Muscular Dystrophy, Oculopharyngeal Clinical Trial
Official title:
Treatment of Dysphagia in Oculopharyngeal Muscular Dystrophy by Autologous Transplantation of Myoblasts
The OCULO-Pharyngeal Muscular Dystrophy (OPMD) is a late onset hereditary muscle disease
which is characterised by the selective affection of the pharyngeal muscles resulting in
swallowing disorders, and by a ptosis from the dysfunction of the levator palpebral
superiors muscles. Swallowing disorders are determinant in the prognosis of the disease, and
potentially life-threatening deglutition, due to aspiration and denutrition. Degenerative
dystrophy of the pharyngeal muscles causes difficulties to prepulse the food bolus in the
pharynx, and the decreased relaxation of the cricopharyngeal muscle induced by the disease
leads to blockage of food in the upper esophageal sphincter. The most common treatment for
the dysphagia in OPMD is a myotomy of the upper esophageal sphincter muscles. However,
although this will relax the constriction of the upper esophageal sphincter muscles and
improve transitory the swallowing, it will not prevent the progressive degradation of the
pharyngeal muscles. This progressive loss of contractility will eventually result in
aspiration and severe difficulty in swallowing, increasing risk of aspiration pneumonia and
severe weight loss which are the most common causes of mortality in OPMD patients.
The protocol which we are proposing is a graft of autologous cell muscles (myoblasts)
isolated from unaffected limb muscles into the pharyngeal muscles of patients diagnosed as
suffering from OPMD. Our aim is to improve both swallowing and the contractile deficit
generated by the dystrophic pharyngeal muscles. A myotomy of the upper esophageal sphincter
will be carried out at the same time as the myoblast transplantation, since we have already
validated the improvement resulting from this surgery. Advantages of this new therapy in
OPMD is the autograft, without risks of rejection, and the graft of myoblasts into the
dystrophic pharyngeal muscles, above the myotomy of the upper esophageal sphincter muscles.
This model of cellular therapy has been studied through a preclinical study performed in
dogs, allowing to valid the procedure and its safety, as well as to study the survival
myoblasts grafted in the pharyngeal muscles.
This protocol is proposed for OPMD patients; it is firstly a safety study of both autograft
and surgical procedure. In addition, the autograft may improve the swallowing disorders and
life-threatening complications induced by aspiration and weight loss, resulting in a
potential individual benefit.
OCULO-Pharyngeal Muscular Dystrophy (OPMD) is characterised by the selective affection of
the superior sphincter muscles of the oesophagus (SSO) and the pharyngeal.muscles resulting
in dysphagia. The most common treatment for the dysphagia induced by this disease is a
myotomy. However, although this will relax the constriction and improve swallowing it will
not prevent the progressive degradation of the pharyngeal muscles. This progressive loss of
contractility will eventually result in false routes and severe difficulty in swallowing,
increased risk of pulmonary infection and severe weight loss which are the most common
causes of mortality in these patients.
Concept:
The protocol which we are proposing is a pilot study in which autologous myoblasts isolated
from unaffected limb muscles will be grafted into the pharyngeal constrictor muscles of
patients diagnosed as suffering from OPMD. Our aim is to improve both swallowing and the
contractile deficit generated by the dystrophic pharyngeal constrictor muscles. A myotomy of
the SSO will be carried out at the same time as the myoblast transplantation, since we have
already validated the improvement resulting from this surgery even though we know that this
will provide only a partial and transitory improvement.
Type of trial: This is a multicentric trial with a direct benefit for the patient in which
10 patients will receive an autologous transplantation of myoblasts. Due to the possibility
that a certain number of patients may withdraw from the study we have decided to include
initially a maximum of 15 patients. The PHRC for this clinical trial was accepted in 2002
and the official promotor is the AP-HP. The patients will be selected by the different
promotors but will be followed in the 'Service d'ORL of TENON Hospital '. The proliferative
capacity of the myoblasts isolated from the muscle biopsies will be carried out by Vincent
MOULY and KAMEL MANCHAOUI in the UMR 7000 CNRS directed by Dr Butler-Browne and the cells
will be amplified prior to grafting in the Cellular laboratory therapy of Dr MAROLLEAU; The
clinical trial will be controlled by a specifically selected committee of five.
Description of the trial In the first step of this study patients will be selected for
inclusion in the trial according to the following criteria : 1: men or women aged between 18
and 75 years ; 2: genetic confirmation and characterisation of OPMD 3: SSO dysfunction
confirmed by the stasis of saliva or food above the sphincter visualised by fibroscopy and a
defect in the opening of the SSO also confirmed by videofluoroscopy of swallowing; the SSO
defect may be associated with a reduction in pharyngeal propulsion as revealed by fibroscopy
and videofluoroscopy of swallowing 4: official signed consent of the patients to participate
in this clinical trial.
The next step will be the selection of the unaffected muscle to be used for the production
of the autologous myoblasts to be used for transplantation. Muscles will be selected for
engraftment on the basis of the proliferative capacity of the cultures made from biopsies
(0.5-1gm) obtained following local anesthesia of either the quadriceps or the
STERNO-CLEIDO-MASTOIDIEN muscles. The muscle which is able to produce the largest number of
myoblasts will be biopsied a second time using the same conditions. Two grams of muscle will
be removed and the myoblasts will be isolated and cultured until there are about 100 million
myoblasts at which point the cells can be injected into the pharyngeal muscles of the
patient. If there is no difference between the two different muscle biopsies then we will
biopsy preferentially the STERNO-CLEIDO-MASTOIDIEN muscle since it is situated directly in
the trajectory that will be used when grafting the myoblasts. The operation by lateral
cervicotomy will be carried out under general anesthesia, in order to expose the SSO and the
pharyngeal muscles. The graft will be carried out by injecting the myoblasts into about 20
different sites in the pharyngeal constrictor muscles above the site of the associated
myotomy of the SSO. The next step will involve a two year evaluation of the trial. For each
patient a descriptive analysis will be carried out based on the comparison of the different
results. The principal evaluation of the efficiency of the graft will be based on the
functional quality of the pharyngeal propulsion as determined by fibroscopy and
videofluoroscopy of swallowing. A secondary evaluation will be based on the global
swallowing properties which will be evaluated by a quantitative test, by a questionnaire and
by an evaluation of the tolerance. This evaluation will include a clinical examination at
each visit consisting of the examination of the pharynx in order to confirm the absence of
muscle tumors and a cervical palpation in order to determine the volume of the muscle and to
survey the site of myoblasts implantation. A rigid tube pharyngeal endoscopy which will be
carried out under general anesthesia 6 to 12 months after the graft in case of abnormal
pharynx at fibroscopy. In addition, a global neuromuscular examination will be carried out
on an annual basis to follow the general evolution of the myopathy. The fibroscopy to
determine the swallowing function, the global quantitative tesy of swallowing and the
questionnaire will be carried out at 2, 6 and 24 months after the graft. A videofluoroscopy
of swallowing will be carried out at 2 months then at 1 and 2 years after the graft.
Risks and Benefits:
The principal benefits to the patients which could be envisioned by this procedure is a
delay in the deterioration of the pharyngeal muscles associated with this disease and
consequently an improvement in the difficulties in swallowing usually associated with this
disease. The potential risk associated with this type of operation are an inflammatory
reaction, the appearance of a tumor or the lack of improvement of the symptoms associated
with the disease.
A parallel preclinical study has been carried out in the dog in order to evaluate the
tolerance and feasibility of the procedure for autografting myoblasts in the pharyngeal
muscles.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Status | Clinical Trial | Phase | |
---|---|---|---|
Terminated |
NCT02878694 -
Treatment of Ptosis to Muscular Dystrophy Oculopharyngeal by Myoblast Autologous Graft
|
Phase 2/Phase 3 | |
Completed |
NCT00001871 -
Study of Muscle Abnormalities in Patients With Specific Genetic Mutations
|
N/A |