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

Marianne Andersen

Status and phase: Enrolling; Phase 4

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

Treatments: Drug: Placebo; Drug: Hydrocortisone

Study type: Interventional

Funder types: Other

Identifiers

NCT05193396

2024-513822-53-00 (EU Trial (CTIS) Number)

REPLACE

journal no. 21/27119 (Other Identifier)

project-ID: S-20210076 (Other Identifier)

2020-006121-65 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 100 estimated patients

Sex: All

Ages: 50+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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100 participants in 4 patient groups, including a placebo group

RCT group - Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

RCT group - Hydrocortisone

Active Comparator group

Description:

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.

Treatment:

Drug: Hydrocortisone

Comparator group 1

No Intervention group

Description:

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 group

Description:

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.