Use of the win ratio approach in individuals with late-onset Pompe disease (PD) has demonstrated that meaningful improvements in respiratory or motor outcomes were more than twice as likely among patients receiving avaglucosidase alfa than in those receiving alglucosidase alfa. The results, a reanalysis of the COMET trial (NCT02782741), were published in the journal Value in Health.

Investigators of the current study proposed the use of a new application as an alternative to hierarchical testing of endpoints to improve the statistical power of small trials such as those involved in the study of rare diseases. The win ratio methodology seeks to improve analyses of composite endpoints in clinical trials by accounting for the relative importance of components of the composite endpoint and enhancing interpretability of the treatment effect measure.

In the current analysis, the focus was on forced vital capacity (FVC) %-predicted and 6-minute walk test (6MWT), which were the first and second endpoints, respectively, in the hierarchical testing sequence in the COMET trial.

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All possible patient pairs from the avaglucosidase alfa and the alglucosidase alfa study arms were compared sequentially with respect to changes at week 49 in FVC %-predicted and 6MWT with the use of thresholds that represented clinically relevant improvement or decline. Each of the comparisons evaluated whether the outcome with avaglucosidase alfa was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa.

If tied on FVC, then 6MWT findings were compared. The treatment effect was the “win/loss ratio, with ties excluded.”

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Results of the study showed that in the 2499 possible pairs—51 of whom received avaglucosidase alfa x 49 of whom received alglucosidase alfa—1237 (49%) ended in a win for avaglucosidase alfa, 523 (21%) were a loss for avaglucosidase alfa, and 739 (30%) were tied when FVC was compared prior to 6MWT in the treatment arms.

The win ratio was 2.37 (95% CI, 1.30-4.29; P =.005). When the order was reversed, however, the win ratio was 2.02 (95% CI, 1.13-3.62; P =.018).

The authors concluded that “the win ratio approach provides a comprehensive assessment of treatment benefits while borrowing strength across the endpoints.”


Ishak KJ, Caro JJ, Hamed A, et al. Win ratio analyses of multiple endpoints in rare disease trials: a case-study based on a trial of avaglucosidase alfa in late-onset Pompe disease (LOPD). Value Health. 2022;25(12 suppl):S487.