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

Официальное название

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.

Обзор

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.

Вмешательства

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

Первичные конечные точки

• Adrenal insufficiency symptoms [Срок оценки: Screening and 16 weeks]

Вторичные конечные точки (12)

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

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Дания · 3 центра

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

Публикации

• 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

Идентификаторы

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

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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