Duchenne Muscular Dystrophy
Conditions
Keywords
DMD, Duchenne Muscular Dystrophy
Brief summary
The proposed clinical trial study of rAAVrh74.MCK.GALGT2 for duchenne muscular dystrophy (DMD) patients. There will be a modified intravascular limb infusion (ILI) procedure that will be used to sequentially deliver vector to each whole lower limb of DMD subjects via a major lower limb artery.
Detailed description
This is an open-label, dose escalation trial where the vector will be delivered via the femoral artery to the muscles of both legs of DMD subjects. The primary objective of this study is the assessment of the safety of intravascular administration of rAAVrh74.MCK.GALGT2 to DMD patients. Safety endpoints will be assessed by changes in hematology, serum chemistry, urinalysis, immunologic response to rAAVrh74 and GALGT2, and reported history and observations of symptoms. Efficacy measures will be used as secondary outcome for this disorder including a combination of functional 6 minute walk test (6MWT) and direct muscle testing for strength (MVICT) of lower limb muscles. Subjects will be evaluated at baseline, infusion visit (days 0-2), and return for follow up visits on days 7, 14, 30, 60, 90, and 180 and months 12, 18 and 24
Interventions
BIOLOGICALrAAVrh74.MCK.GALGT2
Adeno-associated virus serotype rh74 carrying the GALGT2 gene under the control of a MCK promoter (rAAVrh74.MCK.GALGT2) will be delivered one time to each of the lower limbs through the femoral artery using an intravascular limb infusion technique (ILI)
Sponsors
Kevin Flanigan
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a dose escalation trial that will begin with the minimal efficacious dose as determined by preclinical studies and approved by the FDA. During the course of the trial, if safety is shown the dose will be escalated according to the clinical protocol.
Eligibility
Sex/Gender
MALE
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ambulant patients age 4 years or older * Confirmed mutations in the DMD gene using a clinical accepted technique that completely defines the mutation 1,2 * • Measurably impaired muscle function (defined as less than 80% of the predicted value for 100 MWT), but with sufficient muscle preservation to ensure assessment of muscle transfection based on clinical evaluation by the PI and expert colleagues. This degree of preservation will include: * Ability to extend the knee fully against gravity * Preserved ambulation with ability to walk ≥ 350 meters during the 6MWT * A magnetic resonance image of the quadriceps showing preservation of sufficient muscle mass to permit transfection * Males of any ethnic group will be eligible * Ability to cooperate with muscle testing * Stable daily dose of corticosteroid therapy (including either prednisone, prednisolone, deflazacort or their generic forms) for 12 weeks prior to gene transfer
Exclusion criteria
* Active viral infection based on clinical observations * The presence of a DMD mutation without weakness or loss of function * Subject is amenable to or is currently being treated with eteplirsen * 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% * Serological evidence of HIV infection, or Hepatitis B or C infection * Diagnosis of (or ongoing treatment for) an autoimmune disease * 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 * Subjects with rAAVrh74 binding antibody titers ≥ 1:50 as determined by ELISA immunoassay * Presence of circulating anti-Sda antibodies as determined by study approved laboratory * Abnormal laboratory values in the clinically significant range, based upon normal values in the Nationwide Children's Hospital Laboratory
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Unanticipated Grade III or Higher Treatment-Related Toxicities | 2 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Expression of GALGT2 as Demonstrated by Immunofluorescent Staining With Anti-CT Epitope Antibodies or WFA Lectin in Muscle Biopsy Sections at 120 Days Post Injection (Cohort 1) and 90 Days Post-injection (Cohort 2). | Day 90 (Cohort 2) and Day 120 (Cohort 1) | Percentage of fibers expressing GALGT2 in each biopsy sample. |
| GALGT2 Protein Expression Quantified by Western Blot and Assessed by Densitometry in Muscle Biopsy Tissue at 120 Days Post-injection (Cohort 1) and 90 Days Post-injection (Cohort 2) | Day 90 (Cohort 2) and Day 120 (Cohort 1) | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Meters Walked During the 6 Minute Walk Test | Day 90 (Cohort 2) and Day 120 (Cohort 1) and Day 180 for both cohorts | — |
| Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA). | Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24 | The NSAA provides a score between 0 and 34 where higher numbers represent greater muscle function. |
| Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24 | — |
| Time Taken to Walk 100 Meters During the 100 Meter Walk Test. | Days 90 (Cohort 2), 120 (Cohort 1); both Cohorts at Day 180, Months 12, 18 and Cohort 2 at Month 24 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (Minimal Efficacious Dose) rAAVrh74.MCK.GALGT2 N = 3 \[2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)\]
rAAVrh74.MCK.GALGT2: Adeno-associated virus serotype rh74 carrying the GALGT2 gene under the control of a MCK promoter (rAAVrh74.MCK.GALGT2) will be delivered one time to each of the lower limbs through the femoral artery using an intravascular limb infusion technique (ILI) | 1 |
| Cohort 2 (Dose Escalation) rAAVrh74.MCK.GALGT2 N=3 \[5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)\]
rAAVrh74.MCK.GALGT2: Adeno-associated virus serotype rh74 carrying the GALGT2 gene under the control of a MCK promoter (rAAVrh74.MCK.GALGT2) will be delivered one time to each of the lower limbs through the femoral artery using an intravascular limb infusion technique (ILI) | 1 |
| Total | 2 |
Baseline characteristics
| Characteristic | Cohort 1 (Minimal Efficacious Dose) rAAVrh74.MCK.GALGT2 | Total | Cohort 2 (Dose Escalation) rAAVrh74.MCK.GALGT2 |
|---|---|---|---|
| Age, Continuous | 9 years | 8 years | 7 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment United States | 1 participants | 2 participants | 1 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 |
Outcome results
Primary
Number of Unanticipated Grade III or Higher Treatment-Related Toxicities
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Minimal Efficacious Dose) | Number of Unanticipated Grade III or Higher Treatment-Related Toxicities | 0 events |
| Cohort 2 | Number of Unanticipated Grade III or Higher Treatment-Related Toxicities | 0 events |
Secondary
Expression of GALGT2 as Demonstrated by Immunofluorescent Staining With Anti-CT Epitope Antibodies or WFA Lectin in Muscle Biopsy Sections at 120 Days Post Injection (Cohort 1) and 90 Days Post-injection (Cohort 2).
Percentage of fibers expressing GALGT2 in each biopsy sample.
Time frame: Day 90 (Cohort 2) and Day 120 (Cohort 1)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Minimal Efficacious Dose) | Expression of GALGT2 as Demonstrated by Immunofluorescent Staining With Anti-CT Epitope Antibodies or WFA Lectin in Muscle Biopsy Sections at 120 Days Post Injection (Cohort 1) and 90 Days Post-injection (Cohort 2). | 1.95 Percentage of Positive Fibers |
| Cohort 2 | Expression of GALGT2 as Demonstrated by Immunofluorescent Staining With Anti-CT Epitope Antibodies or WFA Lectin in Muscle Biopsy Sections at 120 Days Post Injection (Cohort 1) and 90 Days Post-injection (Cohort 2). | 1.72 Percentage of Positive Fibers |
Secondary
GALGT2 Protein Expression Quantified by Western Blot and Assessed by Densitometry in Muscle Biopsy Tissue at 120 Days Post-injection (Cohort 1) and 90 Days Post-injection (Cohort 2)
Time frame: Day 90 (Cohort 2) and Day 120 (Cohort 1)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Minimal Efficacious Dose) | GALGT2 Protein Expression Quantified by Western Blot and Assessed by Densitometry in Muscle Biopsy Tissue at 120 Days Post-injection (Cohort 1) and 90 Days Post-injection (Cohort 2) | 12 ng/mg total protein |
| Cohort 2 | GALGT2 Protein Expression Quantified by Western Blot and Assessed by Densitometry in Muscle Biopsy Tissue at 120 Days Post-injection (Cohort 1) and 90 Days Post-injection (Cohort 2) | 14.6 ng/mg total protein |
Other Pre-specified
Number of Meters Walked During the 6 Minute Walk Test
Time frame: Day 90 (Cohort 2) and Day 120 (Cohort 1) and Day 180 for both cohorts
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Minimal Efficacious Dose) | Number of Meters Walked During the 6 Minute Walk Test | Day 90 (Cohort 2) /Day 120 (Cohort 1) | 320 meters |
| Cohort 1 (Minimal Efficacious Dose) | Number of Meters Walked During the 6 Minute Walk Test | Day 180 | 324 meters |
| Cohort 2 | Number of Meters Walked During the 6 Minute Walk Test | Day 180 | 416 meters |
| Cohort 2 | Number of Meters Walked During the 6 Minute Walk Test | Day 90 (Cohort 2) /Day 120 (Cohort 1) | 405 meters |
Other Pre-specified
Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA).
The NSAA provides a score between 0 and 34 where higher numbers represent greater muscle function.
Time frame: Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Minimal Efficacious Dose) | Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA). | Day 180 | 14 score on a scale |
| Cohort 1 (Minimal Efficacious Dose) | Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA). | Month 18 | 6 score on a scale |
| Cohort 1 (Minimal Efficacious Dose) | Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA). | Month 12 | 10 score on a scale |
| Cohort 1 (Minimal Efficacious Dose) | Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA). | Month 24 | 2 score on a scale |
| Cohort 1 (Minimal Efficacious Dose) | Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA). | Day 90/Day 120 | 16 score on a scale |
| Cohort 2 | Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA). | Month 24 | 23 score on a scale |
| Cohort 2 | Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA). | Day 90/Day 120 | 21 score on a scale |
| Cohort 2 | Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA). | Day 180 | 23 score on a scale |
| Cohort 2 | Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA). | Month 12 | 23 score on a scale |
| Cohort 2 | Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA). | Month 18 | 23 score on a scale |
Other Pre-specified
Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test.
Time frame: Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 90/Day 120-Right Knee Extension | 7.42 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 90/Day 120-Right Knee Flexion | 6.06 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 90/Day 120- Left Knee Extension | 8.78 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 90/Day 120-Left Knee Flexion | 6.12 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 180-Right Knee Extension | 7.13 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 180-Right Knee Flexion | 6.1 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 180-Left Knee Extension | 8.66 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 180-Left Knee Flexion | 6.69 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 12-Right Knee Extension | 7.49 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 12-Right Knee Flexion | 5.67 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 12-Left Knee Extension | 7.5 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 12-Left Knee Flexion | 5.32 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 18-Right Knee Extension | 4.55 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 18-Right Knee Flexion | 6.11 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 18-Left Knee Extension | 4.96 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 18-Left Knee Flexion | 6.26 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 24-Right Knee Extension | 5.06 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 24-Right Knee Flexion | 4.41 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 24-Left Knee Extension | 6.93 kg |
| Cohort 1 (Minimal Efficacious Dose) | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 24-Left Knee Flexion | 4.17 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 24-Right Knee Flexion | 5.04 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 90/Day 120-Right Knee Extension | 7.04 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 12-Left Knee Extension | 8.02 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 90/Day 120-Right Knee Flexion | 8.12 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 18-Left Knee Flexion | 6.08 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 90/Day 120- Left Knee Extension | 5.9 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 12-Left Knee Flexion | 5.12 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 90/Day 120-Left Knee Flexion | 8.4 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 24-Left Knee Flexion | 4.87 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 180-Right Knee Extension | 9.73 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 18-Right Knee Extension | 7.67 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 180-Right Knee Flexion | 4.24 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 24-Right Knee Extension | 9.81 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 180-Left Knee Extension | 8.19 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 18-Right Knee Flexion | 6.89 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Day 180-Left Knee Flexion | 5.25 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 24-Left Knee Extension | 5.21 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 12-Right Knee Extension | 9.85 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 18-Left Knee Extension | 7.34 kg |
| Cohort 2 | Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. | Month 12-Right Knee Flexion | 5.85 kg |
Other Pre-specified
Time Taken to Walk 100 Meters During the 100 Meter Walk Test.
Time frame: Days 90 (Cohort 2), 120 (Cohort 1); both Cohorts at Day 180, Months 12, 18 and Cohort 2 at Month 24
Population: There is no data for Cohort 1, Month 24 because single subject was unable to perform the test.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Minimal Efficacious Dose) | Time Taken to Walk 100 Meters During the 100 Meter Walk Test. | Day 90/Day 120 | 98.2 seconds |
| Cohort 1 (Minimal Efficacious Dose) | Time Taken to Walk 100 Meters During the 100 Meter Walk Test. | Day 180 | 110.9 seconds |
| Cohort 1 (Minimal Efficacious Dose) | Time Taken to Walk 100 Meters During the 100 Meter Walk Test. | Month 12 | 144.5 seconds |
| Cohort 1 (Minimal Efficacious Dose) | Time Taken to Walk 100 Meters During the 100 Meter Walk Test. | Month 18 | 167.8 seconds |
| Cohort 2 | Time Taken to Walk 100 Meters During the 100 Meter Walk Test. | Month 18 | 65.6 seconds |
| Cohort 2 | Time Taken to Walk 100 Meters During the 100 Meter Walk Test. | Month 12 | 44.7 seconds |
| Cohort 2 | Time Taken to Walk 100 Meters During the 100 Meter Walk Test. | Day 90/Day 120 | 56.1 seconds |
| Cohort 2 | Time Taken to Walk 100 Meters During the 100 Meter Walk Test. | Month 24 | 48.4 seconds |
| Cohort 2 | Time Taken to Walk 100 Meters During the 100 Meter Walk Test. | Day 180 | 44.9 seconds |