Making real world predictions for clinical outcomes in Relapsing-Remitting Multiple Sclerosis

Making real world predictions for clinical outcomes in Relapsing-Remitting Multiple Sclerosis

Background: Multiple Sclerosis (MS) is a chronic disease of young adults, affecting approximately 15000 patients in Switzerland. While the disease has only minor impact on life expectancy, its long duration (mean of 30-40 years) and the fact that it leads to significant disability results in a very important socio-economic impact. Although progress has been made in understanding disease pathogenesis, and partially effective treatment are available, many questions remain unanswered.The development and validation of diagnostic and prognostic markers of spontaneous disease evolution and therapeutic response can help to improve patient care and possibly allows to establish individualized therapy approaches. Aim & Objectives:The aim of the project is to develop a statistical model for real-world predictions for relapse under various treatment options at an individual and population level by linking evidence synthesis techniques and prognostic modelling methods.We will develop a statistical framework in which the evidence obtained from different study designs (randomized clinical trials, single arms, and real-world data) is summarized to estimate treatment effects that depend on patient characteristics.Our research project is methodological. In the MS context, we will develop a model that produces evidence about the treatment associated with the best predictions in terms of relapse and according to patients' characteristics. To achieve this aim, the following objectives have been set: To develop a prognostic risk score model using patients and condition's characteristics to predict the baseline prior-treatment relapse rate in one and two years.To develop a statistical prediction model for heterogeneous treatment effects according to the levels of the risk score, combining several data sources.Methods:The aim is to develop an individualized prediction model for the odds of relapse when a particular treatment is given to a particular patient [3].Central to the methodology is the identification of characteristics that contribute to the heterogeneity in treatment effects and estimation of their impact.In a first stage, we don't take into consideration the intervention and the aim is to estimate the risk of outcome prior to the treatment.For ex. the Framingham risk score estimates the 10-year cardiovascular risk of an individual taking into account several prognostic factors, like age, sex, systolic blood preasure, total cholesterol etc.In a second stage, we will develop a prediction model for relapse under all alternative treatments using Individual Participant Data (IPD) and aggregated data (AD) from several RCTs.The model will have the form of a network meta-regression with the log-odds-ratio of relapse of each treatment versus placebo as dependent variable and the risk score as the independent variable. For this stage, we need many randomized clinical trials (RCTs) to include as many as possible treatment options and to increase as much as possible the precision of the model. Results:A model such that can be used to estimate the predicted probabilities of the outcome of interest under all available treatments. An example is presented in: https://cinema.ispm.unibe.ch/shinies/koms/, where given the relapsing-remitting multiple sclerosis (RRMS) patients' characteristics, the probabilities to relapse within the next two years are estimated under each one of the treatments available at the moment:Dimethyl Fumarate, Glatiramer acetate, and Natalizumab.This model indicates that for high-risk patients, the treatment that minimizes the risk of relapse within the next two years is Natalizumab, whereas Dimethyl Fumarate might be a better option for low-risk patients.Conclusions:Our approach can be easily extended to all outcomes of interest and has the potential to inform a personalized treatment recommendation. Many RCTs are needed before this model is ready to be used, so that as many as possible treatment options can be included.

[{ "PostingID": 494, "Title": "GSK-49653/452", "Description": "A randomized, double-blind, parallel group, placebo-controlled study to investigate the safety, tolerability and efficacy of six months' administration of AVANDIA (rosiglitazone maleate) in subjects with Relapsing-Remitting Multiple Sclerosis (MS)" },{ "PostingID": 3921, "Title": "GSK-H3M116477", "Description": "Proof of Mechanism Study to Assess the Potential of GSK239512 to Remyelinate Lesions in Subjects with Relapsing Remitting Multiple Sclerosis." },{ "PostingID": 4084, "Title": "NOVARTIS-CFTY720D2301", "Description": "A 24-month, Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel-group Study Comparing the Efficacy and Safety of Fingolimod 1.25 mg and 0.5 mg Administered Orally Once Daily Versus Placebo in Patients With Relapsing-remitting Multiple Sclerosis" },{ "PostingID": 4085, "Title": "NOVARTIS-CFTY720D2302", "Description": "A 12-month Double-blind, Randomized, Multicenter, Active-controlled, Parallel-group Study Comparing the Efficacy and Safety of 0.5 mg and 1.25 mg Fingolimod (FTY720) Administered Orally Once Daily Versus Interferon ß-1a (Avonex) Administered im Once Weekly in Patients With Relapsing-remitting Multiple Sclerosis With Optional Extension Phase" },{ "PostingID": 4089, "Title": "NOVARTIS-CFTY720D2309", "Description": "24-month Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel-group Study Comparing the Efficacy and Safety of 0.5 mg and 1.25 mg Fingolimod (FTY720) Administered Orally Once Daily Versus Placebo in Patients With Relapsing-remitting Multiple Sclerosis With Optional Extension Phase" },{ "PostingID": 4415, "Title": "GSK-I7R116702", "Description": "A First Time in Human Study Exploring Preliminary Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2618960 in Healthy Volunteers and Patients with Relapsing Remitting Multiple Sclerosis" },{ "PostingID": 4899, "Title": "NOVARTIS-CFTY720D1201", "Description": "A 6-month, Double-blind, Randomized, Placebo-controlled, Parallel-group, Multicenter Study Comparing Efficacy and Safety of FTY720 0.5 mg and 1.25 mg Administered Orally Once Daily in Patients With Relapsing Multiple Sclerosis" },{ "PostingID": 4900, "Title": "NOVARTIS-CFTY720D1201E1", "Description": "An Extension of the 6-month, Double-blind, Randomized, Placebo-controlled, Parallel-group, Multicenter Study Comparing Efficacy and Safety of FTY720 0.5 mg and 1.25 mg Administered Orally Once Daily in Patients With Relapsing Multiple Sclerosis" },{ "PostingID": 20296, "Title": "NOVARTIS-CBAF312A2201", "Description": "A Phase II, Double-blind, Randomized, Multi-center, Adaptive Dose-ranging, Placebo-controlled, Parallel-group Study Evaluating Safety, Tolerability and Efficacy on MRI Lesion Parameters and Determining the Dose Response Curve of BAF312 Given Orally Once Daily in Patients With Relapsing-remitting Multiple Sclerosis" },{ "PostingID": 20317, "Title": "NOVARTIS-CBAF312A2201E1", "Description": "An Extension Study to the CBAF312A2201 study to evaluate long-term safety, tolerability and efficacy of BAF312 given orally once daily in patients with relapsing- remitting multiple sclerosis" }]

E.M. Peters, L. Balbuena, R. Lodhi Emotional blunting with bupropion and serotonin reuptake inhibitors in three randomized controlled trials for acute major depressive disorder,
Journal of Affective Disorders vol 318 (2022)
https://doi.org/10.1016/j.jad.2022.08.066