Safety and Efficacy of Avalglucosidase Alfa in Patients With Non-classic Pompe Disease Aged ≥ 5 Years

Assessment of the occurrence/number of adverse events / treatment-emergent adverse events, including infusion associated reactions (IARs). Adverse events are scored using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

The titer of antibodies against avalglucosidase alfa, scored as either no to low antibodies (< 1:1,250), intermediate (1:1,250 to < 1:31,250), or high (≥ 1:31,250).

Values of ASAT, ALAT and CK (measured in U/L) as markers for muscle and liver function.

Manual muscle testing (MMT) is performed using the Medical Research Council (MRC) grading scale. Muscle strength is graded from 0-5 by physical examination, in which grade 5 represents normal muscle strength and grade 0 means paralysis of the muscle group tested.

Muscle strength will also be measured with the Cytec handheld dynamometer (HHD). A mean value in Newton is calculated from three consecutive measurements per muscle group.

For the quick motor function test, the patient is asked to perform several activities in supine, sitting and standing position, the performance of the patient is scored on a 5-point ordinal scale (range 0-4). A sumscore is calculated based on the maximum total score.

The 6MWT is a timed test that measures functional endurance. The primary measurement is the distance walked in 6 minutes, measured in meters. The percent of predicted distance and the amount of time walked (to quantify endurance, as not all patients may complete the full 6-minute walk) will also be recorded.

Eventual score is reported as a distance in meters (m) and a percent of the predicted score using the 1000 norms reference values.

Four timed tests will be performed to evaluate the impact of muscle weakness on the ability to perform functional activities of daily living. These timed tests include walking 10 meters, climbing four stairs, getting up from a supine position on the floor, and standing up from a chair. The number of seconds required to perform each activity will be noted.

Forced vital capacity in sitting and supine position will be measured and reported as percentage of predicted values, using the GLI 2012 reference values.

Both MIP and MEP are measured in kPa and then converted to a percentage of predicted values based on reference values.

The Rasch-Built Pompe-specific activity scale (R-PAct) will be performed in all patients who are ≥16 years at baseline. The R-PAct scale is a self-reported, 18-items questionnaire designed specifically for use in patients with Pompe disease, based upon experiences from patients about their most important and limiting aspects in daily life. All items have three response options: [0] unable to perform; [1] able to perform, but with difficulty or [2] able to perform without difficulty. If all items are answered, an appropriate centile metric score (range 0-100) will be calculated.

The SF-36 is a health-related quality of life questionnaire, consisting of 36 items. The items are assigned to the domains of physical functioning, role functioning-physical, role functioning- emotional, social functioning, body pain, mental health, vitality, general health perception and change in health. The questionnaire will be used only for patients aged 16 years and older.

A sumscore will be calculated based on the score on each item, and converted to a percentage of predicted score based on Dutch norm-based values.

The TACQOL (TNO-AZL Child Quality of Life Questionnaire) is a generic instrument that measures quality of life in children aged 6-15 years. The questionnaire includes items representing the following concepts: physical complaints, motor functioning, autonomous functioning, social functioning, cognitive functioning, positive moods, and negative moods. For each of these scales, a scale score is calculated, where a higher score corresponds with a better quality of life.

The modified Borg scale is a patient-reported scale, derived from the original Borg scale, which is used to assess the subjective sensation of dyspnea of a patient. It is quantified from 0 to 10, in which 0 represents no symptoms (i.e. no dyspnea/shortness of breath) and 10 represents maximum symptoms.

Single and multiple dose estimates for Cmax (in µg/mL), AUC (in μg∙hr/ml) and CL (in L/h), measured at two separate avalglucosidase alfa infusions (at baseline and 52 weeks).

Heart rate in beats per minute (bpm), scored prior to infusion, with each change in infusion rate and at the end of infusion.

Systolic and diastolic blood pressure in mmHg, scored prior to infusion, with each change in infusion rate and at the end of infusion.

Respiratory rate measured in number of breaths per minute, scored prior to infusion, with each change in infusion rate and at the end of infusion

A standard 12-lead electrocardiogram (ECG) will be performed using an electrocardiographic device.

The following variables will be assessed: heart rate (beats per minute), rhythm (type), interval from start of the Q wave to the end of the S wave (QRS) in milliseconds (ms), interval between the peaks of successive QRS complexes (RR) in ms, interval from the beginning of the P wave until the beginning of the QRS complex (PR) in ms, interval between the start of the Q wave and the end of the T wave (QT) in ms, QT interval corrected for heart rate (QTc) automatic correction evaluation (by the ECG device) in ms, QRS axis (direction), presence of left ventricular hypertrophy criteria, presence right ventricular hypertrophy criteria, and presence of repolarization charges (yes/no).

These measurements will be aggregated to arrive at one reported outcome measure: abnormal ECG (Yes/No). Abnormal ECG is defined as an abnormality in any of the measurements mentioned above.

At each visit use of mechanical ventilation will be assessed, including the hours of ventilation per day - if applicable.