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Effect of Supplemental Hydrocortisone During Stress in Prednisolone-induced Adrenal Insufficiency (RESCUE)

Primary Purpose

Adrenal Insufficiency, Polymyalgia Rheumatica, Giant Cell Arteritis

Status

Recruiting

Phase

Phase 4

Locations

Denmark

Study Type

Interventional

Intervention

Hydrocortisone

Placebo for hydrocortisone

About this trial

This is an interventional treatment trial for Adrenal Insufficiency focused on measuring Glucocorticoid-induced adrenal insufficiency, Prednisolone, Glucocorticoids, Hypothalamic-pituitary-adrenal axis

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

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. Note: 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.

Sites / Locations

Department of Endocrinology, Aarhus University Hospital
Department of Medical Endocrinology, Copenhagen University Hospital, RigshospitaletRecruiting
Department of Endocrinology, Odense University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Placebo Comparator

No Intervention

Arm Label

RCT group - hydrocortisone

RCT group - placebo

Control group

Arm Description

Patients with polymyalgia rheumatica/giant cell arteritis with glucocorticoid-induced adrenal insufficiency (Synacthen test response <420 nmol/l) that are randomised to receive hydrocortisone

Patients with polymyalgia rheumatica/giant cell arteritis with glucocorticoid-induced adrenal insufficiency (Synacthen test response <420 nmol/l) that are randomised to receive placebo

Patients with polymyalgia rheumatica/giant cell arteritis with normal adrenal function (Synacthen test response ≥420 nmol/l)

Outcomes

Primary Outcome Measures

ecological momentary assessments (EMA) of the Multidimensional Fatigue Inventory (MFI-20) General Fatigue scale, adjusted for EMA

EMA in situations of stress. EMA reporting will be conducted electronically on a smartphone.

Secondary Outcome Measures

Daily 'end-of-day' app-facilitated patient reported outcome (PRO) assessments

Key secondary outcome - obtain information about intercurrent illness, injury, or stress, and symptoms of fatigue, nausea, and general malaise. The questions about symptoms originate from the Danish version of the PRO-CTCAE.

SF-36

Key secondary outcome

AddiQol-30

Key secondary outcome

PMR/GCA treatment characteristics -accumulated glucocorticoid dose

Key secondary outcome. accumulated glucocorticoid dose

PMR/GCA treatment characteristics -prednisolone treatment duration

Key secondary outcome. Duration of prednisolone treatment, duration of prednisolone tapering (5 mg - 0 mg)

Number of 'sick days'

Key secondary outcome

Incidens of adrenal crises and hospitalisations

Incidence rate of adrenal crises and hospitalisations

Adrenal crises grading

Grade of adrenal crises.

Body composition and muscle strength - DXA scan

Safety outcome for exogenous Cushing's Syndrome (Dual-energy X-ray absorptiometry (DXA) scan: fat percentage, body composition

Body composition and muscle strength - Waist, hip, height

Safety outcome for exogenous Cushing's Syndrome (Waist, hip, height)

Body composition and muscle strength -weight

Safety outcome for exogenous Cushing's Syndrome (weight)

Body composition and muscle strength - body mass index (BMI)

Safety outcome for exogenous Cushing's Syndrome (BMI)

Body composition and muscle strength - Timed up and go

Safety outcome for exogenous Cushing's Syndrome (Timed up and go)

Body composition and muscle strength - Handgrip strength

Safety outcome for exogenous Cushing's Syndrome (Handgrip strength)

Body composition and muscle strength - Short Physical Performance Battery

Safety outcome for exogenous Cushing's Syndrome (Short Physical Performance Battery)

Body composition and muscle strength - Chair rising test

Safety outcome for exogenous Cushing's Syndrome (Chair rising test)

Bone quality - Dual-energy X-ray absorptiometry (DXA) scan

Safety outcome for exogenous Cushing's Syndrome (DXA scan, vertebral and hip)

Bone quality - bone markers in blood and urine

Safety outcome for exogenous Cushing's Syndrome (bone markers in blood and urine)

Metabolic and cardiovascular risk - Automated office blood pressure

Safety outcome for exogenous Cushing's Syndrome (Automated office blood pressure)

Metabolic and cardiovascular risk (Coagulation and Inflammation markers in blood)

Safety outcome for exogenous Cushing's Syndrome (Coagulation and Inflammation markers in blood)

Metabolic and cardiovascular risk - Metabolic and cardiovascular markers in blood and urine

Safety outcome for exogenous Cushing's Syndrome (Metabolic and cardiovascular markers in blood and urine)

Patient reported symptoms of hypercortisolism - CushingQol

Safety outcome for exogenous Cushing's Syndrome (CushingQol)

Patient reported symptoms of hypercortisolism - Single item Sleep Quality Scale (SQS))

Safety outcome for exogenous Cushing's Syndrome (Single item Sleep Quality Scale (SQS))

Biological integrated cortisol status assessment - ACTH test

ACTH test for normalization of adrenal function

Biological integrated cortisol status assessment - 24h urine

24h urine for cortisol and metabolites.

Biological integrated cortisol status assessment - Salivary cortisol/cortisone

Salivary cortisol/cortisone

Biological integrated cortisol status assessment - Circulating biomarkers of glucocorticoid effects and adverse effects

Circulating biomarkers of glucocorticoid effects and adverse effects.

Biological integrated cortisol status assessment - P-cortisol after 24 hours prednisolone pause.

P-cortisol after 24 hours prednisolone pause.

ecological momentary assessments (EMA) of the Multidimensional Fatigue Inventory (MFI-20) General Fatigue scale, adjusted for EMA

EMA in situations without stress, key-secondary putcome: EMA reporting will be conducted electronically on a smartphone

Full Information

NCT ID

NCT05435781

First Posted

June 13, 2022

Last Updated

June 23, 2022

Sponsor

Ulla Feldt-Rasmussen

Collaborators

Aarhus University Hospital, Odense University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT05435781

Brief Title

Effect of Supplemental Hydrocortisone During Stress in Prednisolone-induced Adrenal Insufficiency

Acronym

RESCUE

Official Title

RESCUE - Effect of Supplemental Hydrocortisone During Stress in Prednisolone-induced Adrenal Insufficiency; A Multicentre, Randomised, Double Blinded, Placebo-controlled Clinical Trial on Health-related Quality of Life in Patients With Polymyalgia Rheumatica/Giant Cell Arteritis Receiving Ongoing Low-dose Prednisolone Treatment.

Study Type

Interventional

2. Study Status

Record Verification Date

June 2022

Overall Recruitment Status

Recruiting

Study Start Date

June 7, 2022 (Actual)

Primary Completion Date

March 1, 2025 (Anticipated)

Study Completion Date

March 1, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Ulla Feldt-Rasmussen

Collaborators

Aarhus University Hospital, Odense University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

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)/giant cell arteritis (GCA) on ongoing 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.

Detailed Description

The study will include patients with PMR/GCA on ongoing prednisolone treatment in a low dose of > 0 mg/day and ≤5mg/day. Eligible patients will undergo a Synacthen® test and 250 patients with a stimulated cortisol level <420 nmol/l (biochemical adrenal insufficiency) will be randomised to either placebo or hydrocortisone supplemental doses during stress. Patients will continue prednisolone treatment and tapering hereof according to current clinical guidelines for PMR/GCA and add supplemental hydrocortisone/placebo in situations of stress according to study protocol. In situations of severe stress (potential adrenal crisis) patients will receive open label hydrocortisone treatment according to routine clinical care. The duration of RESCUE is 6 months but stops earlier if the patient stops prednisolone treatment earlier. In case of a flare of PMR/GCA during the study where prednisolone is increased to >5mg/day for e.g. 5 weeks the study is prolonged accordingly 5 weeks. Seventy-five patients with stimulated cortisol ≥420 nmol/l (normal adrenal function) will be used as a reference group. The participants will undergo screening and baseline examinations, 3 month's reporting of HRQoL, and with patient consent follow-up through medical records on prednisolone treatment characteristics, and number of hospitalisations.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Adrenal Insufficiency, Polymyalgia Rheumatica, Giant Cell Arteritis

Keywords

Glucocorticoid-induced adrenal insufficiency, Prednisolone, Glucocorticoids, Hypothalamic-pituitary-adrenal axis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

Double-blinded randomised placebo-controlled clinical trial

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Patients and all study personnel are blinded for study medication (hydrocortisone or placebo)

Allocation

Randomized

Enrollment

250 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

RCT group - hydrocortisone

Arm Type

Active Comparator

Arm Description

Patients with polymyalgia rheumatica/giant cell arteritis with glucocorticoid-induced adrenal insufficiency (Synacthen test response <420 nmol/l) that are randomised to receive hydrocortisone

Arm Title

RCT group - placebo

Arm Type

Placebo Comparator

Arm Description

Patients with polymyalgia rheumatica/giant cell arteritis with glucocorticoid-induced adrenal insufficiency (Synacthen test response <420 nmol/l) that are randomised to receive placebo

Arm Title

Control group

Arm Type

No Intervention

Arm Description

Patients with polymyalgia rheumatica/giant cell arteritis with normal adrenal function (Synacthen test response ≥420 nmol/l)

Intervention Type

Drug

Intervention Name(s)

Hydrocortisone

Intervention Description

Patients are randomised to either placebo or hydrocortisone supplemental doses in situations of stress. Patients will continue prednisolone treatment and tapering hereof according to current clinical guidelines for PMR/GCA , prednisolone is not part of the intervention.

Intervention Type

Drug

Intervention Name(s)

Placebo for hydrocortisone

Intervention Description

Primary Outcome Measure Information:

Title

ecological momentary assessments (EMA) of the Multidimensional Fatigue Inventory (MFI-20) General Fatigue scale, adjusted for EMA

Description

EMA in situations of stress. EMA reporting will be conducted electronically on a smartphone.

Time Frame

In situations of stress, participants are asked to answer the EMA items 5 times daily at semi-randomised time points, for 3 days. Diurnal profiles are generated and one diurnal profile summarizes responses during the day across all 'sick-days'.

Secondary Outcome Measure Information:

Title

Daily 'end-of-day' app-facilitated patient reported outcome (PRO) assessments

Description

Time Frame

Patients are asked daily throughout the study period as 'end-of-day' assessments.

Title

SF-36

Description

Key secondary outcome

Time Frame

At baseline, 3 months and 6 months

Title

AddiQol-30

Description

Key secondary outcome

Time Frame

At baseline, 3 months and 6 months

Title

PMR/GCA treatment characteristics -accumulated glucocorticoid dose

Description

Key secondary outcome. accumulated glucocorticoid dose

Time Frame

Information from 6 months before baseline to end-of study

Title

PMR/GCA treatment characteristics -prednisolone treatment duration

Description

Key secondary outcome. Duration of prednisolone treatment, duration of prednisolone tapering (5 mg - 0 mg)

Time Frame

Information from 6 months before baseline to end-of study

Title

Number of 'sick days'

Description

Key secondary outcome

Time Frame

Throughout study period (6 months)

Title

Incidens of adrenal crises and hospitalisations

Description

Incidence rate of adrenal crises and hospitalisations

Time Frame

Throughout study period (6 months)

Title

Adrenal crises grading

Description

Grade of adrenal crises.

Time Frame

Throughout study period (6 months)

Title

Body composition and muscle strength - DXA scan

Description

Safety outcome for exogenous Cushing's Syndrome (Dual-energy X-ray absorptiometry (DXA) scan: fat percentage, body composition

Time Frame

Baseline and 6 months

Title

Body composition and muscle strength - Waist, hip, height

Description

Safety outcome for exogenous Cushing's Syndrome (Waist, hip, height)

Time Frame

Baseline and 6 months

Title

Body composition and muscle strength -weight

Description

Safety outcome for exogenous Cushing's Syndrome (weight)

Time Frame

Baseline and 6 months

Title

Body composition and muscle strength - body mass index (BMI)

Description

Safety outcome for exogenous Cushing's Syndrome (BMI)

Time Frame

Baseline and 6 months

Title

Body composition and muscle strength - Timed up and go

Description

Safety outcome for exogenous Cushing's Syndrome (Timed up and go)

Time Frame

Baseline and 6 months

Title

Body composition and muscle strength - Handgrip strength

Description

Safety outcome for exogenous Cushing's Syndrome (Handgrip strength)

Time Frame

Baseline and 6 months

Title

Body composition and muscle strength - Short Physical Performance Battery

Description

Safety outcome for exogenous Cushing's Syndrome (Short Physical Performance Battery)

Time Frame

Baseline and 6 months

Title

Body composition and muscle strength - Chair rising test

Description

Safety outcome for exogenous Cushing's Syndrome (Chair rising test)

Time Frame

Baseline and 6 months

Title

Bone quality - Dual-energy X-ray absorptiometry (DXA) scan

Description

Safety outcome for exogenous Cushing's Syndrome (DXA scan, vertebral and hip)

Time Frame

Baseline and 6 months

Title

Bone quality - bone markers in blood and urine

Description

Safety outcome for exogenous Cushing's Syndrome (bone markers in blood and urine)

Time Frame

Baseline and 6 months

Title

Metabolic and cardiovascular risk - Automated office blood pressure

Description

Safety outcome for exogenous Cushing's Syndrome (Automated office blood pressure)

Time Frame

Baseline and 6 months

Title

Metabolic and cardiovascular risk (Coagulation and Inflammation markers in blood)

Description

Safety outcome for exogenous Cushing's Syndrome (Coagulation and Inflammation markers in blood)

Time Frame

Baseline and 6 months

Title

Metabolic and cardiovascular risk - Metabolic and cardiovascular markers in blood and urine

Description

Safety outcome for exogenous Cushing's Syndrome (Metabolic and cardiovascular markers in blood and urine)

Time Frame

Baseline and 6 months

Title

Patient reported symptoms of hypercortisolism - CushingQol

Description

Safety outcome for exogenous Cushing's Syndrome (CushingQol)

Time Frame

Baseline and 6 months

Title

Patient reported symptoms of hypercortisolism - Single item Sleep Quality Scale (SQS))

Description

Safety outcome for exogenous Cushing's Syndrome (Single item Sleep Quality Scale (SQS))

Time Frame

Baseline and 6 months

Title

Biological integrated cortisol status assessment - ACTH test

Description

ACTH test for normalization of adrenal function

Time Frame

At baseline, (3 months) and 6 months

Title

Biological integrated cortisol status assessment - 24h urine

Description

24h urine for cortisol and metabolites.

Time Frame

At baseline, (3 months) and 6 months

Title

Biological integrated cortisol status assessment - Salivary cortisol/cortisone

Description

Salivary cortisol/cortisone

Time Frame

At baseline, (3 months) and 6 months

Title

Biological integrated cortisol status assessment - Circulating biomarkers of glucocorticoid effects and adverse effects

Description

Circulating biomarkers of glucocorticoid effects and adverse effects.

Time Frame

At baseline, (3 months) and 6 months

Title

Biological integrated cortisol status assessment - P-cortisol after 24 hours prednisolone pause.

Description

P-cortisol after 24 hours prednisolone pause.

Time Frame

At baseline, (3 months) and 6 months

Title

ecological momentary assessments (EMA) of the Multidimensional Fatigue Inventory (MFI-20) General Fatigue scale, adjusted for EMA

Description

EMA in situations without stress, key-secondary putcome: EMA reporting will be conducted electronically on a smartphone

Time Frame

EMA is used at fixed time points monthly. Participants are asked to answer the EMA items 5 times daily at semi-randomised time points, for 3 days. Diurnal profiles are generated and one diurnal profile summarizes responses during the day across all days.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility Criteria

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. 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. Note: 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Ulla Feldt-Rasmussen, Professor

Phone

+4523829869

ufeldt@rh.dk

First Name & Middle Initial & Last Name or Official Title & Degree

Stina W. Borresen, MD, PhD

Phone

+4525347551

stina.borresen@regionh.dk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ulla Feldt-Rasmussen, Professor

Organizational Affiliation

Rigshospitalet, Denmark

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Endocrinology, Aarhus University Hospital

City

Aarhus

Country

Denmark

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jens Otto L. Jørgensen, Professor

Facility Name

Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet

City

Copenhagen

ZIP/Postal Code

2100

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Ulla Feldt-Rasmussen, Professor

ufeldt@rh.dk

First Name & Middle Initial & Last Name & Degree

Stina W. Borresen, MD, PhD

First Name & Middle Initial & Last Name & Degree

Ulla Feldt-Rasmussen, Professor

Facility Name

Department of Endocrinology, Odense University Hospital

City

Odense

Country

Denmark

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Marianne S. Andersen, professor

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Effect of Supplemental Hydrocortisone During Stress in Prednisolone-induced Adrenal Insufficiency

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