Carbon spectroscopy MRI: a non-invasive tool to detect late-onset Pompe disease (LOPD)
| ISRCTN | ISRCTN11241741 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11241741 |
| IRAS number | 305745 |
| Secondary identifying numbers | NU-003493, IRAS 305745, CPMS 51417 |
- Submission date
- 15/06/2022
- Registration date
- 07/07/2022
- Last edited
- 05/04/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English Summary
Background and study aims
Pompe disease, also known as Glycogen Storage Disease type II, is a genetic disorder produced by mutations in the GAA gene resulting in an absence or low levels of the enzyme alpha-glucosidase which is needed to convert glycogen to glucose in cells. This leads to a build-up of glycogen in the cells of several tissues, particularly cardiac, skeletal, and smooth muscle cells.
Most late-onset Pompe disease (LOPD) patients notice their first symptoms during the third or fourth decade of life. Patients slowly develop progressive muscle weakness leading to a variable degree of motor disability. Most patients need canes for walking during the fourth decade of life and a wheelchair in the fifth or sixth decade of life. Respiratory symptoms and respiratory failure requiring non-invasive ventilation are common. Adult patients can have an increased risk of premature death due to respiratory problems.
Enzyme replacement therapy (ERT) improves muscle weakness and reduces the need for supporting ventilation in patients treated. Guidelines recommend starting the treatment only in symptomatic patients with muscle weakness involving skeletal or respiratory muscles. However, compelling evidence suggests earlier treatment in LOPD can result in better outcomes. The build-up of glycogen inside muscle fibres leads to muscle fibre loss and the replacement of muscle with fatty tissue. Fat replacement is irreversible and can lead to permanent weakness and disability. Therefore, an effort to avoid or slow the process of muscle fibre loss and fatty tissue expansion is essential. Repeated biopsies (tissue samples) of LOPD patients showed a reduction in glycogen in muscles with ERT. Therefore, in theory, earlier treatment of LOPD patients, whose muscles are not replaced by fat yet but contain high levels of glycogen, should delay muscle worsening and avoid permanent motor and respiratory disability. However, we do not currently have a non-invasive test capable of identifying and/or calculating muscle glycogen.
The aim of this study is to use an MRI (Magnetic Resonance Imaging) sequence known as 13C-spectroscopy to identify glycogen in the skeletal muscles of patients with LOPD who are still pre-symptomatic or who have minor symptoms. 13C-spectroscopy has previously been shown to identify glycogen in different organs of the body, including skeletal muscle. One study that included 11 LOPD patients showed the average levels of glycogen in muscles was higher than controls for seven out of the 11 patients. However, it was unclear if there were differences in the amount of glycogen over time.
This study aims to use a second MRI sequence known as T2-weighted imaging that provides information about the composition of the skeletal muscles. Glycogen accumulation in muscles may be associated with a change in the T2 relaxation properties of water in muscle. We will assess whether muscle T2 is different in LOPD patients compared to healthy controls.
Additionally, the researchers will use a series of muscle function tests to confirm that patients do not have any sign of muscle damage, and are pre-symptomatic or mildly symptomatic. It is thought that both 13C-spectroscopy and T2 imaging can be useful to identify the accumulation of glycogen in the muscle tissue of these patients and can be used to monitor changes in the concentration of glycogen in the tissue over time.
Who can participate?
Patients with genetically confirmed pre-symptomatic or early symptomatic late-onset Pompe disease (i.e., started showing symptoms after the age of 3 years) aged 12 years and older; and 10 healthy volunteers who are age- and sex-matched with the Pompe patients.
What does the study involve?
Patients with Pompe disease will attend two visits, at the start of the study and after 12 months. Healthy volunteers will attend once only. During the first visit researchers will perform a clinical assessment, a series of muscle function tests, collect patient-reported outcome measures, obtain blood samples, and perform an MRI scan. Muscle function tests will include muscle strength and muscle performance. At 12 months only the Pompe patients will attend the second visit where all the first visit measures will be repeated.
What are the possible benefits and risks of participating?
There are no potential risks as there are no invasive procedures involved in this study. MRI scanning is a safe repeatable medical imaging method that does not involve the use of ionising radiation. Blood collection does not pose a significant risk nor do the muscle function tests. Participants are not expected to directly benefit from this study. All travel and meal expenses will be reimbursed for the patient and one accompanying person.
Where is the study run from?
Newcastle upon Tyne Hospitals NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
January 2022 to December 2025
Who is funding the study?
Sanofi (France)
Who is the main contact?
Prof. Jordi Diaz-Manera, jordi.diaz-manera@newcastle.ac.uk
Contact information
Principal Investigator
John Walton Muscular Dystrophy Research Centre
Translational and Clinical Research Institute
Newcastle University
International Centre for Life
Newcastle upon Tyne
NE1 3BZ
United Kingdom
 ORCID ID |
0000-0003-2941-7988 |
|---|---|
| Phone | +44 (0)1912418602 |
| jordi.diaz-manera@newcastle.ac.uk |
Scientific
John Walton Muscular Dystrophy Research Centre
Translational and Clinical Research Institute
Newcastle University
International Centre for Life
Newcastle upon Tyne
NE1 3BZ
United Kingdom
| Phone | +44 (0)191 241 8941 |
|---|---|
| steph.clutterbuck@newcastle.ac.uk |
Public
John Walton Muscular Dystrophy Research Centre
Translational and Clinical Research Institute
Newcastle University
International Centre for Life
Newcastle upon Tyne
NE1 3BZ
United Kingdom
| Phone | +44 (0)191 241 8652 |
|---|---|
| alejandro.gonzalez-chamorro@newcastle.ac.uk |
Study information
| Study design | Single-centre prospective observational cohort study |
|---|---|
| Primary study design | Observational |
| Secondary study design | Cohort study |
| Study setting(s) | Hospital |
| Study type | Diagnostic |
| Participant information sheet | 41933_PIS_adult healthy controls_V1.1_14Jan22.pdf |
| Scientific title | Muscle MRI as a tool to detect glycogen in the skeletal muscles of patients with adult-onset Pompe patients |
| Study acronym | MRI in Pompe |
| Study hypothesis | It is hypothesized that 13C spectroscopy can quantify skeletal muscle glycogen content in patients with Pompe disease. |
| Ethics approval(s) | Approved 24/01/2022, Yorkshire & The Humber - Leeds West Research Ethics Committee (NHSBT Newcastle Blood Donor Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ, UK; +44 (0)207 972 2504, +44 (0)207 104 8134; leedswest.rec@hra.nhs.uk), ref: 21/YH/0297 |
| Condition | Pompe disease in adult-onset patients |
| Intervention | This study will consist of clinical assessments, collection of blood samples, a series of muscle function tests and collection of patient-reported outcome measures. The participants with Pompe disease will attend two visits over 1 year (baseline and year 1). 13C-magnetic resonance spectroscopy offers a non-invasive measurement by direct MRI-based detection of a unique signal from natural abundance 13C in glycogen. T2 sequence of muscle water will be obtained from the same MRI as well. |
| Intervention type | Other |
| Primary outcome measure | Glycogen measured using 13C spectroscopy for patients and controls at baseline and at the 12-month visit for patients only |
| Secondary outcome measures | 1. Water accumulation measured using water T2 sequence at baseline for patients and controls and at the 12-month visit for patients only 2. Muscle function measured using muscle strength and performance tests at baseline for patients and controls and at 12 months for patients only |
| Overall study start date | 03/01/2022 |
| Overall study end date | 31/12/2025 |
Eligibility
| Participant type(s) | Mixed |
|---|---|
| Age group | Mixed |
| Lower age limit | 12 Years |
| Sex | Both |
| Target number of participants | 10 Pompe patients and 10 healthy controls |
| Participant inclusion criteria | Current participant inclusion criteria as of 05/04/2024: Patients: 1. Diagnosis of Pompe disease based on recommendations recently proposed by the European Pompe Consortium: reduced enzymatic activity in leukocytes, fibroblasts or skeletal muscle and/or by the presence of two mutations in the GAA gene following the diagnostic 2. Aged 12 years and older 3. No contraindications to MRI 4. No symptoms of muscle weakness or mild symptoms 5. Willingness to complete all muscle function tests at baseline and year 1 visit Healthy controls: 1. Male and female age-matched with the patients (12 years and older) 2. No contraindications to MRI 3. Willingness to complete all study assessments Previous participant inclusion criteria: Patients: 1. Diagnosis of Pompe disease based on recommendations recently proposed by the European Pompe Consortium: reduced enzymatic activity in leukocytes, fibroblasts or skeletal muscle and/or by the presence of two mutations in the GAA gene following the diagnostic 2. Aged 12 years and older 3. No contraindications to MRI 4. No symptoms of muscle weakness or mild symptoms. Patients should score higher than 30 points on the RPact scale 5. Willingness to complete all muscle function tests at baseline and year 1 visit Healthy controls: 1. Male and female age-matched with the patients (12 years and older) 2. No contraindications to MRI 3. Willingness to complete all study assessments |
| Participant exclusion criteria | 1. Contraindications for MRI such as having a metallic prosthesis, pacemaker or any other device that makes the completion of an MRI impossible 2. Not willing to complete all muscle function tests both at baseline and year 1 (just patients) 3. Having claustrophobia or other condition that could limit the capacity of the patient for being located inside the MRI 4. Inability to lie supine for less than 45 min 5. Pregnancy (for female participants of childbearing age only) 6. Not being able to understand and speak English (added 17/01/2023: unless accompanied by a translator) 7. Study team decision that it is not in the best interests of the patient to participate in the study |
| Recruitment start date | 01/06/2022 |
| Recruitment end date | 31/12/2024 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Newcastle University
Newcastle upon Tyne
NE1 3BZ
United Kingdom
Newcastle University
Newcastle upon Tyne
NE4 5PL
United Kingdom
Royal Victoria Infirmary
Queen Victoria Road
Newcastle upon Tyne
NE1 4LP
United Kingdom
Sponsor information
Hospital/treatment centre
Freeman Hospital
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
England
United Kingdom
| Phone | +44 (0)191 233 6161 |
|---|---|
| nuth.nuthsponsorship@nhs.net | |
| Website | http://www.newcastle-hospitals.org.uk/ |
"ROR" |
https://ror.org/05p40t847 |
Funders
Funder type
Industry
Government organisation / For-profit companies (industry)
- Alternative name(s)
- sanofi-aventis, Sanofi US, Sanofi-Aventis U.S. LLC, Sanofi U.S.
- Location
- United States of America
Results and Publications
| Intention to publish date | 01/12/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. Patients have and will be involved in the research process relating to this study. Patients are involved in the assessment of the acceptability of the research and the design of the research by being involved in the protocol review. Patient organisations will be involved in the dissemination of findings as the study results will be presented at the patient organisation’s annual conference. |
| IPD sharing plan | We will not be depositing raw data in publicly available repositories. Larger follow on studies have the participant-level data submitted to public repositories. After the study has ended the site files will be stored securely in the locked filing cabinet. These will be archived following the Newcastle Hospitals NHS Foundation Trust policies for longer-term storage. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | PIS for adult healthy controls version 1.1 |
14/01/2022 | 23/06/2022 | No | Yes |
| Participant information sheet | PIS for adult patients version 1.1 |
14/01/2022 | 23/06/2022 | No | Yes |
| Participant information sheet | PIS for healthy controls aged 12+ version 1.1 |
14/01/2022 | 23/06/2022 | No | Yes |
| Participant information sheet | PIS for parents of healthy controls version 1.1 |
14/01/2022 | 23/06/2022 | No | Yes |
| Participant information sheet | PIS for parents of patients version 1.1 |
14/01/2022 | 23/06/2022 | No | Yes |
| Participant information sheet | PIS for patients aged 12+ version 1.1 |
14/01/2022 | 23/06/2022 | No | Yes |
| Protocol file | version 1.0 | 20/10/2021 | 23/06/2022 | No | No |
| HRA research summary | 26/07/2023 | No | No | ||
| Participant information sheet | version 2.0 | 04/04/2023 | 05/04/2024 | No | Yes |
| Participant information sheet | version 2.0 | 04/04/2023 | 05/04/2024 | No | Yes |
| Participant information sheet | version 2.0 | 04/04/2023 | 05/04/2024 | No | Yes |
| Participant information sheet | version 2.0 | 04/04/2023 | 05/04/2024 | No | Yes |
| Participant information sheet | version 2.0 | 04/04/2023 | 05/04/2024 | No | Yes |
| Participant information sheet | version 2.0 | 04/04/2023 | 05/04/2024 | No | Yes |
| Protocol file | version 2.0 | 04/04/2023 | 05/04/2024 | No | No |
Additional files
- 41933_Protocol_v1.0_20Oct21.pdf
- 41933_PIS_adult patients_V1.1_14Jan22.pdf
- PIS for adult patients
- 41933_PIS_adult healthy controls_V1.1_14Jan22.pdf
- PIS for adult healthy controls
- 41933_PIS_patients aged 12+_V1.1_14Jan22.pdf
- PIS for patients aged 12+
- 41933_ PIS_healthy controls aged 12+_V 1.1_14Jan22.pdf
- PIS for healthy controls aged 12+
- 41933_PIS_parents of patients_V1.1_14Jan22.pdf
- PIS for parents of patients
- 41933_PIS_parents of healthy controls_V1.1_14Jan22.pdf
- PIS for parents of healthy controls
- ISRCTN11241741_Protocol_MRI in Pompe_v2.0_04April2023.pdf
- ISRCTN11241741_PIS_MRI in Pompe_12plusPatient_V2.0_04April2023.pdf
- ISRCTN11241741_PIS_MRI in Pompe_12plus_Healthy Controls_V2.0_04April2023.pdf
- ISRCTN11241741_PIS_MRI in Pompe_AdultHealthyControl_V.2.0_04April2023.pdf
- ISRCTN11241741_PIS_MRI in Pompe_AdultPatient_V2.0_04April2023.pdf
- ISRCTN11241741_PIS_MRI in Pompe_ParentsofHealthyControls_V2.0_04April2023.pdf
- ISRCTN11241741_PIS_MRI in Pompe_ParentsofthePatients_V2.0_04April2023.pdf
Editorial Notes
05/04/2024: The following changes were made:
1. The participant inclusion criteria were amended.
2. The following files have been unloaded as additional files: Protocol V2.0; 12+ Patient PIS_V2.0; 12+Healthy Controls PIS_V2.0; Adult Healthy Control PIS_V.2.0; Adult Patient PIS_V2.0; Parents of Healthy Controls PIS_V2.0 and Parents of the Patients PIS_V2.0.
27/03/2023: The following changes were made to the trial record:
1. The target number of participants was changed from 20 Pompe patients and 20 healthy controls to 10 Pompe patients and 10 healthy controls.
17/01/2023: The following changes were made to the trial record:
1. The target number of participants was changed from 10 Pompe patients and 10 healthy controls to 20 Pompe patients and 20 healthy controls.
2. The recruitment start date was changed from 22/03/2022 to 01/06/2022.
3. The recruitment end date was changed from 22/01/2023 to 31/12/2024.
4. The overall end date was changed from 22/01/2024 to 31/12/2025.
5. The exclusion criteria were updated.
6. The plain English summary was updated to reflect these changes.
7. The intention to publish date was changed from 01/12/2025 to 01/12/2026.
15/08/2022: The following changes have been made:
1. The recruitment start date has been changed from 28/01/2022 to 22/03/2022.
2. The recruitment end date has been changed from 28/08/2022 to 22/01/2023.
3. The overall trial end date has been changed from 31/10/2023 to 22/01/2024 and the plain English summary updated accordingly.
4. The intention to publish date has been changed from 01/09/2025 to 01/12/2025.
5. A scientific contact and a public contact have been added.
04/08/2022: Internal review.
02/08/2022: The sponsor contact details have been changed.
23/06/2022: Trial’s existence confirmed by Yorkshire & The Humber - Leeds West Research Ethics Committee.
