The RESCUE study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rigshospitalet

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

Trial duration

1 Jun 2022 → ongoing

Decision date (initial)

2025-01-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Funding by the Novo Nordic Foundation, grant number: NNF20OC0063280

External identifiers

EU CT number

2024-518272-30-00

EudraCT number

2021-002528-18

ClinicalTrials.gov

NCT05435781

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

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 (PMR) and/or giant cell arteritis (GCA) diagnosed with glucocorticoid-induced adrenal insufficiency while on ongioing low-dose prednisolone treatment. The main emphasis is on fatigue (primary outcome) and daily variation hereof during periods of stress.

Secondary objectives 9

1. Key secondary aim no 1: To determine the association between adrenal function and health related quality of life (HRQoL) at baseline.
2. Key secondary aim no 2: 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.
3. Key secondary aim no 3: 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, aiming to guide differentiated recommendations for the choice of replacement treatment level.
4. Key secondary aim no 4: To determine the effect of treating adrenal insufficiency with hydrocortisone stress doses on the ease of tapering prednisolone treatment for PMR/GCA. We aim to determine differences in accumulated dose of glucocorticoid treatment (prednisolone and hydrocortisone), duration of prednisolone treatment and tapering for PMR/GCA, and PMR/GCA disease activity and flare-ups.
5. Key secondary aim no 5: To determine the effect of stress doses on patient safety regarding hypo- and hypercortisolism. We aim to determine differences in adrenal crises, sick days and hospitalisations, and exogenous cushingoid signs and symptoms.
6. Key secondary aim no 6: To determine whether the outcome of an ACTH test is affected by whether prednisolone is paused 0, 1 or 2 days before the test. We aim to investigate i) early HPA axis recovery (difference in ACTH test response depending on 0-2 days prednisolone pause) and ii) quantify the cross-reactivity of prednisolone at different times after prednisolone intake in the Roche Elecsys cortisol II immunoassay which is the most commonly used assay in Denmark. Results will be crucial for data analysis and interpretation of results in the RESCUE study and we aim to generate evidence-based recommendations when performing an ACTH test in patients treated with prednisolone.
7. Secondary aim: To determine biomarkers for the risk of adrenal insufficiency that could be more easily performed than an ACTH stimulation test.
8. Secondary aim: To determine biomarkers for the adequateness of the overall glucocorticoid replacement treatment dose
9. Secondary aim: To determine biomarkers for glucocorticoid effects and adverse effects

Conditions and MedDRA coding

Glucocorticoid induced adrenal insufficiency

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Age ≥ 50 years
2. Women must be postmenopausal
3. A diagnosis of polymyalgia rheumatica (PMR), giant cell arteritis (GCA), or both conditions combined
4. Treatment with prednisolone ≥12 weeks
5. 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.

Exclusion criteria 8

1. Known primary or secondary adrenal insufficiency
2. Known Cushing’ s Syndrome
3. Known allergy towards study medication ingredients
4. Severe comorbidity defined as: 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).
5. Alcohol consumption >21 units per week
6. Planned major surgery during the study period at study entry.
7. Use of drugs that interfere with cortisol metabolism/measurements defined as: Systemic oestrogen treatment (discontinued < 1 month before inclusion); Treatment with strong CYP3A4 inhibitors or inducers (defined in Table 2 in the study protocol); 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).
8. Inability to provide written informed consent.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Ecological momentary assessments (EMA) of the Multidimensional Fatigue Inventory (MFI-20), the General Fatigue scale, in situations of stress (Stress EMA). Details: EMA reporting will be done using a study smartphone applica-tion. When patients report stress, the app prompts participants to answer the four momentary MFI-20 General Fatigue questions five time daily at semi ran-domized timepoints for three days. A paper version is available for patients who cannot use a smartphone.

Secondary endpoints 14

1. Key secondary outcome: EMA version of the MFI-20 General Fatigue scale at baseline (baseline EMA) and at fixed timepoints monthly (unstressed EMA)
2. Key secondary outcome: SF-36v2 questionnaire
3. Key secondary outcome: Daily ‘end-of-day’ smartphone app facilitated patient reported symptoms of adrenal insufficiency and intercurrent illness and stress. The questions about symptoms originate from the Danish version of the PRO-CTCAE questionnaire.
4. Key secondary outcome: AddiQol-30 questionnaire
5. Key secondary outcome: 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.
6. Key secondary outcome: Number of ‘sick days’
7. Key secondary outcome: ACTH test results depending on the length of the prednisolon pause: ACTH test results (basal and stimulated plasma cortisol) after 0, 1, or 2 days prednisolone pause; Prednisolone cross reactivity in Roche Elecsys cortisol II immunoassay in plasma 2 hours, 4 hours, 1 day and 2 days after last prednisolone intake; ACTH concentrations (central HPA axis recovery).
8. Safety outcomes: Adrenal insufficiency: Incidence rate and grade of adrenal crises; Number of hospitalisations
9. Safety outcome: Exogenous Cushing’s Syndrome - Body composition and muscle strength: Dual-energy X-ray absorptiometry (DXA) scan (fat percentage, body composition, bone mineral density); Waist- and hip circumference, weight, height, body mass index (BMI); Timed up and go; Handgrip strength; Short Physical Performance Battery and chair rising test.
10. Safety outcome: Exogenous Cushing’s Syndrome - Bone quality: Bone markers in blood and urine
11. Safety outcome: Exogenous Cushing’s Syndrome - Metabolic and cardiovascular risk: Automated office blood pressure; Coagulation and Inflammation markers in blood; Metabolic and cardiovascular markers in blood and urine.
12. Safety outcome: Exogenous Cushing’s Syndrome - Patient reported symptoms: CushingQol questionnaire; Single item Sleep Quality Scale (SQS) questionnaire
13. Exploratory outcome: PMR/GCA treatment characteristics: Number of PMR/GCA disease flare up/relapse, and disease activity of the PMR/GCA.
14. Exploratory outcome: Biological integrated cortisol status assessment: ACTH test for normalization of adrenal function; 24h urine; Salivary cortisol and cortisone during ACTH tests (determined by Roche immunoassay and LC-MS); Cortisol binding globulin (CBG) in plasma to calculate Free Cortisol Index (total P-cortisol concentration (nmol/l)/serum CBG (in mg/L). Circulating biomarkers of glucocorticoid effects and adverse effects (incl. glucocorticoid receptor gene polymorphisms).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rigshospitalet

Sponsor organisation

Rigshospitalet

Address

Blegdamsvej 9

City

Copenhagen Oe

Postcode

2100

Country

Denmark

Scientific contact point

Organisation

Rigshospitalet

Contact name

MD PhD Stina Willemoes Borresen (study coordinator) & MD PhD Marianne Klose (sponsor)

Public contact point

Organisation

Rigshospitalet

Contact name

MD PhD Stina Willemoes Borresen (study coordinator) & MD PhD Marianne Klose (sponsor)

Third parties 1

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications