Ignite Creation Date:
2024-05-05 @ 11:52 AM
Last Modification Date:
2024-10-26 @ 9:15 AM
Study NCT ID:
NCT00159250
Status:
COMPLETED
Last Update Posted:
2019-12-05
First Post:
2005-09-08
Brief Title:
Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy
Sponsor:
Imperial College London
Organization:
Imperial College London
Study Overview
Official Title:
Restoring Dystrophin Expression in Duchenne Muscular Dystrophy A Phase III Clinical Trial Using AVI-4658
Status:
COMPLETED
Status Verified Date:
2019-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Duchenne muscular dystrophy DMD a fatal muscle degenerative disorder arises from mutations in the dystrophin gene Antisense therapy with the use of antisense oligonucleotides AON has the potential to restore effectively the production of dystrophin the defective protein in 70 of DMD This could result in increased life expectancy through improved muscle survival and function Recent scientific research has demonstrated the potential of this technique to skip mutated dystrophin exons restore the reading frame and generate functional dystrophin protein Having demonstrated proof-of-principle in human cell culture and animal model studies we now intend to determine efficacy and safety of this approach to induce dystrophin exon skipping in children with DMD
The specific aim of this phase III study is to assess efficacy dystrophin production and safety of intramuscular administered morpholino oligomer directed against exon 51 AVI-4658 PMO We are performing parallel preclinical studies to develop methods of systemic delivery that will be necessary for future phase IIIII clinical studies
The specific aim of this phase III study is to assess efficacy dystrophin production and safety of intramuscular administered morpholino oligomer directed against exon 51 AVI-4658 PMO We are performing parallel preclinical studies to develop methods of systemic delivery that will be necessary for future phase IIIII clinical studies
Detailed Description:
Duchenne Muscular Dystrophy DMD is the most common form of muscular dystrophy affecting 1 in every 3500 live male births The disease is characterised by severe muscle wasting and weakness which becomes clinically evident between the ages of 3 to 5 years Affected individuals stop walking by 12 years of age and usually do not survive beyond the age of 20 unless ventilated In general DMD is caused by mutations that disrupt the reading frame thus leading to a failure to express dystrophin
Recent scientific research has led to the belief that DMD may be treated by correcting the genetic error in the dystrophin gene which causes DMD Most children with DMD have a deletion ie a mutation which removes part of the dystrophin gene A novel technique using antisense technology to skip a specific exon and bypass faulty genetic material thus allowing production of functional dystrophin to be produced has been developedThese antisense oligonucleotides AON target and bypass faulty genetic material and allow production of functional proteinThis has been successfully demonstrated in cultured human DMD cells and in mouse and canine DMD modelsThe restored production of dystrophin is predicted to reduce muscle pathology significantly
In the early part of the study we compared different antisense oligomers chemical modification and concluded that the morpholino backbone is significantly superior when administered to skeletal muscle compared to a number of other types of antisense
The aim of this phase III clinical study is to assess efficacy and safety of AVI-4658 a morpholino antisense directed against exon 51 in DMD individuals with deletions which would benefit from skipping exon 51
The proposed work is presented in 4 sections detailing the main approaches
Study design
This dose escalation IM trial will involve of up to 9 subjects subdivided in three groups of three subjects each Patients in group 1 will be recruited sequentially whilst patients in groups 2 and 3 will be recruited serially
Group 1 3 patients will receive intramuscular administration of a low concentration of study drug extensor digitorum brevis muscle EDB and will undergo a muscle biopsy between days 14 and 28 after intramuscular IM administration of the AVI-4658
Group 2 3 patients will undergo an identical procedure but receiving an intermediate dose of the AVI-4658
Group 3 3 patients will be recruited to receive the highest dose of the AVI-4658 but only if the results in the first 2 cohort of patients show a lack of efficacy of the lower doses Up to an additional 3 subjects may be enrolled in cohorts 1 or 2 should cohort 3 not be enrolled
Screening
A physical examination including body weight height arm span neuromuscular examination and vital signs blood pressure pulse respiration and temperature
Neuropsychiatric assessment of both subject and the family
Molecular genetic on blood sample and dystrophin analysis of original muscle biopsy obtained at diagnosis
Muscle MRI scans of lower limbs to assess the preservation of the muscle to be targeted with the injection of AON
Biochemical blood and urine investigation to include standard biochemistry and haematology full blood count coagulation screen liver function test serum Ig protein electrophoresis inflammatory markers creatinine kinase gamma glutamyl transferase urine biochemistry
Cardiovascular assessments ECG and heart echocardiogram
Pulmonary assessments Forced vital capacity overnight oxygen saturation monitoring
Skin biopsy for MyoD-transfection
Procedure
The muscle to be used is the extensor digitorum brevis a foot muscle with very little function in children with mobility difficulties
Local injection will be performed directly through the skin using a combined EMG-delivery needle While the procedure could be performed under local anaesthetic where possible it will be performed under general anaesthetic in order to reduce distress to the subject A skin tattoo featuring a 1 cm x 1 cm grid with 2 lines in between to divide it in 9 smaller squares will be used to mark the site of the injection precisely and for a subsequent muscle biopsy
The total volume of each injection will be 100 μL containing the AVI-4658 Nine injections will be performed at 3 mm intervals inside the 1 cm2 grid tattoo The depth of the injection will be carefully recorded
Observation
Patients will be closely monitored within the clinical research facility by designated nursing staff educated in the trial protocol and with experience in similar Phase III studies
The clinical research facility has close access to intensive care unit facilities in the event of an unforeseen adverse reaction
Follow-up Day 2 - Patients will be discharged Prior to discharge a brief physical examination and systems review will be performed
Day 3 - A further brief physical examination and systems review including examination of the injection sites and reporting of any reactions This examination can be performed at the local surgery or at the hospital of the referring clinician
Days 5 7 - Contact with the subject and inquire as to current status
Day 14 to 28 - The subject is admitted to hospital Perform systems assessment physical examination body weight and vital signs Blood and urine biochemistry will be repeated then as well as open biopsies of both injected muscles will be performed under general or local anaesthetic
Day 30 - Contact with the subject and inquiry as to current status
Day 60 - Contact the subject and inquiry as to current status
Day 120 - Final Visit at the hospital where the study drug was administered A brief physical examination and systems review will be performed
MDEX Consortium
The PRECLINICAL studies were performed by the following groups who are all members of the MDEX consortium
1 Prof Francesco Muntoni Dr Jennifer Morgan Dubowitz Neuromuscular Centre Department of Paediatrics Imperial College Hammersmith Hospital Campus Du Cane Road London W12 ONN
2 Prof Dominic Wells Dr Kim Wells Gene Targeting Group Department of Cellular and Molecular Neuroscience Division of Neuroscience and Mental Health Imperial College Charing Cross Campus St Dunstans Road London W6 8RP
3 Prof George Dickson Dr Ian Graham Gene Therapy Laboratory Centre for Biomedical Sciences Royal Holloway - University of London Egham
4 Dr Matthew Wood Department of Physiology Anatomy and Genetics South Parks RoadOxford OX1 3QX United Kingdom UK
5 Professor Steve Wilton Experimental Molecular Medicine Group Centre for Neuromuscular and Neurological Disorders University of Western Australia
Additional CLINICAL SUPPORT other than the Study officials will be provided by
Dubowitz Neuromuscular Centre Department of Paediatrics Hammersmith Hospital Campus Du Cane Road W12ONN Prof Caroline Sewry Dr Maria Kinali Dr Virginia Arechavala Dr Lucy Feng
Department of Surgery St Marys Hospital Trust Imperial College Praed Street London W2 1NY Mr David Hunt
DNA Laboratory Genetics Centre 5th Floor Guys Tower Guys Hospital London SE1 9RT Dr Steve Abbs
Academic Unit of Child and Adolescent Psychiatry Division of Neuroscience and Mental Health Imperial College St Marys Campus Norfolk Place PaddingtonLondon W2 1PG Professor Elena Garralda
MDEX Study coordinator
Dr K Ganeshaguru Dubowitz Neuromuscular Centre Department of Paediatrics Hammersmith Hospital Campus Imperial College London Du Cane Road W12ONN kganeshaguruimperialacuk
Recent scientific research has led to the belief that DMD may be treated by correcting the genetic error in the dystrophin gene which causes DMD Most children with DMD have a deletion ie a mutation which removes part of the dystrophin gene A novel technique using antisense technology to skip a specific exon and bypass faulty genetic material thus allowing production of functional dystrophin to be produced has been developedThese antisense oligonucleotides AON target and bypass faulty genetic material and allow production of functional proteinThis has been successfully demonstrated in cultured human DMD cells and in mouse and canine DMD modelsThe restored production of dystrophin is predicted to reduce muscle pathology significantly
In the early part of the study we compared different antisense oligomers chemical modification and concluded that the morpholino backbone is significantly superior when administered to skeletal muscle compared to a number of other types of antisense
The aim of this phase III clinical study is to assess efficacy and safety of AVI-4658 a morpholino antisense directed against exon 51 in DMD individuals with deletions which would benefit from skipping exon 51
The proposed work is presented in 4 sections detailing the main approaches
Study design
This dose escalation IM trial will involve of up to 9 subjects subdivided in three groups of three subjects each Patients in group 1 will be recruited sequentially whilst patients in groups 2 and 3 will be recruited serially
Group 1 3 patients will receive intramuscular administration of a low concentration of study drug extensor digitorum brevis muscle EDB and will undergo a muscle biopsy between days 14 and 28 after intramuscular IM administration of the AVI-4658
Group 2 3 patients will undergo an identical procedure but receiving an intermediate dose of the AVI-4658
Group 3 3 patients will be recruited to receive the highest dose of the AVI-4658 but only if the results in the first 2 cohort of patients show a lack of efficacy of the lower doses Up to an additional 3 subjects may be enrolled in cohorts 1 or 2 should cohort 3 not be enrolled
Screening
A physical examination including body weight height arm span neuromuscular examination and vital signs blood pressure pulse respiration and temperature
Neuropsychiatric assessment of both subject and the family
Molecular genetic on blood sample and dystrophin analysis of original muscle biopsy obtained at diagnosis
Muscle MRI scans of lower limbs to assess the preservation of the muscle to be targeted with the injection of AON
Biochemical blood and urine investigation to include standard biochemistry and haematology full blood count coagulation screen liver function test serum Ig protein electrophoresis inflammatory markers creatinine kinase gamma glutamyl transferase urine biochemistry
Cardiovascular assessments ECG and heart echocardiogram
Pulmonary assessments Forced vital capacity overnight oxygen saturation monitoring
Skin biopsy for MyoD-transfection
Procedure
The muscle to be used is the extensor digitorum brevis a foot muscle with very little function in children with mobility difficulties
Local injection will be performed directly through the skin using a combined EMG-delivery needle While the procedure could be performed under local anaesthetic where possible it will be performed under general anaesthetic in order to reduce distress to the subject A skin tattoo featuring a 1 cm x 1 cm grid with 2 lines in between to divide it in 9 smaller squares will be used to mark the site of the injection precisely and for a subsequent muscle biopsy
The total volume of each injection will be 100 μL containing the AVI-4658 Nine injections will be performed at 3 mm intervals inside the 1 cm2 grid tattoo The depth of the injection will be carefully recorded
Observation
Patients will be closely monitored within the clinical research facility by designated nursing staff educated in the trial protocol and with experience in similar Phase III studies
The clinical research facility has close access to intensive care unit facilities in the event of an unforeseen adverse reaction
Follow-up Day 2 - Patients will be discharged Prior to discharge a brief physical examination and systems review will be performed
Day 3 - A further brief physical examination and systems review including examination of the injection sites and reporting of any reactions This examination can be performed at the local surgery or at the hospital of the referring clinician
Days 5 7 - Contact with the subject and inquire as to current status
Day 14 to 28 - The subject is admitted to hospital Perform systems assessment physical examination body weight and vital signs Blood and urine biochemistry will be repeated then as well as open biopsies of both injected muscles will be performed under general or local anaesthetic
Day 30 - Contact with the subject and inquiry as to current status
Day 60 - Contact the subject and inquiry as to current status
Day 120 - Final Visit at the hospital where the study drug was administered A brief physical examination and systems review will be performed
MDEX Consortium
The PRECLINICAL studies were performed by the following groups who are all members of the MDEX consortium
1 Prof Francesco Muntoni Dr Jennifer Morgan Dubowitz Neuromuscular Centre Department of Paediatrics Imperial College Hammersmith Hospital Campus Du Cane Road London W12 ONN
2 Prof Dominic Wells Dr Kim Wells Gene Targeting Group Department of Cellular and Molecular Neuroscience Division of Neuroscience and Mental Health Imperial College Charing Cross Campus St Dunstans Road London W6 8RP
3 Prof George Dickson Dr Ian Graham Gene Therapy Laboratory Centre for Biomedical Sciences Royal Holloway - University of London Egham
4 Dr Matthew Wood Department of Physiology Anatomy and Genetics South Parks RoadOxford OX1 3QX United Kingdom UK
5 Professor Steve Wilton Experimental Molecular Medicine Group Centre for Neuromuscular and Neurological Disorders University of Western Australia
Additional CLINICAL SUPPORT other than the Study officials will be provided by
Dubowitz Neuromuscular Centre Department of Paediatrics Hammersmith Hospital Campus Du Cane Road W12ONN Prof Caroline Sewry Dr Maria Kinali Dr Virginia Arechavala Dr Lucy Feng
Department of Surgery St Marys Hospital Trust Imperial College Praed Street London W2 1NY Mr David Hunt
DNA Laboratory Genetics Centre 5th Floor Guys Tower Guys Hospital London SE1 9RT Dr Steve Abbs
Academic Unit of Child and Adolescent Psychiatry Division of Neuroscience and Mental Health Imperial College St Marys Campus Norfolk Place PaddingtonLondon W2 1PG Professor Elena Garralda
MDEX Study coordinator
Dr K Ganeshaguru Dubowitz Neuromuscular Centre Department of Paediatrics Hammersmith Hospital Campus Imperial College London Du Cane Road W12ONN kganeshaguruimperialacuk
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2006-003833-33 | EUDRACT_NUMBER | Sarepta | None |
| AVI-4658-33 | OTHER | None | None |