Taper Or Abrupt Steroid Stop: TOASSTtrial

Official title

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

Overview

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

In total, 530 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

Interventions

• Drug Prednisone
  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.
• Other Placebo Arm
  The experimental intervention consists of stopping glucocorticoid treatment abruptly and administering matching placebo over 4 weeks.

Primary outcome measures

• Time to any incidence [Time frame: up to 6 months]

Secondary outcome measures (8)

• Time to specific incidence [Time frame: up to 6 months]
• Cumulative overall systemic glucocorticoid dose [Time frame: up to 6 months]
• Cumulative systemic glucocorticoid dose administered to treat or prevent adrenal failure [Time frame: up to 6 months]
• Cumulative systemic glucocorticoid dose administered to treat relapse [Time frame: up to 6 months]
• General health status [Time frame: assessed at days 1, 7, 28, 35, 90,180]
• Score of symptoms and signs of hypocortisolism [Time frame: up to 6 months]
• Performance in 250 mcg Synacthen® test [Time frame: up to 6 months]
• In patients hospitalized at study entry: length of hospital stay [Time frame: up to 6 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Switzerland · 14 centers

• Departement of Internal Medicine, Kantonsspital Aarau — Aarau
• Kantonsspital Baden — Baden
• Endocrinology/Diabetology/Metabolism; University Hospital Basel — Basel
• St. Claraspital Basel — Basel
• Department of Rheumatology, Immunology, and Allergology, Inselspital — Bern
• Division of Gastroenterology, Spital Bülach AG — Bülach
• Kantonsspital Frauenfeld — Frauenfeld
• Geneva University Hospitals — Geneva
• … and 6 more centers

Germany · 2 centers

• University Hospital Frankfurt — Frankfurt
• University Hospital Würzburg — Würzburg

Publications

• Komminoth M, Donath MY, Hepprich M, Schuetz P, Blum CA, Mueller B, Reny JL, Gosselin P, Breville G, Brandle M, Henzen C, Leuppi JD, Kistler AD, Thurnheer R, Beuschlein F, Rudofsky G, Aeberli D, Villiger PM, Bohm S, Chifu I, Fassnacht M, Meyer G, Bojunga J, Cattaneo M, Sluka C, Schneider H, Rutishauser J; <<TOASST>> study group. Glucocorticoid withdrawal and glucocorticoid-induced adrenal insuffici PMID 37018188

Identifiers

NCT: NCT03153527 · 2016-00487; ex14Rutishauser · 2024-517334-18-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗