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.
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 100
- 试验地点
- 3
- 主要终点
- Adrenal insufficiency symptoms
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Patients and all study personnel are blinded for study medication (hydrocortisone or placebo)
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
RCT group - Placebo
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.
干预措施: Placebo (Drug)
RCT group - Hydrocortisone
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.
干预措施: Hydrocortisone (Drug)
结局指标
主要结局
Adrenal insufficiency symptoms
时间窗: 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/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).
次要结局
- Muscle function and physical activity - TUG(Baseline and 16 weeks.)
- 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)
- International Physical Activity Questionnaire, short form, 7 days (IPAQ-7s)(Baseline and 16 weeks)
- Incidence of adrenal crises(16 weeks)
- Cardiovascular health - Blood pressure(Baseline and 16 weeks)
- Cardiovascular health - PWV(Baseline and 16 weeks)
- Body composition - DXA scan(Only performed at baseline visit)
- Bone quality - DXA scan(Only performed at baseline visit)
- HR-pQCT(Only performed at baseline visit)
- Muscle function and physical activity - Handgrip strength.(Baseline and 16 weeks.)
- Muscle function and physical activity - SPPB(Baseline and 16 weeks.)
- Muscle function and physical activity - Actigraph(Baseline and 16 weeks, duration: 7 days)
- Muscle function and physical activity - Muscle power(Baseline and 16 weeks.)
- Muscle function and physical activity - Isometric muscle strength(Baseline and 16 weeks.)
- Normalization of adrenal function evaluated by SST(Screening/Baseline and 16 weeks)
研究者
Marianne Andersen
Professor
Odense University Hospital