Optimizing timing of glucocorticoid treatment in children with congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a
disorder of adrenal steroid synthesis caused by a deficiency of one of the
enzymes involved in the adrenal steroid synthesis leading to cortisol
deficiency (1,2). The compensatory increase in ACTH secretion by the pituitary
gland results in stimulation of the adrenal cortex and consequently increased
androgen production within the not affected zona reticularis. Females with CAH
are born with ambiguous genitalia due to the virilising effect of increased
androgens already in utero. In the past, CAH was a life-threatening disease
with high morbidity and mortality. Since the introduction of glucocorticoids
about 70 years ago, however, mortality and morbidity have been significantly
decreased (3-6). Current treatment consists of lifelong replacement of
synthetic glucocorticoids. In children usually hydrocortisone is used in a
thrice-daily schedule. Treatment guidelines are described in the Dutch CAH
guidelines form the Dutch Society of pediatrics
(https://www.nvk.nl/Kwaliteit/Werkboeken/Adrenogenitaal-syndroom-AGS). By
treatment with glucocorticoids also suppression of the elevated adrenal
androgen production can be achieved due to restoring the negative feedback on
the pituitary gland. Despite improvement in care and follow-up, many children
do not reach final height within their target range and long-term complications
(e.g. obesity, hypertension, infertility) are often reported. (1). In most
patients, supra-physiological dosages of hydrocortisone are necessary to
decrease androgen production to the normal range in order to prevent side
effects such as early pubertal signs, reduced final height, menstrual
disturbances and acne but with the risk of complications due to the high
glucocorticoid dosages such as also decreased final height, obesity, and
cardiovascular complications. Especially the early morning rise of adrenal
androgens (around 3.00 am) contributes to cumulative androgen exposure in time
and is difficult to suppress. Therefore, balancing of the hydrocortisone dosage
is very important. Treatment can be monitored by measuring of
17-hydroxyprogesterone (17OHP) that accumulates before the enzymatic block and
the main adrenal androgen androstenedione (A). In the Radboudumc we introduced
a non-invasive measurement of this steroids in saliva already more than 20
years ago. Patients usually collect saliva samples three times a day before
taking the medication every 3 months before visiting the outpatient clinic.
There is still no evidence about the best timing of medication use (4,9). Some
centers treat patients with the highest dosage of glucocorticoids in the
morning (2/4 * * - * scheme) because this pattern will most likely simulate
normal diurnal rhythm of the adrenal gland, whereas other centre use the
highest dosage at night around bedtime of the parents (* - * -2/4 scheme) to
suppress the early morning increase of androgens more effectively, but with
probably negative effects on nocturnal blood pressure and sleeping patterns.

To study the effects of 2 standard treatment timing strategies for
glucocorticoid dosage on androgen concentration in CAH children: a. highest
dosage in the morning, b. highest dosage in the evening.

6-week cross-over, non randomized strategical multicentre low-interventional
trial (category A) A double blind randomized trial is not necessary as the
primary and secondary outcome parameters are not influenced by placebo effects
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536
/reg_2014_536_en.pdf
After the informed consent procedure, each patient will receive the same total
daily medication dosage from their own initial pre-study treatment, starting
with either the highest dosage of hydrocortisone in the morning (dosage A:
distribution daily dosage 2/4 * 1/4 * *) or in the evening (dosage B:
distribution daily dosage 1/4 * 1/4 * 2/4). The first dosage scheme (dosage A
or B) will be their own usual medication scheme. Immediately after the first
period, the next period of 3 weeks will start. On days 20 and 21 of each
3-week study period, saliva will be collected before taking the medication and
one additional measurement at 5 am (a total of 4 samples per day). The patient
will collect saliva at home and send the samples to our laboratory by mail. In
saliva steroid hormone levels of 17OHP and A will be measured. In the third
week of each treatment cycle, a 12-hour blood pressure profile measurement
(19.00 * 7.00h) will be performed. Daily activities will be documented daily by
the parents by asking the parents/children to give a daily score ( 0 * 10) to
measure daily activity and sleeping pattern.

After the informed consent procedure, each patient will receive the same total
daily medication dosage from their own initial pre-study treatment, starting
with either the highest dosage of hydrocortisone in the morning (dosage A:
distribution daily dosage 2/4 * 1/4 * *) or in the evening (dosage B:
distribution daily dosage 1/4 * 1/4 * 2/4). The first dosage scheme (dosage A
or B) will be their own usual medication scheme. Immediately after the first
period, the next period of 3 weeks will start. On days 20 and 21 of each
3-week study period, saliva will be collected before taking the medication and
one additional measurement at 5 am (a total of 4 samples per day). The patient
will collect saliva at home and send the samples to our laboratory by mail. In
saliva steroid hormone levels of 17OHP and A will be measured. In the third
week of each treatment cycle, a 12-hour blood pressure profile measurement
(19.00 * 7.00h) will be performed. Daily activities will be documented daily by
the parents by asking the parents/children to give a daily score ( 0 * 10) to
measure daily activity and sleeping pattern.

We consider the current study a low intervention clinical trial, as per the
definition of the EU clinical trial regulation 536/2014. The patient will
receive care as usual with hydrocortisone but in two different time patterns.
The total daily dosage will be the same in both parts of the study and equal to
the pre-study dosage. We do not expect any serious complaints with different
dosage patterns. Both treatment strategies are common care in expert centers.
The patients are asked to collect 4 saliva samples before taking their
medication on 4 different days. For our CAH patients, collecting saliva samples
is a standard procedure, which is painless and without complications. The
saliva samples will be sent to the laboratory by regular mail. The 12-hour
blood pressure profile measurement will be done twice using standard equipment.
Parents and children are asked to fill in a digital diary each day during the
entire study period. Invasive interventions are not necessary. During the
study the patients and their parents will be coached and supported by our
research nurse by phone. The team is 24/7 available for questions. The most
important international guidelines for CAH (Endocrine Society Guidelines from
2010) pointed out the lack of evidence in the field described above. Our
project will lead to better evidence-based guidelines with uniform
recommendations within the Netherlands and elsewhere. Effective dosing may lead
to lower cumulative elevated androgens more efficiently especially in the night
and probably also in lowering of the total hydrocortisone dosage in time.