Treatment Frequency Reduction in Pompe Disease

Muscle strength will be determined by manual muscle testing 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 groups tests will include neck flexors/extensors, shoulder abductors, elbow extensors/flexors, wrist extensors/flexors, hip extension, hip flexors, hip adductors/abductors, knee extensors/flexors, and foot extensors/flexors.

Muscle strength will be measured with the CITEC hand-held dynamometer (HHD). Thirteen muscle groups will be tested: neck extension, neck flexion, and bilateral shoulder abduction, elbow flexion, elbow extension, wrist extension, squeezing, hip flexion, hip extension, hip abduction, knee flexion, knee extension, ankle dorsiflexion, and ankle plantar flexion. A mean value in Newton (N) is calculated from three consecutive measurements per muscle group.

The QMFT will be administered at the time points specified. This 16-item functional test has been developed to evaluate the function of the muscle groups that are specifically affected in patients with Pompe disease. The patient is asked to perform multiple activities in supine, sitting and standing position. The performance of the patient is scored on a 5-point ordinal scale (range 0-4). This standardized test can be performed within 5-10 minutes and can be performed in children and adults with varying disease severity.

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. The patient is instructed to walk the length of a pre-measured hallway for six minutes. It is widely regarded as an objective measure, which is easy to perform and reflects the performance in ADL of the patient.

Pulmonary function testing will be performed at the time points specified. Forced vital capacity will be measured during sitting and supine positions as a measure of lung volume (and indirect measure of the strength of the diaphragm and abdominal muscles).

The pulmonary testing protocol is standardized in accordance with ATS/ERS Guidelines36.

Three repeated reproducible flow volume curves will be made. The best effort will be used for further analyses. Values will be expressed as a percentage of the predicted normal values or as z-score, based on age, gender, race, and height. Global Lung Initiative (GLI) 2012 reference equations will be used.

In addition to the vital capacity, inspiratory (MIP) and expiratory (MEP) mouth pressures will be measured in upright seated position to determine the maximum force that can be exerted by the respiratory muscles.

MIP will be measured at residual volume after maximal expiration, while MEP is registered at total lung capacity after maximal inspiration. Pressures must be maintained at least 1 second. Maneuvers will be repeated until three reproducible methods are obtained. The highest value will be taken for analyses.

The Rasch-built Pompe-specific activity (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.

Body weight will be measured in kilograms (kg).

Heart rate will be measured in beats per minute (bpm).

Systolic and diastolic blood pressure will be measured in millimeter of mercury (mmHg).

Respiratory rate will be measured in breaths per minute.

Body composition will be measured conform DEXA technology (currently at Erasmus MC: GE Healthcare Lunar iDXA equipment: densitometer and encore software). This is a low-cost technology and simultaneously accurate, easy to perform and involves very low radiation dose (8 µSv per scan) to the patient which brings no harm. This imaging technique is the gold standard technique for the assessment of body composition.

Body composition will be presented as mineral bone, fat and fatty free body mass in kilograms.

Percentages of total body fat mass, android and gynoid fat will be measured. Percentages of fat mass will also be measured at regional level (arms, trunk and legs).

Bone mineral density is measured at total body in g/cm2.

For the purpose of stabilization and if deemed necessary by the investigator, the patient may use a walking device during the assessment, such as cane or walker. If such a device is used during the assessment, this must be recorded in the CRF/HiX. It will also be determined whether patients may need non-invasive or invasive ventilation during the study, including the hours of ventilation per day.

Blood samples will be collected before and after infusion of alglucosidase alfa at week 13 and week 39. Sampling times are as follows: pre-dose, 15 minutes before end of infusion, directly after end of infusion and 9 hours after start of infusion. The activity of alglucosidase alfa will be analyzed by the clinical chemistry laboratory of the Erasmus MC and expressed as nanomol 4-methylumbelliferyl-α-glucopyranoside (MU)/hour/10 microliter.

Blood samples will be drawn at baseline and at every 3 months for determination of serum creatine kinase (CK). Potential antibodies against alglucosidase alfa will be determined at baseline, after 9 months and at the end of the study (21 months).

Urine tetraglucoside (Glc4) will be measured in micromol/millimol kreatinine.

At each study visit, patients will be evaluated for new TEAEs in regard to the intervention (extension of the dosing interval, possibly followed by discontinuation of therapy). Adverse events potentially associated with (accelerated) deterioration of muscle and pulmonary function will also be evaluated. Any signs and symptoms experienced by the patient from the time of signing the informed consent through the final study visit will be documented.