Comparative Study of Strategies for Management of Duchenne Myopathy (DM)
Primary Purpose
Myopathy
Status
Unknown status
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Sildenafil (Phosphodiesterase inhibitors)
Prednisolone (Steroids)
Mesenchymal stem cell transplantation
Sponsored by
About this trial
This is an interventional treatment trial for Myopathy
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of DMD confirmed by electromyogram (EMG) , Creatine phosphokinase (CPK) level and/ or DNA analysis or muscle biopsy.
- Male patients
- Age 5-15y.
- Ambulatory (loss of ambulation was only seen in those with baseline 6 Minute Walk Distance {6MWD} <325 meters.)
- No clinical evidence of heart failure.
Exclusion Criteria:
- Female patients
- Any injury which may impact functional testing, e.g. upper or lower limb fracture.
- hypertension, diabetes,
- Wheelchair bound.
- Cardiac rhythm disorder, specifically: rhythm other than sinus, supraventricular tachycardia (SVT), atrial fibrillation, ventricular tachycardia.or heart failure (left ventricle ejection fraction {LVEF < 50%}.
- Continuous ventilatory support.
- Liver disease (acute, chronic liver disease)
- Renal impairment
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Active Comparator
Active Comparator
Experimental
Arm Label
Steroid
Phosphodiestrase inhibitors
Mesenchymal stem cell transplantation
Arm Description
prednisolone 20 mg tablet by mouth taken once daily for 10 days each month for 2 years
sildenafil 25 mg tablet by mouth once daily for 2 years
The cells can be injected intramuscular in several points in the muscle alternatively they can be injected in the motor point of the muscle. A motor point is the point at which the motor branch of the innervating nerve enters the muscle). This injection is repeated every 6 month up to 2 years.
Outcomes
Primary Outcome Measures
6 Minute Walk Distance (6MWD)
It is used as measure of motor strength in patients with Duchenne Myopathy. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03633565
Brief Title
Comparative Study of Strategies for Management of Duchenne Myopathy (DM)
Official Title
A Comparative Study of Strategies for Management of Duchenne Myopathy in Assiut University Children Hospital
Study Type
Interventional
2. Study Status
Record Verification Date
August 2018
Overall Recruitment Status
Unknown status
Study Start Date
September 2018 (Anticipated)
Primary Completion Date
September 2021 (Anticipated)
Study Completion Date
November 2021 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Assiut University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
Comparing different lines of treatment of Duchenne Myopathy (DM) and assessment of new lines of treatment (mesenchymal stem cell, phosphodiesterase inhibitors) in reducing the impact of disability in the patients with Duchenne Myopathy and slowing the progression of cardiomyopathy
Upsetting and implementation of the best treatment plan for those children with Duchenne myopathy which is suitable for the available resources in Assiut University Children Hospital
Detailed Description
Duchenne muscular dystrophy(DMD) is the most commonly inherited pediatric muscular disorder. It is an X-linked genetic progressive and degenerative myopathy characterized by progressive weakness, which can lead to loss of motor functions in puberty as well as cardiac,respiratory involvement and premature death. The disease is one of a group of myopathies that differ depending on the degree of severity and the affected muscle types. It occurs at a rate of approximately 1:3500 male births and arises due to spontaneous mutations in the Dystrophin gene (locus Xp21.2); 65% of causative mutations are intragenic deletions, 6-10% are intragenic duplications and 30-35% are point mutations (along with other sequence variations). The disease is caused by a deficiency of Dystrophin or the synthesis of functionally impotent Dystrophin, a critical protein component of the Dystrophin glycoprotein complex acting as a link between the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. A consequence of Dystrophin glycoprotein complex inefficiency is muscle fragility, contraction-induced damage, necrosis and inflammation.
Glucocorticoid can prolong ambulation by 2 to 3 years, reduce scoliosis, and temper pulmonary and cardiac decline in the second decade of life. However, glucocorticoids causes well-known side effects, which are intolerable in more than 25% of patients. Thus, a disease-specific treatment is a major unmet need. Investigators have proposed various possibilities for the beneficial effects of corticosteroid based mainly on observations in mouse models of muscular dystrophy and on a limited number of studies in patients.
These possibilities include
Reducing cytotoxic T lymphocytes
Increasing Laminin expression and myogenic repair
Retarding muscle apoptosis and cellular infiltration
Enhancing Dystrophin expression
Affecting neuromuscular transmission
Some patients with Duchenne Myopathy treated early with steroids appear to have an improved long-term prognosis in muscle, myocardial outcome, and can help keep patients ambulatory for more years than expected without treatment. One protocol gives prednisone (0.75 mg/kg/day) for the 1st 10 days of each month to avoid chronic complications. Deflazacort, administered as 0.9 mg/kg/day, may be more effective than prednisone. The American Academy of Neurology and the Child Neurology Society recommend administering corticosteroids during the ambulatory stage of the disease.Published recommendations suggest starting therapy between 2 and 5 years of age in boys whose strength has plateaued or is declining, but earlier treatment may be more beneficial.
Skeletal muscle has a great capacity to regenerate following muscle wasting caused by trauma or disease.This regenerative potential is attributed primarily to skeletal-muscle resident stem cells called satellite cells. In Duchenne Myopathy, satellite cells are exhausted following many rounds of muscle degeneration and regeneration. Hence, satellite cells and their progeny (myoblasts) have been considered as a promising candidate for cell replacement therapy for DMD and other types of muscle disease. Small quantities of adult stem cells exist in most tissues throughout the body where they remain quiescent for long periods of time prior to being activated in response to disease or tissue injury. Adult stem cells can be isolated from cells of the hematopoietic, neural, dermal, muscle and hepatic systems. Adult stem cells give rise to cell types of the tissue from which they originated, but according to scientific reports, they can differentiate into lineages other than their tissue of origin, e.g. transplanted bone marrow or enriched hematopoietic stem cells (HSCs) were reported to give rise to cells of the mesoderm, endoderm and ectoderm.
Two main types of stem cells usually derived from adult bone marrow are HSCs and mesenchymal stem cells (MSC). They can sometimes be obtained from fat, skin, periosteum, synovial membrane and muscle as well. MSCs are multipotent and capable of differentiating into several connective tissue types including osteocytes, chondrocytes, adipocytes, tenocytes and myoblasts. They can also impose an additional anti-inflammatory and paracrine effect on differentiation and tissue regeneration via cytokine pathways and have anti-apoptotic features. These genetically determined pluripotent cells may be easily isolated from bone marrow because they have membrane proteins (marker called cluster of differentiation (CD34 +) and specific marker STRO-I). Compared with pluripotent embryonic stem cells or induced pluripotent stem cells, mesenchymal stem cell have a greater biosafety profile and lower risk of tumorigenicity, and perhaps that is why numerous -mesenchymal stem cell based therapies have made it to the clinical trial stage. Stem cell based therapies for the treatment of Duchenne Myopathy can proceed via two strategies.
The first is autologous stem cell transfer involving cells from a patient with Duchenne Myopathy that are genetically altered in vitro to restore dystrophin expression and are subsequently re-implanted. The second is allogenic stem cell transfer, containing cells from an individual with functional dystrophin, which are transplanted into a dystrophic patient.
Intramuscular route of administration can be considered most appropriate as muscular dystrophy is primarily a muscle disease. The cells can be injected in several points in the muscle alternatively they can be injected in the motor point of the muscle. A motor point is the point at which the motor branch of the innervating nerve enters the muscle. It is the point with the highest concentration of motor endplates and myoneural synapses. Due to high numbers of neuromuscular junctions at this point, a muscle contraction can be easily elicited using minimal electric stimulus. Motor points can therefore be identified as superficial points directly over the points on the muscles with help of external electrical stimulation. Limitation of this method is that only superficial muscles can be stimulated using this method.
In an open study, Sharma and colleagues demonstrated the efficacy of autologous bone marrow mononuclear transplantation by intramuscularly to patients with Duchenne Myopathy, Becker muscular dystrophy and limb girdle muscular dystrophy. However, they did not provide the molecular diagnosis of these dystrophies. No significant adverse events were noted. An increase in trunk muscle strength was seen in 53% of the cases, 48% showed an increase in upper limb strength, 59% showed an increase in lower limb strength and approximately 10% showed improved gait. Eighty seven percent of 150 patients had functional improvement upon physical examination and electromyogram studies after 12 month.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myopathy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
45 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Steroid
Arm Type
Active Comparator
Arm Description
prednisolone 20 mg tablet by mouth taken once daily for 10 days each month for 2 years
Arm Title
Phosphodiestrase inhibitors
Arm Type
Active Comparator
Arm Description
sildenafil 25 mg tablet by mouth once daily for 2 years
Arm Title
Mesenchymal stem cell transplantation
Arm Type
Experimental
Arm Description
The cells can be injected intramuscular in several points in the muscle alternatively they can be injected in the motor point of the muscle. A motor point is the point at which the motor branch of the innervating nerve enters the muscle). This injection is repeated every 6 month up to 2 years.
Intervention Type
Drug
Intervention Name(s)
Sildenafil (Phosphodiesterase inhibitors)
Other Intervention Name(s)
sildenafil, viagra
Intervention Description
tablet 25mg
Intervention Type
Drug
Intervention Name(s)
Prednisolone (Steroids)
Other Intervention Name(s)
Prednisolone 20 mg
Intervention Description
tablet 20 mg
Intervention Type
Procedure
Intervention Name(s)
Mesenchymal stem cell transplantation
Intervention Description
stem cell transplantation intramuscular
Primary Outcome Measure Information:
Title
6 Minute Walk Distance (6MWD)
Description
It is used as measure of motor strength in patients with Duchenne Myopathy. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters
Time Frame
6 month
10. Eligibility
Sex
Male
Gender Based
Yes
Gender Eligibility Description
only male
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
15 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis of DMD confirmed by electromyogram (EMG) , Creatine phosphokinase (CPK) level and/ or DNA analysis or muscle biopsy.
Male patients
Age 5-15y.
Ambulatory (loss of ambulation was only seen in those with baseline 6 Minute Walk Distance {6MWD} <325 meters.)
No clinical evidence of heart failure.
Exclusion Criteria:
Female patients
Any injury which may impact functional testing, e.g. upper or lower limb fracture.
hypertension, diabetes,
Wheelchair bound.
Cardiac rhythm disorder, specifically: rhythm other than sinus, supraventricular tachycardia (SVT), atrial fibrillation, ventricular tachycardia.or heart failure (left ventricle ejection fraction {LVEF < 50%}.
Continuous ventilatory support.
Liver disease (acute, chronic liver disease)
Renal impairment
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Duaa Mahmoud, Assistant professor
Phone
01223112124
Email
duaa-raafat@hotmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Mervat Youssef, Lecturer
Phone
01142606221
Email
mamuosif2000@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Emad EL Daly, Professor
Organizational Affiliation
Assiut University
Official's Role
Study Director
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
23465426
Citation
Mercuri E, Muntoni F. Muscular dystrophies. Lancet. 2013 Mar 9;381(9869):845-60. doi: 10.1016/S0140-6736(12)61897-2.
Results Reference
background
PubMed Identifier
25271841
Citation
Nallamilli BR, Ankala A, Hegde M. Molecular diagnosis of Duchenne muscular dystrophy. Curr Protoc Hum Genet. 2014 Oct 1;83:9.25.1-29. doi: 10.1002/0471142905.hg0925s83.
Results Reference
background
PubMed Identifier
15117830
Citation
Lapidos KA, Kakkar R, McNally EM. The dystrophin glycoprotein complex: signaling strength and integrity for the sarcolemma. Circ Res. 2004 Apr 30;94(8):1023-31. doi: 10.1161/01.RES.0000126574.61061.25.
Results Reference
background
PubMed Identifier
11879882
Citation
Emery AE. The muscular dystrophies. Lancet. 2002 Feb 23;359(9307):687-95. doi: 10.1016/S0140-6736(02)07815-7.
Results Reference
background
PubMed Identifier
12026233
Citation
Wong BL, Christopher C. Corticosteroids in Duchenne muscular dystrophy: a reappraisal. J Child Neurol. 2002 Mar;17(3):183-90. doi: 10.1177/088307380201700306.
Results Reference
background
PubMed Identifier
8289083
Citation
Khan MA. Corticosteroid therapy in Duchenne muscular dystrophy. J Neurol Sci. 1993 Dec 1;120(1):8-14. doi: 10.1016/0022-510x(93)90017-s.
Results Reference
background
PubMed Identifier
10689931
Citation
Kojima S, Takagi A, Watanabe T. [Effect of prednisolone on apoptosis and cellular infiltration in mdx mouse muscle]. Rinsho Shinkeigaku. 1999 Nov;39(11):1109-13. Japanese.
Results Reference
background
PubMed Identifier
11249150
Citation
Fukudome T, Shibuya N, Yoshimura T, Eguchi K. Short-term effects of prednisolone on neuromuscular transmission in the isolated mdx mouse diaphragm. Tohoku J Exp Med. 2000 Nov;192(3):211-7. doi: 10.1620/tjem.192.211. Erratum In: Tohoku J Exp Med. 2004 Aug;203(4):359.
Results Reference
background
PubMed Identifier
22186952
Citation
Wang YX, Rudnicki MA. Satellite cells, the engines of muscle repair. Nat Rev Mol Cell Biol. 2011 Dec 21;13(2):127-33. doi: 10.1038/nrm3265.
Results Reference
background
PubMed Identifier
10825301
Citation
Heslop L, Morgan JE, Partridge TA. Evidence for a myogenic stem cell that is exhausted in dystrophic muscle. J Cell Sci. 2000 Jun;113 ( Pt 12):2299-308. doi: 10.1242/jcs.113.12.2299.
Results Reference
background
PubMed Identifier
11017170
Citation
Galli R, Borello U, Gritti A, Minasi MG, Bjornson C, Coletta M, Mora M, De Angelis MG, Fiocco R, Cossu G, Vescovi AL. Skeletal myogenic potential of human and mouse neural stem cells. Nat Neurosci. 2000 Oct;3(10):986-91. doi: 10.1038/79924.
Results Reference
background
PubMed Identifier
11533656
Citation
Toma JG, Akhavan M, Fernandes KJ, Barnabe-Heider F, Sadikot A, Kaplan DR, Miller FD. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol. 2001 Sep;3(9):778-84. doi: 10.1038/ncb0901-778.
Results Reference
background
PubMed Identifier
12021255
Citation
Qu-Petersen Z, Deasy B, Jankowski R, Ikezawa M, Cummins J, Pruchnic R, Mytinger J, Cao B, Gates C, Wernig A, Huard J. Identification of a novel population of muscle stem cells in mice: potential for muscle regeneration. J Cell Biol. 2002 May 27;157(5):851-64. doi: 10.1083/jcb.200108150. Epub 2002 May 20.
Results Reference
background
PubMed Identifier
16447292
Citation
Shafritz DA, Oertel M, Menthena A, Nierhoff D, Dabeva MD. Liver stem cells and prospects for liver reconstitution by transplanted cells. Hepatology. 2006 Feb;43(2 Suppl 1):S89-98. doi: 10.1002/hep.21047.
Results Reference
background
PubMed Identifier
17034994
Citation
Price FD, Kuroda K, Rudnicki MA. Stem cell based therapies to treat muscular dystrophy. Biochim Biophys Acta. 2007 Feb;1772(2):272-83. doi: 10.1016/j.bbadis.2006.08.011. Epub 2006 Sep 6.
Results Reference
background
PubMed Identifier
22704511
Citation
Keating A. Mesenchymal stromal cells: new directions. Cell Stem Cell. 2012 Jun 14;10(6):709-716. doi: 10.1016/j.stem.2012.05.015. Erratum In: Cell Stem Cell. 2012 Jul 6;11(1):136.
Results Reference
background
PubMed Identifier
16469271
Citation
Mendell JR, Clark KR. Challenges for gene therapy for muscular dystrophy. Curr Neurol Neurosci Rep. 2006 Jan;6(1):47-56. doi: 10.1007/s11910-996-0009-8.
Results Reference
background
PubMed Identifier
15742603
Citation
Partridge TA. Stem cell therapies for neuromuscular diseases. Acta Neurol Belg. 2004 Dec;104(4):141-7.
Results Reference
background
Learn more about this trial
Comparative Study of Strategies for Management of Duchenne Myopathy (DM)
We'll reach out to this number within 24 hrs