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

NCT05193396 | Recruiting Phase 4 DMC

• 5 other identifiers: REPLACE2024-513822-53-002020-006121-65journal no. 21/27119project-ID: S-20210076
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Adrenal Insufficiency; Polymyalgia Rheumatica (PMR); Giant Cell Arteritis (GCA)

Keywords

tertiary adrenal insufficiency

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (19)

• Patient-reported symptoms via mobile phone app - PRO-CTCAETM

  Patients are asked daily throughout the study period.

• Patient-reported symptoms via mobile phone app - EMA-MFI

  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)

  Baseline and 16 weeks

• The short form 36 (SF-36)

  Baseline and 16 weeks

• Sleep Quality Scale (SQS)

  Baseline and 16 weeks

Other Outcomes (20)

• Blood samples (unit: 10E12/L)

  Baseline and 16 weeks

• Blood samples (unit: fmol)

  Baseline and 16 weeks

• Blood samples (unit: 10E9/L).

  Baseline and 16 weeks

Study Arms (4)

RCT group - Placebo

PLACEBO COMPARATOR

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

RCT group - Hydrocortisone

ACTIVE COMPARATOR

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

Comparator group 1

NO INTERVENTION

Patients with an AddiQoL-30 score \> 85 and short Synacthen test stimulated plasma cortisol level \> 420 nmol/L. Patients undergo baseline examination only.

Comparator group 2

NO INTERVENTION

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.

Interventions

Hydrocortisone DRUG

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

RCT group - Hydrocortisone

Placebo DRUG

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

RCT group - Placebo

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:
• 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

Sponsors & Collaborators

• Marianne Andersen: lead
• Aarhus University Hospital: collaborator
• Copenhagen University Hospital, Denmark: collaborator

Study Sites (3)

Department of Endocrinology and Internal Medicine, Aarhus University Hospital

Aarhus, Denmark

RECRUITING

Department of Nephrology and Endocrinology, Rigshospitalet

Copenhagen, Denmark

RECRUITING

Department of Endocrinology, Odense University Hospital

Odense, 5230, Denmark

RECRUITING

Related Publications (1)

• 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, placebo-controlled, 16-week study protocol. BMJ Open. 2026 Feb 4;16(2):e111334. doi: 10.1136/bmjopen-2025-111334.

  PMID: 41638742 DERIVED

MeSH Terms

Conditions

Adrenal Insufficiency; Polymyalgia Rheumatica; Giant Cell Arteritis

Interventions

Hydrocortisone

Condition Hierarchy (Ancestors)

Adrenal Gland Diseases; Endocrine System Diseases; Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Vasculitis, Central Nervous System; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Arteritis; Vasculitis; Skin Diseases, Vascular; Skin Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids

Study Officials

• Marianne S Andersen

  Odense University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Marianne S Andersen

CONTACT

+4565411807; marianne.andersen1@rsyd.dk

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Patients and all study personnel are blinded for study medication (hydrocortisone or placebo)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: Double-blinded randomised placebo-controlled clinical trial

Study Record Dates

• First Submitted: January 2, 2022
• First Posted: January 14, 2022
• Study Start: February 1, 2022
• Primary Completion: January 1, 2026
• Study Completion: January 1, 2026
• Last Updated: December 22, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

DK (3)