Related Experiment Video
Updated: Jun 27, 2025
A Method of Trigonometric Modelling of Seasonal Variation Demonstrated with Multiple Sclerosis Relapse Data
Published on: December 9, 2015
Adult and pediatric relapsing multiple sclerosis phase II and phase III trial design and their primary end points:
Katsutoshi Hiramatsu1, Hideki Maeda1
1Department of Regulatory Science, Faculty of Pharmacy, Meiji Pharmaceutical University, Tokyo, Japan.
Abstract:
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.
Insights
This review analyzed clinical trial designs for relapsing multiple sclerosis (RMS). Annual relapse rate (ARR) and no evidence of disease activity-3 (NEDA-3) were common primary endpoints, suggesting guideline revisions are needed.
Area of Science:
- Clinical trial design
- Multiple Sclerosis Therapeutics
- Regulatory Science
Background:
- No prior systematic review focused on clinical trial designs for relapsing multiple sclerosis (RMS).
- Understanding current trial methodologies is crucial for advancing RMS treatment.
Purpose of the Study:
- To systematically review trial designs and primary endpoints (PEs) in Phase II and III RMS trials.
- To identify trends in clinical trial design and PEs.
- To compare these trends with existing regulatory guidelines and expert recommendations.
Main Methods:
- Systematic review of 60 trials across ClinicalTrials.gov, EU Clinical Trials Register, and Japan Registry of Clinical Trials.
- Analysis of trial designs (e.g., randomized controlled parallel-arms, double-blind trials) and primary endpoints (e.g., ARR, NEDA-3, MRI lesion counts).
- Categorization by trial phase (II/III), patient population (adult/pediatric), and control type (placebo/active).
Main Results:
- Randomized controlled parallel-arms trials were dominant.
- In adult Phase III trials, active-controlled double-blind trials (53%) were most common. Primary endpoints included annual relapse rate (ARR) (56%) and no evidence of disease activity-3 (NEDA-3) (13%).
- In adult Phase II trials, placebo- and active-controlled double-blind trials (44%) were most common. Primary endpoints focused on MRI activity and disability response.
Conclusions:
- Identified dominant trial designs and primary endpoints in RMS clinical trials.
- Highlighted discrepancies between current practices and regulatory/expert recommendations.
- Suggested that certain regulatory guidelines and expert recommendations require revision to align with contemporary trial designs and endpoints.
