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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Adrenal Insufficiency
• Intervention / Treatment: Drug: Prednisolone; Drug: Hydrocortisone

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.

• Study Type: Interventional
• Enrollment (Estimated): 44
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, W12 8RF
    • Imperial College Healthcare NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

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.

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: National Institute for Health Research, United Kingdom; Imperial Health Charity
• Investigators: Principal Investigator: Karim Meeran, MBBS BSc MD, Imperial College London

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2019
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: April 29, 2019
• First Submitted That Met QC Criteria: April 29, 2019
• First Posted (Actual): May 3, 2019

Study Record Updates

• Last Update Posted (Actual): September 1, 2023
• Last Update Submitted That Met QC Criteria: August 31, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Cortisol; Prednisolone; Glucocorticoids; Hydrocortisone
• Additional Relevant MeSH Terms: Endocrine System Diseases; Adrenal Gland Diseases; Adrenal Insufficiency; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisolone; Hydrocortisone
• Other Study ID Numbers: 18IC4546; 2018-001502-28 (EudraCT Number); 201045 (Other Identifier: IRAS); ISRCTN41325341 (Registry Identifier: ISRCTN); 19/LO/0083 (Other Identifier: Research Ethics Committee)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No