A randomized double blind cross-over trial of the effects of low dose and high dose hydrocortisone replacement therapy on cognition, quality of life, metabolic profile and somatosensation in patients with secondary adrenal insufficiency

A wide variety in HC substitution dose-regimens are considered physiological
for patients with adrenal insufficiency. However, it is likely that cognition
is negatively influenced by higher cortisol exposure to the brain. No studies
have been performed to assess the effects of treatment regimens with a low
physiological HC substitution dose on cognition in comparison to a high
physiological dose. These treatment regimens should take body weight and
multiple dosing into account. In addition, substitution doses should be
monitored by clinical evaluation and biochemical analysis for adverse effects
associated with over- or under-replacement.

We hypothesize that a low physiological HC dose results in better cognitive
performance and improved metabolic profile, but in decreased quality of life
with excess common somatic complaints and in increased sensitivity when
compared to a high physiological HC dose.

The aim of this study is to investigate whether a physiologically low
hydrocortisone (HC) dose is better for cognition as compared to a high
hydrocortisone dose. In addition, quality of life, metabolic profile and
somatosensation will be described in relation to HC dose.

Randomized, double blind cross-over design.

Patients receive either a low dose HC (0.2-0.3 mg/kg body weight) for 10 weeks
followed by 10 weeks of high dose HC (0.4-0.6 mg/kg body weight) or high dose
HC followed by a low dose of HC.

Burden: At baseline and after completion of both treatment arms patients will
undergo neuropsychological evaluation. One week before the three visits
(duration ± 4 hours) they will also fill in quality of life questionnaires.
Blood samples will be drawn before and after the test battery. The day before
each visit to the hospital, patients will collect a 24-h urine collection.
During both treatment periods patients will keep a diary regarding common
somatic complaints and mood.

Risks: Additional hydrocortisone dose escalation (max. of seven days per
treatment arm) to prevend hypocortisolism is allowed, however not in the week
preceding the hospital visit. The risk of severe hypocortisolism on study
dose-regimens of HC is small and estimated to be similar to conventional
treatment at the outpatient clinic.