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Trial record 2 of 2 for:    Danon Disease

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

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ClinicalTrials.gov Identifier: NCT03882437
Recruitment Status : Recruiting
First Posted : March 20, 2019
Last Update Posted : June 25, 2019
Sponsor:
Information provided by (Responsible Party):
Rocket Pharmaceuticals Inc.

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).

Condition or disease Intervention/treatment Phase
Danon Disease Biological: RP-A501 Phase 1

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 12-24 subjects will receive a single intravenous (IV) infusion of the IP, with up to 4 specific cohorts receiving RP-A501 at sequentially higher dose levels. Two dose levels are planned to be investigated in 4 distinct cohorts:

  • Cohort 1: Age 15 years and older: Low Dose (n=3-6 subjects)
  • Cohort 2: Age 15 years and older: High Dose (n=3-6 subjects)
  • Cohort 3: Age 8-14 years: Low Dose (n=3-6 subjects)
  • Cohort 4: Age 8-14 years: High Dose (n=3-6 subjects)

Pending determination of safety in Cohort I, concomitant enrollment in Cohorts 2 and 3 is permissible.

The study will also enable an initial evaluation of whether or not the investigational therapy 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Sequential Assignment
Intervention Model Description:

Subjects will receive RP-A501 according to a 3+3 dose escalation design as follows:

  • Cohort 1: Age 15 years and older: Low Dose (n=3-6 subjects)
  • Cohort 2: Age 15 years and older: High Dose (n=3-6 subjects)
  • Cohort 3: Age 8-14 years: Low Dose (n=3-6 subjects)
  • Cohort 4: Age 8-14 years: High Dose (n=3-6 subjects)

Evaluation of RP-A501 in pediatric patients (ages 8-14) at either dose level will commence only pending determination of safety in the older (adult and age ≥15 and generally capable of providing assent) population.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Gene Therapy for Danon Disease (DD): A Clinical Study Evaluating the Infusion of 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 Danon Disease
Actual Study Start Date : April 17, 2019
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2023


Arm Intervention/treatment
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 two dose levels depending on the cohort.
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.




Primary Outcome Measures :
  1. 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

  2. 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)

  3. Detection of target tissue transduction following administration of RP-A501 [ Time Frame: 3 years ]
    Assessment of target tissue transduction by gene expression

  4. 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

  5. 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


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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

  4. Determination and characterization of immunologic response to RP-A501 [ Time Frame: 3 years ]
    Assessment of potential immunogenicity to the components of the investigational product

  5. 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

  6. Assessment of PRO/QOL [ Time Frame: 3 years ]
    Evaluation of PRO/QOL will be performed via the Pediatric Cardiac Quality of Life Inventory

  7. 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.

  8. Evaluation of overall survival [ Time Frame: 3 years ]
    Assessment of overall survival post RP-A501

  9. 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

  10. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   8 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  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 and 2; 8-14 years for cohorts 3 and 4.
  4. Male gender.
  5. New York Heart Association (NYHA) Class of 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 ≥1500/mm^3 (1.5×10^9/L; Grade ≤1 neutropenia).
    3. Platelet count ≥75,000/mm^3 (75×10^9/L; Grade ≤1 thrombocytopenia).
  7. Hepatic function as defined by:

    1. AST and ALT ≤10×ULN (transaminase elevations in DD are considered largely to result from muscle injury; hence the relatively high upper limit for these parameters, 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/1.73m^2 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.

Exclusion Criteria:

  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 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 >1:5.
  9. Concurrent enrollment in any other clinical investigation involving use of an investigational agent for the treatment of congestive heart failure or cardiomyopathy.
  10. Active hepatitis B or C infection (including patients with positive HBsAg, HBeAg or detectable HBV or HCV viral load). Patients with previous, adequately resolved HBV or HCV are eligible.
  11. Significant medical conditions including documented 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03882437


Contacts
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Contact: Barry H Greenberg, MD 858-246-2987 bgreenberg@ucsd.edu

Locations
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United States, California
University of California, San Diego Recruiting
La Jolla, California, United States, 92037
Contact: Phirum Nguyen    858-822-3108    psnguyen@ucsd.edu   
Sponsors and Collaborators
Rocket Pharmaceuticals Inc.

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Responsible Party: Rocket Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT03882437     History of Changes
Other Study ID Numbers: RP-A501-0219
First Posted: March 20, 2019    Key Record Dates
Last Update Posted: June 25, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Rocket Pharmaceuticals Inc.:
hypertrophic cardiomyopathy
HCM
Additional relevant MeSH terms:
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Glycogen Storage Disease Type IIb
Nervous System Diseases
Heart Diseases
Cardiovascular Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Glycogen Storage Disease
Metabolic Diseases
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Cardiomyopathies
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors