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Glucocorticoid withdrawal and glucocorticoid-induced adrenal insufficiency: a randomized controlled multicenter trial.

English title Glucocorticoid withdrawal and glucocorticoid-induced adrenal insufficiency: a randomized controlled multicenter trial.
Applicant Rutishauser Jonas
Number 163133
Funding scheme Project funding
Research institution Medizinische Universitätsklinik Kantonsspital Bruderholz Universität Basel
Institution of higher education University of Basel - BS
Main discipline Clinical Endocrinology
Start/End 01.06.2017 - 31.05.2022
Approved amount 525'000.00
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Keywords (5)

Adrenal; Hypocortisolism; Glucocorticoid; Steroid; Withdrawal

Lay Summary (German)

Lead
TOASST* - Studie: Cortisolbehandlung ausschleichen oder direkt stoppen? (*“Taper Or Abrupt Steroid STop“)Cortisol ist ein Hormon aus den Nebennieren, das wichtige Stoffwechselfunktionen steuert. Cortisol-verwandte Medikamente, wie Prednison, werden zur Entzündungshemmung bei vielen Krankheiten eingesetzt, z.B. bei Rheuma oder Darmentzündungen. Diese Medikamente haben zahlreichen Nebenwirkungen, weshalb man versucht, die Behandlung so kurz als möglich zu halten. Üblicherweise wird bei gutem Ansprechen die Therapie in kleinen Schritten ausgeschlichen, aber ob dies nötig ist und wie die Dosisreduktion erfolgen soll, wurde bisher nie untersucht.
Lay summary

Ziel des Forschungsprojektes

Unsere Studie prüft  die Hypothese, dass auch nach längerer Behandlungsdauer mit Prednison das Medikament abrupt gestoppt werden darf, ohne dass dadurch ein schlechterer Verlauf resultiert. Die Teilnehmenden werden durch das Zufallsprinzip in 2 Gruppen eingeteilt. Die Prednisonbehandlung wird bei der einen Gruppe über vier Wochen ausgeschlichen und bei der anderen durch eingleich aussehendes Schein-Präparat (Placebo) ersetzt. Zur Beurteilung des Verlaufs wird während 6 Monaten in beiden Gruppen die Zeit verglichen, die verstreicht bis zum erstmaligen Auftreten eines oder mehrerer der folgenden Ereignisse: Hospitalisation, Anzeichen eines Cortisolmangels, Tod, oder ungeplante Wiederbehandlung mit Prednison oder einem anderen Cortisol-ähnlichen Medikament. Es soll zudem untersucht werden, ob der in der Routine oft angewandte Synacthentest geeignet ist, das Auftreten dieser Ereginisse vorherzusagen.

 

Wissenschaftlicher Kontext

TOASST ist die erste Studie überhaupt, in der das Absetzen von Prednison mit einem Ausschleich-Schema direkt verglichen wird. Bestätigt sich die Studienhypothese, kann künftig auf die unnötige Verlängerung von Prednisonbehandlungen verzichtet werden, was angesichts des ungünstigen Nebenwirkungsprofils wünschbar wäre. Falls sich zeigt, dass das abrupte Stoppen doch Nachteile hat gegenüber dem Ausschleichen, gäbe es auch für letzteres Vorgehen erstmals eine wissenschaftlich fundierte Grundlage.

Direct link to Lay Summary Last update: 12.02.2016

Responsible applicant and co-applicants

Employees

Collaboration

Group / person Country
Types of collaboration
Dr. Irina Chifu, Prof. Martin Fassnacht, Dept. Medizin, Univ.spital Würzburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. M. Brändle, Department of Medicine, Kantonsspital St. Gallen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Dr. Jörg Bojunga, PD Dr. med Gesine Meyer, Endokrinologie, Diabetologie, Univ.klinik Frankfurt Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Daniel Aeberli, Dept. Rheumatologie und Immunologie; Inselspital bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Dr. Robert Thurnheer, Medizinische Klinik, Kantonsspital Münsterlingen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. P. Villiger, Department of Rheumatology, Immunology, and Allergology, University Hospital Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Dr. Gottfried Rudofsky, Abteilung Endokrinologie/Diabetologie; Kantonsspital Olten Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. C. Pauli-Magnus, Dept. of Clinical Research/Clinical Trial Unit, University Hospita Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Philipp Schütz, University Clinic of Medicine, Aarau. Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
PD Dr. Stephan Böhm, Medizinische Klinik, Spital Bülach Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. M. Y. Donath, Clinic of Endocrinology, University Hospital Basel, Switzerland Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
PD Dr. Andreas Kistler, medizinische Klinik, Kantonsspital Frauenfeld Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. J.D. Leuppi, University Clinic of Internal Medicine, Kantonsspital Baselland, Liestal Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Jean-Luc Reny, Department of Medicine, University Hospital Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. A. Zeller, Institute of Primary Care, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Felix Beuschlein, Klinik für Endokrinologie und Diabetologie, Universitätsstpial Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. C. Henzen, Department of Medicine, Lucerne Hospital Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SGAIM Herbsttagung 2021 Talk given at a conference Glucocorticoid Treatment 17.09.2021 Interlaken, Switzerland Rutishauser Jonas;
SGAIM Frühjahrstagung 2021 Talk given at a conference Beyond Guidelines – Steroid therapy: How do we terminate it? 21.05.2021 Basel, Switzerland Rutishauser Jonas;
Seminar, Department of Endocrinology, Severance Hospital, Yonsei University, Seoul Korea Individual talk How should we terminate prolonged systemic glucocorticoid treatment? Review of data and presentation of the “TOASST” trial (Taper Or Abrupt Steroid Stop) NCT03153527 26.11.2019 Seoul, Korean Republic (South Korea) Rutishauser Jonas;
Weiterbildung Pharmazeutisches Institut Basel Individual talk Systemische Glucocortidoidtherapie: Wie und wann ausschleichen? 30.10.2019 Basel, Switzerland Rutishauser Jonas;
CHUV Grand Rounds Individual talk How should we terminate prolonged systemic glucocorticoid treatment? Review of data and presentation of the “TOASST” trial (Taper Or Abrupt Steroid Stop) NCT03153527 09.10.2019 Lausane, Switzerland Rutishauser Jonas;
Weiterbildung Medizinische Klinik, Wetzikon Individual talk Wie beende ich eine längerdauernde Glucocorticoidtherapie? “TOASST” Trial 26.09.2019 Wetzikon, Switzerland Rutishauser Jonas;
Tagung Kollegium für Hausaztmedizin Talk given at a conference Steroide: Wie lange geben? Wie stoppen? 28.06.2019 Luzern, Switzerland Rutishauser Jonas;
Weiterbildung Rheumatologie, Bethesdaspital Basel Individual talk Wie beende ich eine längerdauernde Glucocorticoidtherapie? 24.01.2019 Basel, Switzerland Rutishauser Jonas;
Weiterbildung Medizinische Universitätsklinik, Kantonsspital Baselland-Bruderholz Individual talk Glucocorticoide in der Praxis 19.06.2018 Bruderholz, Switzerland Rutishauser Jonas;
Endkorinologie Symposium Kantonsspital St. Gallen Talk given at a conference Glucocorticoide – Absetzen oder ausschleichen? 14.06.2018 St. Gallen, Switzerland Rutishauser Jonas;
Rheumatologie-Fortbildung, Inselspital Bern Talk given at a conference Ausschleichen der Steroidmedikation? Der Blickwinkel des Endokrinologen 01.06.2018 Bern, Switzerland Rutishauser Jonas;
Hausarztfortbildung UniHam bB Individual talk Steroide in der Hausarztpraxis 30.01.2018 Liestal, Switzerland Rutishauser Jonas;
Weiterbildung Departement Medizin, Kantonsspital Baden Individual talk Glucocorticoidtherapie und NNR-Insuffizienz 24.01.2018 Baden, Switzerland Rutishauser Jonas;
Hausarztfortbildung UniHam bB Individual talk Steroide in der Hausarztpraxis 23.01.2018 Basel, Switzerland Rutishauser Jonas;
Konferenz der Vertreter der Schweizerischen IBD-Kohorte; Inselspital Bern Individual talk How to stop Glucocorticoids: The “TOASST” trial (Taper Or Abrupt Steroid Stop) NCT03153527 07.12.2017 Bern, Switzerland Rutishauser Jonas;
Seminar Endokrinologie, Universitätsspital Basel Individual talk How to stop Glucocorticoids: The “TOASST” trial (Taper Or Abrupt Steroid Stop) NCT03153527 18.10.2017 Basel, Switzerland Rutishauser Jonas;


Abstract

Background:Systemic glucocorticoids are widely used to treat inflammatory, autoimmune, or malignant disorders and to prevent transplant rejection. They suppress the hypothalamic-pituitary-adrenal (HPA) axis by feedback inhibition at the hypothalamic and pituitary levels. However, the duration of treatment and/or cumulative glucocorticoid dose are unreliable measures to estimate functional adrenal capacity. It is impossible to predict whether endogenous cortisol production will suffice for situations of stress in an individual patient after treatment with pharmacological glucocorticoid doses. Dynamic tests are therefore used to assess adrenal function. In clinical practice, performance in the 250 µg ACTH stimulation test is often used to decide whether a patient will need glucocorticoid cover under stressful circumstances, and whether the therapeutic agent should be tapered or can be stopped abruptly. Potential dangers of glucocorticoid deficiency include relapse of the underlying disease, more or less subtle signs and symptoms of adrenal failure, or overt adrenal crisis. Reports unequivocally linking poor clinical outcome to glucocorticoid-induced hypocortisolism are exceedingly rare, and available data that correlate biochemical test results with clinical outcome suggest that the risk of secondary adrenal failure is overestimated. We did not find any evidence from randomized controlled trials on any particular disorder elucidating i) at which daily dose glucocorticoid tapering should be initiated, if at all; ii) the superiority of one particular tapering scheme over another; or iii) the value of any particular adrenal function test in guiding further treatment or in predicting clinical outcome. Our own data from the “REDUCE” trial (JAMA 2013; 309:2223-21) in patients with acute exacerbations of COPD show that none of the patients with biochemically suppressed adrenals suffered an adrenal crisis during 6 months of follow-up. Patients with normal and failed ACTH stimulation test could not be differentiated clinically.Hypothesis:Based on these findings, we hypothesize that in patients treated with systemic glucocorticoids for various disorders, rapid termination of treatment will not result in a worse clinical outcome than a tapering regime over four weeks.Objective:To evaluate feasibility and safety of rapid termination of steroid therapy irrespective of biochemical status of the HPA axis.Study design and methods:This is a randomized, placebo-controlled, multicenter noninferiority trial, comparing rapid termination of systemic glucocorticoid treatment with a tapering regime over 4 weeks. Patients must have been treated with = 420 mg prednisone-equivalent cumulatively over = 28 days (average daily dose of = 15 mg prednisone-equivalent) to be eligible. The power of the 250 µg ACTH test to predict clinical outcome will be analyzed. Participants will be instructed about symptoms of hypocortisolism and provided with an emergency prednisone dose. Primary outcome will be time to first occurrence of hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis, over a follow-up period of 6 months. To achieve a power of 80%, assuming an event rate of 40% and a drop-out rate of 15%, with an absolute increase in event rates set to 13% as tolerable noninferiority margin, 573 patients will have to be included.Relevance:This will be the first randomized controlled trial to evaluate the feasibility and safety of rapid glucocorticoid withdrawal in comparison with a tapering regime.
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