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Gene Therapy for Male Patients With Danon Disease (DD) Using RP-A501; AAV9.LAMP2B

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ClinicalTrials.gov Identifier: NCT03882437
Recruitment Status : Recruiting
First Posted : March 20, 2019
Last Update Posted : March 16, 2021
Sponsor:
Information provided by (Responsible Party):
Rocket Pharmaceuticals Inc.

Tracking Information
First Submitted Date  ICMJE March 12, 2019
First Posted Date  ICMJE March 20, 2019
Last Update Posted Date March 16, 2021
Actual Study Start Date  ICMJE April 17, 2019
Estimated Primary Completion Date October 21, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 12, 2021)
  • Number of participants with treatment-related adverse events as assessed by United States (US) National Cancer Institute Common Terminology Criteria (NCI CTCAE) [ Time Frame: 3 years ]
    Evaluation of safety associated with RP-A501
  • Number of participants within each dose level cohort with treatment-related adverse events as assessed by United States (US) National Cancer Institute Common Terminology Criteria (NCI CTCAE) [ Time Frame: 3 years ]
    Assessment of safety at both doses (single IV administration)
  • Evaluation of cardiomyocyte histologic correction following administration of RP-A501 via endomyocardial biopsy [ Time Frame: 3 years ]
    Assessment of cardiomyocyte histologic correction following administration of RP-A501 via endomyocardial biopsy
  • Preliminary evaluation of clinical stabilization of cardiomyopathy following administration of RP-A501 via cardiopulmonary testing [ Time Frame: 3 years ]
    Assessment of clinical stabilization of cardiomyopathy following infusion of RP-A501 via cardiopulmonary testing
Original Primary Outcome Measures  ICMJE
 (submitted: March 18, 2019)
  • Number of participants with treatment-related adverse events as assessed by United States (US) National Cancer Institute Common Terminology Criteria (NCI CTCAE) [ Time Frame: 3 years ]
    Evaluation of safety associated with RP-A501
  • Number of participants within each dose level cohort with treatment-related adverse events as assessed by United States (US) National Cancer Institute Common Terminology Criteria (NCI CTCAE) [ Time Frame: 3 years ]
    Assessment of safety at both doses (single IV administration)
  • Detection of target tissue transduction following administration of RP-A501 [ Time Frame: 3 years ]
    Assessment of target tissue transduction by gene expression
  • Evaluation of cardiomyocyte histologic correction following administration of RP-A501 via endomyocardial biopsy [ Time Frame: 3 years ]
    Assessment of cardiomyocyte histologic correction following administration of RP-A501 via endomyocardial biopsy
  • Preliminary evaluation of clinical stabilization of cardiomyopathy following administration of RP-A501 via cardiopulmonary testing [ Time Frame: 3 years ]
    Assessment of clinical stabilization of cardiomyopathy following infusion of RP-A501 via cardiopulmonary testing
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2021)
  • Determination of the percentage of patients in whom RP-A501 resulted in a sustained improvement or stabilization in cardiovascular pathophysiology [ Time Frame: 3 years ]
    Evaluation of sustained improvement or stabilization in cardiovascular pathophysiology as assessed by medical evaluation, radiographic evaluation of cardiac structure and function, and cardiopulmonary exercise/physiologic parameters
  • Determination of the percentage of patients in whom cardiomyocytes corrected LAMP2B gene and/or protein [ Time Frame: 3 years ]
    Evaluation of the percentage of patients in whom cardiomyocytes contain the corrected LAMP2B gene and/or protein and improvement in DD-associated histologic abnormalities and when feasible to quantify the extent of genetic and histologic correction in the myocardium.
  • Determination and characterization of immunologic response to RP-A501 [ Time Frame: 3 years ]
    Assessment of potential immunogenicity to the components of the investigational product
  • Determination of the percentage of patients who require and/or receive treatment for heart failure following RP-A501 [ Time Frame: 3 years ]
    Assessment of the percentage of patients who require and/or receive subsequent cardiac transplantation, left ventricular assist device (LVAD), implantable cardioverter-defibrillator or pacemaker placement, electrophysiologic ablative procedure for cardiac conduction aberrancy or subsequent hospitalizations for heart failure.
  • Evaluation of overall survival [ Time Frame: 3 years ]
    Assessment of overall survival post RP-A501
Original Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2019)
  • Determination of the percentage of patients in whom RP-A501 resulted in a sustained improvement or stabilization in cardiovascular pathophysiology [ Time Frame: 3 years ]
    Evaluation of sustained improvement or stabilization in cardiovascular pathophysiology as assessed by medical evaluation, radiographic evaluation of cardiac structure and function, and cardiopulmonary exercise/physiologic parameters
  • Determination of the percentage of patients in whom cardiomyocytes corrected LAMP2B gene and/or protein [ Time Frame: 3 years ]
    Evaluation of the percentage of patients in whom cardiomyocytes contain the corrected LAMP2B gene and/or protein and improvement in DD-associated histologic abnormalities and when feasible to quantify the extent of genetic and histologic correction in the myocardium.
  • Evaluation of serologic markers of muscle injury and congestive heart failure following administration of RP-A501 [ Time Frame: 3 years ]
    Assessment of serologic markers (creatinine phosphokinase, brain natriuretic peptide, etc) will be performed as potential surrogates of clinical, structural and histologic modification of DD
  • Determination and characterization of immunologic response to RP-A501 [ Time Frame: 3 years ]
    Assessment of potential immunogenicity to the components of the investigational product
  • Evaluation of patient-reported outcomes/quality-of-life (PRO/QOL) [ Time Frame: 3 years ]
    Assessment of PRO/QOL will be performed via the Kansas City Cardiomyopathy Questionnaire
  • Assessment of PRO/QOL [ Time Frame: 3 years ]
    Evaluation of PRO/QOL will be performed via the Pediatric Cardiac Quality of Life Inventory
  • Determination of the percentage of patients who require and/or receive treatment for heart failure following RP-A501 [ Time Frame: 3 years ]
    Assessment of the percentage of patients who require and/or receive subsequent cardiac transplantation, left ventricular assist device (LVAD), implantable cardioverter-defibrillator or pacemaker placement, electrophysiologic ablative procedure for cardiac conduction aberrancy or subsequent hospitalizations for heart failure.
  • Evaluation of overall survival [ Time Frame: 3 years ]
    Assessment of overall survival post RP-A501
  • Determination of the percentage of patients with stabilization in neuromuscular function via timed test of essential neuromuscular activities [ Time Frame: 3 years ]
    Assessment of the percentage of patients with stabilization in neuromuscular function via timed test of essential neuromuscular activities
  • Determination of the percentage of patients with stabilization in ophthalmologic function via ophthalmologic examination [ Time Frame: 3 years ]
    Assessment of the percentage of patients with stabilization in ophthalmologic function via ophthalmologic examination
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Gene Therapy for Male Patients With Danon Disease (DD) Using RP-A501; AAV9.LAMP2B
Official Title  ICMJE A Clinical Study Evaluating a Recombinant Adeno-Associated Virus Serotype 9 (rAAV9) Capsid Containing the Human Lysosome-Associated Membrane Protein 2 Isoform B (LAMP2B) Transgene (RP-A501; AAV9.LAMP2B) in Male Patients With DD
Brief Summary This is a non-randomized open-label Phase 1 study to evaluate the safety and toxicity of gene therapy using a recombinant adeno-associated virus serotype 9 (AAV9) containing the human lysosome-associated membrane protein 2 isoform B (LAMP2B) transgene (investigational product (IP), RP-A501) in male patients with Danon Disease (DD).
Detailed Description

The study is a non-randomized open-label Phase I clinical trial to characterize the safety and toxicity associated with infusion of a recombinant adeno-associated serotype 9 (rAAV9) capsid containing the human lysosome-associated membrane protein 2 isoform B (LAMP2B) transgene (investigational product (IP), RP-A501) in male patients with Danon Disease (DD).

During the course of the study, approximately 11-23 subjects will receive a single intravenous (IV) infusion of the IP with each cohort receiving RP-A501 at sequentially higher dose levels. Three dose levels are planned to be investigated in 6 distinct cohorts. Prior to infusion of IP, rituximab and tacrolimus will be administered prophylactically.

  • Cohort 1: Age 15 -17 years: Low Dose (n=3 subjects)
  • Cohort 2: Age 15 - 17 years: Intermediate Dose (n=2-4)
  • Cohort 3: Age 15 - 17 years: High Dose (n=2-4)
  • Cohort 1A: Age 8 - 14 years: Low Dose (n=2-4)
  • Cohort 2A: Age 8 - 14 years : Intermediate Dose (n=2-4)
  • Cohort 3A: Age 8 - 14 years: High Dose (n=2-4)

Pending determination of safety in the current cohort, concomitant enrollment in subsequent cohort is permissible.

The study will also enable an initial evaluation of whether or not the IP results in cardiomyocyte and skeletal muscle transduction and gene expression and preliminary assessment of the extent of cardiomyocyte and histologic correction. Additionally, a preliminary evaluation of clinical stabilization following infusion will also be made.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description:

Enrollment within each cohort will be staggered - initial patient must be followed for safety before subsequent patients in a cohort may receive IP.

Cohort 1: Age 15 -17 years: Low Dose (n=3 subjects)

Cohort 2: Age 15 - 17 years: Intermediate Dose (n=2-4)

Cohort 3: Age 15 - 17 years: High Dose (n=2-4)

Cohort 1A: Age 8 - 14 years: Low Dose (n=2-4)

Cohort 2A: Age 8 - 14 years : Intermediate Dose (n=2-4)

Cohort 3A: Age 8 - 14 years: High Dose (n=2-4)

Evaluation of RP-A501 in pediatric patients (ages 8-14) will commence only pending determination of safety in the older (adult and age 15-17) population.

Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Danon Disease
Intervention  ICMJE Biological: RP-A501
RP-A501 is a gene therapy product consisting of a rAAV9 capsid containing the human LAMP2B transgene which will be administered as a single IV infusion.
Study Arms  ICMJE Experimental: RP-A501
RP-A501 is a gene therapy product consisting of a rAAV9 capsid containing the human LAMP2B transgene which will be administered as a single intravenous (IV) infusion. Subjects will receive one of three dose levels depending on the cohort.
Intervention: Biological: RP-A501
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 12, 2021)
23
Original Estimated Enrollment  ICMJE
 (submitted: March 18, 2019)
24
Estimated Study Completion Date  ICMJE October 21, 2024
Estimated Primary Completion Date October 21, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Main Criteria for Inclusion:

The study will enroll adult and pediatric males with a confirmed diagnosis of DD. Patients may be of any race or ethnicity. Patients and/or competent custodial parents must provide informed written consent and meet all of the enrollment criteria as detailed subsequently to be eligible to participate.

  1. DD diagnosis with any confirmed LAMP2 mutation(s).
  2. Cardiac involvement as documented by at least one abnormal finding on electrocardiogram (ECG), echocardiogram, gadolinium-enhanced cardiac magnetic resonance imaging (MRI), or electrophysiology study.
  3. Age ≥15 years for cohorts 1, 2, and 3; 8-14 years for cohorts 1A, 2A, and 3A.
  4. Male gender.
  5. New York Heart Association (NYHA) Class II or III. Patients with NYHA Class I are eligible if unable to walk ≥450 meters during the 6-Minute Walk Test (6MWT).
  6. Adequate hematologic function as defined by:

    1. Hemoglobin ≥10 g/dL (6.2 mmol/L; Grade £1 anemia, per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0).
    2. Absolute neutrophil count ≥1,500/mm3 (1.5×109/L; Grade £1 neutropenia).
    3. Platelet count ≥75,000/mm3 (75×109/L; Grade £1 thrombocytopenia).
  7. Hepatic function as defined by:

    1. AST and ALT ≤10.0×ULN or GGT ≤2.0×ULN (transaminase elevations in DD are considered extensively to result from muscle injury; hence the relatively high upper limit for transaminases and consideration of GGT level, and the presence of additional hepatic eligibility markers of bilirubin and PT/INR).
    2. Serum bilirubin ≤1.5×ULN (i.e., Grade £1 bilirubin increase).
    3. PT/INR ≤1.5×ULN (in the absence of anticoagulation).
    4. Absence of cirrhosis on liver ultrasound
  8. Renal function as follows: creatinine ≤1.5×ULN; (if creatinine is >1.5×ULN, then creatinine clearance ≥50 mL/min/1.73m2 is required, as calculated by Modification of Diet in Renal Disease equation (Stevens 2006), the revised Schwartz formula (for patients under 18 years old) (Schwartz 2009), or 24-hour urine collection).
  9. Ability to provide informed consent (for adult patients and parents/legal guardians of pediatric patients) and assent (for patients age 15-17).
  10. Ability to comply with study procedures including investigational therapy and follow-up evaluations.
  11. Able to walk >150 meters unassisted during the 6MWT.
  12. Patient has received meningococcal vaccination recommended by Centers for Disease Control as appropriate for age and health condition.

Main Criteria of Exclusion:

Patients meeting any of the following criteria are not eligible for study participation:

  1. IV therapy with positive inotropes, vasodilators, or diuretics within the 30 days prior to enrollment (i.e., patient must be stable on oral medical therapy).
  2. Prior cardiac transplantation or prior transplant of other organ (lung, liver, other).
  3. Cardiac surgery, percutaneous cardiac intervention, or valvuloplasty within 30 days prior to enrollment.
  4. Presence or requirement of a Left Ventricular Assisted Device (LVAD).
  5. Myocardial infarction, unstable angina, stroke, or transient ischemic attack (TIA) within 90 days prior to enrollment.
  6. Significant (greater than moderate) valvular stenosis or regurgitation on echocardiogram.
  7. Requires mechanical ventilation.
  8. Anti-AAV9 neutralizing antibody titer >1:40.
  9. Concurrent enrollment in any other clinical investigation involving use of an investigational agent for the treatment of CHF or cardiomyopathy.
  10. Active hepatitis B or C infection (including patients with positive hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), or detectable hepatitis B virus (HBV) or hepatitis C virus (HCV) viral load). Patients with previous, adequately resolved HBV or HCV are eligible.
  11. Significant medical conditions including documented human immunodeficiency virus (HIV) infection, active viral or other hepatitis, poorly-controlled hypertension or diabetes, poorly controlled cardiac arrhythmia, or uncontrolled viral, bacterial, or fungal infection.
  12. Any concomitant medical or psychiatric condition that in the opinion of the Investigator renders the patient unfit for study participation or at higher than acceptable risk for study participation.
  13. Active hematologic or solid organ malignancy, not including non-melanoma skin cancer or other carcinoma in situ. Patients with previously resected solid organ malignancies or definitively treated hematologic malignancies may be eligible if there has been no evidence of active malignancy during the prior 3 years.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 8 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Clinical Information +1 646-627-0033 Danonclinicaltrial@rocketpharma.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03882437
Other Study ID Numbers  ICMJE RP-A501-0219
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Rocket Pharmaceuticals Inc.
Study Sponsor  ICMJE Rocket Pharmaceuticals Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Barry Greenberg, MD University of California, San Diego
Principal Investigator: Matthew Taylor, MD, PhD University of Colorado, Anschutz Medical Ctr
Principal Investigator: Joseph Rossano, MD Children's Hospital of Philadelphia
PRS Account Rocket Pharmaceuticals Inc.
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP