DysferlinopathyPhase 1NCT02710500
rAAVrh74.MHCK7.DYSF.DV for Treatment of Dysferlinopathies
A Phase 1 study testing rAAVrh74.MHCK7.DYSF.DV in people with Dysferlinopathy, run by Sarepta Therapeutics, Inc. at 1 site in United States.
Trial summary
The proposed clinical trial is a double-blind, randomized controlled study with direct intramuscular injection of rAAVrh.74.MHCK7.DYSF.DV gene vector to the extensor digitorum brevis muscle (EDB). Two cohorts of subjects with dysferlin deficiency, each with proven mutations will undergo gene transfer. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Dysferlinopathy
- What is being tested?
- rAAVrh74.MHCK7.DYSF.DV
- Type of treatment
- Vaccines, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2016to Jul 2019
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Must be Non-ambulant (cannot walk 10 meters in ≤ 30 sec) and age 18 years or older
- Established mutations of the dysferlin gene on both alleles
- Impaired muscle function but with sufficient muscle preservation to ensure muscle transfection based on magnetic resonance image of the EDB showing sufficient muscle preservation to permit transfection
- Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (If appropriate), during the first six months after gene transfer (females) or until two negative sperm samples are obtained post gene transfer (males).
Who cannot join
- Active viral infection based on clinical observations or serological evidence of HIV, or Hepatitis A, B or C infection
- The presence of a Dysferlin mutations without weakness or loss of function
- Symptoms or signs of cardiomyopathy, including:
- Dyspnea on exertion, pedal edema, shortness of breath upon lying flat, or rales at the base of the lungs
- Echocardiogram with ejection fraction below 40%
- Diagnosis of (or ongoing treatment for) an autoimmune disease
Show all 11Show fewer
- Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute neutrophil count < 1.5K/µL
- Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
- Pregnancy
- AAVrh74 or AAV8 binding antibody titers > 1:50 as determined by ELISA immunoassay
- Abnormal laboratory values in the clinically significant range in the table below, based upon normal values in the Nationwide Children's Hospital Laboratory: GGT, Total Bilirubin, Cystatine, Hemoglobin, White Blood Cells
Trial locations and contacts
1 site in 1 country.
United States1 site
Nationwide Children's Hosptial
Columbus, Ohio, 43205
About this study
Official title: Phase I Intramuscular Gene Transfer Clinical Trial for Dysferlin Deficiency Delivering the Dysferlin Gene by AAVrh74
The proposed clinical trial is a double-blind, randomized controlled study with direct intramuscular injection of rAAVrh.74.MHCK7.DYSF.DV gene vector to the extensor digitorum brevis muscle (EDB). Two cohorts of subjects with dysferlin deficiency, each with proven mutations will undergo gene transfer. A minimum of three subjects will be enrolled into each cohort.
Read the detailed description
This is a phase I safety and tolerability study with a direct intramuscular injection of rAAVrh.74.MHCK7.DYSF.DV transferred to the extensor digitorum brevis muscle (EDB). The study is designed as a randomized, controlled, dose escalation trial with one EDB receiving the rAAVrh.74.MHCK7.DYSF.DV and the other side receiving saline alone. It will follow the previously safe and effective IM gene transfer to EDB for LGMD2D.2, 3 The first cohort, inclusive of three Dysferlinopathy subjects, will receive a gene transfer total dose of 2 x 10^12 vector genomes. Muscle biopsies will be performed at Day 45 (two subjects) and Day 90 (one subject). If there are no safety concerns, three additional subjects will be enrolled and receive an escalated dose at 6 X 10^12 vg (total dose). Muscle biopsies in the second cohort will be performed at Day 90 (one subject) and Day 180 (two subjects). This protocol design gives us a maximum period of observation ranging from 6 weeks to 6 months to capture both transient and delayed gene expression, and to recognize sustained expression.
- Conditions
- Dysferlinopathy
- Being tested
- rAAVrh74.MHCK7.DYSF.DV
- Keywords
- LGMD2B, Limb Girdle Muscular Dystrophy, Miyoshi, Gene Transfer, Dysferlin
- Medical subject headings
- Dysferlinopathy, Limb-girdle muscular dystrophy, type 2B, Muscular Dystrophies, Limb-Girdle
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
rAAVrh74.MHCK7.DYSF.DVDrug
Biological/Vaccine: rAAVrh74.MHCK7.DYSF.DV Recombinant adeno-associated virus carrying a dysferlin transgene under control of a muscle specific MHCK7 promoter.
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 (Low Dose) | Experimental | Three (n=3) dysferlin deficiency subjects will receive bilateral injections with one extensor digitorum brevis muscle (EDB) receiving the rAAVrh74.MHCK7.DYSF.DV and the other side receiving saline alone.Subjects will receive a total dose of 2 x 10^12 in one muscle.
Intervention Drug: rAAVrh.MHCK7.DYSF.DV Receives: Drug: rAAVrh74.MHCK7.DYSF.DV |
| Cohort 2 (High Dose) | Experimental | Three (n=3) dysferlin deficiency subjects will receive bilateral injections with one extensor digitorum brevis muscle (EDB) receiving the rAAVrh74.MHCK7.DYSF.DV and the other side receiving saline alone.Subjects will receive a total dose of 6 x 10^12 vg in one muscle.
Intervention Drug: rAAVrh74.MHCK7.DYSF.DV Receives: Drug: rAAVrh74.MHCK7.DYSF.DV |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determination of safety based on the development of unacceptable toxicity
Defined as the occurrence of any one Grade III or higher, unanticipated, treatment-related toxicity
Measured: 2 Years
Secondary outcomes (4)
Number of participants showing dysferlin protein expression in muscle tissue
More than 3 fold increase in dysferlin protein expression in muscle compared to control side by western blot or more than 30% increase in dysferlin-expressing fibers
Dysferlin protein expression as demonstrated with N -terminal anti-dysferlin antibodies will be quantified using BioQuant
Measured: 2 Years
Leukocyte marker counts including CD45, CD3, CD4, CD8, and MAC 387.
Number of CD4+ cells/ mm2 area; Number of CD8+ cells/ mm2 area; Number of muscle fibers expressing MHCI staining / mm2 area; Number of muscle fibers expressing MHCII staining / mm2 area
Measured: 2 Years
Binding antibodies counts and ELISpot counts to both rAAVrh74 capsid and dysferlin protein.
AAVrh74 or AAV8 binding antibody titers > 1:50 as determined by ELISA immunoassay
Measured: 2 Years
Number of inflammatory cells in muscle
Number of inflammatory cells per mm2 area
Measured: 2 Years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Mar 2016 (estimated)
- Study startMar 2016
- Primary completionJul 2019
- Study completionJul 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for DysferlinopathyStudies of the same condition, open and under way.
- More trials run by Sarepta Therapeutics, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- Sarepta Therapeutics, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Jerry R Mendell, MD, Principal investigator, Director, Center for Gene Therapy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02710500
- Sponsor's protocol ID
- IRB15-00669
- Status last verified
- May 2021
- First submitted
- 11 Feb 2016
- Last updated
- 13 May 2021
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Sondergaard PC, Griffin DA, Pozsgai ER, Johnson RW, Grose WE, Heller KN, Shontz KM, Montgomery CL, Liu J, Clark KR, Sahenk Z, Mendell JR, Rodino-Klapac LR. AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models. Ann Clin Transl Neurol. 2015 Mar;2(3):256-70. doi: 10.1002/acn3.172. Epub 2015 Jan 20.
PubMed 25815352Grose WE, Clark KR, Griffin D, Malik V, Shontz KM, Montgomery CL, Lewis S, Brown RH Jr, Janssen PM, Mendell JR, Rodino-Klapac LR. Homologous recombination mediates functional recovery of dysferlin deficiency following AAV5 gene transfer. PLoS One. 2012;7(6):e39233. doi: 10.1371/journal.pone.0039233. Epub 2012 Jun 15.
PubMed 22720081
Study at a glance
From the registry record, last updated by the sponsor on 13 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Intramuscular Gene Transfer Clinical Trial for Dysferlin Deficiency Delivering the Dysferlin Gene by AAVrh74
- ClinicalTrials.gov ID
- NCT02710500
- Acronym / sponsor ID
- IRB15-00669
- Conditions
- Dysferlinopathy
- Keywords
- LGMD2B, Limb Girdle Muscular Dystrophy, Miyoshi, Gene Transfer, Dysferlin
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 2 participants (actual)
- Lead sponsor
- Sarepta Therapeutics, Inc.Industry (pharma, biotech, devices)
- Study start
- Mar 2016
- Primary completion
- Jul 2019 (actual)
- Study completion
- Jul 2019 (actual)
- First posted
- 16 Mar 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The proposed clinical trial is a double-blind, randomized controlled study with direct intramuscular injection of rAAVrh.74.MHCK7.DYSF.DV gene vector to the extensor digitorum brevis muscle (EDB). Two cohorts of subjects with dysferlin deficiency, each with proven mutations will undergo gene transfer. A minimum of three subjects will be enrolled into each cohort.
Detailed description
This is a phase I safety and tolerability study with a direct intramuscular injection of rAAVrh.74.MHCK7.DYSF.DV transferred to the extensor digitorum brevis muscle (EDB). The study is designed as a randomized, controlled, dose escalation trial with one EDB receiving the rAAVrh.74.MHCK7.DYSF.DV and the other side receiving saline alone. It will follow the previously safe and effective IM gene transfer to EDB for LGMD2D.2, 3 The first cohort, inclusive of three Dysferlinopathy subjects, will receive a gene transfer total dose of 2 x 10^12 vector genomes. Muscle biopsies will be performed at Day 45 (two subjects) and Day 90 (one subject). If there are no safety concerns, three additional subjects will be enrolled and receive an escalated dose at 6 X 10^12 vg (total dose). Muscle biopsies in the second cohort will be performed at Day 90 (one subject) and Day 180 (two subjects). This protocol design gives us a maximum period of observation ranging from 6 weeks to 6 months to capture both transient and delayed gene expression, and to recognize sustained expression.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 (Low Dose) | Experimental | Drug: rAAVrh74.MHCK7.DYSF.DVThree (n=3) dysferlin deficiency subjects will receive bilateral injections with one extensor digitorum brevis muscle (EDB) receiving the rAAVrh74.MHCK7.DYSF.DV and the other side receiving saline alone.Subjects will receive a total dose of 2 x 10^12 in one muscle. Intervention Drug: rAAVrh.MHCK7.DYSF.DV |
| Cohort 2 (High Dose) | Experimental | Drug: rAAVrh74.MHCK7.DYSF.DVThree (n=3) dysferlin deficiency subjects will receive bilateral injections with one extensor digitorum brevis muscle (EDB) receiving the rAAVrh74.MHCK7.DYSF.DV and the other side receiving saline alone.Subjects will receive a total dose of 6 x 10^12 vg in one muscle. Intervention Drug: rAAVrh74.MHCK7.DYSF.DV |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Must be Non-ambulant (cannot walk 10 meters in ≤ 30 sec) and age 18 years or older
- Established mutations of the dysferlin gene on both alleles
- Impaired muscle function but with sufficient muscle preservation to ensure muscle transfection based on magnetic resonance image of the EDB showing sufficient muscle preservation to permit transfection
- Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (If appropriate), during the first six months after gene transfer (females) or until two negative sperm samples are obtained post gene transfer (males).
Key exclusion criteria (11 listed)
- Active viral infection based on clinical observations or serological evidence of HIV, or Hepatitis A, B or C infection
- The presence of a Dysferlin mutations without weakness or loss of function
- Symptoms or signs of cardiomyopathy, including:
- Dyspnea on exertion, pedal edema, shortness of breath upon lying flat, or rales at the base of the lungs
- Echocardiogram with ejection fraction below 40%
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| rAAVrh74.MHCK7.DYSF.DVBiological/Vaccine: rAAVrh74.MHCK7.DYSF.DV Recombinant adeno-associated virus carrying a dysferlin transgene under control of a muscle specific MHCK7 promoter. | Drug | Cohort 1 (Low Dose), Cohort 2 (High Dose) |
Primary outcome
Determination of safety based on the development of unacceptable toxicity
Time frame: 2 Years
Defined as the occurrence of any one Grade III or higher, unanticipated, treatment-related toxicity
4 secondary outcomes
Number of participants showing dysferlin protein expression in muscle tissue
Time frame: 2 Years
Leukocyte marker counts including CD45, CD3, CD4, CD8, and MAC 387.
Time frame: 2 Years
Binding antibodies counts and ELISpot counts to both rAAVrh74 capsid and dysferlin protein.
Time frame: 2 Years
Number of inflammatory cells in muscle
Time frame: 2 Years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 May 2021.
- Background: PubMed 25815352Sondergaard PC, Griffin DA, Pozsgai ER, Johnson RW, Grose WE, Heller KN, Shontz KM, Montgomery CL, Liu J, Clark KR, Sahenk Z, Mendell JR, Rodino-Klapac LR. AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models. Ann Clin Transl Neurol. 2015 Mar;2(3):256-70. doi: 10.1002/acn3.172. Epub 2015 Jan 20.
- Background: PubMed 22720081Grose WE, Clark KR, Griffin D, Malik V, Shontz KM, Montgomery CL, Lewis S, Brown RH Jr, Janssen PM, Mendell JR, Rodino-Klapac LR. Homologous recombination mediates functional recovery of dysferlin deficiency following AAV5 gene transfer. PLoS One. 2012;7(6):e39233. doi: 10.1371/journal.pone.0039233. Epub 2012 Jun 15.
- Center for Gene Therapy, The Research Institute at Nationwide Children's HospitalLink provided by the sponsor.
Related trials for Dysferlinopathy
Active, not recruitingObservational study
A Study of the Natural History of Participants With LGMD2E/R4, LGMD2D/R3, LGMD2C/R5, and LGMD2A/R1 ≥ 4 Years of Age, Who Are Managed in Routine Clinical Practice
Limb-girdle Muscular Dystrophy
Enrolling by invitationObservational study
Clinical, Immunological, Morphological and Genetic Characteristics of Patients With Dysferlinopathy (LGMD R2) in the RF
Dysferlinopathy, Miyoshi Myopathy
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jerry R Mendell, MD principal investigator
Director, Center for Gene Therapy
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing rAAVrh74.MHCK7.DYSF.DV in people with Dysferlinopathy, run by Sarepta Therapeutics, Inc. at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 May 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determination of safety based on the development of unacceptable toxicity (time frame: 2 Years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02710500, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 May 2021.