A Phase 1/2 interventional study of rAAV1.CMV.huFollistin344 in Duchenne Muscular Dystrophy, sponsored by Jerry R. Mendell. Completed at 1 site in United States. Open to male participants aged 7 Years and older. Per ClinicalTrials.gov, last updated 2023-10-11.
Sponsored by Jerry R. Mendell · Phase 1/2, Interventional, and Other
The proposed clinical trial is an outgrowth of the safety record and functional improvement seen in the BMD follistatin gene therapy trial. In this study the investigators propose to inject AAV1.CMV.huFS344 at a total dose of 2.4E12 vg/kg to six DMD patients. This dose will be divided between gluteal muscles, quadriceps and tibialis anterior. This is a wider distribution of vector than given to BMD patients, who overall improved the distance walked on the 6MWT without adverse events related to viral transduction into a single muscle.
The primary objective of this study is safety and endpoints will include hematology, serum chemistry, urinalysis, immunologic response to rAAV1 and follistatin, and reported history and observations of symptoms. Efficacy measures will be used as secondary outcomes and include the distance walked on the 6MWT, functional tests by PT, life quality questionnaire, MRI, EIM, and muscle biopsy. Subject will have follow up visits on days 7, 14, 30, 45, 60, 90, 180 and 9,12, 18 and 24 months post-gene transfer.
548 studies on the registry are indexed under Muscular Dystrophies; 89 are open to participants now.
This study's enrollment of 3 is below the median of 24 across 344 interventional studies indexed under Muscular Dystrophies.
Browse Muscular Dystrophies studies →Jerry R. Mendell is the lead sponsor of 2 studies on the registry; none are open to participants now.
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Exclusion Criteria:
The vector will be delivered to both limbs via multiple, direct intramuscular injections of rAAV1.CMV.huFollistin344; the number of injections per muscle will depend on the size of the patient. A total dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) will be delivered to the lower limbs of 6 DMD subjects
Biological: rAAV1.CMV.huFollistin344
Six DMD patients will receive rAAV1.CMV.huFollistatin344 to both limbs by multiple injections to gluteal muscles, quadriceps and tibialis anterior muscles.
Number of Dose Limiting Toxicity (DLT) Adverse Events as Assessed by 21 CFR 312.32.
Dose limiting toxicity (DLT) is defined as any adverse event that is possibly, probably, or definitely related to the study agent. This would include any grade 3 according to the classification given above. Study enrollment will be halted by the investigators when any subject experiences a Grade 3, or higher adverse event toxicity that is possibly, probably, or definitely related to the study drug. Only those adverse events requiring treatment will qualify as DLT. The classification for adverse events to be used is the following: 1. Mild adverse event; did not require treatment 2. Moderate adverse event; resolved with treatment 3. Severe adverse event; inability to carry on normal activities; required professional medical attention 4. Life-threatening or permanently disabling adverse event 5. Fatal adverse event In this grading system, "severe" is not equivalent to seriousness.
Time frame: DLT Adverse events will be recorded from the date of dosing and through the time of the subject's last study visit. Serious adverse events will be recorded from the date of dosing and for up to 2 years after gene therapy administration.
Muscle Function Measured by Six-minute Walk Test (6MWT)
Number of subjects with increased distance walked in meters on the Six Minute Walk Test. The participant was asked to walk a set course of 25 meters for 6 minutes (timed) and the distance walked in meters was recorded. Increases from baseline in 6MWT distance are indicative of improvement and decreases from baseline indicate worsening.
Time frame: 2 years
Expression of Viral DNA (qPCR), and Follistatin Transgene in Muscle Tissue
Muscle biopsies on quadriceps muscles a muscle biopsy on one leg at baseline screening visit and the post gene transfer biopsy on the opposite leg at day 180. Muscle tissue obtained at biopsy will also be assessed for viral DNA (qPCR), and follistatin transgene expression. Measured in CMV.FS344 Gene Copy Number in Genomic DNA (Copies/ug DNA)
Time frame: 180.days
Improvement of Muscle Function as Measured by North Star Ambulatory Assessment (NSAA)
Overall Improvement in North Star Ambulatory Assessment The activities are graded as follows: 2 - "Normal" - no obvious modification of activity 1 - Modified method but achieves goal independent of physical assistance from another 0 - Unable to achieve independently This scale is ordinal with 34 as the maximum score indicating fully-independent function.
Time frame: 2 years
| Milestone | 2.4E12 vg/kg CMV.huFollistatin344 |
|---|---|
| Started | 3 |
| Completed | 3 |
| Not completed | 0 |
Dose limiting toxicity (DLT) is defined as any adverse event that is possibly, probably, or definitely related to the study agent. This would include any grade 3 according to the classification given above. Study enrollment will be halted by the investigators when any subject experiences a Grade 3, or higher adverse event toxicity that is possibly, probably, or definitely related to the study drug. Only those adverse events requiring treatment will qualify as DLT. The classification for adverse events to be used is the following: 1. Mild adverse event; did not require treatment 2. Moderate adverse event; resolved with treatment 3. Severe adverse event; inability to carry on normal activities; required professional medical attention 4. Life-threatening or permanently disabling adverse event 5. Fatal adverse event In this grading system, "severe" is not equivalent to seriousness.
| Number of Events | 2.4E12 vg/kg CMV.huFollistatin344 |
|---|---|
| Number of Dose Limiting Toxicity (DLT) Adverse Events as Assessed by 21 CFR 312.32. | 0 |
Number of subjects with increased distance walked in meters on the Six Minute Walk Test. The participant was asked to walk a set course of 25 meters for 6 minutes (timed) and the distance walked in meters was recorded. Increases from baseline in 6MWT distance are indicative of improvement and decreases from baseline indicate worsening.
| Participants | 2.4E12 vg/kg CMV.huFollistatin344 |
|---|---|
| Muscle Function Measured by Six-minute Walk Test (6MWT) | 0 |
Muscle biopsies on quadriceps muscles a muscle biopsy on one leg at baseline screening visit and the post gene transfer biopsy on the opposite leg at day 180. Muscle tissue obtained at biopsy will also be assessed for viral DNA (qPCR), and follistatin transgene expression. Measured in CMV.FS344 Gene Copy Number in Genomic DNA (Copies/ug DNA)
No measurements were reported for this outcome.
Overall Improvement in North Star Ambulatory Assessment The activities are graded as follows: 2 - "Normal" - no obvious modification of activity 1 - Modified method but achieves goal independent of physical assistance from another 0 - Unable to achieve independently This scale is ordinal with 34 as the maximum score indicating fully-independent function.
| Participants | 2.4E12 vg/kg CMV.huFollistatin344 |
|---|---|
| Improvement of Muscle Function as Measured by North Star Ambulatory Assessment (NSAA) | 1 |
Collected over Adverse events will be recorded from the date of informed consent and for up to 2 years after gene therapy administration, the subject's last study visit. Serious adverse events will be recorded from the date of informed consent and for up to 2 years after gene therapy administration, the subject's last study visit.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| 2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344 | 0/3 (0%) | 1/3 (33.3%) | 3/3 (100%) |
| Event | 2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344 |
|---|---|
| Head Injury From FallInjury, poisoning and procedural complications | 1/3 |
| Event | 2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344 |
|---|---|
| PainInjury, poisoning and procedural complications | 3/3 |
| BruisingSkin and subcutaneous tissue disorders | 2/3 |
| PharyngitisRespiratory, thoracic and mediastinal disorders | 1/3 |
| RhinorrheaRespiratory, thoracic and mediastinal disorders | 1/3 |
| AbrasionSkin and subcutaneous tissue disorders | 1/3 |
| AnxietyPsychiatric disorders | 1/3 |
| Behavioral Changes/AgitationPsychiatric disorders | 1/3 |
| InsomniaPsychiatric disorders | 1/3 |
| GERDGastrointestinal disorders | 1/3 |
| ConstipationGastrointestinal disorders | 1/3 |
The Safety Population included all subjects who received one dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344. The Safety Population is the primary analysis population for safety assessments
| Age, Categorical(Participants) | Dose Group 1 |
|---|---|
| <=18 years | 3 |
| Between 18 and 65 years | 0 |
| >=65 years | 0 |
| Sex: Female, Male(Participants) | Dose Group 1 |
|---|---|
| Female | 0 |
| Male | 3 |
| Ethnicity (NIH/OMB)(Participants) | Dose Group 1 |
|---|---|
| Hispanic or Latino | 0 |
| Not Hispanic or Latino | 3 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | Dose Group 1 |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 0 |
| White | 3 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Dose Group 1 |
|---|---|
| United States | 3 |
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Jerry R. Mendell