NCT05193396: 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.

Recruiting now Phase 4 Last updated 15 December 2025

What this trial tests

Phase 4 trial testing Hydrocortisone in Adrenal Insufficiency in 100 participants. Currently enrolling.

Timeline

1 February 2022

Primary endpoint
1 January 2026

1 January 2026

Quick facts

Lead sponsor	Marianne Andersen
Phase	Phase 4
Status	Recruiting now
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	100
Start date	1 February 2022
Primary completion	1 January 2026
Estimated completion	1 January 2026
Sites	3 locations across Denmark

Drugs / interventions tested

• Hydrocortisone (hydrocortisone) — full drug profile →
• Placebo

Conditions studied

• Adrenal Insufficiency — all drugs for Adrenal Insufficiency →
• Polymyalgia Rheumatica (PMR) — all drugs for Polymyalgia Rheumatica (PMR) →
• Giant Cell Arteritis (GCA) — all drugs for Giant Cell Arteritis (GCA) →

Sponsor

Marianne Andersen

Who can join

50 and older, any sex, with Adrenal Insufficiency or Polymyalgia Rheumatica (PMR). Patients with the condition only — healthy volunteers not accepted.

What's being measured

Primary outcomes are the specific endpoints the trial is designed to prove or disprove.

• Adrenal insufficiency symptoms
  Time frame: Screening and 16 weeks
  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/st

Sponsor's own description

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.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. Changes in Adrenal Function and Insufficiency Symptoms After Cessation of Prednisolone.
   Hansen SB, Dreyer AF, Jørgensen NT, Al-Jorani H, et al · · 2025 · cited 6× · PMID 40100216 · DOI 10.1001/jamanetworkopen.2025.1029
2. Hydrocortisone replacement therapy in patients with glucocorticoid withdrawal syndrome after cessation of glucocorticoid treatment: REPLACE, a multicentre, randomised, double-blinded, placebo-controlled, 16-week study protocol.
   Dreyer AF, Hansen SB, Borresen SW, Al-Jorani H, et al · · 2026 · PMID 41638742 · DOI 10.1136/bmjopen-2025-111334