Natural History of Pompe Disease (POMPE)

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ClinicalTrials.gov Identifier: NCT03564561

Recruitment Status : Recruiting

First Posted : June 21, 2018

Last Update Posted : April 8, 2024

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Sponsor:

Information provided by (Responsible Party):

Assistance Publique - Hôpitaux de Paris

Study Description

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.

Condition or disease
Glycogen Storage Disease Type II, Adult

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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 Design

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Study Type :	Observational
Estimated Enrollment :	20 participants
Observational Model:	Cohort
Time Perspective:	Prospective
Official Title:	Clinical and Molecular Aspects of Adult Onset Pompe Disease: a Natural History Study
Actual Study Start Date :	June 7, 2019
Estimated Primary Completion Date :	March 2033
Estimated Study Completion Date :	March 2033

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Pompe disease

Genetic and Rare Diseases Information Center resources: Glycogen Storage Disease Type 2

U.S. FDA Resources

Groups and Cohorts

Outcome Measures

Primary Outcome Measures :

The Six-Minute Walk Test [ Time Frame: At baseline ]
The Six-Minute Walk Test [ Time Frame: at 6 months ]
The Six-Minute Walk Test [ Time Frame: at 12 months ]
The Six-Minute Walk Test [ Time Frame: at 18 months ]
The Six-Minute Walk Test [ Time Frame: at 24 months ]

Secondary Outcome Measures :

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

Dosing of CPK, GPT and GOT level in serum.

Biospecimen Retention: Samples With DNA

Blood, urine, skeletal muscle biopsy, skin biopsy:

Blood for serum markers, DNA and white blood cell culture (lymphoblastoid cell line).
Skeletal muscle biopsy for histology, RNA and protein analysis, myoblast culture.
Skin biopsy for RNA and protein analysis, fibroblast culture.
Urine for biomarker analysis.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
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.

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03564561

Contacts

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Contact: Helge Amthor, MD, PhD	+ 33 1 47 10 78 90	helge.amthor@aphp.fr
Contact: Pascal Laforêt, MD, PhD	+ 33 1 47 10 37 76	pascal.laforet@aphp.fr

Locations

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

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators

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Principal Investigator:	Helge Amthor, MD, PhD	Hôpital Raymond Poincaré
Study Director:	Pascal Laforêt, MD, PhD	Hôpital Raymond Poincaré

More Information

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Responsible Party:	Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:	NCT03564561
Other Study ID Numbers:	P160405J 2017-A02458-45 ( Registry Identifier: N° ID RCB )
First Posted:	June 21, 2018 Key Record Dates
Last Update Posted:	April 8, 2024
Last Verified:	April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Assistance Publique - Hôpitaux de Paris:


glycogen storage disease type II, adult Pompe disease clinical evolution molecular evolution	follow-up c.-32-13T>G mutation antisense oligonucleotide treatment in vitro

Additional relevant MeSH terms:

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Glycogen Storage Disease Type II Glycogen Storage Disease Disease Lysosomal Storage Diseases, Nervous System Brain Diseases, Metabolic, Inborn Brain Diseases, Metabolic Brain Diseases Central Nervous System Diseases	Nervous System Diseases Metabolism, Inborn Errors Genetic Diseases, Inborn Carbohydrate Metabolism, Inborn Errors Lysosomal Storage Diseases Metabolic Diseases Pathologic Processes

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