Small changes in walking ability can be meaningful in advanced LOPD

Slowing of decline 'could be considered as improvement' in these patients: Study

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A woman is walking while holding a water bottle.

For most adults with late-onset Pompe disease (LOPD), a fairly significant improvement in walking ability is needed to be noticeable, but for patients who are already experiencing difficulty walking, a slowing of decline can be meaningful, a new study reports.

“Patients with severe baseline conditions should not be expected to benefit to the same absolute extent from a therapy as patients with mild or early stage, but that benefit can and should still be considered meaningful,” researchers wrote.

The study, “Minimal clinically important differences in six-minute walking distance in late-onset Pompe disease,” was published in the Orphanet Journal of Rare Diseases. The work was funded by Amicus Therapeutics, the company that sells the approved LOPD treatment Pombiliti + Opfolda (cipaglucosidase alfa/miglustat).

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Study IDs how much improvement is a ‘clinically important’ difference

Six-minute walking distance used in clinical trials to measure exercise capacity

The six-minute walking distance, or 6MWD, is a standardized measure used in clinical trials to measure exercise capacity in people who are able to walk. As its name implies, the 6MWD involves measuring the distance that a person can walk in six minutes. Outcomes may be expressed as the raw distance in meters (m), or as a percentage of predicted (%) taking into account factors like the patient’s height and weight.

In trials, scientists usually are most interested in whether a result is statistically significant, which means that the result is almost certainly not due to chance. However, statistical significance provides information only about whether or not the finding is chance. Saying a result is statistically significant provides little information about a patient’s lived experiences.

The minimal clinically important difference (MCID) is the smallest change in a measure that’s beneficial or harmful for patients. Understanding the MCID can help contextualize findings from clinical trials.

The MCID for the six-minute walk test has been established for some conditions. For example, in children with Duchenne muscular dystrophy, the MCID is typically about 30 meters (slightly less than 100 feet), but it’s not been determined for adults with LOPD.

In this study, an international team of scientists analyzed data from the Phase 3 PROPEL clinical trial (NCT03729362) to estimate the MCID for adults with LOPD. The trial tested Pombiliti + Opfolda against the older Pompe treatment Lumizyme (alglucosidase alfa) in 123 adults with LOPD. Results indicated patients given Pombiliti + Opfolda tended to have better 6MWD outcomes, though the difference was only statistically significant in a subgroup of patients who’d been on a treatment before entering the trial.

A few different standardized methods were used to calculate MCID for 6MWD from the trial data. Results indicated that, for the overall population of adults with LOPD in the trial, the MCID ranged from 2.27% to 8.11% predicted, which works out to around 23.7 to 57.2 m (about 78 to 188 feet).

Stability or even a small decline in 6MWD could be considered as improvement for patients in a severe and potentially rapidly progressing phase of the disease.

MCID lower for patients with walking difficulty

The MCID was notably lower for patients who started in the study with a 6MWD of less than 150 m (just shy of 500 feet). In these patients who already had notable walking difficulty, the highest predicted MCID was an improvement of 3.37% predicted (about 11 m or 36 feet). The lowest MCID in these patients was a decrease or worsening of 0.74% (about 2 m or 7 feet).

This result suggests “stability or even a small decline in 6MWD could be considered as improvement for patients in a severe and potentially rapidly progressing phase of the disease,” the researchers wrote.

“For a progressive disease such as LOPD, the findings suggest that a single MCID that can be applied to all patients can be misleading,” the researchers added. “Instead, when estimating MCIDs, we suggest that a range of possible MCIDs should be considered that incorporates the degree of the patient’s disease progression at baseline.”

The team noted this analysis was limited to participants in the PROPEL study, so additional work will be needed to see if these findings can be generalized to the wider population of adults with LOPD.