Safety and Efficacy of Prednisolone in Adrenal Insufficiency Disease (PRED-AID Study)

Study Overview
=================
Brief Summary
-----------------
This study compares low-dose prednisolone therapy against standard regimens of hydrocortisone therapy for the treatment of adrenal insufficiency (AI). AI is a condition in which, individuals are unable to sufficiently produce the natural stress hormone, cortisol.

Detailed Description
-----------------
Steroid replacement therapy is vital for the health of patients with adrenal insufficiency (AI), who are unable to produce the natural stress hormone, cortisol. The objectives of steroid replacement therapy are to replace the body's physiological requirements for cortisol without over-replacement and consequent Cushing's syndrome. Equally, under-replacement presents the risk of patients experiencing potentially fatal Addisonian crises. Appropriately replacing a patient's steroid requirement is a significant challenge. Hydrocortisone (HC) is used in the majority of patients with AI in the UK. However, HC has a short duration of action, necessitating dosing 3 times a day. Low-dose prednisolone (PR) is an alternative to HC which needs only once-daily. There have been no studies directly comparing low-dose PR to HC treatment. This is a two-arm, two-period, double-blind, randomised, cross-over study comparing the low dose PR and standard regimens of HC in the treatment of AI.

Official Title
-----------------
Safety and Efficacy of Prednisolone in Adrenal Insufficiency Disease (PRED-AID Study)

Conditions
-----------------
Adrenal Insufficiency

Intervention / Treatment
-----------------
* Drug: Prednisolone
* Drug: Hydrocortisone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged 18 - 70 years Male or female Diagnosed with AI for over 6 months according to standard diagnostic criteria Established on stable HC replacement or prednisolone replacement, dose not altered for at least 3 months Established on a stable dose of Fludrocortisone, if taking, dose not altered for at least 3 months Participants taking other hormone replacements (e.g. levothyroxine, testosterone or growth hormone in secondary adrenal insufficiency) are accepted providing that their replacement doses have not altered for at least 3 months Participants who are otherwise healthy enough to participate, as determined by pre-study medical history and physical examination. Participants who are able and willing to give written informed consent to participate in the study. Exclusion Criteria: Participants with a diagnosis of Type 1 or Type 2 diabetes mellitus. Unable to give informed consent. Taking supplements or herbal medications that the participant is unwilling or unable to stop prior to and during the study period e.g. St John's Wort (may decrease prednisolone levels), Cat's claw, Echinacea (immunomodulatory properties). Currently taking medications that alter CYP3A4 metabolism of glucocorticoids that the participant is unwilling or unable to stop prior to and during the study period e.g. phenytoin, phenobarbital, rifampicin, rifabutin, carbamazepine, primidone, aminoglutethimide, itraconazole, ketoconazole, ciclosporin or ritonavir. Pregnancy, taking the combined oral contraceptive pill, or oral oestrogen replacement therapy due to the effects on cortisol binding globulin levels and determination of prednisolone levels. Transdermal oestrogen replacement is permitted. Diagnosis of congenital adrenal hyperplasia, untreated

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Two-arm, two-period, double-blind randomised crossover study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Prednisolone first; hydrocortisone second<br>Participant will receive 4 months of prednisolone in the first study period and 4 months of hydrocortisone in the second study period. | Drug: Prednisolone<br>* Low dose prednisolone for the treatment of adrenal insufficiency. Usually administered once daily<br>Drug: Hydrocortisone<br>* Standard regimens of hydrocortisone for the treatment of adrenal insufficiency. Usually administered thrice daily.<br>|
| Other: Hydrocortisone first; prednisolone second<br>Participant will receive 4 months of hydrocortisone in the first study period and 4 months of prednisolone in the second study period. | Drug: Prednisolone<br>* Low dose prednisolone for the treatment of adrenal insufficiency. Usually administered once daily<br>Drug: Hydrocortisone<br>* Standard regimens of hydrocortisone for the treatment of adrenal insufficiency. Usually administered thrice daily.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in concentration of Osteocalcin | Assesses bone health of each group by comparing total osteocalcin and undercarboxylated osterocalcin | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in concentration of P1NP | Assesses bone health of each group by comparing P1NP | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 
| Change in concentration of BALP | Assesses bone health of each group by comparing BALP | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 
| Change in concentration of NTX | Assesses bone health of each group by comparing NTX | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 
| Heart Rate | recording observations- heart rate | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 
| Systolic and diastolic blood pressure | recording observations- blood pressure | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 
| Waist-Hip circumference | recording observations- Waist-Hip circumference ratios | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 
| Change in concentration of Lipid profile (Total cholesterol, HDL, LDL and triglycerides) | measuring biochemical indicators of cardiovascular risk: total cholesterol, HDL, LDL and triglycerides | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 
| Change in concentration of high sensitivity CRP | measuring biochemical indicators of cardiovascular risk: high sensitivity CRP | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 
| Change in concentration of Glucose | measuring glucose | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 
| Change in concentration of HbA1c | measuring HbA1c | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 
| Infection rates and severity | assessed by completion of the German National Cohort Questionnaire (GNCQ). Frequency (None; 1; 2; 3; >3; Unknown) of 1. Upper respiratory tract infections; 2. Lower respiratory tract infections; 3.Gastroenteritis; 4. Mucosal infections; 5. Urinary tract infections; 6. Influenza; will be recorded. The frequencies of each type of infection will be compared between time points. | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 
| Wellbeing assessed by completion the short form health survey | assessed by completion the short form health survey-36 (SF-36). Scores will be produced in each of 8 domains (Physical functioning, Role functioning/physical, Role functioning/emotional, Energy/fatigue, Emotional wellbeing, Social functioning, Pain, General Health and Health Change). Each domain is scored from 0 to 100, with higher scores suggesting more positive outcomes. Scores will be compared in each domain between time points. | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 
| Wellbeing assessed by completion the Addi-QoL questionnaire | assessed by completion the Addi-QoL questionnaire. A total score between 30 and 120 is produced, with higher scores suggesting a more positive outcome. The score is compared between time points. | Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Glucocorticoids, Hydrocortisone, Prednisolone, Cortisol