Hydrocortisone and Placebo in Patients With Symptoms of Adrenal Insufficiency After Cessation of Glucocorticoid Treatment

ConditionsAdrenal Insufficiency Polymyalgia Rheumatica (PMR)Giant Cell Arteritis (GCA)

Trial statusRecruiting

Trial phasePhase 4

Trial typeInterventional

Biological sexAll

Age50+

SponsorMarianne Andersen

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

Disqualifiers

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

Trial design

Design model

Parallel

Treatments tested in this trial

Hydrocortisone
Drug
Patients are randomized to oral hydrocortisone (10 mg twice daily) or placebo for 16 weeks.
Placebo
Drug
Patients are randomized to oral hydrocortisone (10 mg twice daily) or placebo for 16 weeks.

Treatment groups

100 Participants

are divided into 4 treatment groups

Group A: RCT group - PlaceboPlacebo comparator 1 intervention

Group B: RCT group - HydrocortisoneActive comparator 1 intervention

Group C: Comparator group 1No intervention 0 interventions

Group D: Comparator group 2No intervention 0 interventions

Trial outcomes

Primary outcomes

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).

Time frame

Screening and 16 weeks

Secondary outcomes

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).

Time frame

Patients are asked daily throughout the study period.

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).

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.

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).

Time frame

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.

Time frame

Baseline and 16 weeks

Other outcomes

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.

Time frame

Baseline and 16 weeks

Blood samples (unit: fmol)

Standardised fasting morning blood samples will be drawn after the patient has been resting in a sitting position for 15 minutes. MCH.

Time frame

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.

Time frame

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.

Time frame

Baseline and 16 weeks