Taper Or Abrupt Steroid Stop: TOASSTtrial

Study Overview
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Brief Summary
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This study is an Investigator-initiated, placebo-controlled, multicenter noninferiority trial, comparing rapid termination of systemic glucocorticoid treatment with a tapering regime over 4 weeks.

Detailed Description
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In total, 573 patients will be enrolled. Patients will be randomly assigned in a 1:1 ratio to either prednisone in decreasing doses over 4 weeks or placebo. Patients, treating physicians, and study personnel will be blinded to treatment allocation to either prednisone or matching placebo. At inclusion, we will perform a 250 micrograms Synacthen® stimulation test. The results of the test will be blinded to treating physicians and investigators, and its value to predict clinical outcome will only be assessed after completion of the trial. As a safety measure, all patients will be instructed about stress coverage as well as signs and symptoms of hypocortisolism and will be provided with emergency medication. Patients will be randomized to the standard (tapering) or the experimental (matching placebo) arm. Follow-up will be for six months. In order to improve adherence to the study and ensure feasibility, follow-up visits in most study centers will be by telephone only. Visits will be performed early after stopping glucocorticoids in both arms (i.e. at days 7 and 35) to ensure safety; the other two visits will be on days 90 and 180. Amendment approved in 1-2018: former exclusion criterion 'status post organ transplantation' was revised and deleted

Official Title
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Glucocorticoid Withdrawal and Glucocorticoid-induced Adrenal Insufficiency: a Randomized Controlled Multicenter Trial

Conditions
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Inflammatory Disorder, Autoimmune

Intervention / Treatment
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* Drug: Prednisone
* Other: Placebo Arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed Consent as documented by signature (Appendix Informed Consent Form) Age ≥ 18 years Daily glucocorticoid dose ≥ 7.5 mg prednisone-equivalent at the time of inclusion Therapy over ≥ 28 days, ≥ 7.5 mg average daily dose, with a cumulative glucocorticoid dose ≥ 420 mg prednisone-equivalent prior to inclusion Tapering not or no longer mandatory to treat underlying disease Exclusion Criteria: Primary adrenal failure Treatment with systemic depot glucocorticoids (e.g. intramuscular, epidural) Incapability to administer glucocorticoid cover treatment in situations of stress Inability or unwillingness to provide informed consent Women who are pregnant or breast feeding, Intention to become pregnant during the course of the study, Lack of safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases. Known or suspected non-compliance Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant, Participation in another study with investigational drug within the 30 days preceding and during the present study, Previous enrolment into the current study, Enrolment of the investigator, his/her family members, employees and other dependent persons

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Standard treatment arm: Prednisone, a synthetic glucocorticoid with intermediate duration of action (biological half-life 18-35 hrs). The detailed characteristics of the compound, marketed under several brand names, can be found at www.swissmedicinfo.ch: Prednison Streuli (Swissmedic registration number: 29349); Prednison Axapharm (Swissmedic registration number: 58761); Prednison Galepharm (Swissmedic registration number: 50821). Interventional treatment arm: matching placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo arm (intervention arm)<br>Stop glucocorticoid treatment; administer placebo matching the verum preparation in weekly intervals. | Other: Placebo Arm<br>* The experimental intervention consists of stopping glucocorticoid treatment abruptly and administering matching placebo over 4 weeks.<br>|
| Active Comparator: Verum group (control/standard arm)<br>If patient is on > 7.5 mg prednisone-equivalent daily: administer 7.5 mg q.d. for 7 days, then 5 mg q.d. for 7 days, then 2.5 mg q.d. for 7 days, then 2.5 mg q.d. every second day, then stop. If patient on 7.5 mg q.d.: maintain for 7 days, then taper as above. | Drug: Prednisone<br>* The control intervention (standard treatment) consists of prednisone treatment in decreasing doses, starting with 7.5 mg q.d. and reducing the dose every 7 days, such that prednisone treatment is stopped after a total of 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to any incidence | Time to first occurrence of hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis (defined as glucocorticoid-responsive hypotension or shock with or without accompanying symptoms and signs such as weakness, apathy, nausea, vomiting, abdominal pain, hypothermia, hyponatremia [serum sodium < 135 millimole (mM)], hyperkalemia [serum potassium > 5 mM], hypoglycemia [plasma glucose < 3.5 mM]); whichever occurs first. | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to specific incidence | Time to first occurrence of individual components of the primary outcome; | up to 6 months | 
| Cumulative overall systemic glucocorticoid dose | Cumulative overall systemic glucocorticoid dose | up to 6 months | 
| Cumulative systemic glucocorticoid dose administered to treat or prevent adrenal failure | Cumulative systemic glucocorticoid dose administered to treat or prevent adrenal failure | up to 6 months | 
| Cumulative systemic glucocorticoid dose administered to treat relapse | Cumulative systemic glucocorticoid dose administered to treat relapse of disease, specified for each disease | up to 6 months | 
| General health status | General health status as self-assessed by the participant on a visual analog scale (VAS) from 0 to 100 | assessed at days 1, 7, 28, 35, 90,180 | 
| Score of symptoms and signs of hypocortisolism | Score of symptoms and signs of hypocortisolism: weakness, hypothermia, nausea, vomiting, abdominal pain, fatigue, dizziness, Blood pressure, serum Na and serum glucose concentrations. | up to 6 months | 
| Performance in 250 mcg Synacthen® test | Performance in 250 mcg Synacthen® test: test assessed day 1 in all participants, plus days 7 and 35 in those followed in centers Bruderholz, Luzern, Aarau | up to 6 months | 
| In patients hospitalized at study entry: length of hospital stay | In patients hospitalized at study entry: length of hospital stay | up to 6 months |