Autoimmune, Inflammatory Disorder
Conditions
Brief summary
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
DRUGPrednisone
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.
OTHERPlacebo Arm
The experimental intervention consists of stopping glucocorticoid treatment abruptly and administering matching placebo over 4 weeks.
Sponsors
University Hospital, Basel, Switzerland
Kantonsspital Baselland Bruderholz
Swiss National Science Foundation
HEMMI Stiftung Switzerland
Gebauer Stiftung Zurich
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Blinding of trial participants, treating physicians, study doctors, study nurses, outcome assessors and data analysts will be ensured by using identical-looking placebo, packaged in identical vials as the prednisone verum. Vials will be labeled with "Prednisone or Placebo" in an identical fashion.
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to any incidence | up to 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to specific incidence | up to 6 months | Time to first occurrence of individual components of the primary outcome; |
| Cumulative overall systemic glucocorticoid dose | up to 6 months | Cumulative overall systemic glucocorticoid dose |
| Cumulative systemic glucocorticoid dose administered to treat or prevent adrenal failure | up to 6 months | Cumulative systemic glucocorticoid dose administered to treat or prevent adrenal failure |
| Cumulative systemic glucocorticoid dose administered to treat relapse | up to 6 months | Cumulative systemic glucocorticoid dose administered to treat relapse of disease, specified for each disease |
| General health status | assessed at days 1, 7, 28, 35, 90,180 | General health status as self-assessed by the participant on a visual analog scale (VAS) from 0 to 100 |
| Score of symptoms and signs of hypocortisolism | up to 6 months | Score of symptoms and signs of hypocortisolism: weakness, hypothermia, nausea, vomiting, abdominal pain, fatigue, dizziness, Blood pressure, serum Na and serum glucose concentrations. |
| Performance in 250 mcg Synacthen® test | up to 6 months | 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 |
| In patients hospitalized at study entry: length of hospital stay | up to 6 months | In patients hospitalized at study entry: length of hospital stay |
Countries
Germany, Switzerland
Contacts
CONTACTJonas Rutishauser, Prof MD
PRINCIPAL_INVESTIGATORJonas Rutishauser, Prof MD
Departement Medizin, Kantonsspital Baden
Outcome results
None listed