Transplantation of Myoblasts to Duchenne Muscular Dystrophy (DMD) Patients
|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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02196467|
Recruitment Status : Recruiting
First Posted : July 22, 2014
Last Update Posted : July 25, 2018
|Condition or disease||Intervention/treatment||Phase|
|Duchenne Muscular Dystrophy||Biological: Myoblast transplantation Procedure: Saline injection||Phase 1 Phase 2|
Hide Detailed Description
Duchenne Muscular Dystrophy (DMD) is a degenerative disease of genetic origin, due to a mutation in the gene coding for the protein dystrophin. This mutation leads to deficiency of dystrophin in the myofibers, causing progressive muscle degeneration by the following mechanism: (1) dystrophin deficiency leads to myofibers being very vulnerable to muscle contraction-relaxation, causing frequent damage and necrosis of myofibers; (2) necrosis is followed by myofiber regeneration, as long as the regenerative capacity of muscle is not exhausted; (3) when the regenerative capacity of the muscle is exhausted, myofibers become atrophic and are ultimately lost; (4) fibrosis and fat infiltration replace the lost myofibers. This progressive muscle destruction takes place in most muscles of the limbs and trunk, leading to progressive loss of muscle strength, musculotendinous contractures, restrictive respiratory insufficiency and premature death between 17 and 30 years.
The transplantation of myoblasts obtained from a healthy donor is a potential treatment of DMD. Following intramuscular injection, donor myoblasts fuse with the myofibers of the patient, introducing the normal dystrophin gene in them. In a previous Phase 1A clinical trial, the investigators proved that transplantation of myoblasts grown from the muscle biopsy of a healthy donor introduced the normal dystrophin gene in the DMD myofibers, with the consequent expression of the normal dystrophin mRNA and restoration of the dystrophin protein in several myofibers.
The aim of this Phase I/II of the clinical trial is to investigate whether the transplantation of normal myoblasts throughout one muscle (in this case, the extensor carpi radialis) of DMD patients is safe and will improve the strength of that muscle. The patients will be transplanted with myoblasts grown from the muscle biopsy of a healthy donor. Thirty million myoblasts will be injected per cm cube in a progressively higher volume of muscle (i.e., 3, 6 and 9 cm cube). The contralateral muscle will be injected with saline as a control. The patients and the investigators will be blind to the side injected with cells. The strength of both muscles will be measured at 3 months post transplant to verify if myoblast transplantation increased muscle strength. If there is no significant strength increase, the protocol will be terminated immediately for that patient. If there is a significant strength increase, the patient will be maintained under immunosuppression until 6 months and the muscle strength will be re-evaluated.
The objectives of this Phase I/II clinical trial with DMD patients are thus:
To evaluate the safety of a procedure of high-density injections of donor myoblasts throughout a muscle (under immunosuppression by tacrolimus).
- To evaluate whether myoblast transplantation resulted in the presence of dystrophin-positive myofibers of donor origin.
To evaluate whether myoblast transplantation improved the muscle strength or prevent or slowed down the progression of the muscle weakness as shown by the following parameters:
2.1) Increase of the voluntary strength of the subject's wrist extension done by the extensor carpi radialis 12 or 24 weeks after myoblast transplantation compared with the pre-transplant values of the same muscle.
2.2) Reduction of the fatigue of the voluntary strength of the subject's wrist extension done by the extensor carpi radialis 12 or 24 weeks after myoblast transplantation compared with the pre-transplant fatigue values of the same muscle.
2.3) Reduce the progression of the muscle weakness in the myoblast injected muscle compared with the control contralateral muscle.
- To verify the long term effectiveness of the tacrolimus immunosuppression to control acute rejection in myoblast transplantation (by examining the presence of muscle fibers expressing normal dystrophin and the absence of specific immune responses)
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||10 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Transplantation of Myoblasts to Duchenne Muscular Dystrophy (DMD) Patients|
|Study Start Date :||May 2014|
|Estimated Primary Completion Date :||January 2019|
|Estimated Study Completion Date :||February 2019|
Experimental: Myoblast transplantation & strength
30 million myoblasts will be transplanted per centimeter cube in the Extensor carpi radialis of one of the patient's forearms, resuspended in saline. The strength will be evaluated after 3 and 6 months and the presence of dystrophin after 3 or 6 months.
Biological: Myoblast transplantation
30 million myoblasts will be transplanted per centimeter cube in the Extensor carpi radialis of one of the patient's forearm, resuspended in saline (a total of 0.5 ml of suspension per centimetre cube of muscle).
Sham Comparator: Saline injection & strength
The same saline solution used in the previous arm, but without cells, will be injected similarly per centimeter cube in the Extensor carpi radialis of the contralateral patient's forearm. The strength will be evaluated after 3 and 6 months and the presence of dystrophin after 3 or 6 months.
Procedure: Saline injection
A saline solution (the same used to resuspend de myoblasts in the first intervention) will be injected similarly in the Extensor carpi radialis of the contralateral patient's forearm (a total of 0.5 ml of saline per centimetre cube of muscle).
- Number of Participants with Serious and Non-Serious Adverse Events as a measure of safety. [ Time Frame: Up to 6 months ]The patients will be monitored for local and systemic potential adverse effects due to the transplantation and for adverse effects associated with immunosuppression with tacrolimus.
- Percentage of dystrophin-positive fibers in a muscle biopsy 3 or 6 months after myoblast transplantation. [ Time Frame: 6 months after the myoblast transplantation ]The presence of dystrophin positive fibers will be assessed in a muscle biopsy done 6 months after the myoblast transplantation.
- Strength of the Extensor carpi radialis muscles. [ Time Frame: At 3 and 6 months after myoblast transplantation. ]The strength of both Extensor carpi radialis will be evaluated 3 and 6 months after the myoblast transplantation to evaluate whether this transplantation improved the muscle strength, prevented or slowed down the progression of the muscle weakness.
- Presence of a cellular and humoral reaction against the donor antigens [ Time Frame: Every 4 weeks after transplantation for 6 months ]To assess antibody-mediated immune responses, a blood sample will be obtained at days D-14 and D15, at week 4 and every 4 weeks until the end of the treatment schedule according to the transplant pattern of the subject, and at the 3 and 6 month follow ups. These blood samples will be used to make cross-matches to determine whether the subject is producing antibodies reacting with the donor myoblasts. The antibodies against donor myoblasts will be detected by flow cytometry. Antibodies against donor HLA class I and II antigens will also be assessed by flow cytometry using single HLA antigen-coated beads (Flow PRA beads, One Lambda, Canoga Park, CA).
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): NCT02196467
|Contact: Craig Campbell, MD MSc FRCPC||(519) email@example.com|
|Contact: Jacques Tremblay, PhD||(418)-525-4444 ext 47307||Jacques-P.Tremblay@crchul.ulaval.ca|
|Children's Hospital London Health Sciences Centre||Recruiting|
|London, Ontario, Canada, N6A 4G5|
|Centre de recherche du CHU de Quebec - CHUL||Recruiting|
|Quebec, Canada, G1V 4G2|
|Principal Investigator:||Craig Campbell, MD MSc FRCPC||University of Western Ontario, Canada|
|Principal Investigator:||Jack Puymirat, MD||Centre de recherche du CHU de Quebec|