Combined Assessment of Function and Survival to Demonstrate the Effect of Treatment on Progressive Supranuclear Palsy

Germani, Massimiliano; Rebollo Mesa, Irene ; Buchanan, Tim J.; De Bruyn, Steven; Gasalla, Teresa; Tricht, Hans Lieve G. Van; Ewen, Colin; Golbe, Lawrence I.; Boxer, Adam und Höglinger, Günter (2024): Combined Assessment of Function and Survival to Demonstrate the Effect of Treatment on Progressive Supranuclear Palsy. In: Movement Disorders [Forthcoming]

Abstract

Background

Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative disorder for which there are currently no disease-modifying treatments. Recent trials of potential therapies had durations of 12 months, which may be insufficient because of nonrandom missingness due to death. Longer durations, incorporating PSP Rating Scale and survival, can reduce the potential for type II error. Selecting efficacy measures more sensitive to disease modification may facilitate identification of treatment effect.

Objective

The objective of this study was to evaluate the simulated phase 3 PSP trial assessing the effect of disease-modifying intervention on a novel combined primary endpoint comprising function (PSP Rating Scale) and survival, the Combined Assessment of Function and Survival (CAFS), and to determine operating characteristics of the CAFS.

Methods

To simulate PSP progression in the trial population, we developed models of PSP Rating Scale and survival using data from published clinical studies. These models were used to define operating characteristics of the CAFS for use in a phase 3 trial.

Results

The sample size determined (N = 384; 1:1 randomization) would provide >80% power to detect significant treatment effects on the CAFS compared with placebo. The CAFS provides good operating characteristics and increased power to detect moderate treatment effects on the PSP Rating Scale. We propose a trial design allowing potential detection of treatment effects at a preplanned interim analysis after participants complete 12 months of treatment, with assessment of effects of treatment (≤24 months) on survival.

Conclusions

Use of the CAFS could provide a comprehensive and robust estimate of the clinical benefit of future therapies.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy) ; Medizin > Klinikum der LMU München > Neurologische Klinik und Poliklinik mit Friedrich-Baur-Institut
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0885-3185
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198