Studies on the relationship between corticosteroids and unfavorable medical effects. A study based on the BLISS-52 and BLISS-76 clinical trials.

Proposal
1084

Title of Proposed Research

Lead Researcher

Ronald van Vollenhoven, MD, PhD

Affiliation

Karolinska InstituteDepartment of MedicineStockholm, Sweden

Funding Source

This project will require personnel resources that are funded the by the Karolinska Institute.

Potential Conflicts of Interest

None

Data Sharing Agreement Date

20 February 2015

Lay Summary

Corticosteroids are widely used medications for the treatment of systemic lupus erythematosus. They have rapid and strong favorable effects in controlling the disease manifestations but very significant side-effect and long-term adverse consequences especially when used at high dosages for prolonged periods of time. Many of these side-effects are known but the exact relationship between the exposures, i.e., how long the patient has been taking which dosages and the specific side-effects have not been characterized very well. In order to weigh the benefits of other therapies against the use of corticosteroids it would be very beneficial to have a better understanding of the exact relationship between corticosteroids and their side-effects.

This proposal is not only relevant for the specific disease under study. Corticosteroids are used very widely in many areas of medicine and the total numbers of patients affected by the negative consequences of corticosteroid treatment are innumerable. Thus, the results of this study may have bearing on many areas in medicine.

Here, we are proposing to use data from two large clinical trials in SLE to study the relationship between corticosteroid exposure and a range of negative consequences of this. The results will be directly applicable to patients with SLE which is a not uncommon disease of the immune system where autoimmune reactions cause inflammation in many different organs and organ systems. However the results will also be applicable to other patient categories who are treated with corticosteroids.

Aims and objectives of the research: We aim to obtain a better understanding of the exact relationship between exposure to corticosteroids and possible negative consequences.

How the research will be conducted: We will be using data from the BLISS- 52 and BLISS-76 clinical trials which were done in patients with moderately active systemic lupus erythematosus. We will tally those adverse events that were reported in these trials where a causal relationship with corticosteroids can be suspected. We will then correlate this with the dosages of corticosteroids that the patients where on prior to the trial and during the trial and obtain information about the relationship between duration, dosages, and cumulative exposure. In the end we expect to achieve an improvement in our ability to inform patients about the benefits versus risks of treatment with corticosterioids which indirectly will also inform about the benefits and risk of treatment with other medications. However, note that this research project will not address the specific risk-benefit relationships in the treatment of SLE with other medicines.

Study Data Provided

[{ "PostingID": 1416, "Title": "GSK-HGS1006-C1056", "Description": "A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 76-Week Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006, LymphoStat-B™), a Fully Human Monoclonal Anti-BLyS Antibody, in Subjects with Systemic Lupus Erythematosus (SLE)" },{ "PostingID": 1417, "Title": "GSK-HGS1006-C1057", "Description": "A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 52-Wk Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006, LymphoStat-B™), a Fully Human Monoclonal Anti-BLyS Antibody, in Subjects With Systemic Lupus Erythematosus (SLE)" }]

Statistical Analysis Plan

The statistical analysis plan for this study is quite straight forward but may be difficult to understand because so many different variables will in fact be studied. We therefore first propose to use an example to illustrate. The expert opinion will most likely identify cataracts as an adverse event that can reasonably be attributed to exposure to corticosteroids. So for this particular outcome of interest the data will be analyzed as follows:A logistic regression model will be created where the total duration of corticosteroid exposure, the cumulative exposure of corticosteroids, the maximum dosage of corticosteroids, and the current dosage (i.e. the dose at the time the adverse event is recorded) will be used as independent variables. The occurrence of the adverse event of interest will be the dependent variable and range of covariates will be introduced in the model as outlined above. This regression model will then hopefully result in the identification of a number of independent variables that determine the risk of the adverse event under investigation. We may then arrive at a conclusion that could be formulated as follows (as a completely hypothetical example): “the cumulative exposure to corticosteroids contributes 70% of the risk of the adverse event of cataract occurring at any point over the duration of the study, and each increase in the cumulative corticosteroid exposure by 1 gram is associated with a 3.5% increase of this risk.” This risk estimate will of course be associated with a confidence interval. It will then also be possible to identify that a number of other characteristic for example age or gender do modify this risk and it can be specified for example by age decades or by gender what the exact risk would be. This is a illustration, the same procedure will be applied to all adverse events that can be reasonably expected to be associated with corticosteroid exposure. For control purposes a number adverse events that are believed to be not associated with cumulative corticosteroid exposure at all, for example the common cold, will also be analyzed and these results will be used to provide the contacts for the first set of data. Finally a number of adverse events will have been identified where an association with corticosteroids is possible and this will also be analyzed and the results used to further define the relationship between such adverse events and the corticosteroid exposure.

Publication Citation

"Relationship between glucocorticoid dose and adverse events in systemic lupus erythematosus: data from a randomized clinical trial."
DOI:10.1080/03009742.2017.1336570

https://www.tandfonline.com/doi/abs/10.1080/03009742.2017.1336570