E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Glucocorticoid-induced adrenal insufficiency |
Glukokortikoid-induceret binyrebarkinsufficiens |
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E.1.1.1 | Medical condition in easily understood language |
Impaired adrenal hormone function induced by treatment with pharmaceutical glucocorticoids |
Nedsat binyrebarkfunktion som følge af behandling med glukokortikoidholdige lægemidler |
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E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001369 |
E.1.2 | Term | Adrenal insufficiency NOS |
E.1.2 | System Organ Class | 100000004860 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
In this double-blinded randomised placebo-controlled clinical trial, the aim is to determine the effect of supplemental hydrocortisone compared with placebo during mild to moderate physical or mental stress on health related quality of life in patients with polymyalgia rheumatica/giant cell arteritis (PMR/GCA) on ongioing low-dose prednisolone diagnosed with glucocorticoid-induced adrenal insufficiency. The main emphasis is on fatigue (primary outcome) and daily variation hereof during periods of stress. |
Forsøgets formål er at undersøge, om patienter med hæmmet egenproduktion af binyrebarkhormon på fortsat lavdosis prednisolonbehandling oplever effekt på den helbredsrelaterede livskvalitet, når de modtager stress-doser af hydrokortison ved sygdom og stress. |
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E.2.2 | Secondary objectives of the trial |
Key secondary aims are • to determine the association between adrenal function and HRQoL at baseline • to determine the effect of hydrocortisone stress doses not only in situations of stress, but for general daily symptom reporting and generic and disease specific HRQoL reported with 4 weeks reference periods. • To determine the association between HRQoL and the severity of glucocorticoid-induced adrenal insufficiency (e.g. mild, moderate and severe) i) at baseline and ii) in patients receiving hydrocortisone stress doses compared with placebo. • To determine the effect of treating adrenal insufficiency with hydrocortisone stress doses on the ease of tapering prednisolone treatment for PMR/GCA. • To determine the effect of stress doses on patient safety regarding hypo- and hypercortisolism (adrenal crises, sick days and hospitalisations, and exogenous cushingoid signs and symptoms)
Further aims are to investigate biomarkers of glucocorticoid sensitivity and action
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Nøgle sekundære formål: • at bestemme sammenhængen mellem binyrebarkfunktionen og helbredsrelateret livskvalitet ved baseline • at bestemme effekten af hydrokortison stressdoser ikke kun dage med stres, men for generelle daglige symptomer og generisk og sygdomsspesifikt livskvalitet over længere tid. • at bestemme associationen mellem helbredsrelateret livskvalitet og graden af binyrebarkinfussiciens (mild, moderat og svær) dels i) ved baseline og ii) i patienter behandlet med hydrokortison stressdoser vs. placebo. • at bestemme om behandling af binyrebarkinsufficiens med stressdoser hydrokortison gør at prednioslonbehandlingen for PMR/GCA kan aftrappes hurtigere. • At bestemme effekten af hydrokortison stressdoser på patientsikkerhed ift. symptomer og tegn på hyper- og hypokortisolism (binyrekrise, sygedage, indlæggelser og tegn på exogen Cushing)
Yderligere formål: at undersøge biomarkører for glukokortikoid sensitivitet og virkning. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age ≥ 50 years • Women must be postmenopausal (FSH is measured at the screening visit) • A diagnosis of PMR/GCA, or both conditions combined. • Treatment with prednisolone ≥12 weeks • Ongoing prednisolone treatment, with current daily prednisolone dose > 0 mg and ≤5 mg. The dose must have been ≤5 mg for minimum 2 weeks at the time of the screening visit.
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• ≥ 50 år • kvinder skal være postmenopausale • Diagnosticeret med polymyalgia rheumatica og/eller kæmpecellearteritis • Behandling med prednisolon ≥ 12 uger • Prednisolon-dosis på højst 5 mg om dagen gennem mindst 2 uger på tidspunktet for screeningsbesøget
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E.4 | Principal exclusion criteria |
• Known primary or secondary adrenal insufficiency • Known Cushing’ s Syndrome • Known allergy towards study medication ingredients • Severe comorbidity (Heart failure (New York Heart Association class IV); Kidney failure with an estimated glomerular filtration rate <30 mL/min (Chronic kidney disease stage 4-5); Liver disease in the form of 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 (discontinued < 1 month before inclusion); Treatment with strong CYP3A4 inhibitors or inducers; Use of other glucocorticoid formulations: Inhaled corticosteroids, intraarticular or intramuscular injections, steroid creams European steroid group IV-V used in the genital area. Permitted glucocorticoid formulations: Eye-drops, nasal spray, glucocorticoid creams European steroid group I-III, and European steroid group IV-V used in the non-genital area only. • Inability to provide written informed consent.
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• Kendt nedsat binyrebarkfunktion der ikke er udløst af prednisolonforbrug • Kendt Cushings Syndrom • Alvorlig komorbiditet herunder: hjertesvigt, nyresvigt, levercirrose, aktiv kræftsygdom, immundefekt samt psykisk sygdom der tidligere har krævet indlæggelse (tilstande med depression eller mani, dog kun hvis indenfor det seneste år) • Alkoholindtagelse over 21 genstande om ugen • Planlagt større kirurgi inden for studieperioden • Brug af medicin der påvirker omsætning eller måling af kortisol, herunder østrogen, CYP3A4hæmmere og glukokortikoider • Hvis deltageren er ude af stand til at give et informeret samtykke
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E.5 End points |
E.5.1 | Primary end point(s) |
Symptoms of adrenal insufficiency: daily variation of fatigue (Ecological Momentary Assessments (EMA) of the Multidimensional Fatigue Inventory 20 questions (MFI-20) General Fatigue scale) |
Symptomer på binyrebarkinsufficiens: daglig variation af træthed (Ecological Momentary Assessments (EMA) af Multidimensional Fatigue Inventory 20 questions (MFI-20) General Fatigue skala) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Days with ilness or stress |
Dage med sygdom eller stress |
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E.5.2 | Secondary end point(s) |
Key secondary outcomes • SF-36, the Physical Health Component Summary • PRO-CTCAE symptoms fatigue, nausea and pain • AddiQol-30 • PMR/GCA treatment characteristics (duration of prednisolone tapering from 5 mg to complete withdrawal, accumulated dose of glucocorticoid treatment, duration of prednisolone treatment for PMR/GCA) • Number of ‘sick days’
Safety outcomes Adrenal insufficiency • Incidence rate and grade of adrenal crises • Number of hospitalisations Exogenous Cushing’s Syndrome • Body composition and muscle strength (Dual-energy X-ray absorptiometry (DXA) scan: fat percentage, body composition, bone mineral density, Waist, hip, weight, height, body mass index (BMI), Timed up and go, Handgrip strength, Short Physical Performance Battery and chair rising test • Bone quality (Bone markers in blood and urine) • Metabolic and cardiovascular risk (Automated office blood pressure, Coagulation and Inflammation markers in blood, Metabolic and cardiovascular markers in blood and urine) • Patient reported symptoms (CushingQol, Single item Sleep Quality Scale (SQS)
Exploratory outcomes • Health-Related Quality of Life measured by SF-36 eight domain scores and Mental Health Component Summary • PMR/GCA treatment characteristics: Number of PMR/GCA disease flare up/relapse, and disease activity of the PMR/GCA. • Biological integrated cortisol status assessment (ACTH test for normalization of adrenal function, 24h urine, Salivary cortisol, Circulating biomarkers of glucocorticoid effects and adverse effects, P-cortisol after 24 hours prednisolone pause analysed with several methods) |
Centrale sekundære endepunkter: • SF-36, the Physical Health Component Summary • PRO-CTCAE symptomer: træthed, kvalme, smerte • AddiQol-30 • PMR/GCA behandlingskarakteristika (varighed af prednioslon aftrapning fra 5 mg/dag til seponering, akkumuleret dosis glukokortikoidbehandling, varighed af prednisolonbehandling for PMR/GCA • Antal sygedage
Sikkerheds endepunkter Binyrebarkinsufficiens • Incidens rate og graden af binyre kriser • antal hospitalsindlæggelser Exogen Cushing’s Syndrom • Kropssammensætning og muskelstyrke (Dual-energy X-ray absorptiometry (DXA) scanning: fedtprocent, kropssammensætning, knogle mineralindhold; hofte- og talje omfang, højde kropsvægt, body mass index (BMI), Timed up and go, Handgrip strength, Short Physical Performance Battery og chair rising test • Knogle kvalitet (knoglemarkører i blod og urin) • Metabolsk og kardiovaskulær risiko (blodtryk samt koagulations, inflammations- metaboliske- og kardiovaskulære markører i blod og urin • Patient reporteret symptomer (CushingQol, Single item Sleep Quality Scale (SQS)
Exploratoriske endepunkter • Helbredsrelateretlivskvalitet: SF-36 8 domain scores og Mental Health Component Summary • PMR/GCA behandlingskarakteristika: antal PMR/GCA flares/relapse, sygdomsaktivitet. • Biologisk integreret kortisol status undersøgelse |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
baseline, 3 months, 6 months |
baseline, 3 mdr., 6. mdr. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |