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

Researchers sought to estimate minimum gains important to patients given ERT

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Using self-reported outcomes by adults with Pompe disease, researchers were able to estimate the minimal clinically important difference or MCID — the smallest outcome change that a patient perceives as important following treatment — after one year of enzyme replacement therapy (ERT).

The differences reported by patients as clinically important to them, on standard measures of walking and breathing, will help to provide researchers with a threshold to determine how much a treatment group should improve in studies and clinical trials, according to the team.

For lung function, the patient-reported MCID for an improvement ranged from 2.47% to 4.83%, while for motor function —  assessed in tests of walking ability — the MCID for improvement ranged from 0.35% to 7.47%.

The MCIDs derived in this study “can be used to interpret differences between and within groups of patients with Pompe disease in clinical trials and cohort [group-based] studies,” the researchers wrote.

The study, “Establishing how much improvement in lung function and distance walked is clinically important for adult patients with Pompe disease,” was published in the European Journal of Neurology.

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Researchers seek to set threshold for clinically important gains after ERT

Pompe disease is caused by partial or total deficiency of the enzyme acid alpha-glucosidase, resulting in the toxic buildup of glycogen, a sugar storage molecule, in tissues, particularly in muscles. Symptoms of Pompe include progressive muscle weakness, motor function limitations, and breathing difficulties.

Enzyme replacement therapy, known simply as ERT, is the standard Pompe treatment, and uses a lab-made human alpha-glucosidase to break down glycogen. ERT has been shown to improve or stabilize patient symptoms.

Clinical trial outcomes for treating people with Pompe include positive results on tests of lung function, such as forced vital capacity (FVC), and motor function, typically the 6-minute walk test (6MWT). However, there are no thresholds to determine the point at which these outcomes are clinically important. Further, the researchers note, reaching a statistically significant difference in testing does not necessarily imply clinical importance for the patient.

MCID has been proposed as an outcome measure, defined as the smallest outcome change a patient perceives as important, either beneficial or harmful.

Still, there are no published MCID values available for Pompe disease, thus limiting the interpretation of clinical trials.

That led a team of scientists at the Erasmus MC University Medical Centre, in the Netherlands, to estimate the minimal clinically important difference for changes for FVC in the upright seated position — called the FVCup — and the 6MWT after a year of ERT.

Data were obtained from two follow-up studies that enrolled a total of 102 Pompe patients who had at least one FVCup or 6MWT measurement during ERT. Among them, 55% were women, 30% were wheelchair-bound, and 25% needed breathing support. The median age at symptom onset was 32.5, and the median age at the start of ERT was 50.

MCIDs were estimated using anchor-based methods, which established whether participants were better after ERT than before treatment (baseline) according to the patient’s experience.

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Patient-reported outcomes included the International Pompe Association (IPA)/Erasmus MC Pompe survey, the Short-Form 36 physical component summary scores, and a Pompe-specific questionnaire. These assessed changes in health, physical functioning, and shortness of breath. Based on these outcomes, patients were categorized into three groups — better, same, or worse after ERT.

The researchers calculated the between-group and within-group MCIDs. Between-group MCIDs measured the differences in outcome changes, from baseline to follow-up, between the “better” and “same” groups — which, the scientists noted, can be used to assess differences in both future and past trials. Within-group MCIDs measured the outcome changes within the “better” group, which can be used to evaluate changes over time in one treatment group.

For between-group calculations, the MCID for an FVCup improvement ranged from 2.47% to 4.83%. Using within-group calculations, the MCID was slightly lower, ranging from 1.26% to 3.74%.

“This means that if one treatment group improves 2.5% points more than another this may already be clinically important and a 5% point difference is,” the team wrote.

For the 6MWT, the between-group MCID for an improvement ranged from 0.35% to 7.47%. These MCID changes were equivalent to an increased walking distance of 2.18 to 46.61 meters for men and 1.97 to 42.13 meters for women, both aged 50, with a height of 1.75 meters and weight of 80 kg (176 pounds).

For those aged 70, the increased walking distance for MCID was 34.97 meters for men and 31 meters for women, both with a height of 1.70 meters and weight of 90 kg (198 pounds).

The thresholds presented in this study can be used to interpret group-level results from Pompe disease trials and cohort studies.

The within-group 6MWT MCID estimate was 11.53%, which was higher than the between-group estimates “because patients remaining the ‘same’ on the anchor showed an improvement on the 6MWT,” the researchers noted.

“The thresholds presented in this study can be used to interpret group-level results from Pompe disease trials and cohort studies,” the scientists wrote. “Also, they can be used in sample size calculations for adequate powering of a study on Pompe disease.”

According to the researchers, “to our knowledge this is the first paper estimating MCIDs for FVCup and the 6MWT in adult patients with Pompe disease who were treated with ERT.”