Effects of Steroid Replacement Therapy on Metabolic, Cardiovascular and Bone Outcomes in Adrenal Insufficiency

Conventional Glucocorticoids vs. Dual-release Hydrocortisone Effects on Metabolic, Cardiovascular, and Bone Outcomes in Treatment-naïve Patients With Adrenal Insufficiency: a 10-year Prospective Randomised Study

The current study is a randomized, open study aimed to compare the effects of conventional glucocorticoid replacement treatment and dual-release hydrocortisone on anthropometric, metabolic, cardiovascular and bone outcomes in treatment-naïve patients with primary adrenal insufficiency and secondary adrenal insufficiency in a 10 year-observation period.

Study Overview

• Status: Completed
• Conditions: Adrenal Insufficiency
• Intervention / Treatment: Drug: Conventional glucocortidois; Drug: dual-release hydrocortisone

Detailed Description

Adrenal insufficiency (AI) can be caused by a disease involving the adrenal gland resulting in inadequate secretion of adrenal cortex hormones, primary adrenal insufficiency (PAI). Secondary adrenal insufficiency (SAI) results from a decreased level of adrenocorticotrophin hormone (ACTH) released from the pituitary gland.

The mainstay of treatment of PAI and SAI is glucocorticoid (GC) replacement therapy. Conventional steroid replacement therapy includes cortisone acetate and hydrocortisone administered 2-3 times a day with the highest dose in the morning and the lowest dose in the afternoon. These dosing regimens have been designed to mimic the peak of cortisol secretion in the morning and avoid overdosing during the night hours, even though a higher risk of developing comorbidities has been shown, notably in patients treated with higher evening doses.

In patients with AI on conventional steroid replacement therapy, mortality remains higher than in the general population, mainly due to non-physiological daily GC overexposure and to inadequate cortisol exposure during stress-related events and illness.

Studies aiming to evaluate the long-term clinical outcomes of patients with AI on conventional steroid replacement therapy clearly showed increased comorbidities, mainly related to the dose used.

By contrast, dual-release hydrocortisone (DR-HC) is characterized by once-daily administration with high release of hydrocortisone immediately after intake and a very low release in the evening and nocturnal hours. The switch from conventional GC therapy to DR-HC has been shown to be associated with improvement in BMI, hepatic, bone and glucometabolic parameters and QoL. However, long-term clinical outcomes of patients treated with DR-HC in patients naïve to steroid treatment are not known.

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adrenal insufficiency

Exclusion Criteria:

• Exclusion criteria were adrenocortical carcinoma and congenital adrenal hyperplasia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Conventional steroid treatment; Cortisone acetate and hydorocortisone will be administered in two daily doses	Drug: Conventional glucocortidois; Oral tablets 10-15-20-25-37,5-50-62,5 mg/day; Other Names: hydrocortisone; cortisone acetate
Experimental: Dual-release hydrocortisone; Dual-release hydrocortisone will be administered once daily	Drug: dual-release hydrocortisone; Oral tablets 20-25-30-40 mg/day; Other Names: Plenadren

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of body weight	Single outcome measurement of body weight (kg).	0, 5 years, 10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of anthropometric parameters	waist circumference	0, 5 years and 10 years
Change of metabolic parameters	Composite outcome including evaluation of total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides, HbA1c and fasting blood glucose	0, 5 years and 10 years
Change of insulin sensitivity parameters	the Isi-Matsuda index	0, 5 years and 10 years
Change of cardiovascular parameters	Measurement of interventricular septum at diastole (IVSd) and the thickness of the posterior wall (PWT) by high-resolution M-B-mode transthoracic echocardiography	0, 5 years and 10 years
Change of bone metabolic parameters	Composite outcome including calcium, phosphorus, Vitamin D, PTH, creatinine (all measured in mg/dL)	0, 5 years and 10 years
Change of bone density	Bone mineral density quantified by Dual X-Ray Absorptiometry (DEXA)	0, 5 years and 10 years
Change of vascular parameters	Measurement carotid intima media thickness by high-resolution M-B-mode echography	0, 5 years and 10 years

Collaborators and Investigators

• Sponsor: University of Palermo

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2012
• Primary Completion (Actual): September 30, 2022
• Study Completion (Actual): December 30, 2023

Study Registration Dates

• First Submitted: January 24, 2024
• First Submitted That Met QC Criteria: February 13, 2024
• First Posted (Actual): February 15, 2024

Study Record Updates

• Last Update Posted (Actual): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Adrenal Gland Diseases; Adrenal Insufficiency; Anti-Inflammatory Agents; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cortisone
• Other Study ID Numbers: 10 years adrenal insufficiency

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study protocol could be available on request
• IPD Sharing Time Frame: 2 years
• IPD Sharing Access Criteria: Send an email to carla.giordano@unipa.it
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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