Tapering or stopping cortisol treatment directly? The TOASST study.

Summary description of the study

The prerequisite for participation in the study is a treatment duration of at least 4 weeks. If your treating physician wants to discontinue prednisone therapy and you are still taking at least a daily dose of 7.5 mg (a corresponding dose of another preparation is also possible), you may be included. First, the body's cortisol production is measured using the so-called "Synacthen test". This involves a blood draw before and after the administration of a stimulating hormone to measure the cortisol concentration in the blood. The result remains confidential until the end of the study, even for the study physicians. You will then be randomly assigned to one of two treatment groups: one group receives prednisone, which is tapered over 4 weeks, while the other receives a placebo without active ingredient, resulting in an abrupt cessation of prednisone. Neither you nor the study physician nor any other doctor knows which group you have been assigned to. After 1, 5, 12, and 26 weeks, you will be contacted by phone and systematically asked about your disease progression, well-being, and any potential resumption of prednisone. If you live near Basel, Lucerne, or Aarau, we will also ask you to come to the hospital at these times for a physical examination and blood draw (including "Synacthen test"). After the study is completed, we will analyze whether the disease progression and the need for unforeseen prednisone treatment differ between the two groups.

(BASEC)

Intervention under investigation

Cortisol is a hormone produced by the adrenal glands that regulates important metabolic functions and helps maintain adequate blood pressure and blood sugar levels in stressful situations. Prednisone and other synthetically produced cortisol-like medications are administered in tablet form or as injections to reduce inflammation in a variety of diseases. Examples include rheumatic diseases, inflammatory bowel diseases, certain diseases of the hematopoietic system, neurological diseases, or tumor diseases. Prednisone has many undesirable drug effects, such as weight gain, weakening of bone and connective tissue, increased blood pressure, or elevated blood sugar levels up to diabetes. A commonly observed side effect of prednisone is the suppression of the body's own cortisol production. This effect lasts beyond the cessation of prednisone therapy. However, it is impossible to predict on a case-by-case basis whether such suppression of adrenal function will occur or not and how long it may last. Therefore, in clinical medicine, a laboratory test is often performed before the planned cessation of prednisone therapy to answer this question. In this so-called Synacthen test, a second hormone, Synacthen, is injected, which stimulates the adrenal glands to produce and release cortisol into the bloodstream, and the cortisol level in the blood is measured 30 and 60 minutes after the injection. If the measured cortisol levels are low, prednisone is not abruptly stopped, but the dose is reduced in small steps before it is finally stopped after weeks. Although this approach is medically reasonable, it has not yet been scientifically proven. It has not been studied at what dose, in what steps, and over what duration the prednisone medication should be tapered. It is not even clear whether tapering is necessary, even if low cortisol levels are measured in the Synacthen test. In a separate investigation with over 200 patients treated with prednisone, we observed no adverse consequences even with insufficient results in the Synacthen test and despite abrupt cessation of therapy, and targeted questioning about symptoms of cortisol deficiency showed no difference compared to individuals with normal test results. It is therefore reasonable to assume that in many cases where prednisone is tapered, an unnecessary prolongation of treatment occurs, which increases the risk of side effects. This study aims to test the hypothesis that even after a longer treatment duration with prednisone (at least over 4 weeks with a total of at least 420 milligrams), the medication can be stopped abruptly without resulting in a worse outcome. The observation period is 6 months after study inclusion. To achieve sufficient statistical power, 573 patients are needed for the investigation, half of whom will have their prednisone treatment tapered over four weeks and the other half will have it stopped abruptly. Participants in the latter group will receive placebo preparations identical to prednisone. Group allocation is determined by chance, and neither participants nor the investigator know the group assignment (double-blind principle). To assess the course, the time until the first occurrence of one or more of the following events will be compared in both groups: hospitalization, signs of cortisol deficiency, death, or unplanned re-treatment with prednisone or another cortisol-like medication (for example, due to a relapse of the originally treated disease with prednisone). It will also be investigated whether the Synacthen test is suitable for predicting the occurrence of these events. All participants will be provided with prednisone tablets as a precaution; these should be taken in situations of increased cortisol demand, such as during febrile illnesses (so-called stress prophylaxis). This is the first study ever to directly compare the cessation of prednisone with a tapering scheme. If the study hypothesis is confirmed, unnecessary prolongation of prednisone treatments may be avoided in the future, which would be desirable given the unfavorable side effect profile. If it turns out that abrupt cessation does have disadvantages compared to tapering, there would also be a scientifically grounded basis for the latter approach.

(BASEC)

Disease under investigation

Patients can participate in the study who, due to an inflammatory disease, have been treated for at least 4 weeks with a synthetic cortisol preparation (usually prednisone or prednisolone) and for whom the treating physician wishes to discontinue this treatment. Examples of such diseases include: various forms of rheumatism (e.g., rheumatoid arthritis, giant cell arteritis, polymyalgia), inflammatory bowel diseases (e.g., Crohn's disease or ulcerative colitis), diseases of the hematopoietic system (e.g., autoimmune hemolytic anemia), pneumonia (e.g., cryptogenic organizing pneumonia), or tumor diseases (e.g., lymphomas).

(BASEC)

Sponsor

Kantonsspital Baden AG

(BASEC)

Name of the authorising ethics committee (for multicentre studies, only the lead committee)

Ethics Committee northwest/central Switzerland EKNZ

(BASEC)

Date of authorisation

13.07.2016

(BASEC)

Results of the trial