Hydrocortisone and Placebo in Patients With Symptoms of Adrenal Insufficiency After Cessation of Glucocorticoid Treatment (REPLACE)

A Multi-centre, Randomised, Double-blinded, Placebo Controlled 16-weeks Study to Compare the Effect of Hydrocortisone and Placebo in Patients With Giant Cell Arteritis (GCA)/ Polymyalgia Rheumatica (PMR) With Patient-reported Symptoms of Adrenal Insufficiency After Cessation of Glucocorticoid Treatment.

Cortisol, a glucocorticoid (GC) hormone secreted from the adrenal glands, is essential for survival. Cortisol also possesses anti-inflammatory actions and GC formulations (prednisolone) are used to treat many inflammatory diseases and conditions. Indeed, three percent of the Danish population (≈ 180.000 individuals) redeems at least one prescription of synthetic GC per year and at least 20,000 patients annually discontinue GC treatment. Pharmacological GC therapy suppresses endogenous cortisol production and thereby induce relative adrenal insufficiency (GIA). The risk of GIA as determined by the adrenal corticotrophic hormone (ACTH) stimulation test has previously been reported to ≈ 25 %, but testing after GC treatment is not routinely performed. Indeed, new evidence suggest that the risk of GIA after planned cessation of prednisolone treatment for polymyalgia rheumatic (PMR) or giant cell arteritis (GCA) is substantially lower, probably 2%. The reason for this discrepancy is undoubtedly selection bias in the previous publications and the use of inaccurate cortisol assays. At the same time, however, it was observed that 25% exhibited pronounced symptoms of adrenal insufficiency based on a questionnaire specific for detecting symptoms of adrenal insufficiency, the so-called AddiQoL-30. Concomitantly, the basal cortisol levels in the same group were significantly lower as compared to the group, who exhibited milder or no symptoms attributable to adrenal insufficiency. This observation aligns with the clinical experience that PMR/GCA patients often complain of fatigue after planned cessation of prednisolone treatment. This often occurs in the absence of objective symptoms or signs of residual PMR/GCA disease activity. The scenario has been designated as "the steroid withdrawal syndrome". This may represent a state of relative adrenal insufficiency prompted by long term, high dose prednisolone treatment. The proper way to tackle this clinical conundrum is to perform a proper randomized trial, which so far has not been conducted.

Therefore, investigators of this study will perform the first placebo-controlled randomised controlled trial (RCT) in patients with PMR and GCA after planned cessation of GC treatment. Investigators argue that neither watchful waiting nor routine hydrocortisone replacement are infallible. The study will be the first evidence-based guidance and aid to GIA patients and thus meet an important need for many thousand patients.

Study Overview

• Status: Recruiting
• Conditions: Adrenal Insufficiency; Polymyalgia Rheumatica (PMR); Giant Cell Arteritis (GCA)
• Intervention / Treatment: Drug: Placebo; Drug: Hydrocortisone

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Marianne S Andersen; Phone Number: +4565411807; Email: marianne.andersen1@rsyd.dk

Study Locations

• Denmark
  • Aarhus, Denmark
    • Recruiting
    • Department of Endocrinology and Internal Medicine, Aarhus University Hospital
    • Contact: Jens Otto L Jørgensen, Professor; Phone Number: +45 20727383; Email: joj@clin.au.dk
  • Copenhagen, Denmark
    • Recruiting
    • Department of Nephrology and Endocrinology, Rigshospitalet
    • Contact: Ulla Feldt-Rasmussen, Professor; Phone Number: +45 35451023; Email: Ulla.Feldt-Rasmussen@regionh.dk
  • Odense, Denmark, 5230
    • Recruiting
    • Department of Endocrinology, Odense University Hospital
    • Principal Investigator: Marianne Andersen, DMSci
    • Contact: Marianne S Andersen, Professor; Phone Number: +45 65411807; Email: Marianne.Andersen1@rsyd.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 50 years
• A diagnosis of PMR or GCA in GC free remission for >2 week and <12 weeks after treatment with prednisolone (any dosage) for ≥12 weeks

Exclusion Criteria:

• Known primary or secondary adrenal insufficiency
• Known Cushing´s syndrome
• Heart failure (New York Heart Association class IV)
• Kidney failure with an estimated glomerular filtration rate <30 mL/min
• Liver cirrhosis
• Active cancer
• Known severe immune deficiency
• A history of psychiatric disease requiring treatment by a psychiatric department (for affective disorders only if within the last year before study entry)
• Alcohol consumption >21 units per week
• Planned major surgery during the study period at study entry
• Use of drugs that interfere with cortisol metabolism/measurements:
• Systemic oestrogen treatment within 1 month before study inclusion
• Strong CYP3A4 inhibitors or inducers
• Use of other glucocorticoid formulations: inhaled, intra-articular or intramuscular injections, creams European steroid group IV applied in genital area
• Permitted glucocorticoid formulations: eye-drops, nasal spray, creams European group I-III, and European group IV applied in non-genital area
• Inability to provide written informed consent

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: RCT group - Placebo; Included patients with an AddiQoL-30 score < 85 and/or short Synacthen test stimulated plasma cortisol levels > 100 and < 420 nmol/L that are radomized to recieve placebo tablets.	Drug: Placebo; Patients are randomized to oral hydrocortisone (10 mg twice daily) or placebo for 16 weeks.
Active Comparator: RCT group - Hydrocortisone; Included patients with an AddiQoL-30 score < 85 and/or short Synacthen test stimulated plasma cortisol levels > 100 and < 420 nmol/L that are radomized to recieve hydrocortisone tablets.	Drug: Hydrocortisone; Patients are randomized to oral hydrocortisone (10 mg twice daily) or placebo for 16 weeks.
No Intervention: Comparator group 1; Patients with an AddiQoL-30 score > 85 and short Synacthen test stimulated plasma cortisol level > 420 nmol/L. Patients undergo baseline examination only.
No Intervention: Comparator group 2; Patients with pronounced adrenal insufficiency (short Synacthen test stimulated plasma cortisol levels < 100 nmol/L) - regardless of AddiQoL-30 score. These patients undergo baseline examination and commence open hydrocortisone replacement according to standard clinical practice.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adrenal insufficiency symptoms	Symptoms measured by the Addison's disease-specific quality of life questionnaire (AddiQoL-30), which consists of 30 questions focusing on common symptoms of adrenal insufficiency related to quality of life. Each item belongs to one of following subthemes: fatigue, symptoms, emotions and miscellaneous. Each question can be scored from 1 (none of the time/strongly disagree) to 6 (all of the time/strongly agree) and yields a score between 1 - 4 arbitrary units. This adds up to a total score ranging from 30 (worst quality of life) to 120 (best quality of life).	Screening and 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-reported symptoms via mobile phone app - PRO-CTCAETM	Symptoms of fatigue, nausea, dizziness, and "feeling generally unwell" assessed by the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAETM). Each symptom is evaluated in terms of frequency and severity with a score from 1 (never/nothing) to 5 (almost constant/very strong).	Patients are asked daily throughout the study period.
Patient-reported symptoms via mobile phone app - EMA-MFI	Four statements regarding diurnal fatigue based on the validated General Fatigue Scale from the Multidimensional Fatigue Inventory (MFI-20) adapted for Ecological Momentary Assessments (EMA). Each statement is answered by a visuel scale from left (yes, that is correct) to right (no, that is not correct).	In situations of stress, participants are asked to answer the EMA items 5 times daily at semi-randomised time points, for 3 days.
Cushing quality of life (CushingQoL)	Cushing quality of life (CushingQoL) is a disease-specific questionnaire for patients with endogenous cortisol excess. It consists of 12 items about mental and physical adverse effects of cortisol excess. The total score os normalised to a scale ranging from 0 (lowest quality of lige) to 100 (highest quality of life).	Baseline and 16 weeks
The short form 36 (SF-36)	SF-36 is a genereic qeustionnaire evaluating general health perception with 36 items related to 8 dimensions: physical functioning for the limitation in performing all physical activities; role physical for problems with work or other daily activities; bodily pain; general health; vitality; social functioning; role emotional; and mental health.	Baseline and 16 weeks
Sleep Quality Scale (SQS)	SQS is a single item questionnaire consisting of a numerical rating scale to evaluate the overall sleep quality over the last 7 nights. The scale is ranging from 0 (terrible sleep) to 10 (excellent sleep).	Baseline and 16 weeks
International Physical Activity Questionnaire, short form, 7 days (IPAQ-7s)	The IPAQ-7s records types and intensity of physical activity. The questionnaire consists of seven open items covering 4 types of activity (energetic activity, moderate activity, walk, and sitting). The first three is measured in "number of days per week", "hours per day", and "minutes per day". The last activity (sitting) is measured in "hours per day" and "minutes per day".	Baseline and 16 weeks
Incidence of adrenal crises	Incidence of adrenal crises, including information on hospitalizations, number of sick days, diagnoses and therapy.	16 weeks
Cardiovascular health - Blood pressure	Office blood pressure (OBP) and automated blood pressure (AOBP). Blood pressure measurements will be performed with (OBP) and without (AOBP) the presence of investigator. Unit is mmHg.	Baseline and 16 weeks
Cardiovascular health - PWV	Arterial stiffness and pulse wave velocity (PWV). PVW is measured three times, unit is m/s.	Baseline and 16 weeks
Body composition - DXA scan	Body composition by dual X-ray absorptiometry (DXA) scan. Body composition is measured in the distribution of fat and lean mass in grams (g).	Only performed at baseline visit
Bone quality - DXA scan	Bone quality by dual X-ray absorptiometry (DXA) scan. Bone mineral density (g/cm^2) and T-score of the lumbal spine and hip.	Only performed at baseline visit
HR-pQCT	High-resolution peripheral quantitative computed tomography (HR-pQCT) in order to obtain three-dimensional BMD.	Only performed at baseline visit
Muscle function and physical activity - Handgrip strength.	Handgrip strength is measured in kg using a hydraulic hand dynamometer.	Baseline and 16 weeks.
Muscle function and physical activity - TUG	Timed Up and Go (TUG) test measures the time taken to stand up, walk three meters in a straight line, and immediately return to the chair.	Baseline and 16 weeks.
Muscle function and physical activity - SPPB	The Short Physical Performance Battery including Chair Rising Test (SPPB) evaluates the lower extremity function of the patient.	Baseline and 16 weeks.
Muscle function and physical activity - Actigraph	Patients are asked to wear an accelerometer device on their non-dominant wrist to measure physical activity and sleep. Time of physical activity and sleep will be measured in minutes.	Baseline and 16 weeks, duration: 7 days
Muscle function and physical activity - Muscle power	The muscle power of the dominant arm and upper back, as well as elbow, hip, and knee extension and flexion, are evaluated by use of a exercise machine. Power is measured in watt.	Baseline and 16 weeks.
Muscle function and physical activity - Isometric muscle strength	The isometric muscle strength of the dominant arm and upper back, as well as elbow, hip, and knee extension and flexion, are evaluated by use of a exercise machine. Strength is measured in kg.	Baseline and 16 weeks.
Normalization of adrenal function evaluated by SST	Short Synacthen® test. Cortisol is measured in nmol/L before (0 min) and after (30 min) administration of 1 ml Synacthen (0.25 mg/ml).	Screening/Baseline and 16 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood samples (unit: 10E12/L)	Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. Erythrocytes.	Baseline and 16 weeks
Blood samples (unit: fmol)	Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. MCH.	Baseline and 16 weeks
Blood samples (unit: 10E9/L).	Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. Leokocytes; neutrophils; lymphocytes; monocytes; basophilocytes; eosinophils; metamyelocytes; thrombocytes.	Baseline and 16 weeks
Blood samples (unit: mmol/L)	Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. Hemoglobin; MCHC; glucose; glucose derived from HbA1c, cholesterol; HDL; LDL; non-HDL; triglycerid; calcium ion, free.	Baseline and 16 weeks
Blood samples (unit: mmol/mol)	Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. HbA1c.	Baseline and 16 weeks
Blood samples (unit: IU/L)	Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. FSH; LH.	Baseline and 16 weeks
Blood samples (unit: µg/L).	Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. IGF-1.	Baseline and 16 weeks
Blood samples (unit: pmol/L)	Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. ACTH.	Baseline and 16 weeks
Blood samples (unit: 10E-3IU/L)	Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. Prolactin; TSH.	Baseline and 16 weeks
Blood samples (unit: nmol/L)	Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. SHBG; testosterone; T4; estradiol.	Baseline and 16 weeks
Blood samples (unit: mg/L)	Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. C-reactive protein (CRP).	Baseline and 16 weeks
Diurnal urine samples	24 hours urine sampling are stored at -80C until analysis. Cortisol metabolites will be measured in nmol/24h.	Baseline and 16 weeks
Hair samples	Two hair samples are collected. Each sample is a section of hair strands approximately 3 mm in diameter and cut as close as possible to the scalp with a scissor. The hair samples are collected from the posterior vertex area. The cut end of the hair strands is marked. The samples are stored in a dry and cool place for later analysis of hair cortisol levels.	Baseline and 16 weeks
Saliva samples	Fasting saliva samples are collected to measure salivary cortisol.	Baseline and 16 weeks
Continous glucose monitoring (CGM)	Patients will wear a Dexcom G6 sensor to measure glucose levels.	Baseline and 16 weeks, duration: 7 days
Muscle biopsies	Patients attending Aarhus University Hospital will be requested to provide muscle and fat biopsies. During sterile conditions and local anaesthesia, muscle biopsies (≈ 500 mg) are obtained from the vastus lateralis of the quadriceps femoris muscle 10-15 cm proximal to the patella using a Bergström biopsy needle.	Baseline and 16 weeks
Fat biopsies	Patients attending Aarhus University Hospital will be requested to provide muscle and fat biopsies. Adipose tissue biopsies (≈ 20 ml) are obtained by liposuction from the abdominal subcutaneous fat depots during local anaesthesia.	Baseline and 16 weeks
Physical examination - Height	Height is measured in cm.	Baseline and 16 weeks
Physical examination - Weight	Weight is measured in kg.	Baseline and 16 weeks
Physical examination - waist and hip circumference.	Waist and hip circumference are measured in cm.	Baseline and 16 weeks

Collaborators and Investigators

• Sponsor: Marianne Andersen
• Collaborators: Aarhus University Hospital; Copenhagen University Hospital, Denmark
• Investigators: Principal Investigator: Marianne S Andersen, Odense University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: January 2, 2022
• First Submitted That Met QC Criteria: January 2, 2022
• First Posted (Actual): January 14, 2022

Study Record Updates

• Last Update Posted (Estimated): December 22, 2025
• Last Update Submitted That Met QC Criteria: December 15, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: tertiary adrenal insufficiency
• Additional Relevant MeSH Terms: Endocrine System Diseases; Musculoskeletal Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Muscular Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Autoimmune Diseases of the Nervous System; Skin Diseases; Skin Diseases, Vascular; Adrenal Gland Diseases; Vasculitis; Vasculitis, Central Nervous System; Arteritis; Skin and Connective Tissue Diseases; Adrenal Insufficiency; Polymyalgia Rheumatica; Giant Cell Arteritis; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Pregnanes; Steroids; Fused-Ring Compounds; Pregnenediones; Pregnenes; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; 17-Hydroxycorticosteroids; Hydrocortisone
• Other Study ID Numbers: REPLACE; 2024-513822-53-00 (Ctis); 2020-006121-65 (EudraCT Number); journal no. 21/27119 (Other Identifier: Danish Data Protection Agency); project-ID: S-20210076 (Other Identifier: Regional Committees on Health Research Ethics for Southern Denmark)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Deidentified participant data will be made available after completion of the study and publication of the main results, upon reasonable request. Data sharing will comply with GDPR and national data protection regulations.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No