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Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus
D Moreno-Martinez1, P Aguiar2, C Auray-Blais3
1Lysosomal Storage Disorders Unit, Royal Free Hospital NHS Foundation Trust and University College London, London, UK.
Background:
Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD.
Methods And Findings:
A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial.
Conclusion:
This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.
Insights
This study developed a framework for standardizing Fabry disease clinical trials. Experts agreed on adaptive trial designs, agalsidase beta as a comparator, and prioritized renal and cardiac outcomes for future Fabry disease research.
Area of Science:
- Rare disease clinical research
- Fabry disease therapeutics
- Clinical trial methodology
Background:
- Fabry disease (FD) clinical trials are increasing, but lack of standardization hinders interpretation.
- A common framework is needed to standardize investigational programs for FD.
Purpose of the Study:
- To establish a consensus on clinical trial design for Fabry disease.
- To standardize outcome measures and patient selection criteria in FD trials.
Main Methods:
- Delphi methodology involving 35 international FD experts representing 3389 patients.
- Three rounds of consensus-building on trial design, comparators, outcomes, and inclusion/exclusion criteria.
Main Results:
- Consensus reached on adaptive trial design and agalsidase beta as the comparator.
- Prioritization of renal (e.g., GFR, proteinuria) and cardiac (e.g., LV mass index) outcomes.
- Inclusion of patient-reported outcomes (quality of life, pain, GI symptoms) and surrogate markers (lysoGb3, Gb3 deposits).
- Exclusion of patients with end-stage renal disease/transplant unless specifically studied.
Conclusions:
- The developed consensus framework will guide future clinical trials in Fabry disease.
- This initiative aligns with recent FDA draft guidelines for FD clinical trials.
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