Natural History of Pompe Disease
- Conditions
- Glycogen Storage Disease Type II, Adult
- Registration Number
- NCT03564561
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief Summary
The project is a prospective study in which patients affected by adult-onset Pompe disease with c.-32-13T\>G mutation in the GAA gene will be followed-up during two years to describe the natural history using clinical, imaging, histological and molecular parameters.
Secondary objectives are:
* To identify biomarkers for assessing efficacy of future therapies based on correcting aberrant alternative splicing in Pompe patients with c.-32-13T\>G mutations.
* To determine effectiveness of antisense oligonucleotide chemistries to restore full length GAA transcripts, GAA protein and GAA enzyme activity in fibroblasts and myoblasts obtained from skin and muscle biopsies as well as leucocytes of Pompe patients with c.-32-13T\>G mutations.
- Detailed Description
Study aim:
The principal objective of the study is to find biomarkers and clinical criteria that correlate with the disease progression.
Methods:
Clinical information will be obtained according to a pre-defined protocol including six visits: screening visit, visit at baseline, visits at 6 months, 12 months, 18 months and 24 months.
At visits following tests will be performed:
Respiratory assessment (including clinical assessment using the Borg scale, identification of clinical signs of alveolar hypoventilation, documentation of the daily duration on and off mechanical ventilation, spirometry, determination of lung volumes and slow vital capacity, peak cough flow, blood gazes, measurement of maximal inspiratory and expiratory pressures during the Müller maneuver, sniff nasal inspiratory pressure, mouth inspiratory pressure, twitch mouth pressure, esophageal and transdiaphragmatic pressures during voluntary respiration and following magnetic stimulation of diaphragmatic nerves, optoelectronic measurement of abdominal contribution to vital capacity, inspiratory capacity and tidal volume, measure of diaphragm mobility using ultrasound, sleep studies using polysomnography for non-ventilated patients and oximetry for patients using non-invasive mechanical ventilation, coupled with ECG recording).
Motor assessment (including the MFM motor function measure scale, timed 10 meters run/walk test, timed test for standing up from sitting positions, timed test for standing up from supine position, time taken to climb 4 stairs, 6-minute walk test, three-dimensional analysis of walk, quadriceps muscle strength assessed following magnetic stimulation of femoral nerve, EMG).
Assessment of body composition (including determination of lean mass, body mass index and bone mineral density by dual X-ray absorptiometry).
Assessment of skeletal muscle structure using whole body magnetic resonance imaging.
Assessment of heart function using heart echography and ECG. Assessment of live quality (including "Rotterdam handicap scale", "Rasch-built Pompe-specific Activity (R-Pact) scale " and EQ5D-5L questionnaires).
Biomaterial collection of biomarker analysis (including dosing serum CPK, GPT and GOT, GAA mutational analysis of both alleles, biobanking of serum, DNA and urine, muscle biopsy for histological analysis, quantification of exon 2 alternative splicing and residual GAA enzyme activity, myoblast culture for quantification of alternative splicing and residual GAA enzyme activity, muscle biopsy and myoblast culture biobanking, skin biopsy for quantification of alternative splicing and residual GAA enzyme activity, fibroblast cultures for quantification of alternative splicing and residual GAA enzyme activity, biobanking of fibroblasts).
In vitro treatment of myoblasts and fibroblasts with antisense oligonucleotide chemistries and quantification of restoration of normal splicing, GAA protein and GAA enzyme activity.
All data collect will be introduced in a database and afterwards statistically analyzed.
Expected results:
To determine exact natural history of Pompe disease, to identify biomarkers useful to follow-up the progression of Pompe disease and for quantifying therapy effects of future therapies that aim at restoring a normal splicing in patients with c.-32-13T\>G mutations.
Funding:
This project is funded by the French Agence National de la Recherche, the French Direction Générale de l'Offre de Soins and the Acid Maltase Deficiency Association.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 20
- Pompe disease Patient with c.-32-13T>G mutation in at least one allele of GAA gene.
- Ambulating patient : six-minute walk test distance > 50 m.
- Patient aged between 18 and 80 years.
- Informed consent signed par patient.
- Patient covered by a health insurance.
- Invasive mechanical ventilation
- Pregnant woman
- Presence of comorbidity, in particular preexisting diseases like chronic infectious diseases (VIH infection, hepatitis or others), asthma, malignant tumour, hematologic diseases
- Patient who participate in another clinical trial
- Life expectancy < 12 months
- Unable to understand instructions and restraints of the study
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method The Six-Minute Walk Test at 24 months
- Secondary Outcome Measures
Name Time Method Moter assessment: timed test for standing up from sitting position At baseline, at 6, 12, 18 and 24 months Time for getting up from a chair.
Moter assessment: timed test for standing up from supine position At baseline, at 6, 12, 18 and 24 months Time for getting up from decubitus position.
Moter assessment: 6-minute walk test At baseline, at 6, 12, 18 and 24 months The 6-minute walk test.
Histological features At baseline Histological study by using muscular biopsy culture with Periodic acid-Schiff stain and H\&E stain.
Moter assessment: : the MFM moter function measure scale At baseline, at 6, 12, 18 and 24 months Measurement of motor function by MFM (Motor Function Measure) scale.
Body composition At baseline, 12th and 24th months Body Mass Index (BMI).
Evaluation of skeletal muscle by MRI imaging At baseline, 12th and 24th months Whole-body muscle MRI protocol :
* Short tau inversion recovery (STIR).
* T2-axial and coronal 3D.
* IDEAL IQ.Respiratory parameters: dyspnea using Borg scale At baseline, at 6, 12, 18 and 24 months Evaluation of dyspnea using Borg scale.
Respiratory assessment: alveolar hypoventilation identification At baseline, at 6, 12, 18 and 24 months Identification of clinical signs of alveolar hypoventilation.
Molecular and biochemical parameters: muscular biopsy At baseline Muscular biopsy:
Quantification of alternative splicing and residual enzymatic activity of acid alpha-glucosidase (GAA) of Pompe patient with c.-32 -13T\>G mutation of GAA gene.Moter assessment: quadriceps strength At baseline, at 6, 12, 18 and 24 months Quadriceps muscle strength assessed following magnetic stimulated of femoral nerve.
Moter assessment: timed 10 meters run/walk test At baseline, at 6, 12, 18 and 24 months Time for a 10-meter walk.
Moter assessment: time taken to climb 4 stairs At baseline, at 6, 12, 18 and 24 months Time for climbing 4 stairs.
Moter assessment: three-dimensional analysis of walk At baseline, at 6, 12, 18 and 24 months 3D analysis of walking.
Respiratory parameters: daily duration of non-ventilation for ventilated patients At baseline, at 6, 12, 18 and 24 months Daily duration of non-ventilation for ventilated patients.
Biomarkers At baseline Blood sample (serum):
Dosing of CPK, GPT and GOT level in serum.Heart function assessment At baseline, at 6, 12, 18 and 24 months Assessment of heart assessment using ECG
Quality of life assessment At baseline Evaluate by Rasch-built Pompe-specific activity (R-Pact) scale.
Genotype At baseline Determination of patient's GAA genotypes on blood sample.
Molecular and biochemical parameters: cutaneous biopsy At baseline Cutaneous biopsy:
Quantification of alternative splicing and residual enzymatic activity of acid alpha-glucosidase (GAA) of Pompe patient with c.-32 -13T\>G mutation of GAA gene.
Trial Locations
- Locations (1)
Hôpital Raymond Poincaré
🇫🇷Garches, Hauts-de-Seine, France