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

Overview

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 Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: February 1, 2023

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.

Interventions

  • 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.

Arms, Groups and Cohorts

  • 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.
  • 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.

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

  • Change in concentration of P1NP
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • Assesses bone health of each group by comparing P1NP
  • Change in concentration of BALP
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • Assesses bone health of each group by comparing BALP
  • Change in concentration of NTX
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • Assesses bone health of each group by comparing NTX
  • Heart Rate
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • recording observations- heart rate
  • Systolic and diastolic blood pressure
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • recording observations- blood pressure
  • Waist-Hip circumference
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • recording observations- Waist-Hip circumference ratios
  • Change in concentration of Lipid profile (Total cholesterol, HDL, LDL and triglycerides)
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • measuring biochemical indicators of cardiovascular risk: total cholesterol, HDL, LDL and triglycerides
  • Change in concentration of high sensitivity CRP
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • measuring biochemical indicators of cardiovascular risk: high sensitivity CRP
  • Change in concentration of Glucose
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • measuring glucose
  • Change in concentration of HbA1c
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • measuring HbA1c
  • Infection rates and severity
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • 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.
  • Wellbeing assessed by completion the short form health survey
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • 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.
  • Wellbeing assessed by completion the Addi-QoL questionnaire
    • Time Frame: Between Day 1 and Day 120 within each study period; and between Day 120 of Period 1 and Period 2.
    • 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.

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 70 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Imperial College London
  • Collaborator
    • National Institute for Health Research, United Kingdom
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Karim Meeran, MBBS BSc MD, Principal Investigator, Imperial College London
  • Overall Contact(s)
    • Sirazum Choudhury, MBBS BSc, 07555717544, steroids@imperial.ac.uk

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