A 5-year Natural History Study in LAMA2-related Muscular Dystrophy and SELENON-related Myopathy.

November 9, 2023 updated by: Radboud University Medical Center

A 5-year Natural History Study in LAMA2-related Muscular Dystrophy and SELENON-related Myopathy: the Extended LAST STRONG Study

SELENON-related myopathy (SELENON-RM) and LAMA2-related muscular dystrophy (LAMA2-MD) are congenital neuromuscular disorders presenting with slowly, progressive axial muscle weakness, spinal rigidity, scoliosis and respiratory insufficiency. Currently, no curative treatment options exist, yet promising preclinical trials are ongoing. Clinical trials are expected to start within 5 years. Natural history data and outcome measures for measuring therapy effectiveness were lacking. Therefore, the LAST STRONG Study (a 1.5-year natural history study) started in 2020. With the extended LAST STRONG Study, we aim to further analyze and expand the 1.5-year natural history data on SELENON-RM or LAMA2-MD to provide a detailed clinical description of the Dutch and Flemish cohort. This will enable a smooth transition towards implementation into clinical care and clinical trials.

The extended LAST STRONG Study is a prospective, observational natural history study in Dutch-speaking patients of all ages diagnosed with SELENON-RM and LAMA2-MD. Patients will be invited to visit our hospital two times (3- and 5-years) after the first visit in the LAST STRONG Study. During both visits, patients will undergo a subset of tests (neurological examination, functional measurements, questionnaires, muscle ultrasound, MRI, pulmonary assessment and accelerometry). All measurements are adapted to the patient's age and functional disabilities.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Rationale: A long-term prospective natural history study in an unselected group of patients including clinical and functional outcome measures is lacking in both SELENON-related myopathy (SELENON-RM) and LAMA2-related muscular dystrophy (LAMA2-MD). Due to the promising ongoing preclinical trials, there is a high need to obtain natural history data in order to reach trial readiness for both diseases. With the extended LAST STRONG study, we aim to further analyze and expand our 1.5-year natural history data on SELENON-RM and LAMA2-MD to provide a detailed clinical description of the Dutch and Flemish cohort. This will enable a smooth transition towards implementation into clinical care and clinical trials that are expected to start within 5 years.

Objective: (1) To collect 3- and 5-year natural history data in patients with SELENON-RM and LAMA2-MD. (2) Implementation of natural history data collection into clinical care and international guidelines, and reach trial readiness.

Study design: This is an observational study. A variety of tests will be performed to get a full impression of the patient's abilities and disabilities (standard medical history, neurological examination, functional measurements, questionnaires, imaging, pulmonary assessment and accelerometry). The tests that the patient undergoes depend on the age/abilities/wishes. The tests are selected based on our previously performed 1.5-year natural history study in LAMA2-MD and SELENON-RM. Each participant will perform these measurements during the two scheduled visits at 3- and 5-year after the first visit during the LAST STRONG Study.

Risk and benefit assessment: This study does not concern any product (medicinal product, food product or medical device). There is a small risk for minor injury, e.g. when a participant falls. However since the investigators use all functional tests using movements to which most participants are familiar (i.e. walking, transfers, etc.), the participant will be able to estimate his/her own risk. The investigators don't include tests in which they push participants to their physical limits. the investigators conclude that this study has a negligible risk. A benefit includes the possibility for participants to get a detailed analysis on their own health. Additionally, participants will contribute to the design of future clinical trials on possible treatment options.

Study Type

Observational

Enrollment (Estimated)

40

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

SELENON-RM patients (prevalence: 0.5 in 1.000.000) and LAMA2-RM patients (prevalence: 4 in 500.000) are rare and no Dutch registry exists. Therefore, the investigators can only estimate the number of patients in the Netherlands and Belgium. All patients with SELENON-RM and LAMA2-MD mutations will be identified through contact with genetic diagnostic services, rehabilitation centers, and muscle disease experts in The Netherlands and Dutch-speaking Belgium.

In the LAST STRONG Study, 27 LAMA2-MD patients (21±13 years) and 11 SELENON-RM (20±13 years) patients were included. Based on this high participation rate and the minimal loss from follow-up, we expect between 35 to 40 patients to participate in the extended LAST STRONG Study.

Description

Inclusion Criteria:

  • Willing and able to complete (part of) the measurement protocol at the Radboudumc, Nijmegen. If patients do not wish or not able to visit our neuromuscular center, they are offered to participate in our study through home visits.
  • Genetic conformation of LAMA2-related muscular dystrophy or SELENON-related myopathy by two recessive (likely) pathologic mutations in the LAMA2 or SELENON gene.
  • Typical clinical and histological characteristics combined with genetic confirmation in a first degree relative.
  • Dutch speaking

Exclusion Criteria:

  • Insufficient understanding of the Dutch language

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
SELENON-related myopathy or LAMA2-related muscular dystrophy

Participants diagnosed with congenital myopathy/muscular dystrophy due to mutations in the SEPN1 (SELENON) or LAMA2 gene

Interventions: No intervention
Other: No intervention
No intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of Motor Function Measure (MFM)-32 (older than 7 years) of MFM-20 (2 to 7 years old)
Time Frame: Change from baseline to 3 years and 5 years
Global motor functioning. The items of the MFM are classified in 3 domains: D1: standing and transfers, D2: Axial and proximal motor function, D3: Distal motor function. Higher scored indicate a better outcome. The range of the total score is 0-96. The main point of interest includes the change of MFM score over a period of 5 years.
Change from baseline to 3 years and 5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of physical activity in daily life assessed by an accelerometer (GENEActiv original devices) for 7 days
Time Frame: Change from baseline to 3 years and 5 years
Physical activity in daily life will be assessed by wearing an accelerometer (GENEActiv original devices) for 7 days.
Change from baseline to 3 years and 5 years
Change of activity limitations assessed using ACTIVLIM (6 years and older)
Time Frame: Change from baseline at 3 years and 5 years
ACTIVLIM assesses the ability to perform 22 activities of daily life on a 3-point scale from impossible to easy.
Change from baseline at 3 years and 5 years
Change of bone density assessed using DEXA-scan (2 years and older)
Time Frame: Change from baseline at 3 years and 5 years
The bone density of the spine and hip will be measured by a DEXA scan.
Change from baseline at 3 years and 5 years
Change of The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score (children under the age of 2 years)
Time Frame: Change from baseline at 3 years and 5 years
CHOP INTEND assesses motor skills of children below 2 years of age.
Change from baseline at 3 years and 5 years
Change of fatigue (pediatric 2-17 years old) assessed by PedsQL Multidimensional Fatigue Scale (MFS)
Time Frame: Change from baseline at 3 years and 5 years
PedsQL MFS assesses subjective fatigue in three domains.
Change from baseline at 3 years and 5 years
Change of functional ability in daily life assessed by Egen klassification scale version 2 (EK2) (16 years and older)
Time Frame: Change from baseline at 3 years and 5 years
The EK2 is a questionnaire that was designed to measure functional ability of activities in daily living in non-ambulant Duchenne muscular dystrophy patients. This questionnaire is only available in English. Therefore, only participants of 16 years and older who have a sufficient understanding of the English language will be asked to complete this questionnaire.
Change from baseline at 3 years and 5 years
Change of Functional Ambulation Category (FAC) (5 years and older)
Time Frame: Change from baseline at 3 years and 5 years
The FAC assesses functional ambulation in participants.
Change from baseline at 3 years and 5 years
Change of Graded and Timed function tests
Time Frame: Change from baseline at 3 years and 5 years
The time (in sec) it takes to complete functions of the lower extremity will be assessed with the 30 seconds sit to stand test, the time it takes to climb 4 stairs, the time it takes to descend 4 stairs and the time it takes to rise from the floor.
Change from baseline at 3 years and 5 years
Change of Hammersmith Infant Neurological Examination (HINE) (under the age of 2 years)
Time Frame: Change from baseline at 3 years and 5 years
HINE is designed to be a simple and scorable method for evaluating infants from 2 months to 2 years of age. It includes three sections that assess different aspects of neurologic function, including neurological examination, developmental milestones and behavioral assessment.
Change from baseline at 3 years and 5 years
Change of Impact on Participation and Autonomy (IPA) (18 years and older)
Time Frame: Change from baseline at 3 years and 5 years
Questionnaire about participation and autonomy in daily life.
Change from baseline at 3 years and 5 years
Change of maximal voluntary isometric contraction (5 years and older)
Time Frame: Change from baseline at 3 years and 5 years
Maximal voluntary isometric contraction will be measured by hand-held dynamometry.
Change from baseline at 3 years and 5 years
Change of location, level and characteristics of pain assessed by McGill pain questionnaire (12 years and older)
Time Frame: Change from baseline at 3 years and 5 years
Questionnaire in which the location, level and characteristics of pain are assessed.
Change from baseline at 3 years and 5 years
Change of muscle atrophy (cm) assessed by muscle ultrasound
Time Frame: Change from baseline at 3 years and 5 years
Muscle atrophy of the leg, arm and abdominal muscles will be assessed by muscle ultrasound.
Change from baseline at 3 years and 5 years
Change of muscle fattening (echo-intensity) assessed by muscle ultrasound
Time Frame: Change from baseline at 3 years and 5 years
Muscle fattening of the leg, arm and abdominal muscles will be assessed by muscle ultrasound.
Change from baseline at 3 years and 5 years
Change of muscle fattening by quantitative lower extremity muscle MRI (10 years and older)
Time Frame: Change from baseline at 3 years and 5 years
A lower extremity MRI will be performed in participants who are able to lie supine and still for 20 minutes and who are not dependent on respiratory equipment. Muscle fattening will be assessed by Regions of interest (ROIs) and modified Mercuri score.
Change from baseline at 3 years and 5 years
Change of muscle atrophy by quantitative lower extremity muscle MRI (10 years and older)
Time Frame: Change from baseline at 3 years and 5 years
A lower extremity MRI will be performed in participants who are able to lie supine and still for 20 minutes and who are not dependent on respiratory equipment. Muscle atrophy will be assessed by muscle volume score.
Change from baseline at 3 years and 5 years
Change of muscle power assessed by muscle power measurements (Medical Research Council (MRC) scale) (2 years and older)
Time Frame: Change from baseline at 3 years and 5 years
Muscle power of individual muscle groups can be assessed by muscle power measurements and graded in correspondence with the MRC scale.
Change from baseline at 3 years and 5 years
Pulmonary function (5 years and older) - change of forced vital capacity (percentage predicted)
Time Frame: Change from baseline at 3 years and 5 years
Obtained with handheld spirometry in sit and supine.
Change from baseline at 3 years and 5 years
Pulmonary function (5 years and older) - change of forced expiratory volume in the first second (liter) (percentage predicted)
Time Frame: Change from baseline at 3 years and 5 years
Obtained with handheld spirometry in sit and supine
Change from baseline at 3 years and 5 years
Pulmonary function (5 years and older) - change of peak expiratory flow (liter per second)
Time Frame: Change from baseline at 3 years and 5 years
Obtained with handheld spirometry in sit and supine
Change from baseline at 3 years and 5 years
Pulmonary function (5 years and older) - change of vital capacity (percentage predicted)
Time Frame: Change from baseline at 3 years and 5 years
Obtained with handheld spirometry in sit and supine
Change from baseline at 3 years and 5 years
Pulmonary function (5 years and older) - change of peak cough flow (liter per second)
Time Frame: Change from baseline at 3 years and 5 years
Obtained with handheld spirometry in sit and supine
Change from baseline at 3 years and 5 years
Pulmonary function (5 years and older) - change of maximal expiratory pressure (cmH2O)
Time Frame: Change from baseline at 3 years and 5 years
Obtained with handheld device
Change from baseline at 3 years and 5 years
Pulmonary function (5 years and older) - change of maximal inspiratory pressure (cmH2O)
Time Frame: Change from baseline at 3 years and 5 years
Obtained with handheld device
Change from baseline at 3 years and 5 years
Pulmonary function (5 years and older) - change of sniff nasal inspiratory pressure (cmH2O)
Time Frame: Change from baseline at 3 years and 5 years
Obtained with handheld device
Change from baseline at 3 years and 5 years
Change of Quality of life (adult) assessed by SF36/RAND36
Time Frame: Change from baseline at 3 years and 5 years
The Quality of Life is measured by the SF36/RAND36 questionnaire. This questionnaire addresses eight concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a singe item that provides an indication of perceived change in health.
Change from baseline at 3 years and 5 years
Change of Quality of Life (adult) assessed by Individualized Neuromuscular Quality of Life (INQoL)
Time Frame: Change from baseline at 3 years and 5 years
The INQoL is a validated muscle disease specific measure of quality of life, which can be used for individuals or large samples.
Change from baseline at 3 years and 5 years
Change of Quality of Life (pediatric; 2-17 years old) assessed by PedsQL neuromuscular module (NMM)
Time Frame: Change from baseline at 3 years and 5 years
The PedsQL NMM questionnaire consists of 25 questions in three domains: Neuromuscular disease, communication and family resources.
Change from baseline at 3 years and 5 years
Change of range of motion of elbows, wrist, hips, knee and ankle
Time Frame: Change from baseline at 3 years and 5 years
The range of motion of elbows, wrist, hips, knee and ankle is noted bilaterally by goniometry.
Change from baseline at 3 years and 5 years
Change of Brooke and Vignos scale (2 years and older)
Time Frame: Change from baseline at 3 years and 5 years
The Brooke and Vignos scale provide ordinal data to assess the upper and lower extremity functions.
Change from baseline at 3 years and 5 years
Change of Wong-Baker Faces Pain Scale (2 years and older)
Time Frame: Change from baseline at 3 years and 5 years
The Wong-Baker Faces Pain Scale was originally created for children to help them communicate about their pain.
Change from baseline at 3 years and 5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Radboud University Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 6, 2023

Primary Completion (Estimated)

September 1, 2026

Study Completion (Estimated)

September 1, 2026

Study Registration Dates

First Submitted

October 5, 2023

First Submitted That Met QC Criteria

November 9, 2023

First Posted (Actual)

November 15, 2023

Study Record Updates

Last Update Posted (Actual)

November 15, 2023

Last Update Submitted That Met QC Criteria

November 9, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL84381.091.23

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Research data is open access shared upon publication, provided that this complies with privacy regulations. The Donders Repository is the default repository for sharing the investigators' data.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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