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| ID | Type | Description | Link |
|---|---|---|---|
| 2024-513822-53-00 | EU Trial (CTIS) Number | ||
| 2020-006121-65 | EudraCT Number | ||
| journal no. 21/27119 | Other Identifier | Danish Data Protection Agency | |
| project-ID: S-20210076 | Other Identifier | Regional Committees on Health Research Ethics for Southern Denmark |
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| Name | Class |
|---|---|
| Aarhus University Hospital | OTHER |
| Copenhagen University Hospital, Denmark | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Hydrocortisone | Drug | Patients are randomized to oral hydrocortisone (10 mg twice daily) or placebo for 16 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Patient-reported symptoms via mobile phone app - PRO-CTCAETM | Symptoms of fatigue, nausea, dizziness, and "feeling generally unwell" assessed by the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAETM). Each symptom is evaluated in terms of frequency and severity with a score from 1 (never/nothing) to 5 (almost constant/very strong). | Patients are asked daily throughout the study period. |
| Measure | Description | Time Frame |
|---|---|---|
| Blood samples (unit: 10E12/L) | Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. Erythrocytes. | Baseline and 16 weeks |
| Blood samples (unit: fmol) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Marianne S Andersen | Contact | +4565411807 | marianne.andersen1@rsyd.dk |
| Name | Affiliation | Role |
|---|---|---|
| Marianne S Andersen | Odense University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Endocrinology and Internal Medicine, Aarhus University Hospital | Recruiting | Aarhus | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41638742 | Derived | 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. |
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Deidentified participant data will be made available after completion of the study and publication of the main results, upon reasonable request. Data sharing will comply with GDPR and national data protection regulations.
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Double-blinded randomised placebo-controlled clinical trial
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Patients and all study personnel are blinded for study medication (hydrocortisone or placebo)
| Placebo | Drug | Patients are randomized to oral hydrocortisone (10 mg twice daily) or placebo for 16 weeks. |
|
| Patient-reported symptoms via mobile phone app - EMA-MFI | Four statements regarding diurnal fatigue based on the validated General Fatigue Scale from the Multidimensional Fatigue Inventory (MFI-20) adapted for Ecological Momentary Assessments (EMA). Each statement is answered by a visuel scale from left (yes, that is correct) to right (no, that is not correct). | 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) | Cushing quality of life (CushingQoL) is a disease-specific questionnaire for patients with endogenous cortisol excess. It consists of 12 items about mental and physical adverse effects of cortisol excess. The total score os normalised to a scale ranging from 0 (lowest quality of lige) to 100 (highest quality of life). | Baseline and 16 weeks |
| The short form 36 (SF-36) | SF-36 is a genereic qeustionnaire evaluating general health perception with 36 items related to 8 dimensions: physical functioning for the limitation in performing all physical activities; role physical for problems with work or other daily activities; bodily pain; general health; vitality; social functioning; role emotional; and mental health. | Baseline and 16 weeks |
| Sleep Quality Scale (SQS) | SQS is a single item questionnaire consisting of a numerical rating scale to evaluate the overall sleep quality over the last 7 nights. The scale is ranging from 0 (terrible sleep) to 10 (excellent sleep). | Baseline and 16 weeks |
| International Physical Activity Questionnaire, short form, 7 days (IPAQ-7s) | The IPAQ-7s records types and intensity of physical activity. The questionnaire consists of seven open items covering 4 types of activity (energetic activity, moderate activity, walk, and sitting). The first three is measured in "number of days per week", "hours per day", and "minutes per day". The last activity (sitting) is measured in "hours per day" and "minutes per day". | Baseline and 16 weeks |
| Incidence of adrenal crises | Incidence of adrenal crises, including information on hospitalizations, number of sick days, diagnoses and therapy. | 16 weeks |
| Cardiovascular health - Blood pressure | Office blood pressure (OBP) and automated blood pressure (AOBP). Blood pressure measurements will be performed with (OBP) and without (AOBP) the presence of investigator. Unit is mmHg. | Baseline and 16 weeks |
| Cardiovascular health - PWV | Arterial stiffness and pulse wave velocity (PWV). PVW is measured three times, unit is m/s. | Baseline and 16 weeks |
| Body composition - DXA scan | Body composition by dual X-ray absorptiometry (DXA) scan. Body composition is measured in the distribution of fat and lean mass in grams (g). | Only performed at baseline visit |
| Bone quality - DXA scan | Bone quality by dual X-ray absorptiometry (DXA) scan. Bone mineral density (g/cm^2) and T-score of the lumbal spine and hip. | Only performed at baseline visit |
| HR-pQCT | High-resolution peripheral quantitative computed tomography (HR-pQCT) in order to obtain three-dimensional BMD. | Only performed at baseline visit |
| Muscle function and physical activity - Handgrip strength. | Handgrip strength is measured in kg using a hydraulic hand dynamometer. | Baseline and 16 weeks. |
| Muscle function and physical activity - TUG | Timed Up and Go (TUG) test measures the time taken to stand up, walk three meters in a straight line, and immediately return to the chair. | Baseline and 16 weeks. |
| Muscle function and physical activity - SPPB | The Short Physical Performance Battery including Chair Rising Test (SPPB) evaluates the lower extremity function of the patient. | Baseline and 16 weeks. |
| Muscle function and physical activity - Actigraph | Patients are asked to wear an accelerometer device on their non-dominant wrist to measure physical activity and sleep. Time of physical activity and sleep will be measured in minutes. | Baseline and 16 weeks, duration: 7 days |
| Muscle function and physical activity - Muscle power | The muscle power of the dominant arm and upper back, as well as elbow, hip, and knee extension and flexion, are evaluated by use of a exercise machine. Power is measured in watt. | Baseline and 16 weeks. |
| Muscle function and physical activity - Isometric muscle strength | The isometric muscle strength of the dominant arm and upper back, as well as elbow, hip, and knee extension and flexion, are evaluated by use of a exercise machine. Strength is measured in kg. | Baseline and 16 weeks. |
| Normalization of adrenal function evaluated by SST | Short Synacthen® test. Cortisol is measured in nmol/L before (0 min) and after (30 min) administration of 1 ml Synacthen (0.25 mg/ml). | Screening/Baseline and 16 weeks |
Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes.
MCH.
| Baseline and 16 weeks |
| Blood samples (unit: 10E9/L). | Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. Leokocytes; neutrophils; lymphocytes; monocytes; basophilocytes; eosinophils; metamyelocytes; thrombocytes. | Baseline and 16 weeks |
| Blood samples (unit: mmol/L) | Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. Hemoglobin; MCHC; glucose; glucose derived from HbA1c, cholesterol; HDL; LDL; non-HDL; triglycerid; calcium ion, free. | Baseline and 16 weeks |
| Blood samples (unit: mmol/mol) | Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. HbA1c. | Baseline and 16 weeks |
| Blood samples (unit: IU/L) | Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. FSH; LH. | Baseline and 16 weeks |
| Blood samples (unit: µg/L). | Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. IGF-1. | Baseline and 16 weeks |
| Blood samples (unit: pmol/L) | Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. ACTH. | Baseline and 16 weeks |
| Blood samples (unit: 10E-3IU/L) | Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. Prolactin; TSH. | Baseline and 16 weeks |
| Blood samples (unit: nmol/L) | Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. SHBG; testosterone; T4; estradiol. | Baseline and 16 weeks |
| Blood samples (unit: mg/L) | Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. C-reactive protein (CRP). | Baseline and 16 weeks |
| Diurnal urine samples | 24 hours urine sampling are stored at -80C until analysis. Cortisol metabolites will be measured in nmol/24h. | Baseline and 16 weeks |
| Hair samples | Two hair samples are collected. Each sample is a section of hair strands approximately 3 mm in diameter and cut as close as possible to the scalp with a scissor. The hair samples are collected from the posterior vertex area. The cut end of the hair strands is marked. The samples are stored in a dry and cool place for later analysis of hair cortisol levels. | Baseline and 16 weeks |
| Saliva samples | Fasting saliva samples are collected to measure salivary cortisol. | Baseline and 16 weeks |
| Continous glucose monitoring (CGM) | Patients will wear a Dexcom G6 sensor to measure glucose levels. | Baseline and 16 weeks, duration: 7 days |
| Muscle biopsies | Patients attending Aarhus University Hospital will be requested to provide muscle and fat biopsies. During sterile conditions and local anaesthesia, muscle biopsies (≈ 500 mg) are obtained from the vastus lateralis of the quadriceps femoris muscle 10-15 cm proximal to the patella using a Bergström biopsy needle. | Baseline and 16 weeks |
| Fat biopsies | Patients attending Aarhus University Hospital will be requested to provide muscle and fat biopsies. Adipose tissue biopsies (≈ 20 ml) are obtained by liposuction from the abdominal subcutaneous fat depots during local anaesthesia. | Baseline and 16 weeks |
| Physical examination - Height | Height is measured in cm. | Baseline and 16 weeks |
| Physical examination - Weight | Weight is measured in kg. | Baseline and 16 weeks |
| Physical examination - waist and hip circumference. | Waist and hip circumference are measured in cm. | Baseline and 16 weeks |
| Department of Nephrology and Endocrinology, Rigshospitalet | Recruiting | Copenhagen | Denmark |
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| Department of Endocrinology, Odense University Hospital | Recruiting | Odense | 5230 | Denmark |
|
| ID | Term |
|---|---|
| D000309 | Adrenal Insufficiency |
| D011111 | Polymyalgia Rheumatica |
| D013700 | Giant Cell Arteritis |
| ID | Term |
|---|---|
| D000307 | Adrenal Gland Diseases |
| D004700 | Endocrine System Diseases |
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D020293 | Vasculitis, Central Nervous System |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D001167 | Arteritis |
| D014657 | Vasculitis |
| D017445 | Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D006854 | Hydrocortisone |
| ID | Term |
|---|---|
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D015062 | 11-Hydroxycorticosteroids |
| D006889 | Hydroxycorticosteroids |
| D000305 | Adrenal Cortex Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D015065 | 17-Hydroxycorticosteroids |
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