- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03633565
Comparative Study of Strategies for Management of Duchenne Myopathy (DM)
A Comparative Study of Strategies for Management of Duchenne Myopathy in Assiut University Children Hospital
- 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
Study Overview
Status
Conditions
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.
Study Type
Enrollment (Anticipated)
Phase
- Phase 4
Contacts and Locations
Study Contact
- Name: Duaa Mahmoud, Assistant professor
- Phone Number: 01223112124
- Email: duaa-raafat@hotmail.com
Study Contact Backup
- Name: Mervat Youssef, Lecturer
- Phone Number: 01142606221
- Email: mamuosif2000@gmail.com
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Steroid
prednisolone 20 mg tablet by mouth taken once daily for 10 days each month for 2 years
|
tablet 20 mg
Other Names:
|
Active Comparator: Phosphodiestrase inhibitors
sildenafil 25 mg tablet by mouth once daily for 2 years
|
tablet 25mg
Other Names:
|
Experimental: Mesenchymal stem cell transplantation
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.
|
stem cell transplantation intramuscular
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
6 Minute Walk Distance (6MWD)
Time Frame: 6 month
|
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
|
6 month
|
Collaborators and Investigators
Sponsor
Investigators
- Study Director: Emad EL Daly, Professor, Assiut University
Publications and helpful links
General Publications
- 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.
- Mercuri E, Muntoni F. Muscular dystrophies. Lancet. 2013 Mar 9;381(9869):845-60. doi: 10.1016/S0140-6736(12)61897-2.
- 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.
- 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.
- Emery AE. The muscular dystrophies. Lancet. 2002 Feb 23;359(9307):687-95. doi: 10.1016/S0140-6736(02)07815-7.
- Wong BL, Christopher C. Corticosteroids in Duchenne muscular dystrophy: a reappraisal. J Child Neurol. 2002 Mar;17(3):183-90. doi: 10.1177/088307380201700306.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Partridge TA. Stem cell therapies for neuromuscular diseases. Acta Neurol Belg. 2004 Dec;104(4):141-7.
Study record dates
Study Major Dates
Study Start (Anticipated)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Nervous System Diseases
- Musculoskeletal Diseases
- Neuromuscular Diseases
- Muscular Diseases
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Vasodilator Agents
- Autonomic Agents
- Peripheral Nervous System Agents
- Urological Agents
- Enzyme Inhibitors
- Anti-Inflammatory Agents
- Antineoplastic Agents
- Antiemetics
- Gastrointestinal Agents
- Glucocorticoids
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Neuroprotective Agents
- Protective Agents
- Phosphodiesterase 5 Inhibitors
- Prednisolone
- Methylprednisolone Acetate
- Methylprednisolone
- Methylprednisolone Hemisuccinate
- Prednisolone acetate
- Prednisolone hemisuccinate
- Prednisolone phosphate
- Sildenafil Citrate
- Phosphodiesterase Inhibitors
Other Study ID Numbers
- smdmauch
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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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