Reinterpreting Clinical Trials in Children With Multiple Sclerosis Using a Bayesian Approach

Bovis, Francesca; Ponzano, Marta; Signori, Alessio; Schiavetti, Irene; Bruzzi, Paolo; Sormani, Maria Pia

doi:10.1001/jamaneurol.2022.1735

Cited by 6 publications

(7 citation statements)

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“…Whenever trials of the same agent have been conducted in both adults and children, respectively, a Bayesian approach may allow us to integrate results from trials in adults in the interpretation of pediatric trials. For example, in the TERIKIDS trial, the initial standard frequentist analysis showed no significant difference, but when the Bayesian approach was applied, a significant difference was detected 50 …”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…For example, in the TERIKIDS trial, the initial standard frequentist analysis showed no significant difference, but when the Bayesian approach was applied, a significant difference was detected. 50 Based on the above, we recommend the following trial designs for pediatric RMS phase III confirmatory trials of DMTs approved in adults: randomized, active-controlled, double-blind, parallel-arms trial (non-inferiority trial, double dummy if needed) as the first option. If a placebo arm is required by regulatory authorities, we recommend a design that does not include a placebo arm but instead indirectly compares interferon β-1a with historical data.…”

Section: Statistical Analysis/approachesmentioning

confidence: 99%

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Adult and pediatric relapsing multiple sclerosis phase II and phase III trial design and their primary end points: A systematic review

Hiramatsu,

Maeda

2024

Clinical Translational Sci

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No systematic review of trial designs in patients with relapsing multiple sclerosis (RMS) was reported. This systematic review was conducted on the trial designs and primary end points (PEs) of phase II and III trials intended to modify the natural course of the disease in patients with RMS. The purpose of the study is to explore trends/topics and discussion points in clinical trial design and PE, comparing them to regulatory guidelines and expert recommendations. Three trial registration systems, ClinicalTrials.gov, the EU Clinical Trials Register, and the Japan Registry of Clinical Trials, were used and 60 trials were evaluated. The dominant clinical trial design was a randomized controlled parallel‐arms trial and other details were as follows: in adult phase III confirmatory trials (n = 32), active‐controlled double‐blind trial (DBT) (53%) and active‐controlled open‐label assessor‐masking trial (16%); in adult phase II dose‐finding trials (n = 9), placebo‐ and active‐controlled DBT (44%), placebo‐controlled DBT (22%), and placebo‐controlled add‐on DBT (22%); and in pediatric phase III confirmatory trials (n = 8), active‐controlled DBT (38%) and active‐controlled open‐label non‐masking trial (25%). The most common PEs were as follows: in adult confirmatory trials, annual relapse rate (ARR) (56%) and no evidence of disease activity‐3 (NEDA‐3) (13%); in adult dose‐finding trials, the cumulative number of T1 gadolinium‐enhancing lesions (56%), combined unique active lesions (22%), and overall disability response score (22%); and in pediatric confirmatory trials, ARR (38%) and time to first relapse (25%). It was suggested that some parts of the regulatory guidelines and expert recommendations need to be revised.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Statistical Analysis/approachesmentioning

confidence: 99%

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Adult and pediatric relapsing multiple sclerosis phase II and phase III trial design and their primary end points: A systematic review

Hiramatsu,

Maeda

2024

Clinical Translational Sci

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“…Fingolimod has demonstrated a marked superiority over interferon beta-1a in the 2-Year, Double-Blind, Randomized, Multicenter, Active-Controlled Core Phase to Evaluate Safety & Efficacy of Daily Fingolimod vs Weekly Interferon Beta-1a in Pediatric Patients With Multiple Sclerosis and 5 Year Fingolimod Extension Phase (PARADIGMS) randomized clinical trial (RCT) in reducing both clinical and magnetic resonance imaging (MRI) activity with a relative improvement in quality of life despite a slightly higher incidence of serious adverse events (SAEs) . Teriflunomide and DMF were recently approved by the US Food and Drug Administration and European Medicine Agency following the phase 3 Efficacy, Safety, and Pharmacokinetics of Teriflunomide in Pediatric Patients With Relapsing Forms of Multiple Sclerosis (TERIKIDS) and Phase 3 Efficacy and Safety Study of BG00012 in Pediatric Subjects With Relapsing-Remitting Multiple Sclerosis (CONNECT) RCTs . These successes paved the way for other ongoing RCTs with highly potent drugs like ocrelizumab, ofatumumab, and siponimod…”

Section: Introductionmentioning

confidence: 99%

“…1,2 Teriflunomide and DMF were recently approved by the US Food and Drug Administration and European Medicine Agency following the phase 3 Efficacy, Safety, and Pharmacokinetics of Teriflunomide in Pediatric Patients With Relapsing Forms of Multiple Sclerosis (TERIKIDS) and Phase 3 Efficacy and Safety Study of BG00012 in Pediatric Subjects With Relapsing-Remitting Multiple Sclerosis (CONNECT) RCTs. [3][4][5] These successes paved the way for other ongoing RCTs with highly potent drugs like ocrelizumab, ofatumumab, and siponimod. 6,7 In the last decade, the availability of highly potent drugs led to a decrease in long-term disability accrual.…”

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confidence: 99%

Highly Effective Therapies as First-Line Treatment for Pediatric-Onset Multiple Sclerosis

Benallegue,

Rollot,

Wiertlewski

et al. 2024

JAMA Neurol

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ImportanceModerately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus.ObjectiveTo assess the real-world association of HET as an index treatment compared with MET with disease activity.Design, Setting, and ParticipantsThis was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate.ExposureHET or MET at treatment initiation.Main Outcomes and MeasuresThe primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions.ResultsOf the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR], 0.46; 95% CI, 0.31-0.67; P &lt; .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09).Conclusions and RelevanceResults of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.

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Teriflunomide: an oral therapy for first-line treatment of children and adolescents living with relapsing-remitting multiple sclerosis

Costa

Comi

2023

Expert Review of Neurotherapeutics

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Reinterpreting Clinical Trials in Children With Multiple Sclerosis Using a Bayesian Approach

Cited by 6 publications

References 6 publications

Adult and pediatric relapsing multiple sclerosis phase II and phase III trial design and their primary end points: A systematic review

Adult and pediatric relapsing multiple sclerosis phase II and phase III trial design and their primary end points: A systematic review

Highly Effective Therapies as First-Line Treatment for Pediatric-Onset Multiple Sclerosis

Teriflunomide: an oral therapy for first-line treatment of children and adolescents living with relapsing-remitting multiple sclerosis

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