0.9% saline to 0.9% normal 
saline for consistency in terminology 
• 
Sec 10.3.2 utilizing MedWatch 3500A for reporting 
7/3/2019 
Clarification that only infusion set to use is now branded under the 
Unomedical/Animas® InsetTM. This is brand equivalent to the 
Tandem Diabetes Care AutoSoftTM set and TruSteelTM set.The 
CRONO P is designed to be used with any commercially available 
infusion sets so that the decision of which set to use could be 
made by the healthcare professionals following the patient. 
 
 
8/1/2019 
Clarification that the infusion set to be used in this study is the 
Comfort and Inset Subcutaneous Infusion Sets that are made by 
Unomedical (510K #: K051264) 
 
 
8/12/2019 
Update schedule of events to note that study visits will have a time 
window of +/- 1 day  
Na 
na 
9/10/2019 
Page 19: updated schedule of events to include an unscheduled 
visit column 
 
Page 22: updated to include clarification that if pump treatment is 
delayed/stopped the pump will be resumed to meet the required 6-
week of pump treatment 
No 
 
11/14/2019 
Increase to twelve participants consented to ensure analysis for 
eight completed participants (pgs 11, 12, 14) 
 
Specify that placement of pump is based upon evaluation of body 
composition to ensure best placement for subcutaneous infusion. 
(pgs 13, 19) 
 
Updated 6.2.2.1 regarding use of VEROFY for saliva sampling will 
be based upon availability from supplying company 
YES 
11/14/19 

Interval Bolus Delivery of Cortisol in Children with CAH 
 
 
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2/6/2020 
Update to exclusion criteria in section 5.2.2 to expand body 
surface area to < 0.95m2 or > 2.04 m2   
No 
Na 
10/13/2020 
Remove the exclusion criteria regarding body surface area in 
section 5.2.2 to reflect the following explanation:  
 
This amendment to the exclusion criteria is based on the rationale 
that body surface area should not preclude potential patients from 
participating in this study, as the appropriate dosing of the 
hydrocortisone through the pump is not based on the child's body 
surface area. Use of the pump is based on the need of the volume 
of hydrocortisone that can be delivered through the infusion pump. 
To ensure the pump volume is being met, the investigator(s) will 
review the standard total daily dose and calculate the needed 
dosing for each patient's pump volume. If the appropriate volume 
for dosage cannot be reached with the pump, the child will be 
excluded from participation until that minimum volume can be met.  
 
Addition of exclusion criteria regarding the minimum total daily 
dose for the patient’s HC regimen that is needed in order to 
provide the minimum volume needed for the pump dosing 
No 
Na 
2/17/2021 
Sec 5.2.1 updated to include children aged 3 years old (decreased 
from the prior minimum of 4 years old). This change is reflects the 
patient population that would meet all remainder of 
inclusion/exclusion criteria.  
Yes 
(parent & 
adult)  
2/17/2021 
5/7/2021 
In order to align the approved protocol (2/17/2021) this date’s 
tracked changes are to update missed sections regarding the 
approved change from 4 years to 3 years old. See pages 12 and 
14 in “all markup.” Protocol remains under date of 2/17/2021. 
No 
NA 
9/20/2021 
Update location to Nucleus Network (formerly Prism  Clinical 
Research) as Nucleus Network acquired Prism though conducting 
same procedures and at same physical location 
No 
 
 
 
 
Contact Information: 
 
Principal Investigator 
Kyriakie Sarafoglou, M.D. 
Associate Professor 
Department of Pediatrics 
2450 Riverside Avenue, AO-201 
 
Minneapolis, MN 55454 

Interval Bolus Delivery of Cortisol in Children with CAH 
 
 
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Office: 612.624.5409 
Pager: 612.899.6047 
Email: saraf010@umn.edu  
TABLE OF CONTENTS 
 
1 
Introduction .................................................................................................................................................... 6 
2 
Background and Significance ..................................................................................................................... 7 
3 
Objectives ................................................................................................................................................. 1210 
3.1 
Primary Objectives ...................................................................................................................................... 1210 
3.2 
Secondary/Exploratory Objectives ............................................................................................................. 11 
4 
Study Design ................................................................................................................................................. 11 
5 
Subjects ......................................................................................................................................................... 12 
5.1 
Study Setting ................................................................................................................................................... 12 
5.2 
Eligibility Criteria ........................................................................................................................................... 13 
5.3 
Recruitment ..................................................................................................................................................... 14 
6 
Study Procedures ....................................................................................................................................... 1815 
6.1 
Screening/Baseline .......................................................................................................................................... 15 
6.2 
Treatment period (weeks 1-20) ....................................................................................................................... 16 
7 
Study Drug .................................................................................................................................................... 20 
7.1 
Solu-Cortef® (hydrocortisone sodium succinate for injection) .................................................................. 2220 
7.2 
Cortef® hydrocortisone tablets ....................................................................................................................... 22 
7.3 
Receiving, Storage, and Dispensing ................................................................................................................ 22 
8 
Study Device- CRONO P .............................................................................................................................. 23 
9 
Risks and Benefits ......................................................................................................................................... 23 
9.1 
Potential Risks ................................................................................................................................................. 23 
9.2 
Potential Risks of the CRONO P Device ........................................................................................................ 24 
9.3 
Methods to minimize risk ................................................................................................................................ 25 
9.4 
Potential Benefits ............................................................................................................................................ 25 
10 
Safety and Adverse Events ....................................................................................................................... 25 
10.1 
Definitions ...................................................................................................................................................... 25 
10.2 
Recording of Adverse Events ..................................................................................................................... 27 
10.3 
Reporting of Serious Adverse Events ....................................................................................................... 27 
10.4 
Stopping Rules .............................................................................................................................................. 28 
10.5 
Medical Monitoring ........................................................................................................................................ 28 
11 
Statistical Considerations .............................................................................................................................. 29 
11.1 
Primary Outcomes Measure ............................................................................................................................ 29 
11.2 
Secondary Outcomes Measures ...................................................................................................................... 29 
12 
Administrative Considerations ...................................................................................................................... 29 
12.1 
Conduct of the Trial ........................................................................................................................................ 29 
12.2 
Data Management ........................................................................................................................................... 30 
12.3 
Data Monitoring .............................................................................................................................................. 33 
12.4 
Event Reporting to the IRB ............................................................................................................................. 31 
13 
REFERENCES .............................................................................................................................................. 33 
 

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1 Introduction 
 
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a rare form of adrenal 
insufficiency with a prevalence of 1:16,000,1 characterized by impaired cortisol synthesis leading to 
excessive adrenal androgen production. The currently recommended oral hydrocortisone (HC) 
therapy for children with CAH2 is unsatisfactory because it results in alternating hypo- and 
hypercortisolemia3,4, thereby incurring increased risk for the deleterious effects of both these states. 
Hypocortisolemia triggers increased production of 17-hydroxyprogesterone (17OHP) and the 
adrenal androgen androstenedione (D4A), which can lead to premature fusion of the growth plates, 
genital virilization, precocious puberty, adrenal rests, polycystic ovarian syndrome and infertility.5-9 
Hypercortisolemia also has untoward long-term effects such as osteoporosis, short stature, and 
increased risk for cardiovascular disease in adulthood.10-16 Current oral therapy is suboptimal due to 
resulting non-physiologic levels of cortisol and the inability to replicate circadian and ultradian cortisol 
secretion rhythms associated with normal adrenal function.17-26 Therefore, an improved and 
personalized drug delivery system is needed27 which more closely replicates physiological pulsatile 
cortisol secretion and limits periods of hyper- and hypocortisolemia in children with a resulting tighter 
control of adrenal androgens.  
 
Various strategies to “optimize” glucocorticoid (GC) replacement therapy include modified or 
dual-release preparations,28,29 continuous subcutaneous (SQ) infusions30-33 and personalized 
treatment based on oral cortisol pharmacokinetic (PK) and 17OHP and D4A pharmacodynamic (PD) 
response studies. However, none of these strategies addresses that endogenous GCs are released 
in a pulsatile manner and that this ultradian rhythm is important in maintaining homeostatic control 
through GC receptor-dependent transcriptional regulation, which rapidly responds to changes in 
circulating cortisol levels.17-20,25,34 The diametrically opposite effects of SQ pulsatile vs continuous 
hormone delivery are well described in other hormone systems. Pulsatile delivery of gonadotropin 
releasing hormone results in ovulation induction35 whereas continuous delivery causes anovulation 
and suppresses the hypothalamic-pituitary-gonadal axis.36,37 We propose to more closely replicate 
normal cortisol physiology by conducting the first clinical trial in children with CAH of a SQ 
hydrocortisone (SQHC) pump that will mimic pulsatility through interval bolus delivery system. An 
open-label, non-randomized crossover design will be used for this proof-of-concept study to inform 
the design of a larger clinical trial. Our long term goal is to improve clinical outcomes in children 
with CAH through optimizing the dosing and scheduling of replacement therapy and avoid the 
hyperandrogenemia that is specific to CAH. This study's objective is to demonstrate that a SQHC 
pump with interval bolus delivery more closely replicates circadian and ultradian rhythms of cortisol 
and improves control of adrenal androgens. Our study's rationale is that cortisol profiles more 
consistent with physiologic rhythms of cortisol secretion will produce better health outcomes. 
 
 
 
 
 
 
 
 
 
 
 

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2 Background and Significance 
Congenital adrenal hyperplasia (CAH) and the inadequacy of current therapy.  
 
Classic 
CAH 
due 
to 
21-hydroxylase 
deficiency (21OHD) is a rare form of adrenal 
insufficiency 
(prevalence 
1:16,000)1 
characterized by both impaired cortisol 
synthesis 
and 
excessive 
androgen 
production starting in utero. Normally, in the 
hypothalamic-pituitary-adrenal (HPA) axis a 
negative feedback loop exists wherein 
cortisol and adrenocorticotropic hormone 
(ACTH) are in a state of dynamic equilibrium. 
Hypocortisolemia in CAH leads to ACTH-
driven adrenal gland stimulation where 
cortisol 
precursors, 
such 
as 
17-
hydroxyprogesterone (17OHP), are shunted 
to the androgen pathway as androgen 
synthesis 
does 
not 
require 
the 
21-
hydroxylase enzyme. In turn, this leads to 
excess production of adrenal androgens 
such as androstenedione (D4A) and testosterone (T) (Fig. 1).38 Elevated D4A and T in utero and 
postnatally can cause masculinization of the external genitalia in both sexes. Untreated or poorly 
controlled females will continue to masculinize which in turn can lead to extensive and multiple 
corrective genital surgeries (Fig. 2). 
Patients with CAH require life-long glucocorticoid replacement. 
The main treatment challenge for CAH is to find the right balance 
of delivering sufficient glucocorticoid replacement to suppress 
overproduction of adrenal androgens (hyperandrogenemia), 
while 
avoiding 
the 
effects 
of 
glucocorticoid 
excess 
(hypercortisolemia). The current CAH consensus guidelines 
recommend treating children with oral hydrocortisone (HC; 
cortisol) at a dose of 10-15 mg/m2/day given 3 times per day.2 
Response to HC therapy and disease control is evaluated by 
single measurements of 17OHP and/or D4A at clinic visits only 
every 3 to 6 months along with clinical impressions including 
growth velocity, weight gain, blood pressure, pubertal development and bone age maturation.2 This 
practice provides limited information for several reasons: 1) Clinical findings reflect current drug 
therapy and adverse findings are a consequence of chronic over- and under- exposure to cortisol 
and androgen.  While these findings may indicate the current HC regimen is inadequate, it does not 
indicate which specific aspects of the regimen (dose, timing, frequency) need to be changed. 2) 
Obtaining 17OHP and D4A concentrations three to four times a year does not provide a complete 
picture of disease control. These biomarkers are in a state of dynamic equilibrium in response to the 
HC dosing regimen and its negative feedback loop of the HPA axis. Blood samples obtained at 
various times after a dose can lead to highly variable concentrations, thereby confounding 
interpretation of 17OHP and D4A. 3) Single biomarker determinations only provide assessment of 
control at a single point in time and do not imply control over 24 hours. 

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Another challenge with HC therapy is its short median elimination half-life in CAH children of 58 min 
(range: 41-105 min) allowing most of the HC dose to be eliminated from the body within 4-5 hrs.3,39 
This is of particular concern as the cortisol concentration from the evening HC dose washes out over 
night resulting in unopposed ACTH-stimulated adrenal androgen production and significant 
hyperandrogenemia each morning when ACTH is at its peak 
(~0600). Because of HC’s short half life, the recommended 3 
times a day dosing schedule is inadequate and children are 
inevitably exposed to alternating periods of hypo- and 
hypercortisolemia 
throughout 
each 
day 
(Fig. 
3). 
Hypocortisolemia leading to hyperandrogenemia, besides 
causing genital virilization, can also lead to premature fusion 
of the growth plates, precocious puberty, adrenal rests, 
polycystic ovarian syndrome, infertility and endothelial 
dysfunction.5-9,40 Working memory performance and executive 
function are lower in children with CAH than in unaffected 
relatives41,42 and quality of life is reported to be reduced.43 
Hypercortisolemia or overtreatment also have untoward long-
term effects, such as osteoporosis, short stature, insulin 
resistance and increased risk for cardiovascular disease.10-12,14-16,44,45 Increasing the challenge of 
treatment is the interindividual variability of pharmacokinetic (PK) and pharmacodynamic (PD) 
response to HC due to variations in glucocorticoid receptor and tissue sensitivity.3,46,47 For example, 
about 7% of the general population harbor polymorphisms in the human glucocorticoid receptor that 
enhance responsiveness to GCs.48  
 
Furthermore, cortisol PK in children with CAH differ from those individuals with other forms of adrenal 
insufficiency as their intermittently increased adrenal sex steroid production throughout the day could 
alter the enzyme activity of 11β-hydroxysteroid dehydrogenase (11β-HSD) isoenzymes and other 
enzymes that have a role in cortisol metabolism.49-51 The interindividual cortisol PKPD variability and 
the shortcomings of the current recommended therapy and associated adverse clinical 
outcomes10,11,52 underscore the importance of examining new ways of cortisol delivery that account 
for the inherently dynamic patterns of cortisol secretion and individual cortisol PK and 17OHP and 
D4A PD responses.  
 

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The importance of GC pulsatility for normal function of the hypothalamic-pituitary-adrenal 
(HPA) axis. The HPA axis is characterized by discrete pulses of ACTH and cortisol secretion. 
Cortisol secretion has a classically circadian pattern: 
cortisol levels reach nadir at midnight, begin to rise 
around 0200 hrs, peak early in the morning (cortisol 
awakening response) and gradually decrease throughout 
the day.53,54 The circadian cortisol secretion pattern is 
actually derived from a dynamic ultradian rhythm of 
discrete cortisol pulses that follow ACTH pulses55-57, with 
larger and more frequent pulses occurring early in the 
morning.53,57 In humans, secretory pulses of cortisol 
occur every 80–110 min.17,19,55,57,58 The mean number of 
pulses in 18 healthy subjects was 12±0.7, and the 
circadian and ultradian pattern of cortisol concentrations 
(lower panel) and derived cortisol secretory rate (upper 
panel) is shown for a representative volunteer in Fig. 4.57 
Ultradian cortisol rhythms can be generated through a 
mechanism independent of input from the hypothalamic 
circadian pacemaker (suprachiasmatic nucleus)26 and 
are 
evolutionarily 
conserved 
across 
mammals, 
supporting the importance of pulsatility in normal GC signaling.59-61  
Pulsatile access of glucocorticoids to their receptors has been previously shown in vitro and in vivo 
in animal models to be of critical importance for gene regulation, non-genomic glucocorticoid 
signaling, HPA axis regulation, and endocrine and behavioral responses.23,25,62-64,22 Pulsatile 
changes in plasma GC levels result in gene pulsing mediated by transient GC receptor activation, 
which rapidly responds to circulating hormone levels. Conversely, constant, non-oscillatory hormone 
levels result in continuous transcription, aberrant mRNA accumulation, abnormal protein levels, and 
GC resistance.25,59 Rodent experiments show a differential c-fos response in the amygdala, 
hippocampus, and prefrontal cortex depending on a constant versus pulsatile pattern of GC 
presentation, underscoring the significance of gene pulsing.23 The different and often completely 
opposite effects of pulsatile vs continuous hormone presentation is well described in other hormone 
systems. For example, pulsatile delivery of gonadotropin releasing hormone (GnRH) induces 
ovulation35 whereas continuous delivery results in anovulation and suppression of the hypothalamic-
pituitary-gonadal axis.36,37 Deregulation of the ultradian GC rhythm influences gene transcription63 
and neuroendocrine responsiveness to GC challenge,23,24 and alters electro-physiological properties 
of the hippocampus.65 These effects can even be brain-region specific.18 For example, the Per 1 
gene is rapidly and robustly induced after a single GC dose in the hippocampus in rodents, but 
requires two or three pulses before transcription can proceed in the prefrontal cortex.18 Such tissue 
specificity likely allows differential physiological induction of appropriate genes under different 
conditions. Although yet to be determined, if such differential effects are present in cardio-metabolic 
tissues, this may have important implications for therapeutic development of ultradian delivery of GC 
replacement.34,66 While recent advances in GC replacement have attempted to mimic the circadian 
pattern of cortisol secretion, we will be the first to use subcutaneous (SQ) hydrocortisone (HC) pump 
with interval bolus delivery to provide both circadian rhythm and ultradian pulsatility in children with 
CAH. 
 
Alternative GC delivery modalities tested so far do not address cortisol pulsatility. Recent 
efforts to improve treatment of patients with adrenal insufficiency have focused on continuous SQHC 
infusions and modified release oral GC preparations, with mixed results. Studies, nearly all in adults, 

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have shown that SQHC via a pump is safe and can closely mimic the circadian rhythm.30-33,67 Oksnes 
et al., found no differences in height, weight, blood pressure, and sleep patterns between oral and 
SQHC therapy, although Health Related Quality of Life was improved with SQHC.31 Gagliardi et al., 
found no improvement in subjective health status.32 A recent study in 8 adults by Nella, et al, found 
that that continuous SQHC was a well-tolerated and safe modality of HC replacement over 6 months 
resulting in improved adrenal steroid control and positive effects on quality of life and fatigue.67 The 
study concluded earlier (childhood) intervention strategies are needed. Although all three studies 
tried to replicate circadian rhythm, they did not address pulsatile, ultradian rhythm of cortisol 
secretion. Johannson et al. showed modest improvement in blood pressure and weight reduction 
with a dual-release HC tablet therapy compared to immediate-release HC at the same daily dose 
(despite lower bioavailability) but patients were hypocortisolemic in the evening and early morning 
hrs.28 Another twice daily modified-release HC preparation reduces the magnitude of 
hypocortisolemia at night, but again does not provide ultradian pulsatility.29,68  
Current treatment guidelines for children with CAH2 do not consider individual cortisol PK or adrenal 
steroid PD parameters, or the inherent circadian and ultradian patterns of cortisol secretion. The 
methodology used in this proposed research is conceptually and in praxis novel for 2 reasons. First, 
in contrast to studies that used continuous SQHC to parallel circadian rhythm,30-33 we will be the first 
to use SQHC interval bolus delivery to capture physiologic cortisol circadian rhythm and ultradian 
pulsatility in children with CAH. Second, our study incorporates a single integrated PKPD model able 
to simultaneously describe the time courses of cortisol, 17OHP and D4A concentrations over 24 
hours in CAH patients. Our approaches could result in an important therapeutic paradigm shift in 
treating children with CAH and significantly improve health outcomes, and establish a new standard 
of care for dosing of patients with any form of adrenal insufficiency. 
 
3 Objectives 
3.1 Primary Objectives  
 
1. To implement an interval bolus SQHC dosing regimen that more closely mimics 
cortisol, 17OHP and D4A circadian and ultradian rhythms than conventional oral HC 
dosing. Up to twelve children (eight analyzable) with CAH, ages 4-18 yrs, will have 24-hr 
PKPD profiles of cortisol, 17OHP and D4A serum concentrations measured while on oral HC 
therapy (admission 1), during an initial trial of the SQHC pump (admission 2), and after 6 
weeks of SQHC pump treatment (admission 3). An integrated PKPD model will be used to 
determine cortisol, 17OHP and D4A parameters to compare the duration of time subjects 
have these concentrations outside their acceptable ranges. 
Hypothesis 1: Duration of hypocortisolemia and hypercortisolemia will be significantly shorter on 
SQHC pump therapy (admissions 2 and 3) than with conventional oral HC dosing (admission 1). 
Hypothesis 2: Duration of time 17OHP and D4A serum concentrations are outside an acceptable 
range of suppression will be significantly shorter while on the SQHC pump (admissions 2 and 3) 
than with oral dosing (admission 1).  
 

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3.2 Secondary/Exploratory Objectives 
1. Physical activity levels: Daily activity and sleep patterns will be assessed by wearing an 
Actigraph Link accelerometer (Pensacola, FL) for 7 full days (5 weekdays and 2 weekend 
days) during each study period.    
 
2. Quality of Life and cognitive measures: Quality of life (QoL) measures including NIH 
toolbox will be measured four times during the study (baseline, and once during each study 
period).  QoL will be measured through the validated PedsQL™ Generic Core Scale and 
the PedsQL™ Fatigue Scale. NIH Toolbox Cognitive Tasks: We will use NIH Toolbox 
Dimensional Change Card Sort Test (DCCS) from the computer-administered NIH Toolbox 
to measure children’s attention and executive functioning and cognitive flexibility, along with 
the Flanker Inhibitory Control & Attention Test A validated sleep and mood survey will also 
be administered. 
 
3. This proposal will include a utility assessment of a real-time (20 minutes) noninvasive point-
of-care salivary testing device [VerOFy® cortisol (VCORT)] in a home setting. While we are 
not using VCORT to make dosing decisions or diagnoses and formal monitoring will be 
accomplished using serum cortisol sampling within the protocol, we believe it is important 
to determine the utility of such a device.  
 
4. An analysis to determine whether PKPD system parameters change with the switch in the 
route of HC administration from oral to SQHC pump, and after six weeks of SQHC 
treatment. A preferred pharmacometric analysis for this outcome is to use nonlinear mixed-
effects (NLME) regression modeling to estimate PKPD parameters from all data at weeks 
1, 7 and 14 simultaneously.   
 
 
 
4 Study Design 
This is an open-label, non-randomized crossover feasibility trial which will compare oral HC 
administration with SQHC pump administration in pediatric patients with CAH.  Up to twelve children 
(eight analyzable) with CAH, ages 3-18 years, will have serial cortisol, 17OHP, ACTH and D4A 
serum concentrations determined over 24 hours while taking conventional oral therapy (Admission 
1).  
 
Admission 2 will serve three purposes: a 33-hr SQHC pump evaluation period, patient and parent 
training with the pump, and a 24-hr PKPD study. During admission 2, we will use each patient’s total 
daily dose (TDD) of HC to determine the doses to be delivered during the 33-hr period. The 24-hr 
schedule and percentage of the TDD of HC will be as follows: approximately 60% of the TDD of HC 
will be delivered in 3 equal pulses at 0300, 0600 and 0900. Another 35% will be delivered in 3 equal 
pulses at 1200, 1500 and 1800 and the remaining 5% at 2100 and 2400. Following delivery of the 
9:00 pm, 12:00 am, and 3:00 am pulses, a 24-hr PKPD study will be initiated at the 6:00 am pulse 
using the same sampling schedule of cortisol, 17OHP, ACTH and D4A as the first admission. After 
the 24-hr serum sample at 0600 the next morning, the pump will be disconnected and the subject 
will be sent home on their usual oral HC dosing regimen.  
 
After the SQHC pump therapy PKPD study during admission 2 at week 7, an analysis of the pattern 
of concentrations will be performed as a safety check. If the cortisol or adrenal steroid concentrations 

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are generally within acceptable ranges (defined in Aim 1), the same pump settings will be used when 
initiating the ambulatory pump phase at week 9. If concentrations are outside acceptable ranges, 
the initial SQHC pump settings will be adjusted from the Admission 2 dosing as needed to attain 
acceptable concentration ranges. Individual pulse doses may be increased or decreased but the 
frequency of pulses will be fixed to every 3 hours.  After determining appropriate SQHC pump 
settings, the subjects will return to clinic at week 9 to initiate the 6-week SQHC ambulatory pump 
therapy phase.  
 
 
6-WEEK PUMP TREATMENT 
All subcutaneous pump settings of hydrocortisone (timing and dose) can only be set by the 
researchers. The SQ infusion site will be changed every 3 days. As there may be variability in drug 
absorption associated with different sites of SQ infusion therapy,69,70.Each subject will be evaluated 
for appropriate site for SQ infusion (i.e. gluteal area, abdominal area) to ensure proper placement.. 
A clinician will establish contact every day for the first week via telephone. All patients will be seen 
at home twice each week during the first and second week at the time of injection site changes and 
once a week thereafter while on the pump to evaluate proficiency in changing the injection site; to 
collect blood for cortisol, 17OHP, ACTH, and D4A concentrations; and to inspect the injection site 
integrity.  
 
Dose Adjustments During Pump Therapy. During the 6-week pump treatment, multiple cortisol, D4A, 
ACTH and 17OHP concentrations will become available and they may suggest, along with clinical 
impressions, that the pump dosing setting needs to be revised. It is critical to note that subjects will 
not be required to stay on the initial dosing schedule for 6 weeks. Rather, standard clinical practice 
will be used to guide SQHC pump dosing adjustments. Specifically, D4A and 17OHP concentrations 
will be evaluated along with clinical information provided by the patient that are indicative of 
hypocortisolemia such as fatigue, nausea, diaphoresis, low blood pressure, dizziness or headache. 
This is currently the standard of care for pediatric CAH patients. Should incongruous information be 
observed, clinical impressions take precedence along with D4A concentrations, and then 17OHP 
concentration. Cortisol concentrations are not generally part of routine patient care and will play a 
lesser role in dosing changes. The changes in dose settings may involve increasing or decreasing 
the HC TDD, or perhaps changing the percentage of TDD administered at a given time, but the 3-hr 
dosing intervals will remain fixed.   
 
 
A 24-hr PKPD study will be performed during admission 3 (week 14) using the same sampling 
schedule as admission 2.  
 
5 Subjects 
5.1 Study Setting 
There will be three admissions and three outpatient visits held at Nucleus Network (formerly Prism 
Clinical Research), a 52-bed early phase research site that specializes in complex, phase I and II 
clinical trials in healthy and numerous patient volunteer populations including pediatrics. It is 
located within 1 mile from the University of Minnesota campus.    Aside from close proximity to the 
University of Minnesota, Nucleus Network (Prism Research) is located in the epicenter of the 
Minneapolis/St. Paul Metropolitan area with easy access for all residents to the facility as well as 
ample free parking for clinical research subjects. 

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Nucleus Network (formerly Prism Clinical Research) has performed studies in pediatric populations 
and collaborative trials with University of Minnesota Faculty. Nucleus Network (Prism Clinical 
Research) staff are trained in pediatric phlebotomy.  Volunteers and their guardians will be 
provided a private bedroom with satellite television and wireless internet access that is convenient 
for both children and their guardians. Nucleus Network (formerly Prism Research) also provides 
games and movies suitable for all ages.   
5.2 Eligibility Criteria 
A total of 12 children (6 boys and 6 girls), aged 3-18 years, may be enrolled on this study, to 
ensure available analysis of 8 completed participants. This study entry is open to children 
regardless of gender or ethnic background. 
5.2.1 Inclusion Criteria 
• 
Children 3 - 18 years of age. 
• 
Classic CAH as confirmed by hormonal and molecular testing. 
• 
Patients who have been on the same HC dosing regimen for 1 month 
5.2.2  Exclusion Criteria 
• 
Patients with non-classic CAH. 
• 
Patients on: 
o Dexamethasone 
o Prednisone, or 
o inhaled steroids. 
• 
Patients with total daily dose of HC dosing regimen (min 10 mg) that cannot meet 
the required smallest volume to be delivered by the pump (0.2 mg)  
• 
Non-English speaking patients 
Inclusion of Children 
The proposed study will enroll children 3-18 years of age. Justification for the inclusion of children 
in this study includes: 1) relevance of the disease to the pediatric population; 2) subcutaneous 
infusion pumps are currently used in the pediatric population to treat diabetes; 3) hydrocortisone 
succinate, the injectable form of oral hydrocortisone that will be used for hydrocortisone delivery in 
the subcutaneous infusion pumps, is currently used intramuscularly at home for children with CAH 
for emergency treatment or when children are sick and unable to take their medicine orally; 4) 
subcutaneous continuous delivery of hydrocortisone succinate has been used in adults with 
adrenal insufficiency and in an adolescent with CAH and was well tolerated and safe (Lovas and 
Husebye, Eur J Endocrinol, 2007; Gagliardi, et al., J Clin Endocrinol Metab, 2014; Oksnes, et al, J 
Clin Endocrinol Metab, 2014; Bryan, et al., J Clin Endocrinol Metab, 2009); 5) pulsatile delivery of 
hydrocortisone succinate was performed in normal adults without adverse effects in a study 
conducted by our collaborator Professor Stafford Lightman (Russell, et al., Clin Endocrinol, 2014); 
6) The Crono P ambulatory subcutaneous infusion pump (CANÈ S.p.A. Medical Technology, Italy) 
used in Professor Lightman’s study is the only pump specifically designed for preprogrammed 
(bolus) delivery of glucocorticoids. Inclusion of children in this trial is in accordance with 45 CFR 
part 46.406—research involving greater than minimal risk and no prospect of direct benefit to 
individual subjects, but likely to yield generalizable knowledge about the subject's disorder or 
condition.  
Rationale for specific age range 

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We propose to include children 3-18 years of age because the sequelae of the disease and 
treatment with steroids such as early epiphyseal closure and short stature, precocious puberty, 
virilization, adrenal rests, polycystic ovarian disease, and increased risk for osteoporosis and 
developing metabolic syndrome-related atherosclerotic cardiovascular disease in adult life impact 
children at an early age and some of them may not be reversible. It is therefore important in this 
disease to improve treatment early in life to avoid these adverse outcomes. 
Expertise of the investigative team for working with the age group   
Dr. Kyriakie Sarafoglou, a pediatric endocrinologist at the University of Minnesota, and has worked 
extensively with children with CAH for over 20 years and established a dedicated multidisciplinary 
CAH center in 2005. Dr. Richard Brundage has modeled PK/PD systems in many pediatric studies. 
Dr. Megan Gunnar is Director of the Institute of Child Development at the University of Minnesota. 
Her work focuses on stress responses of the hypothalamic pituitary-adrenocortical axis and its 
dysregulation in children and adolescents under various adverse conditions She has extensively 
studied correlations between cortisol levels and neurobehavioral outcomes in children. Dr. Zan 
Gao’s Kinesiology Laboratory focuses on field-based physical activity intervention to fight 
childhood obesity and application of modern technology in interventions to promote physical 
activity and health. 
 
5.3 Recruitment 
Subjects will be recruited from the current CAH patient population at the University of Minnesota 
Masonic Children’s Hospital. The study will be offered to all subjects with CAH at their routine 
clinical visits.  
Resources available 
 
The multidisciplinary pediatric CAH center at the University of Minnesota, which is the primary 
referral center for the State and neighboring states, follows over 120 children. Over 50 children 
have already participated in 6 hour cortisol pharmacokinetic studies (Sarafoglou, et al., J Invest 
Med, 2015; Sarafoglou, et al., J of Clin Pharma, 2014). 98 children and their families with CAH 
have participated in an ongoing Dr. Sarafoglou’s March of Dimes (#6-FY14-440) funded study 
“Can Molecular Testing Improve Newborn Screening Performance and Outcomes for Congenital 
Adrenal Hyperplasia?” Overall our experience is that this is a population eager to participate in 
clinical research because of limitations in current treatments.  The PI will delegate much of the 
screening and recruitment responsibilities to a research nurse and research coordinator. The PI 
has dedicated research time in her faculty appointment, allowing ample time to provide appropriate 
oversight and review eligibility of potential participants with study staff. 
 
Provisions to Protect the Privacy Interests of Participants 
 
Protecting Privacy: The study consent form will describe in detail any intrusive, uncomfortable, or 
unfamiliar questions, procedures, or interactions with researchers or study personnel that the 
participant will be asked to complete. Furthermore, the study consent form will communicate that it 
is the participant’s right to opt-out of any study procedures or the study as a whole or withdraw 
from the study at any time and this information will be reiterated and revisited periodically 
throughout the study in advance of intrusive, uncomfortable, or unfamiliar questions procedures or 
interactions. Participants will not be compelled or pressured to provide information or specimens or 
study data that they do not wish to provide. 
 

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Access to Participants: Participants have been fully informed of the ways in which their data 
will/may be used during the informed consent process. The research team has been trained in 
conducting these conversations and the participants are also assessed for their understanding of 
consent prior to signing the consent form or initiating any study procedures 
 
Consent Process 
 
Consent forms describing in detail the study procedures, and risks are given to the participant and 
written documentation of informed consent is required prior to starting intervention/administering 
study product.  Consent will take place at CAH clinic at the University of Minnesota Children’s 
Hospital in a private and confidential room. Participants will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. The participants will be given the 
opportunity to take the consent home to discuss with family and caregivers and return on a 
subsequent day to sign the consent and enroll in the study. Informed consent is a process that is 
initiated prior to the individual’s agreeing to participate in the study and continues throughout the 
individual’s study participation. Extensive discussion of risks and possible benefits of participation 
will be provided to the participants and their families. Consent forms will be IRB-approved and the 
participant will be asked to read and review the document. The investigator will explain the 
research study to the participant and answer any questions that may arise. All participants will 
receive a verbal explanation in terms suited to their comprehension of the purposes, procedures, 
and potential risks of the study and of their rights as research participants. Participants will have 
the opportunity to carefully review the written consent form and ask questions prior to signing. The 
participants should have the opportunity to discuss the study with others or think about it prior to 
agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. The participants may withdraw consent at any 
time throughout the course of the trial. A copy of the informed consent document will be given to 
the participants for their records. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study.    
 
Consent Process for Participants Who Are Not Yet Adults (infants, children, teenagers under 18 
years of age): Prior to screening for the study each participant and parent(s)/legal guardian will be 
informed in detail about the study with its risks and discomforts to be expected. A written parental 
permission will be obtained from each patient to be involved in the clinical trial by using the IRB-
approved Informed Consent Form (ICF) prior to the conduct of any study-related activity. Each 
participant will be given a copy of the written ICF. The participants will also be instructed that they 
are free to withdraw their consent and discontinue their participation in the study at any time.  The 
assent from the child or adolescent will be obtained when this is appropriate and when the 
potential participant is capable of providing assent. The determination of appropriateness and 
capacity of children in the study to provide assent is made by the PI.  For clinical investigations 
involving greater than minimal risk, permission is generally required from both parents unless only 
one parent has legal custody, or one parent is deceased, unknown, incompetent, or not reasonably 
available. 
 
Compensation for Research-Related Injury 
 
In the event that this research activity results in an injury, treatment will be available, including first 
aid, emergency treatment and follow-up care as needed.  Care for such injuries will be billed in the 
ordinary manner, to the participant or his/her insurance company. 
 
 

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6 Study Procedures 
6.1 Screening/Baseline  
Once consent has been obtained, the following tests and procedures will be done to determine if 
the subject is eligible: 
• 
Physical Exam 
• 
Medical History 
 
A subject diary will be provided after consent. This diary will be used by the subject throughout the 
study to log items such as signs & symptoms, adverse events, medications and dosing. 
6.2 Treatment period (weeks 1-20) 
6.2.1 Weeks 1-8 (Oral HC) 
6.2.1.1 Week 1 
Once eligibility has been determined, subjects will be admitted into the research unit. Subjects will 
be admitted for approximately 36 hours. Subjects will have a physical exam and quality of life 
questionnaire, sleep and mood surveys and NIH toolbox cognitive domain measures administered 
for baseline values. During Admission 1, the subject’s usual doses will be administered at 3 
standardized dosing times for the PKPD study: 0600, 1200 and 1800. Changes from usual dosing 
times are expected to be small and inconsequential for the patient. Immediately prior to the 
morning dose at 6am, a 3-mL blood sample will be obtained for quantification of cortisol, 17OHP, 
ACTH and D4A. Samples will then be obtained at 0.5, 1, 1.5, 2, 3, 4, and 6 (noon) hrs after the first 
dose. The same sampling intervals will be used following the 1200 and 1800 doses, with additional 
samples collected during the night at 0200, 0400 and 0600. The total blood volume over 36 hrs will 
be 75 ml, which is well within the acceptable blood volume for this patient population and age 
range. If a patient is <35 kg, the blood draw will be adjusted based on weight. Also during 
admission, a 24-hour urine collection will be performed and an aliquot of 20mLwill be extracted 
from two timed 12 hour timed urine collections over the course of 24 hours. Urine samples will be 
stored under PI supervision for necessary analysis in the future. The IRB will be notified of these 
analyses when determined. In addition, a total of six saliva samples will be collected at: 0600 (prior 
to first dose), 0700, 1200 (prior to second dose), 1300, 1800 (prior to third dose) and 1900. 
Salivary samples will be sent to Quest Diagnostics for adrenal steroid measurements through LC-
MS/MS assay. After processing, any remaining saliva samples (during week 1 and the remainder 
of the study) will be retained by Quest for future research, per subject/family consent. The nurse 
coordinator will review adverse events, medications and the subject’s dairy 
 
6.2.1.2 Weeks 1-6 
Upon discharge, subjects will continue their standard of care oral administration of HC for 6 weeks. 
  
6.2.1.3 Weeks 6 
 
At the home visit, an Actigraph Link accelerometer will be provided and used to monitor daily 
activity and sleep patterns for one week. These will be monitored by study personnel. The nurse 
coordinator will complete their assessment and will review adverse events, medications and the 
subject’s dairy. 
 

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6.2.1.4 Week 7 (SQHC Pump 33 hours) 
 
At week 7, subjects will be re-admitted for Crono P subcutaneous HC (SQHC) infusion pump 
training in which the device will be used for 33 hrs and include a 24-hr PKPD study while on the 
SQHC pump. Training will emphasize proper aseptic catheter placement, care of the insertion site, 
reconstituting the solution and filling the infusion syringe. HC sodium succinate (SOLU-CORTEF) 
sterile powder will be used for the SQHC pump as it is FDA approved for intramuscular and 
intravenous routes for CAH and Addison's disease. HC sodium succinate comes in a two-
compartment vial (Act-O-Vial) containing a 100 mg dose in the lower compartment and 2 ml sterile 
water in the upper compartment (100 mg/2 ml). Parents will be instructed to further dilute the 
solution with another 8 ml of 0.9% normal salineinto the infusion syringe, for a final concentration 
of 100 mg/10 ml (10 mg/ml). Parents will be trained to visually inspect the HC sodium succinate 
solution for particulate matter and discoloration. The parents of the children seen at the CAH 
Center are already familiar with the 100 mg Act-O-Vial as the IM HC sodium succinate injection is 
used at home in cases of acute stress or illness when the children are not able to take oral 
medication.  
 
Subjects will have a physical exam. Pump therapy during this admission will begin at 9 pm and 
continue for 33 hours. We will use each patient’s total daily dose (TDD) of HC to determine the 
doses to be delivered during the 33-hr period. The 24-hr schedule and percentage of the TDD of 
HC will be as follows: approximately 60% of the TDD of HC will be delivered in 3 equal pulses at 
0300, 0600 and 0900. Another 35% will be delivered in 3 equal pulses at 1200, 1500 and 1800 and 
the remaining 5% at 2100 and 2400. Following delivery of the 9:00 pm, 12:00 am, and 3:00 am 
pulses, a 24-hr PKPD study will be initiated at the 6:00 am pulse using the same sampling 
schedule of cortisol, 17OHP, ACTH and D4A as the first admission. Urine collection will proceed 
as the first admission beginning at 0600. Saliva samples will be collected at the same time points 
as in admission 1 (0600, 0700, 1200, 1300, 1800, and 1900) irrespective of dosing. Salivary 
samples will be sent to Quest Diagnostics for adrenal steroid measurements through LC-MS/MS 
assay.     
 
Subjects and families will be given and instructed on how to use an automatic, upper arm blood 
pressure monitor with a cuff appropriate for the child’s size. Subjects will begin monitoring of daily 
blood pressure upon discharge (see section 9.3 for instructions), to week 13. The staff will review 
adverse events, medications and the subject’s dairy. The Actigraph will be returned at this visit. 
 
6.2.1.5 Weeks 7-8 
 
After completing the 24-hr PKPD study, subjects will be discharged from the research facility and 
continue on their usual HC oral dosing schedule for 1 week prior to initiation of the SQHC pump. 
During this time, cortisol, 17OHP, and D4A concentrations will be analyzed to determine that the 
pump has delivered HC as expected and cortisol, 17OHP, and D4A concentrations are in an 
acceptable range. SQHC will be recalculated as needed before initiating the pump if cortisol, 
17OHP, or D4A concentrations are not generally in a desired range.   
 
6.2.1.6 Week 8 
The nurse coordinator will call the subject/family to review daily blood pressure readings, adverse 
events, medications and the subject’s dairy. 
 
6.2.2 Weeks 9-14 (SQHC Pump) 
 

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6.2.2.1 Weeks 9-13 
 
Week 9 (outpatient visit) The patient will meet Dr. Sarafoglou and the study nurse coordinator at 
Nucleus (Prism) for initiating the 6-wk SQHC pump phase. The patient will have a physical exam 
and the nurse coordinator will review the patient’s recorded daily blood pressure, subject diary, 
adverse events and any medications taken. It is our standard policy to make sure that families 
have parenteral hydrocortisone to use during emergencies. We will instruct the patients to call Dr. 
Sarafoglou before administering any parenteral dose during this phase. After the first four 
supervised home visits by the nurse coordinator, the family, as instructed will replace the HC 
infusion syringe and solution, and the site of SQ infusion every 72 hours. As with insulin, we 
recognize that there may be variability in drug absorption associated with different sites of SQ 
injection pump infusion therapy. Each subject will be evaluated for appropriate site for SQ infusion 
(i.e. gluteal area, abdominal area)..  Parents will be instructed to visually inspect the parenteral HC 
solution for particulate matter and discoloration prior to administration into the pump.  
 
After the outpatient visit, during week 9, the subject/family will be called on the days that the RN 
coordinator is not completing home visits. This call is the review pump use, adverse events and 
other questions or concerns. 
 
Weeks 9-13: The nurse coordinator will visit subjects at home seven times for safety monitoring, 
which includes a nursing assessment, and measurement of cortisol, 17OHP, ACTH and D4A 
concentrations during the SQHC pump period. During the home visits, along with the blood draws, 
saliva will be collected and measured through VerOFy® cortisol (VCORT) with the remaining 
salivary sample sent to Quest Diagnostics for free cortisol measurements through LC-MS/MS 
assay.  VCORT is IDE exempt per the requirements outlined in 21CFR812.2(c) and in 
21CFR809.10(c). The nurse coordinator will complete their assessment and review the patient’s 
recorded daily blood pressure, subject diary, adverse events and any medications taken. At Visit 
13, an Actigraph Link accelerometer will be provided for monitoring daily activity and sleep patterns 
for one week. 
To note, the use of the VerOFy® may be restricted based upon the company’s availability to 
provide the device to our site site. As noted under the secondary/exploratory objectives, the 
VerOFy® will not be used to “make dosing decisions or diagnoses and formal monitoring will be 
accomplished using serum cortisol sampling.” We therefore will collect and record results only at 
time of availability for use of the device. The informed consent will notify participants/families that 
this sampling and measurement will be based upon when the device is available at the time of 
study visit.. 
 
6.2.2.2 Week 14 + 5 days 
 
At week 14 + 5days, subjects will be admitted for a final SQHC pump 24-hr PKPD study. A 
physical exam will be performed. This study will occur at the 6:00 am pulse using the same 
sampling schedule of cortisol, 17OHP, ACTH and D4A as the previous two admissions. Urine 
collection will proceed as the first admission. Saliva samples will be collected at the same time 
points as in admission 1 and 2. Salivary samples will be sent to Quest Diagnostics for adrenal 
steroid measurements through LC-MS/MS assay. QoL, sleep and mood surveys and NIH toolbox 
cognitive domain measures will be repeated. Once the PKPD study is complete, subject will 
discontinue use of the pump and resume their usual oral HC regimen. The subject’s diary, adverse 
events and medications taken will be reviewed. The Actigraph will be returned. 
 

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6.2.3 Weeks 15 (+ 1 day)-20 (Oral HC follow-up) 
 
6.2.3.1 Week 15 (+ 1 day)-18 
 
We will continue to follow subjects with weekly phone calls while they are on their usual oral HC 
dose regimen. The coordinator will discuss any adverse events and medications taken, along with 
reviewing the subject’s diary. 
6.2.3.2 Week 19 
 
The nurse coordinator will visit the subject at home. The will include a nurse coordinator 
assessment that includes reviewing the patient’s diary, adverse events and medications taken. An 
Actigraph Link accelerometer will be provided and used to monitor daily activity and sleep patterns 
for one week. These will be monitored by study personnel.  
 
6.2.3.3 Week 20 
 
Outpatient visit. Subjects will have a physical exam. Quality of life questionnaire, sleep and mood 
surveys and NIH toolbox cognitive domain measures administered. Patient’s diary will be reviewed 
and collected by the study staff. Adverse events and medications will be reviewed. 
 
 
* Schedule of events will follow as described above with a time window of +/- 1 day for completion of study 
visits 
 

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6.2.4 Subject Withdrawal 
Subjects make be taken off the study by the Principal Investigator for the following reasons: 
• 
Safety reasons 
• 
Failure to adhere to the protocol requirements 
• 
Subject withdraws consent 
• 
The study terminates early. 
Subjects will be instructed not to stop taking the cortisol if they withdraw from the study. Subjects 
receiving SQHC pump therapy will be asked to return to the clinic for pump removal and to resume 
taking oral steroids. If subjects are willing, we will ask them to complete the follow up visit at the 
time they withdraw from study to capture any final data. 
 
7 Study Drug 
7.1  Solu-Cortef® (hydrocortisone sodium succinate for injection) 
7.1.1 Description 
SOLU-CORTEF Sterile Powder is an anti-inflammatory glucocorticoid, which contains 
hydrocortisone sodium succinate as the active ingredient. SOLU-CORTEF Sterile Powder is 
available in several packages for intravenous or intramuscular administration. Our patients use the 
single-dose 100 mg ACT-O-VIAL that reconstitutes the hydrocortisone powder to provide a final 
concentration of 100mg/2 mL . 
DIRECTIONS FOR USING THE ACT-O-VIAL SYSTEM 
1. Press down on plastic activator to force diluent into the lower compartment. 
2. Gently agitate to effect solution. 
3. Remove plastic tab covering center of stopper. 
4. Sterilize top of stopper with a suitable germicide. 
5. Insert needle squarely through center of stopper until tip is just visible. Invert vial and 
withdraw dose. 
Further dilution is not necessary for intravenous or intramuscular injection. For intravenous 
infusion, first prepare solution as just described. The 100 mg solution may then be added to 100 
to 1000 mL of 5% dextrose in water (or isotonic saline solution or 5% dextrose in isotonic saline 
solution if patient is not on sodium restriction). The 250 mg solution may be added to 250 to 1000 
mL, the 500 mg solution may be added to 500 to 1000 mL and the 1000 mg solution to 1000 mL of 
the same diluents. In cases where administration of a small volume of fluid is desirable, 100 mg to 

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3000 mg of SOLU-CORTEF may be added to 50 mL of the above diluents. The resulting solutions 
are stable for at least 4 hours and may be administered either directly or by IV piggyback. 
When reconstituted as directed, pH's of the solutions range from 7 to 8 and the tonicities are: 100 
mg ACT-O-VIAL, .36 osmolar; 250 mg ACT-O-VIAL, 500 mg ACT-O-VIAL, and the 1000 mg ACT-
O-VIAL, .57 osmolar. (Isotonic saline=.28 osmolar.) 
7.1.2 Dosage and Administration 
The parents of our children are already familiar with as the 100 mg ACT-O-VIAL as IM 
hydrocortisone injection is used at home in cases of acute stress or illness when the children are 
not able to take oral medication. Parents will be instructed to further dilute the solution with another 
8 mL of 0.9% normal saline into the infusion syringe and visually inspect the hydrocortisone 
solution for particulate matter and discoloration.   
 
The patients will receive their usual oral hydrocortisone dosing throughout and the first treatment 
period until the SQHC pump is initiated at admission 2. During admission 2, we will use each patient’s 
total daily dose (TDD) of HC to determine the doses to be delivered during the 33-hr period. The 
infusion pump will be set to rapidly deliver a hydrocortisone pulse dose every 3 hr to attain an 
ultradian rhythm. The 24-hr schedule and percentage of the TDD of HC will be as follows: 
approximately 60% of the TDD of HC will be delivered in 3 equal pulses at 0300, 0600 and 0900. 
Another 35% will be delivered in 3 equal pulses at 1200, 1500 and 1800 and the remaining 5% at 
2100 and 2400.After the 24-hr serum sample at 0600 the next morning, the pump will be 
disconnected and the subject will be sent home on their usual oral HC dosing regimen. If 
concentrations are outside acceptable ranges, the initial SQHC pump settings will be adjusted from 
the Admission 2 dosing as needed to attain acceptable concentration ranges. Individual pulse doses 
may be increased or decreased but the frequency of pulses will be fixed to every 3 hours.  After 
determining appropriate SQHC pump settings, the subjects will return to clinic at week 9 to initiate 
the 6-week SQHC ambulatory pump therapy phase.  
 
During the 6-week pump treatment, multiple cortisol, D4A and 17OHP concentrations will become 
available and they may suggest, along with clinical impressions, that the pump dosing setting needs 
to be revised. It is critical to note that subjects will not be required to stay on the initial bolus dosing 
schedule for 6 weeks. Rather, standard clinical practice will be used to guide SQHC pump dosing 
adjustments. Specifically, D4A and 17OHP concentrations will be evaluated along with clinical 
information provided by the patient that are indicative of hypocortisolemia such as fatigue, nausea, 
diaphoresis, low blood pressure, dizziness or headache. This is currently the standard of care for 
pediatric CAH patients. Should incongruous information be observed, clinical impressions take 
precedence along with D4A concentrations, and then 17OHP concentration. Cortisol concentrations 
are not generally part of routine patient care and will play a lesser role in dosing changes. The 
changes in dose settings may involve increasing or decreasing the HC TDD, or perhaps changing 
the percentage of TDD administered at a given time, but the 3-hr dosing intervals will remain fixed.   
 
Every 72 hours, the family will be instructed to replace the hydrocortisone infusion syringe and 
solution, and the site of subcutaneous infusion will be changed. 
 
Parents will be instructed to visually inspect the parenteral hydrocortisone solution for particulate 
matter and discoloration prior to administration into the pump cassette.  Parents are already 
familiar with this process as IM hydrocortisone injection is used at home in cases of acute stress or 
illness when the children are not able to take oral medication. 
 

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7.1.3 Dosage adjustments 
The following dosage adjustments may be made during the course of the study in the event of 
intercurrent illness, pump failure or symptoms of adrenal insufficiency occur. 
• 
For fever > 101 degrees F: add oral hydrocortisone to the patient’s regimen, which will be 
double the amount of the daily dose that the patient receives through the SQ pump. The 
additional oral stress hydrocortisone dose will be divided in 4 equal doses every 6 hours. 
The subject’s family will be instructed to administer an antipyretic (Tylenol, ibuprofen, etc).  
• 
For a serious physical injury or broken bone(s), administer a stress dose of hydrocortisone 
as described above.  
• 
In the event of severe illness, trauma, or inability to tolerate oral hydrocortisone, 
unconsciousness, or repeated vomiting: 75 mg/m2/day of Solucortef intramuscular injection 
will be administered immediately. The family will be instructed to seek Emergency 
Department care to initiate IV hydrocortisone and fluid replacement as they typically do as 
part of the standard therapy to prevent adrenal crisis. 
• 
In the event of pump failure, patients will be instructed to resume their usual oral 
hydrocortisone dose until a replacement pump is given to the family.  
• 
In the event of an occlusion that results in missed hydrocortisone dosing, patients will be 
instructed to change the infusion set and notify the investigators. If occlusion persists, 
patients will be instructed to resume their usual oral hydrocortisone dose until occlusion is 
resolved.  
• 
A pump malfunction that results in delivery of the entire reservoir (worst case scenario 100 
mg of hydrocortisone) is not a life threatening event as children receive similar or greater 
amounts of hydrocortisone during illness. If the entire reservoir is delivered, patients will be 
instructed to notify the investigators and return to their usual oral hydrocortisone dosing 
until a replacement pump is given to the family.  
At all times the PI will be available to the families. If pump therapy is stopped at any point the 
investigator will evaluate the participant and re-initiate the pump treatment when deemed 
clinically appropriate. Once the pump is resumed, pump treatment will be continued in order to 
meet the total 6 weeks of pump treatment.  
7.2 Cortef® hydrocortisone tablets 
7.2.1  Description 
Cortef Tablets contain hydrocortisone which is a glucocorticoid. Glucocorticoids are adrenocortical 
steroids, both naturally occurring and synthetic, which are readily absorbed from the 
gastrointestinal tract. Hydrocortisone USP is white to practically white, odorless, crystalline powder 
with a melting point of about 215° C. It is very slightly soluble in water and in ether; sparingly 
soluble in acetone and in alcohol; slightly soluble in chloroform. 
 
7.2.2 Dosage and Administration 
Patients will be receiving their usual dosing regimen of hydrocortisone tablets during the first 
treatment period. 

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7.3 Receiving, Storage, and Dispensing 
7.3.1 Receipt of Drug Supplies 
Upon receipt of the of the study treatment supplies, an inventory will be performed and a drug receipt 
log filled out and signed by the person accepting the shipment.  The designated study staff will count 
and verify that the shipment contains all the items noted in the shipment inventory.  Any damaged 
or unusable study drug in a given shipment (active drug or comparator) will be documented in the 
study files.   
7.3.2 Storage 
Store unreconstituted product at controlled room temperature 20° to 25(C(68° to 77( F). Store 
solution at controlled room temperature 20° to 25(C (68° to 77( F) and protect from light. Use 
solution only if it is clear. Unused solution should be discarded after 3 days. 
7.3.3 Dispensing of Study Drug 
Drug will be prepared and dispensed by the Investigational Drug Services Pharmacy at the 
Nucleus Network (Prism Clinical Research) center.  
8 Study Device- CRONO P 
CRONO P is an ambulatory infusion pump with reservoir, intended for bolus subcutaneous 
administration for long-term treatment with glucocorticoids. 
 
A mechanism pushes against the reservoir's rubber plunger, enabling the pump to combine high 
delivery pressure with excellent precision while administering the drug. 
 
An innovative infusion control system allows the pump to automatically restart and finish an 
infusion after an occlusion has been removed. 
 
CRONO P has a liquid crystal display (LCD) which provides the doctor and patient with useful 
information regarding the settings, operations and diagnostics of the pump. 
 
The CRONO P is designed to be used with any commercially available infusion sets with luer lock 
connector so that the decision of which set to use could be made by the healthcare professionals 
following the patient.  For this protocol we are going to use the following set:  
 
Comfort and Inset Subcutaneous Infusion Sets made by Unomedical (510K #: K051264) 
The Unomedical infusion set uses the standard luer lock which is compatible with all pumps that 
use a luer lock, like the Cane` Crono P that we are using in our study. The Unomedical set is 
commercially available and cleared for use in the United States. This infusion Set is an all-in-one 
straight-set infusion system. The 90-degree soft cannula is pre-loaded in an automatic spring 
inserter, to allow for one-handed insertions and it also has a built-in needle cover. 
 
 

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9 Risks and Benefits 
9.1 Potential Risks 
Risks of Hydrocortisone 
While there are risks associated with chronic corticosteroid use, this CAH patient population does 
not produce adequate levels of cortisol and therefore require this treatment for survival. Patients 
with CAH, whether in the study or not, take corticosteroids every day of their life. The potential 
risks specific to this study are mainly dermatologic: Allergic dermatitis, cutaneous and 
subcutaneous atrophy, erythema, hyperpigmentation, hypopigmentation, rash, sterile abscess, 
striae, urticaria.  
Potential risks of hydrocortisone in children and adults not specific to our study population and 
study design include: 
• 
Gasping syndrome due to the presence of benzyl alcohol in the injectable cortisol. 
• 
Allergic reactions: allergic or hypersensitivity reactions, anaphylactoid reaction, 
anaphylaxis, angioedema.  
• 
Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, 
circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic 
cardiomyopathy in premature infants, myocardial rupture following recent myocardial 
infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, 
thrombophlebitis, vasculitis.  
• 
Dermatologic: Acne, allergic dermatitis, burning or tingling (especially in the perineal area, 
after intravenous injection), cutaneous and subcutaneous atrophy, dry scaly skin, 
ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, 
impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed 
reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.  
• 
Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid 
state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral 
hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual 
irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times 
of stress, as in trauma, surgery, or illness). 
• 
Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid 
retention, hypokalemic alkalosis, potassium loss, sodium retention. 
• 
Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal 
administration), elevation in serum liver enzyme levels (usually reversible upon 
discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with 
possible perforation and hemorrhage, perforation of the small and large intestine 
(particularly in patients with inflammatory bowel disease), ulcerative esophagitis. 
• 
Metabolic: Negative nitrogen balance due to protein catabolism. 
• 
Musculoskeletal: Aseptic necrosis of femoral and humeral heads, Charcot-like arthropathy, 
loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, 
postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral 
compression fractures. 
• 
Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, 
increased intracranial pressure with papilledema (pseudotumor cerebri) usually following 
discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, 
personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, 

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paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal 
administration (see WARNINGS, Neurologic). 
• 
Ophthalmic: Exophthalmoses, glaucoma, increased intraocular pressure, posterior 
subcapsular cataracts, rare instances of blindness associated with periocular injections. 
• 
Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or 
decreased motility and number of spermatozoa, injection site infections following non-
sterile administration (see WARNINGS), malaise, moon face, weight gain. 
 
 
9.2 Potential Risks of the CRONO P Device 
The major risk of this device that could cause serious harm to the patient is the use of incorrect 
settings and/or incomplete understanding of the operational functions and of the alarms. 
 
9.3 Methods to minimize risk 
Subjects will be monitored as per standard of care during treatment with oral cortisol. During the 
treatment with the SQHC pump, subjects will be monitored inpatient through physical exams for 
the first 36 hours. Following discharge, for the first four changes in SQ infusion site, a nurse 
coordinator will travel to the patient’s home to evaluate proficiency in changing the injection site; to 
collect blood for cortisol, 17OHP, ACTH and D4A concentrations; and to inspect the injection site 
integrity. All patients will be seen at home twice during the first week and second week and once a 
week thereafter while on the pump. As an additional safety measure for monitoring pump failure 
that does not trigger an alarm, families will be given and instructed on how to use an automatic, 
upper arm blood pressure monitor with a cuff appropriate for the child’s size. One week prior to the 
SQHC pump treatment, patients while on oral HC will measure and log child’s blood pressure daily 
in the morning, after 5 minutes rest. When the child is on the pump, families will be instructed to 
measure and log the child’s blood pressure daily. If the mean arterial pressure [MAP = [(2 x 
diastolic)+systolic] / 3] is less than 20 percent of the lowest MAP observed during oral treatment, 
the blood pressure will be measured 2 more times at 5-minute intervals. Instructions will be 
provided to the families to notify the PI if 2 of the 3 MAP measurements are below 20 percent of 
the lowest MAP obtained during oral HC treatment. Parents will be asked to inspect the injection 
site, tubing, and syringe volume. If no issues are identified and if the blood pressure remains 
outside the appropriate range after three measures, the parents will be instructed to bring the child 
to the clinic for clinical evaluation and assessment of pump function. Subjects and their parents will 
be instructed to contact the Principal Investigator immediately if they develop any signs of 
symptoms of adrenal insufficiency (e.g. fatigue, nausea, dizziness). The PI can be reached 24 
hours a day by her pager number. 
The parents of the subjects will be thoroughly trained on the use of the pump, the infusion sets 
which will be used, and the operational functions of the alarms.   
9.4 Potential Benefits 
Based upon guidance provided in 45 CFR 46, subpart D regarding research in children, the 
proposed study presents greater than minimal risk without direct benefit to the individual subject 
(45 CFR part 46.406). However, this study has potential to yield generalizable knowledge about 
the subject’s pharmacokinetics and dynamic response (45 CFR 46.406) to cortisol. An indirect 
benefit is this alternative pulse dosing strategy could spur the development of novel methods of HC 
drug delivery that could improve long term outcomes of patients with CAH. 

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10 Safety and Adverse Events 
10.1  Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries will be regarded as adverse 
events.  Abnormal results of diagnostic procedures are considered to be adverse events if the 
abnormality: 
• 
results in study withdrawal 
• 
is associated with a serious adverse event 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that 
is:  
• 
fatal 
• 
life-threatening 
• 
requires or prolongs a hospital stay 
• 
results in persistent or significant disability or incapacity 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of 
major clinical significance.   They may jeopardize the subject, and may require intervention to prevent 
one of the other serious outcomes noted above.  For example, drug overdose or abuse, a seizure 
that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in an 
emergency department would typically be considered serious.  
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures to the end of the study treatment follow-up.  For this study, 
the study treatment follow-up is defined as 30 days following the last administration of study 
treatment.  
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition will be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens 
during the study period. 
General Physical Examination Findings 

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At screening, any clinically significant abnormality will be recorded as a preexisting condition.  At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an 
adverse event will also be recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, 
the investigator will instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.   
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization will be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any 
condition responsible for surgery should be documented as an adverse event if the condition meets 
the criteria for an adverse event.  
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
a preexisting condition.  Surgery should not be reported as an outcome of an adverse event 
if the purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
• 
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
10.2  Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events will be 
recorded immediately in the source document, and also in the appropriate adverse event module 
of the case report form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results will be recorded in the source document, though should be grouped under one 
diagnosis. 
All adverse events occurring during the study period must be recorded.  The clinical course of each 
event will be followed until resolution, stabilization, or until it has been determined that the study 
treatment or participation is not the cause.  Serious adverse events that are still ongoing at the end 
of the study period must be followed up to determine the final outcome.  Any serious adverse event 
that occurs after the study period and is considered to be possibly related to the study treatment or 
study participation should be recorded and reported immediately. 
10.3  Reporting of Serious Adverse Events 
10.3.1 IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be submitted to the IRB 
within 5 working days if it falls under the UPIRTSO guidelines.  Copies of each report and 
documentation of IRB notification and receipt will be kept in the Clinical Investigator’s binder. 

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10.3.2 FDA Notification by Sponsor 
The study sponsor shall notify the FDA by telephone or by facsimile transmission of any unexpected 
fatal or life-threatening experience associated with the use of the drug as soon as possible but no 
later than 7 calendar days from the sponsor’s original receipt of the information. 
If a previous adverse event that was not initially deemed reportable is later found to fit the criteria for 
reporting, the study sponsor will submit the adverse event in a written report to the FDA as soon as 
possible, but no later than 15 calendar days from the time the determination is made. 
 
Agency 
Criteria for 
Reporting 
Timeframe 
Form to Use  
Submission 
address/fax numbers  
U of MN IRB 
SAE: fatal, life-
threatening or 
serious, 
unexpected, at 
least possibly 
related  
5 working days 
MedWatch 3500A 
Form 
MMC 820 
FDA 
SAE: fatal, life-
threatening, 
unexpected, at 
least possible 
related 
7 calendar days  
MedWatch 3500a 
Form but 
alternative formats 
are acceptable 
(e.g. summary 
letter) 
Fax: 1 (800) FDA - 
0178 
SAE: serious, 
unexpected, at 
least possibly 
related 
15 calendar days 
 
10.4  Stopping Rules  
Subjects will be removed from the study if the following occur: 
• 
An infection at the site of SQ cannulation. On the first and second occasion of an infected 
site, the cannula will be changed and moved to a new SQ location, and the family will receive 
additional training in proper hygienic technique. If infection occurs on more than two 
occasions, poor hygienic technique might be a cause and the patient will be removed from 
the study.  
• 
A systemic allergic reaction at the site of the SQ infusion cannula; if this happens we will 
discontinue using the pump and return a child to their oral HC therapy.  
• 
If a patient experiences more than two episodes of adrenal crisis (defined as a constellation 
of signs and symptoms caused by low cortisol that include:  lethargy, hypoglycemia, low 
blood pressure, vomiting/nausea, abdominal pain, weakness, dizziness and cardiovascular 
collapse) in the SQ treatment period, the patient will be removed from the study. Periods of 
increased stress or illness can result in adrenal crisis and can occur in any CAH patients at 
any time. The adrenal crisis would be attributed to the pump if there are no other triggers 
such as trauma, febrile illness, gastroenteritis. Patients will be instructed to take stress dose 
oral steroids during physical stress as per emergency protocol that all children with CAH 
receive as part of standard care, in addition to the cortisol provided by the SQ pump 
  

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10.5  Medical Monitoring 
The Principal Investigator will oversee the safety of the study at the University of Minnesota site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as 
noted above.  Medical monitoring will include a regular assessment of the number and type of 
adverse events. 
This study will have a medical monitor, a University of Minnesota physician, not involved in the 
trial. The medical monitor will review adverse events, Serious Adverse Events, and any other event 
considered to be reportable to the University of Minnesota Institutional Review Board. The 
Principal Investigator will submit copies of these reports to the medical monitor.. The medical 
monitor will summarize its findings and/or recommendations in a letter to the Principal Investigator. 
The Principal Investigator will submit a copy of the monitor’s report to the Institutional Review 
Board per their policy.  
 
11 Statistical Considerations 
11.1 Primary Outcomes Measure 
Primary objective 1: Time periods of hyper- and hypocortisolemia and over- and under-
suppression of 17OHP and D4A will be compared between the oral and SQHC PKPD admissions 
using a paired t-test (with times log-transformed if needed to satisfy the normality assumption). A 
sample of 8 children gives 80% power to detect a population-average difference in outcome 
(undesired time period) between oral HC and SQHC pump of 1.2 times the standard deviation 
describing variation between children in the outcome for oral HC minus the outcome for SQHC 
pump (Cohen's d=1.2). This study design and analysis have not been performed to our knowledge 
in humans or animals, and data to estimate this standard deviation do not exist. 
11.2 Secondary Outcomes Measures 
Statistical analysis for secondary measures of actigraph, quality of life, sleep survey and NIH toolbox: 
Descriptive statistics for each outcome variable will be provided and used to discern changes in the 
outcome variables. Repeated measures ANOVAs will be used to examine differences in each 
outcome variable from Oral HC to SQHC Pump, and then back to Oral HC. 
Statistical analysis for VCORT: Correspondence between VCORT and salivary cortisol by LC-
MS/MS (56 samples total) will be described using a scatter plot identifying the child who provided 
each measurement; the intra-class correlation (ICC) describing association of VCORT with LC-
MS/MS; a test for bias of VCORT relative to LC-MS/MS using a paired t-test; and percentiles of 
absolute differences between the VCORT and LC-MS/MS measurements (e.g., "90% of differences 
were less than X"). 
The Likelihood Ratio Test will be used to determine the statistical significance of the changes in 
PKPD parameters. The difference between objective function values (OFV; a goodness of fit 
measure similar to a sum of squares) is approximately chi-square distributed and if the OFV 
decreases by more than 3.8 (chi-square, p=0.05, df=1) the model with the added parameter is 
significantly better. No formal power calculations are currently available for the NLME modeling 
approach. If a persistent difference within subjects exists among the TVCL estimates across the 3 
PKPD treatment arms, it will be detected as a significant difference among THETA1, THETA2 and 
THETA3. 
 

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12 Administrative Considerations 
12.1 Conduct of the Trial 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP), the Declaration of Helsinki, and the appropriate regulatory 
requirement(s).   
The University Of Minnesota IRB will review all appropriate study documentation in order to 
safeguard the rights, safety and well-being of the patients.  The study will only be conducted at 
sites where IRB/EC or Campus Administrator approval has been obtained.  The protocol, informed 
consent, written information given to the patients, annual progress reports, and any revisions to 
these documents will be provided to the IRB by the investigator.   
Essential clinical documents will be maintained to demonstrate the validity of the study and the 
integrity of the data collected.  Master files should be established at the beginning of the study, 
maintained for the duration of the study and retained according to the appropriate regulations.   
12.2 Data Management  
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents. Data generated by the methods described in the protocol will be 
recorded on paper forms and transcribed to electronic case report forms (eCRFs).  
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the 
CRF is left blank because the procedure was not done or the question was not asked, write “N/D”.  
If the item is not applicable to the individual case, write “N/A”. Electronic data capture will be 
utilized for case report forms. Data will be entered into a secure, password-protected REDCap 
database set up for this study and administered at the University of Minnesota. 
Confidentiality – Data Security 
All data obtained from this study will be linked to a study specific code and not to personal 
identifying information (e.g., name, social security number, medical record number). Data will be 
entered into REDCap database which will be password secured, and encrypted and only 
accessible to the investigator and research staff of this project. The REDCap database uses a 
MySQL database via a secure web interface with data checks used during data entry to ensure 
data quality. REDCap includes a complete suite of features to support HIPAA compliance, 
including a full audit trail, user-based privileges, and integration with the institutional LDAP server. 
The MySQL database and the web server will both be housed on secure servers operated by the 
University of Minnesota Academic Health Center’s Information Systems group (AHC-IS). The 
servers are in a physically secure location on campus and are backed up nightly, with the backups 
stored in accordance with the AHC-IS retention schedule of daily, weekly, and monthly tapes 
retained for 1 month, 3 months, and 6 months, respectively. Weekly backup tapes are stored 
offsite. The AHC-IS servers provide a stable, secure, well-maintained, and high-capacity data 
storage environment, and both REDCap and MySQL are widely-used, powerful, reliable, well-
supported systems. Access to the study's data in REDCap will be restricted to the members of the 
study team by username and password.Only members of the study team will be granted access to 
the REDCap database and will receive protocol and data entry training prior to access being 
granted. Study data will not be shared outside the study team. The consent and study data will not 
be placed in medical, employment, or educational records. 

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Data Banking 
Storage and Access: Data will be stored indefinitely in the study REDCap database. Only the study 
team will have access to these records for the duration of storage.  
Data: This data set will include no identifying information, simply the study ID and participant name 
as maintained in paper form as part of the participants file (original signed ICF, enrollment CRF). 
Release/Sharing: Data will not be released or shared outside the study team 
Sharing of Results with Participants 
Data will not be released or shared outside the study team. 
12.3 Data Monitoring 
Data will be monitored by the clinical monitors at the University of Minnesota Clinical and 
Translational Science Institute. This study will be monitored according to FDA/GCP guidelines.  
The investigator will allocate adequate time for such monitoring activities.  The Investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access to 
all the above noted study-related documents and study related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.), and has adequate space to conduct the monitoring visit. 
12.4 Event Reporting to the IRB 
Safety concerns for this project are expected to be minimal with (with list of any expected risk(s)) 
as the primary expected concern.   Any events meeting an unexpected, serious adverse event 
defined as reportable (such as hospitalization) on the IRB’s website at 
http://www.research.umn.edu/irb/ae/.    
In addition, to be in compliance with local and federal regulations the following events/problems will 
be reported to the IRB within the 5 working day time frame: 
• 
Any serious event (including on-site and off-site adverse events, injuries, side effects, 
deaths or other problems) which in the opinion of the local researcher was unanticipated, 
involved risk to subjects or others, and was possibly related to the research procedures 
• 
Any serious accidental or unintentional change to the IRB-approved protocol that involves 
risk or has the potential to recur;  
• 
Any deviation from the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research subject; 
• 
Any publication in the literature, safety monitoring report (including Data and Safety 
Monitoring Reports), interim result or other finding that indicates an unexpected change to 
the risk/benefit ratio of the research; 
• 
Any breach in confidentiality that may involve risk to the subject or others; 
• 
Any complaint of a subject that indicates an unanticipated risk or that cannot be resolved by 
the research staff.  
 
 

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13 REFERENCES 
1. 
Therrell BL. Newborn screening for congenital adrenal hyperplasia. Endocrinology and metabolism 
clinics of North America. Mar 2001;30(1):15-30. 
2. 
Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase 
deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. Sep 
2010;95(9):4133-4160. 
3. 
Sarafoglou K, Zimmerman CL, Gonzalez-Bolanos MT, Willis BA, Brundage R. Interrelationships 
among cortisol, 17-hydroxyprogesterone, and androstenendione exposures in the management of 
children with congenital adrenal hyperplasia. Journal of investigative medicine : the official 
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