Comparison of various remission criteria for SLE. A study based on the BLISS-52 and BLISS-76 clinical trials.

Proposal
1430

Title of Proposed Research

Lead Researcher

Ronald van Vollenhoven

Affiliation

Department of Medicine, Solna

Funding Source

Unrestricted grant for treat to target remission definitions.

Potential Conflicts of Interest

None

Data Sharing Agreement Date

19 Aug 2016

Lay Summary

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that can affect almost any organ and can cause many different symptoms. In the last decades the treatments have gotten better but people who have SLE are still at considerable risk to develop complications and may even die earlier because of the disease. The disease makes the patients feel tired and listless (malaise) and may cause damage to the internal organs in some cases. The patients often need to be treated with medications such as steroids and drugs that fight the immune system, which may cause additional problems. International experts agree that the goals of the treatment for SLE must be to have the disease be completely under control, which is called “remission”. Even if the patient is not completely cured that would still be a very good result.
However, this concept of “remission” needs a clear definition so that people know exactly what is meant when they use the term: we need a definition of remission. For this reason, we gathered an international task force with patients and specialists to achieve agreement on a definition of remission in SLE, called DORIS—Definition Of Remission In SLE. This task force agreed that remission in SLE can be described as a desirable disease state for patients with, at the very least, the absence of major symptoms and signs of SLE, and has proposed several definitions of remission in SLE.
In this study, we would like to use data from two previously done studies, called BLISS-52 and BLISS-76, and examine how the definitions of remissions that were proposed by the DORIS task force work out. We will calculate how many patients fulfill these definitions at how many time points; how stable this is in the individual patient; how it relates to other aspects of the disease; and we will see if patients who have a remission using the DORIS-definitions, have less problems with their SLE disease such as flare-ups of the disease, damage the internal organs, and a better quality of life.

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

During Step 1, descriptive statistical analysis will be used to report the mean (±SD) proportion of patients who fulfill the DORIS-remission definitions at any given time point (Point prevalence), the proportion of patients who ever achieve the DORIS-remission definitions (Cumulative incidence), and the proportion of patients who fulfill the DORIS-remission definitions at least once during the study for at least the following time interval: 4 weeks, 8 weeks, 12 weeks, and 24 weeks (durability of remission). Then a logistic regression model will be created where the DORIS-remission definitions will be considered the dichotomous dependent variables, and both the characteristics of patients (age, gender, ethnicity, disease duration, smoking status, SLE organ involvement, comorbidities), as well the SLE-related parameters at the time of remission for patients (SLEDAI, BILAG, , physician global, anti-DNA, hypocomplementemia, patient global activity, HR-QOL, ESR, CRP, and other laboratory parameters of interest) will be used as independent variables.During Step 2, the occurrence of flare and of death will be compared for for 52 weeks in the BLISS-52 trial and 76 weeks for BLISS-76 trial following the DORIS-remission definition's fulfillment using life-table analysis (Kaplan-Meyer curves), using the most appropriate flare definition given the constraints of the particular data set. Damage and HR-QOL measures will also be compared for 52 weeks in the BLISS-52 trial and 76 weeks for BLISS-76 trial following the DORIS-remission definition's fulfillment using the SLICC-damage index and appropriate QoL instruments given the constraints of the particular data set.During Step 1, we will study the following metric properties of the DORIS-remission definitions:•Point prevalence: proportion of patients who fullfill each of the DORIS-remission definitions at each follow-up visit (every four weeks).•Cumulative incidence: proportion of patients who ever achieve the DORIS-remission definitions at each follow-up visit (every four weeks).•Durability: the proportions of patients who fullfill the DORIS-remission definitions at least once during the study for at least the following time interval: 4 weeks, 8 weeks, 12 weeks, and 24 weeks.We will also describe the characteristics of patients who fullfill the DORIS-remission definitions, as compared to the overall study population: age, gender, ethnicity, disease duration, smoking status, SLE organ involvement, comorbidities; as well as compare the SLE-related parameters at the time of remission for patients who are versus those who are not in remission: SLEDAI, BILAG, , physician global, anti-DNA, hypocomplementemia, patient global activity, HR-QOL, ESR, CRP, and other laboratory parameters of interest.During Step 2, the DORIS-definitions of remission will be tested for the following predictive properties (testing will be done for each definition and for the different durabilities as defined above, and for each of the outcomes as given below, if available):•Flares: to be compared for 52 weeks in the BLISS-52 trial and 76 weeks for BLISS-76 trial following the DORIS-remission definition's fulfillment using life-table analysis (Kaplan-Meyer curves) and using Selena Flare Index given the constraints of the particular data set.•Damage: to be compared for 52 weeks in the BLISS-52 trial and 76 weeks for BLISS-76 trial following the DORIS-remission definition's fulfillment using the SLICC-damage index as a nominal variable.•Death: to be compared at any time point following the DORIS-remission definition's fulfillment using life-table analysis (Kaplan-Meyer curves).•HR-QOL measures: to be compared for 52 weeks in the BLISS-52 trial and 76 weeks for BLISS-76 trial following the DORIS-remission definition's fulfillment using SF36, FACIT and EQ-5D data given the constraints of the particular data set. Covariates that will be included in the models will include demographic (age, gender, ethnicity, etc.), clinical disease characteristics (disease characteristics, disease duration, prior therapies other than corticosteroids, organ systems involved, others) and treatments. The outcome of interest or the dependent variables will be the DORIS-remission applied to the BLISS-52 and BLISS-76 clinical trial datasets. List of variables to be included in data extraction:For baseline and each follow-up visit•Unique patient number•Age•Gender•Ethnicity•SLE organ involvement•Comorbidities•Disease duration•Smoking status•Prior therapies•SLEDAI and its individual items•cECLAM and its individual items•BILAG and its individual items•Physician global assessment of disease activity•Detailed treatment: o study arm [Belimumab, including dose or placebo] o corticosteroid use and dose o use and dose of other immunosuppressive treatments (methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide) o antimalarial use and dose•Patient global assessment of disease activity•Biological data: o Anti-DNA levels o Hypocomplementemia (C3 and C4 levels) o ESR o CRP •Selena Flare Index and its individual items •SLICC-damage index and its individual items •SF36 and its individual items •FACIT and its individual items •EQ-5D and its individual items •Occurence and date of death

Publication Citation

Parodis I#, Emamikia S#, Gomez A, Gentline C, Arkema EV, Chatzidionysiou K, van Vollenhoven RF. Evaluation of Definitions Of Remission In Systemic Lupus Erythematosus (DORIS): a post-hoc analysis of two randomised clinical trials. The Lancet Rheumatology. 2019 Sep; [Accepted; In production] #Contributed equally
https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(19)30049-9/fulltext