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

Official title

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.

Overview

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.

Interventions

• Drug Hydrocortisone
  Patients are randomized to oral hydrocortisone (10 mg twice daily) or placebo for 16 weeks.
• Drug Placebo
  Patients are randomized to oral hydrocortisone (10 mg twice daily) or placebo for 16 weeks.

Primary outcome measures

• Adrenal insufficiency symptoms [Time frame: Screening and 16 weeks]

Secondary outcome measures (12)

• Patient-reported symptoms via mobile phone app - PRO-CTCAETM [Time frame: Patients are asked daily throughout the study period.]
• Patient-reported symptoms via mobile phone app - EMA-MFI [Time frame: 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) [Time frame: Baseline and 16 weeks]
• The short form 36 (SF-36) [Time frame: Baseline and 16 weeks]
• Sleep Quality Scale (SQS) [Time frame: Baseline and 16 weeks]
• International Physical Activity Questionnaire, short form, 7 days (IPAQ-7s) [Time frame: Baseline and 16 weeks]
• Incidence of adrenal crises [Time frame: 16 weeks]
• Cardiovascular health - Blood pressure [Time frame: Baseline and 16 weeks]
• Cardiovascular health - PWV [Time frame: Baseline and 16 weeks]
• Body composition - DXA scan [Time frame: Only performed at baseline visit]
• Bone quality - DXA scan [Time frame: Only performed at baseline visit]
• HR-pQCT [Time frame: Only performed at baseline visit]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Denmark · 3 centers

• Department of Endocrinology and Internal Medicine, Aarhus University Hospital — Aarhus
• Department of Nephrology and Endocrinology, Rigshospitalet — Copenhagen
• Department of Endocrinology, Odense University Hospital — Odense

Publications

• Dreyer AF, Hansen SB, Borresen SW, Al-Jorani H, Bislev LS, Boesen VB, Christensen LL, Glintborg D, Jensen RC, Jorgensen NT, Klose MC, Lund ML, Frederiksen JSS, Tei R, Feldt-Rasmussen U, Jorgensen JOL, Andersen MS. Hydrocortisone replacement therapy in patients with glucocorticoid withdrawal syndrome after cessation of glucocorticoid treatment: REPLACE, a multicentre, randomised, double-blinded, pl PMID 41638742

Identifiers

NCT: NCT05193396 · REPLACE · 2024-513822-53-00 · 2020-006121-65 · journal no. 21/27119 · project-ID: S-20210076

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗