Condition category
Nutritional, Metabolic, Endocrine
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Cortisol (also called hydrocortisone) is a hormone produced by the adrenal glands that is essential for life. It is produced in a daily (circadian) rhythm with high levels first thing in the morning, falling to very low levels at night time. There are many medical conditions such as Addison's disease, congenital adrenal hyperplasia (CAH) and pituitary disease where patients cannot produce enough of this hormone and therefore need replacement therapy. At present patients are given standard replacement therapy with tablets in an attempt to mimic a normal hormonal profile. However, despite this, their death rates remain twice that of the general population (similar to the increased risk from smoking) and patients often feel generally unwell with severe fatigue (tiredness). It is now known that cortisol is released into the blood stream in pulses, and that this pattern is vital for the body's normal responses. Unfortunately this pulsatile pattern is not the pattern of replacement that is currently given and this could contribute to the excess death rate and poor quality of life of these patients. At the University of Bristol researchers have developed a system using a commercially available infusion pump that can deliver pulses of hydrocortisone under the skin in a way that closely mimics natural hormone release. They want to use this to compare the hormonal responses of patients with Addison's disease and congenital adrenal hyperplasia on standard oral and pulsatile subcutaneous hydrocortisone replacement therapy.

Who can participate?
Adults aged 18-64 years that are right handed and have been diagnosed with Addison’s disease and CAH.

What does the study involve?
Participants are randomly allocated into one of two groups. Those in group 1 receive their standard dose of oral medications (tablets) and a placebo infusion via an automated pump for six weeks. Those in group 2 receive an oral placebo and pulsatile hydrocortisone via the pump for six weeks. The pump must be worn 24 hours a day (although can be taken off for showering etc.) and the syringes in the pump need changing twice a week. Participants are taught how to do this, but until confident must see a study investigator twice a week (this can be done at a location convenient to the patient) to have their syringe and line changed. After the initial six week period, the participants swap treatments, so those in group 1 are treated as if they were in group 2 and vice versa for a further six weeks. The researchers look at how well the different treatments work by measuring hormone levels before the start of treatment then again after each six week treatment period. The participants metabolic profile, quality of life and energy and activity levels are also tested regularly throughout the study period. The participants mental (cognitive) abilities and emotional health are measured using psychological tests and MRI scanning in week six of each treatment period, which are specifically tailored to the symptoms of each individual.

What are the possible benefits and risks of participating?
The benefits of taking part is that it will help researchers understand if it is the lack of pulsatile hormone replacement that is contributing to patients symptoms and improve their knowledge on how steroids can cause side effects. The main risk of taking part is the potential of having an adrenal crisis. Participants are therefore asked a carry an emergency kit with them at all times and stay local to the Bristol area whilst on the trial.

Where is the study run from?
University of Bristol (UK)

When is the study starting and how long is it expected to run for?
November 2014 to December 2016

Who is funding the study?
Medical Research Council (UK)

Who is the main contact?
Dr Georgina Russell

Trial website

Contact information



Primary contact

Dr Georgina Russell


Contact details

University of Bristol
Dorothy Hodgkin Building
Whitson Street
United Kingdom

Additional identifiers

EudraCT number

2012-001104-37 number

Protocol/serial number


Study information

Scientific title

Pulsed glucocorticoid replacement therapy for patients with adrenocortical insufficiency secondary to Addison’s disease and congenital adrenal hyperplasia


Study hypothesis

1. To compare the hormonal responses of patients with Addison's disease and congenital adrenal hyperplasia on standard oral and pulsatile subcutaneous hydrocortisone replacement therapy.
2. To compare the metabolic, psychological (cognitive and emotional processing) and quality of life measures of patients with Addison's disease and congenital adrenal hyperplasia on standard oral replacement and pulsatile subcutaneous hydrocortisone replacement therapy.

Ethics approval

NRES Committee South West - Central Bristol, 06/10/2014, ref: 14/SW/1050

Study design

Randomised, interventional

Primary study design


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet


Topic: Metabolic & Endocrine; Subtopic: Metabolic & Endocrine; Disease: Metabolic & Endocrine


Patients will receive hydrocortisone in a double blinded randomised cross over fashion either:
1. Their standard dose of oral hydrocortisone (over encapsulated) for 6 weeks and a placebo subcutaneously via an automated pump
2. A comparative oral placebo and hydrocortisone (same dose as usual oral dose) subcutaneously via a portable infusion pump.
The infusion pump shall deliver either the hydrocortisone or placebo (normal saline) continuously over a 24 hour period as discrete pulses.

Intervention type



Not Applicable

Drug names


Primary outcome measures

Physiological cortisol profiles with adequate suppression of ACTH in all patients and 17-OHP in CAH patients using subcutaneous pulsatile hydrocortisone replacement.

Timepoint(s): baseline and 6 weeks

Secondary outcome measures

1. Cognitive: Timepoint(s): 6 weeks
2. EMA: Timepoint(s): time -1, 0, 1, 2, 3, 4, 5, 6, 7 weeks;
3. Fatigue: Timpoint(s): baseline and 6 weeks;
4. Metabolic profile: Timepoint(s): baseline and 6 weeks

Overall trial start date


Overall trial end date


Reason abandoned


Participant inclusion criteria

1. Male and female patients with confirmed Addison’s disease and CAH
2. Aged 18 to 64 years
3. Females of child bearing potential must be using a highly effective method of contraception / birth control as defined in ICH (M3) if sexually active
4. Right handed
5. Able to give informed consent

Participant type


Age group




Target number of participants

Planned Sample Size: 20; UK Sample Size: 20

Participant exclusion criteria

1. Any significant current cerebral, cardiovascular, respiratory, hepatobiliary, pancreatic disease, renal dysfunction, gastrointestinal emptying or motility disturbances.
2. No current treatment or within the last 3 months of another underlying disease that could necessitate treatment with glucocorticoids
3. Taking of medications that interfere with cortisol metabolism (antiepileptics, St Johns wart, rifampicin)
4. Diagnosis of Addison’s disease less than 6 months ago
5. Pregnant or lactating women
6. Greater than 21 units of alcohol per week
7. Taking of any investigational drug within the past two months
8. Known allergy to any of the study medications and /or materials used in the pump
9. Needle phobia
10. Contraindication to fMRI scan i.e. metal implant/shrapnel
11. Claustrophobia
12. Left handed/significant ambidexterity
13. Dyslexia

Recruitment start date


Recruitment end date



Countries of recruitment

United Kingdom

Trial participating centre

University of Bristol
Dorothy Hodgkin Building Whitson Street
United Kingdom

Sponsor information


University Hospitals Bristol NHS Foundation Trust

Sponsor details

Research & Development
Upper Maudlin Street
United Kingdom

Sponsor type

Hospital/treatment centre



Funder type


Funder name

Medical Research Council

Alternative name(s)


Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit


United Kingdom

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not expected to be available

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes