Natural History of Pompe Disease (POMPE)

Clinical and Molecular Aspects of Adult Onset Pompe Disease: a Natural History Study

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.

Study Overview

• Status: Recruiting
• Conditions: Glycogen Storage Disease Type II, Adult

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.

• Study Type: Observational
• Enrollment (Estimated): 20

Contacts and Locations

• Study Contact: Name: Helge Amthor, MD, PhD; Phone Number: + 33 1 47 10 78 90; Email: helge.amthor@aphp.fr
• Study Contact Backup: Name: Pascal Laforêt, MD, PhD; Phone Number: + 33 1 47 10 37 76; Email: pascal.laforet@aphp.fr

Study Locations

• France
  • Hauts-de-Seine
    • Garches, Hauts-de-Seine, France, 92380
      • Recruiting
      • Hôpital Raymond Poincaré

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The Six-Minute Walk Test	At baseline
The Six-Minute Walk Test	at 6 months
The Six-Minute Walk Test	at 12 months
The Six-Minute Walk Test	at 18 months
The Six-Minute Walk Test	at 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Moter assessment: quadriceps strength	Quadriceps muscle strength assessed following magnetic stimulated of femoral nerve.	At baseline, at 6, 12, 18 and 24 months
Moter assessment: : the MFM moter function measure scale	Measurement of motor function by MFM (Motor Function Measure) scale.	At baseline, at 6, 12, 18 and 24 months
Moter assessment: timed 10 meters run/walk test	Time for a 10-meter walk.	At baseline, at 6, 12, 18 and 24 months
Moter assessment: timed test for standing up from sitting position	Time for getting up from a chair.	At baseline, at 6, 12, 18 and 24 months
Moter assessment: timed test for standing up from supine position	Time for getting up from decubitus position.	At baseline, at 6, 12, 18 and 24 months
Moter assessment: time taken to climb 4 stairs	Time for climbing 4 stairs.	At baseline, at 6, 12, 18 and 24 months
Moter assessment: three-dimensional analysis of walk	3D analysis of walking.	At baseline, at 6, 12, 18 and 24 months
Moter assessment: 6-minute walk test	The 6-minute walk test.	At baseline, at 6, 12, 18 and 24 months
Body composition	Osteodensitometry.	At baseline, 12th and 24th months
Body composition	Body composition (ratio lean mass / fat mass) measure by dual-energy X-ray absorptiometry.	At baseline, 12th and 24th months
Body composition	Body Mass Index (BMI).	At baseline, 12th and 24th months
Evaluation of skeletal muscle by MRI imaging	Whole-body muscle MRI protocol : Short tau inversion recovery (STIR).; T2-axial and coronal 3D.; IDEAL IQ.	At baseline, 12th and 24th months
Respiratory parameters: dyspnea using Borg scale	Evaluation of dyspnea using Borg scale.	At baseline, at 6, 12, 18 and 24 months
Respiratory assessment: alveolar hypoventilation identification	Identification of clinical signs of alveolar hypoventilation.	At baseline, at 6, 12, 18 and 24 months
Respiratory parameters: daily duration of non-ventilation for ventilated patients	Daily duration of non-ventilation for ventilated patients.	At baseline, at 6, 12, 18 and 24 months
Heart function assessment	Assessment of heart assessment using heart echography	At baseline, at 6, 12, 18 and 24 months
Heart function assessment	Assessment of heart assessment using ECG	At baseline, at 6, 12, 18 and 24 months
Quality of life assessment	Evaluate by Questionnaire EQ5D-5L.	At baseline
Quality of life assessment	Evaluate by Rotterdam handicap scale.	At baseline
Quality of life assessment	Evaluate by Rasch-built Pompe-specific activity (R-Pact) scale.	At baseline
Histological features	Histological study by using muscular biopsy culture with Periodic acid-Schiff stain and H&E stain.	At baseline
Genotype	Determination of patient's GAA genotypes on blood sample.	At baseline
Molecular and biochemical parameters: muscular biopsy	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.	At baseline
Molecular and biochemical parameters: cutaneous biopsy	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.	At baseline
Biomarkers	Blood sample (serum): Dosing of CPK, GPT and GOT level in serum.	At baseline

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Helge Amthor, MD, PhD, Hôpital Raymond Poincaré; Study Director: Pascal Laforêt, MD, PhD, Hôpital Raymond Poincaré

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2019
• Primary Completion (Estimated): March 1, 2033
• Study Completion (Estimated): March 1, 2033

Study Registration Dates

• First Submitted: March 27, 2018
• First Submitted That Met QC Criteria: June 10, 2018
• First Posted (Actual): June 21, 2018

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 5, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: follow-up; Pompe disease; glycogen storage disease type II, adult; clinical evolution; molecular evolution; c.-32-13T>G mutation; antisense oligonucleotide treatment; in vitro
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Lysosomal Storage Diseases, Nervous System; Disease; Glycogen Storage Disease Type II; Glycogen Storage Disease
• Other Study ID Numbers: P160405J; 2017-A02458-45 (Registry Identifier: N° ID RCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No