Clinical trial NCT03564561: Natural History of Pompe Disease
Official title: Clinical and Molecular Aspects of Adult Onset Pompe Disease: a Natural History Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Glycogen Storage Disease Type II, Adult
Keywords: glycogen storage disease type II, adult
Pompe disease
clinical evolution
molecular evolution
follow-up
c.-32-13T>G mutation
antisense oligonucleotide treatment
in vitro
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2018-06-21
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Adult patients between 18 and 80 years with adult-onset Pompe disease who carry the common c.-32-13T\>G mutation of GAA gene, treated or not by Myozyme.

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.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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

Primary outcomes:
measure: The Six-Minute Walk Test
timeFrame: At baseline
measure: The Six-Minute Walk Test
timeFrame: at 6 months
measure: The Six-Minute Walk Test
timeFrame: at 12 months
measure: The Six-Minute Walk Test
timeFrame: at 18 months
measure: The Six-Minute Walk Test
timeFrame: at 24 months
Secondary outcomes:
measure: Moter assessment: quadriceps strength
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Moter assessment: : the MFM moter function measure scale
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Moter assessment: timed 10 meters run/walk test
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Moter assessment: timed test for standing up from sitting position
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Moter assessment: timed test for standing up from supine position
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Moter assessment: time taken to climb 4 stairs
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Moter assessment: three-dimensional analysis of walk
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Moter assessment: 6-minute walk test
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Body composition
timeFrame: At baseline, 12th and 24th months
measure: Body composition
timeFrame: At baseline, 12th and 24th months
measure: Body composition
timeFrame: At baseline, 12th and 24th months
measure: Evaluation of skeletal muscle by MRI imaging
timeFrame: At baseline, 12th and 24th months
measure: Respiratory parameters: dyspnea using Borg scale
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Respiratory assessment: alveolar hypoventilation identification
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Respiratory parameters: daily duration of non-ventilation for ventilated patients
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Heart function assessment
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Heart function assessment
timeFrame: At baseline, at 6, 12, 18 and 24 months
measure: Quality of life assessment
timeFrame: At baseline
measure: Quality of life assessment
timeFrame: At baseline
measure: Quality of life assessment
timeFrame: At baseline
measure: Histological features
timeFrame: At baseline
measure: Genotype
timeFrame: At baseline
measure: Molecular and biochemical parameters: muscular biopsy
timeFrame: At baseline
measure: Molecular and biochemical parameters: cutaneous biopsy
timeFrame: At baseline
measure: Biomarkers
timeFrame: At baseline
Other outcomes:
Locations:
city: Garches
country: France
facility: Hôpital Raymond Poincaré
state: Hauts-de-Seine
Study officials:
affiliation: Hôpital Raymond Poincaré
name: Helge Amthor, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Raymond Poincaré
name: Pascal Laforêt, MD, PhD
role: STUDY_DIRECTOR
References: