Glycogen Storage Disease Type II Late Onset, Pompe Disease, Pompe Disease (Late-onset), Pompe Disease Late-Onset, Pompe's Disease Juvenile Onset
Conditions
Brief summary
The goal of this clinical trial is to study the efficacy and safety of treatment with avalglucosidase alfa in patients with late onset Pompe disease that previously deteriorated on alglucosidase alfa. The main question it aims to answer is: * Is switching to avalglucosidase alfa in late-onset Pompe patients deteriorating on alglucosidase alfa safe? * Is switching to avalglucosidase alfa in late-onset Pompe patients deteriorating on alglucosidase alfa potentially more effective? Participants will switch to biweekly avalglucosidase alfa infusions (instead of alglucosidase alfa infusions) and perform assessment for: * Efficacy: muscle strength and function, pulmonary function, patient-reported outcomes. * Safety: Adverse events assessment, physical examination, clinical laboratory evaluations, vital signs, ECGs and immunogenicity assessments. * Pharmacokinetic assessments during 2 avalglucosidase alfa infusions.
Detailed description
Rationale: Not all patients with non-classic Pompe disease have a good response to current treatment with alglucosidase alfa. Therefore innovative enzyme replacement therapies are developed. The study drug avalglucosidase alfa has been tested in multiple clinical studies and will now be studied in a small population of patients that are unresponsive to alglucosidase alfa. Objective: To explore safety, tolerability and efficacy of avalglucosidase alfa in patients with non-classic Pompe disease aged ≥ 5 years of whom clinical condition deteriorates while on standard treatment with alglucosidase alfa. Study design: Single-center, open-label, repeated bi-weekly intravenous infusion study of avalglucosidase alfa in patients with non-classic Pompe disease patients aged ≥ 5 years, previously treated with alglucosidase alfa. Study population: Non-classic Pompe disease patients aged ≥ 5 years and ≤ 55 years previously treated ≥ 2 years with alglucosidase alfa, who deteriorate despite treatment with alglucosidase alfa at a dose of 20 or 40 mg/kg bi-weekly. Total number of patients = 6. Intervention: Avalglucosidase alfa. Sterile lyophilized powder administered by intravenous infusion following reconstitution and dilution. 20 mg/kg bi-weekly Main study parameters: * Safety * Assessment of adverse events / treatment-emergent adverse events, including infusion associated reactions (IARs) * Clinical laboratory evaluations including hematology, biochemistry, urinalysis * Immunogenicity assessments * Pharmacokinetics • Single and multiple dose estimates for Cmax, AUC, CL,. * Efficacy * Muscle strength: manual muscle testing (MMT), hand- held dynamometry (HHD). * Muscle function: Quick Motor Function test (QMFT), six Minute Walk Test (6MWT), timed tests. * Pulmonary function: (forced) vital capacity ((F)VC) in sitting and supine positions, Maximum Inspiratory Pressure (MIP), Maximum Expiratory Pressure (MEP). * 'PRO-measures': Rasch-build Pompe Activity scale (R- Pact), Quality of Life (QoL), modified Borg scale, Nature and extent of burden and risks associated with participation, benefit and group relatedness: Blood samples will be collected at 14 time points, the amount of blood will not exceed the maximum amount of 5 ML/kg over a period of 8 weeks. Patients will visit the hospital every other week to receive treatment. This treatment will last 4-6 hours. During every visit the vital signs of the patients will be checked and a physical examination is performed.
Interventions
Enzyme replacement therapy
Sponsors
Iris Plug
Sanofi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
6 patients with late onset Pompe disease will be treated
Eligibility
Sex/Gender
ALL
Age
5 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Age\> 5 years and \< 55 years * Childhood or juvenile/adult onset * Residing in the Netherlands * Current ERT with alglucosidase alfa\> 2 years (dose regimen 20 or 40 mg/kg bi-weekly). * Confirmed diagnosis: enzyme deficiency in any tissue source and/or 2 confirmed disease-causing variants in the GAA gene. * Willing and able to adhere to study procedures * Deterioration in pulmonary function and/or 6MWT and/or muscle strength despite current treatment regimen with alglucosidase alfa. * Disease status: measurable pulmonary (dys)function: (F)VC ≤ 80% predicted (mechanic ventilation during the day or night allowed); Measurable muscle weakness in proximal and/or distal muscle groups (non- ambulant/wheelchair bound patients allowed); measurable functional ability
Exclusion criteria
* Age\>55 years * Invasive mechanical ventilation * No remaining useful functional ability, as decided by the treating physician * Unmanageable, sever IAR's on alglucosidase alfa * Deterioration due to high levels of anti-alglucosidase alfa antibodies interfering with treatment efficacy * Female patient of childbearing potential not protected by highly effective contraceptive method of birth control and/or who is unwilling or unable to be tested for pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence/occurrence of adverse events | From enrollment to the end of study duration at 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 occurence of antibodies against avalglucosidase alfa | From enrollment to the end of study duration at 5 years | 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). |
| Clinical laboratory evaluations aimed at liver and muscle function. | From enrollment to the end of study duration at 5 years | Values of ASAT, ALAT and CK (measured in U/L) as markers for muscle and liver function. |
| Changes in muscle strength using manual muscle testing (MMT) | From enrollment to the end of study duration at 5 years | 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. |
| Changes in muscle strength using hand-held dynamometry (HHD) | From enrollment to the end of study duration at 5 years | 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. |
| Changes in muscle function using Quick Motor Function Test (QMFT) | From enrollment to the end of study duration at 5 years | 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. |
| Changes in muscle function using the 6-Minute Walk Test (6-MWT) | From enrollment to the end of study duration at 5 years | 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. |
| Changes in muscle function using timed tests | From enrollment to the end of study duration at 5 years | 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. |
| Changes in pulmonary function using forced vital capacity (FVC) | From enrollment to the end of study duration at 5 years | Forced vital capacity in sitting and supine position will be measured and reported as percentage of predicted values, using the GLI 2012 reference values. |
| Changes in pulmonary function using Maximum Inspiratory Pressure (MIP) and Maximum Expiratory Pressure (MEP) | From enrollment to the end of study duration at 5 years | Both MIP and MEP are measured in kPa and then converted to a percentage of predicted values based on reference values. |
| Changes in patient reported outcome (PRO) measures using the Rasch-built Pompe-specific Activity scale (R-PAct) | From enrollment to the end of study duration at 5 years | 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. |
| Changes in patient reported outcome (PRO) measures using the 36-Item Short Form Health Survey (SF-36) | From enrollment to the end of study duration at 5 years | 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. |
| Changes in patient reported outcome (PRO) measures using the TNO-AZL Child Quality of Life Questionnaire) | From enrollment to the end of study duration at 5 years | 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. |
| Changes in patient reported outcome (PRO) measures using the modified Borg scale | From enrollment to the end of study duration at 5 years | 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. |
| Pharmacokinetics of avalglucocidase alfa | From enrollment up to 1 year of study duration. | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in vital signs using heart rate | From enrollment to the end of study duration at 5 years | Heart rate in beats per minute (bpm), scored prior to infusion, with each change in infusion rate and at the end of infusion. |
| Changes in vital signs using blood pressure | From enrollment to the end of study duration at 5 years | Systolic and diastolic blood pressure in mmHg, scored prior to infusion, with each change in infusion rate and at the end of infusion. |
| Changes in vital signs using respiratory rate | From enrollment to the end of study duration at 5 years | 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 |
| Changes or abnormalities of cardiac function measured by electrocardiogram (ECG) | From enrollment to the end of study duration at 5 years | 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. |
| Assessment of use of ventilator | From enrollment to the end of study duration at 5 years | At each visit use of mechanical ventilation will be assessed, including the hours of ventilation per day - if applicable. |
Countries
Netherlands
Contacts
PRINCIPAL_INVESTIGATORNadine van der Beek, MD PHD
Erasmus Medical Center
Outcome results
None listed