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Clinical, Immunological, Morphological and Genetic Characteristics of Patients With Dysferlinopathy in the RF (DYSF-RUS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04824040
Recruitment Status : Enrolling by invitation
First Posted : April 1, 2021
Last Update Posted : April 2, 2021
Sponsor:
Collaborator:
S. M. Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation
Information provided by (Responsible Party):
Human Stem Cell Institute, Russia

Brief Summary:
To evaluate specific characteristics of phenotype, immune status, molecular and genetic as well as morphological characteristics of adult patients with limb-girdle muscular dystrophy R2 in various regions of the Russian Federation.

Condition or disease
Dysferlinopathy Miyoshi Myopathy LGMDR2 DMAT

Detailed Description:

A single-center, cohort clinical study. Subjects of both sexes aged 18 to 65 inclusive with genetically confirmed diagnosis of limb-girdle muscular dystrophy type R2, who have signed the written informed consent form for this study.

The control and case groups should be age- and gender-matched.

Study Objectives:

  • To evaluate a clinical status of a subject (MMT score; 6-minute walk test; North Star Assessment for dysferlinopathy (NSAD));
  • To assess blood biochemistry;
  • To characterize muscle involvement based on MRI results;
  • To evaluate the progression of muscle involvement based on repeated MRI;
  • To assess cardiac function with ECG, EchoCG and MRI;
  • To determine a gait pattern and balance characteristics in patients with limb-girdle muscular dystrophy using electrophysiological techniques (Neurosoft Gait Assessment System Steadys; stabilometrics and plantography with "SIDAS");
  • To characterize changes in subpopulation compositions of T- and B-lymphocytes, phagocytic activity of leukocytes (a phagocytic index, a phagocyte number, an index of phagocytosis completeness, lysosomal-cation and NBT tests);
  • To assess average blood cytokine levels in subjects with limb-girdle muscular dystrophy (type R2) in various regions of the Russian Federation;
  • To assess average blood cytokine levels in healthy subjects from various regions of the RF;
  • To analyze the relationship between blood cytokine levels and the presence of a mutation in the dysferlin gene;
  • To study the expression (immunohistochemistry and western-blotting) and distribution of dysferlin in impaired muscles of subjects with LGMDR2.

The clinical study includes the stages as follows:

  1. Subject enrollment - 24 months
  2. Data collection and analysis - 12 months
  3. Study Report - 30 days.

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 100 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 2 Years
Official Title: Evaluation of Clinical, Immunological, Morphological, Molecular and Genetic Characteristics of Patients With Limb-girdle Muscular Dystrophy Type R2 (Type 2B) in the Russian Federation
Actual Study Start Date : January 15, 2020
Estimated Primary Completion Date : February 25, 2022
Estimated Study Completion Date : July 2022


Group/Cohort
Study group
Patients with a genetically confirmed dysferlinopathy.
Control group
Healthy Volunteers



Primary Outcome Measures :
  1. Сlinical status of patients with dysferlinopathy (MMT score) [ Time Frame: Through study completion at 24 months ]
    Muscle strength will be assessed using MMT and will be expressed in points for each of the muscle groups assessed.

  2. Сlinical status of patients with dysferlinopathy ( North Star Assessment for dysferlinopathy) [ Time Frame: Through study completion at 24 months ]
    North Star Assessment for Dysferlinopathy (NSAD) is a functional scale that will be used to measure motor performance in individuals with dysferlinopathy (includes 29 items).

  3. Сlinical status of patients with dysferlinopathy (Hand Held Dynamometry). [ Time Frame: Through study completion at 24 months ]
    Hand held dynamometry using the MicroFET2 myometer will be utilized to capture isometric muscle strength. Maximum strength in kilograms will be reported for each muscle group.

  4. Сlinical status of patients with dysferlinopathy (6-minute walk test) [ Time Frame: Through study completion at 24 months ]
    The participant will be asked to complete maximal distance in 6 minet as quickly as safely possible and the time in seconds is recorded.

  5. Clinical blood test (level of hemoglobin) [ Time Frame: Through study completion at 24 months. ]
    Level of hemoglobin is planned to be assessed in patients with dysferlinopathy.

  6. Clinical blood test. Level of hematocrit [ Time Frame: Through study completion at 24 months. ]
    Level of hematocrit (%) is planned to be assessed in patients with dysferlinopathy.

  7. Clinical blood test. Level of RBC [ Time Frame: Through study completion at 24 months. ]
    Level of RBC is planned to be assessed in patients with dysferlinopathy.

  8. Clinical blood test. Level of WBC [ Time Frame: Through study completion at 24 months. ]
    Level of WBC is planned to be assessed in patients with dysferlinopathy.

  9. Clinical blood test. Levels of ESR [ Time Frame: Through study completion at 24 months. ]
    Levels of ESR (mm/h) is planned to be assessed in patients with dysferlinopathy.

  10. Clinical blood test. Level of platelets [ Time Frame: Through study completion at 24 months. ]
    Level of platelets is planned to be assessed in patients with dysferlinopathy.

  11. Biochemical blood test. [ Time Frame: Through study completion at 24 months ]
    Levels of potassium (mmol/l) is planned to be assessed in patients with dysferlinopathy.

  12. Biochemical blood test. Level of sodium [ Time Frame: Through study completion at 24 months. ]
    Level of sodium (mmol/l) is planned to be assessed in patients with dysferlinopathy.

  13. Biochemical blood test. Level of calcium [ Time Frame: Through study completion at 24 months. ]
    Level of calcium (mmol/l) is planned to be assessed in patients with dysferlinopathy.

  14. Biochemical blood test. Level of creatinine [ Time Frame: Through study completion at 24 months. ]
    Level of creatinine (μmol/l) is planned to be assessed in patients with dysferlinopathy.

  15. Biochemical blood test. Level of glucose [ Time Frame: Through study completion at 24 months. ]
    Level of glucose (mmol/l) is planned to be assessed in patients with dysferlinopathy.

  16. Biochemical blood test. Level of uric acid [ Time Frame: Through study completion at 24 months. ]
    Level of uric acid (μmol/l) is planned to be assessed in patients with dysferlinopathy.

  17. Biochemical blood test. Level of urea [ Time Frame: Through study completion at 24 months. ]
    Level of urea (mmol/l) is planned to be assessed in patients with dysferlinopathy.

  18. Biochemical blood test. Level of ALT [ Time Frame: Through study completion at 24 months. ]
    Level of ALT (U/l) is planned to be assessed in patients with dysferlinopathy.

  19. Biochemical blood test. Level of AST [ Time Frame: Through study completion at 24 months. ]
    Level of AST (U/l) is planned to be assessed in patients with dysferlinopathy.

  20. Biochemical blood test. Level of total protein [ Time Frame: Through study completion at 24 months. ]
    Level of total protein (g/l) is planned to be assessed in patients with dysferlinopathy.

  21. Biochemical blood test. Level of CPK [ Time Frame: Through study completion at 24 months. ]
    Level of CPK (U/l) is planned to be assessed in patients with dysferlinopathy.

  22. Biochemical blood test. Level of triglycerides [ Time Frame: Through study completion at 24 months. ]
    Level of triglycerides (mmol/l) is planned to be assessed in patients with dysferlinopathy.

  23. Biochemical blood test. Level of CRP [ Time Frame: Through study completion at 24 months. ]
    Level of CRP (mg/l) is planned to be assessed in patients with dysferlinopathy.

  24. Blood cytokine levels in subjects with dysferlinopathy and healthy volunteers. [ Time Frame: Through study completion at 24 months ]
    • To assess average blood cytokine levels in subjects with dysferlinopathy in various regions of the Russian Federation;
    • To assess average blood cytokine levels in healthy subjects.

    Blood serum cytokine profiling will be performed with the use of the multiparameter fluorescent diagnostic system Luminex 200 and the Bio-Plex Pro Human 27-Plex Panel (Bio-Rad, Hercules, USA) in accordance with the manufacturer's instructions. The data obtained will be processed with the use of MasterPlex CT control and MasterPlex QT analysis software (Hitachi Software, San Bruno, USA).

    The following cytokine Levels will be assessed in the study:FGF2, Eotaxin,G-CSF, GM-CSF, IFN-γ, IL-1β, 1IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 p70, IL-13, IL-15, IL-17, IP-10, MCP-1/MCAF, MIP-1α, MIP-1β,PDGF-BB, RANTES, TNF-α, VEGF.


  25. Autoantibodies in patients with dysferlinopathy. [ Time Frame: Through study completion at 24 months ]
    Assessment of antibodу level against skeletal muscle antigens; an antinuclear factor (ANA), an extractable nuclear antigen.

  26. Muscle MRI in patients with dysferlinopathy. [ Time Frame: Through study completion at 24 months. ]
    • To characterize muscle involvement based on MRI results;
    • To evaluate the progression of muscle involvement based on repeated MRI once year;

  27. Subpopulation compositions of T-lymphocytes in subjects with dysferlinopathy. [ Time Frame: Through study completion at 24 months ]
    • To characterize changes in subpopulation compositions of T-lymphocytes in %.

  28. Subpopulation compositions of B-lymphocytes in subjects with dysferlinopathy. [ Time Frame: Through study completion at 24 months ]
    • To characterize changes in subpopulation compositions of B-lymphocytes in %.

  29. Subpopulation compositions of phagocytic activity of leukocytes in subjects with dysferlinopathy (NBT test) [ Time Frame: Through study completion at 24 months ]
    • To characterize changes in phagocytic activity of leukocytes (NBT test in CU).

  30. Subpopulation compositions of phagocytic activity of leukocytes in subjects with dysferlinopathy. [ Time Frame: Through study completion at 24 months ]
    • To characterize changes in phagocytic activity of leukocytes (a phagocyte number in CU).

  31. Subpopulation compositions of phagocytic activity of leukocytes in subjects with dysferlinopathy (lysosomal-cation test). [ Time Frame: Through study completion at 24 months ]
    • To characterize changes in phagocytic activity of leukocytes (lysosomal-cation test in CU).

  32. Subpopulation compositions of phagocytic activity of leukocytes (a phagocytic index) in subjects with dysferlinopathy. [ Time Frame: Through study completion at 24 months ]
    • To characterize changes in phagocytic activity of leukocytes (a phagocytic index).

  33. Gait pattern and balance characteristics in patients with limb-girdle muscular dystrophy R2. [ Time Frame: Through study completion at 24 months. ]
    To determine a gait pattern characteristics in patients with limb-girdle muscular dystrophy R2 using electrophysiological techniques (Neurosoft Gait Assessment System "STEDIS").

  34. Cardiac function (assessed by Echocardiography). LV [ Time Frame: Through study completion at 24 months. ]
    The absolute and relative sizes of the left ventricle (LV) index will be determin.

  35. Cardiac function (assessed by Echocardiography). LV mass [ Time Frame: Through study completion at 24 months. ]
    The absolute and relative sizes of the LV mass index will be determin.

  36. Cardiac function (assessed by Echocardiography). Myocardium mass [ Time Frame: Through study completion at 24 months. ]
    The absolute and relative sizes of the myocardium mass index will be determin.

  37. Cardiac function (assessed by Echocardiography). RV [ Time Frame: Through study completion at 24 months. ]
    The absolute and relative sizes of the right ventricle (RV) index will be determin.

  38. Cardiac function (assessed by MRI scan with a gadolinium-based contrast agent). Volumetric evaluation of LV mass [ Time Frame: Through study completion at 24 months. ]
    Volumetric evaluation of LV mass by manual tracing will be perform. An MRI of the heart will assess fibrosis.

  39. Cardiac function (assessed by Echocardiography). LA [ Time Frame: Through study completion at 24 months. ]
    The absolute and relative sizes of the left atrium (LA) index will be determin.

  40. Cardiac function (assessed by Electrocardiography). Outcome 13 [ Time Frame: Through study completion at 24 months. ]
    To assess rhythm characteristic, P-wave, QRS, T-wave duration; PR, RR, QT intervals; PR, ST segments.

  41. Cardiac function (assessed by MRI scan with a gadolinium-based contrast agent). Volumetric evaluation of EF [ Time Frame: Through study completion at 24 months. ]
    Volumetric evaluation of EF by manual tracing will be perform.

  42. Cardiac function (assessed by MRI scan with a gadolinium-based contrast agent). [ Time Frame: Through study completion at 24 months. ]
    Volumetric evaluation of volume by manual tracing will be perform.

  43. Morphological muscle study [ Time Frame: Through study completion at 24 months. ]
    If it was necessary to confirm the causation of mutations in the dysferlin gene, the patients underwent muscle biopsy. To study the expression (immunohistochemistry and western-blotting) and distribution of dysferlin in impaired muscles of subjects with LGMDR2.


Biospecimen Retention:   Samples With DNA
Serum, Plasma, DNA, RNA


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Study participants will be identified through self-selection and direct recruitment options. Participants will be identified from the population of individuals who are followed at the neuromuscular clinics. Participants will also be solicited from the DYSF Russian registry.
Criteria

Inclusion Criteria:

  • 18 to 85 (inclusive) years-old subjects of both sexes;
  • A signed written informed consent form;
  • Genetically confirmed diagnosis of limb-girdle muscular dystrophy (type 2B) (a case group)

Exclusion Criteria:

  • A subject who is an investigator, study assistant, study coordinator and a member of the other personnel indirectly or directly associated with the conduct of the study;
  • Acute medical conditions associated with visceral dysfunction, life-threatening conditions which occurred less than 6 months prior to enrollment into the study such as acute cardiac, renal, hepatic insufficiency, myocardial infarction or an acute cerebrovascular accident (stroke) as well as infectious diseases;
  • Excessive alcohol consumption (> 20 g/day).

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): NCT04824040


Locations
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Russian Federation
S.M. Kirov Military Medical Academy
Saint Petersburg, Russian Federation, 194044
Sponsors and Collaborators
Human Stem Cell Institute, Russia
S. M. Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation
Investigators
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Study Chair: Roman Deev, PhD HSCI, Russia
Publications:
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Responsible Party: Human Stem Cell Institute, Russia
ClinicalTrials.gov Identifier: NCT04824040    
Other Study ID Numbers: DYSF-Observation (RUS)
First Posted: April 1, 2021    Key Record Dates
Last Update Posted: April 2, 2021
Last Verified: March 2021

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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 Human Stem Cell Institute, Russia:
LGMDR2
Miyoshi Myopathy
Dysferlinopathy
DYSF
DMAT
Additional relevant MeSH terms:
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Muscular Diseases
Muscular Dystrophies, Limb-Girdle
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Muscular Dystrophies
Muscular Disorders, Atrophic
Genetic Diseases, Inborn