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Gene Therapy for APOE4 Homozygote of Alzheimer's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03634007
Recruitment Status : Recruiting
First Posted : August 16, 2018
Last Update Posted : November 20, 2019
Sponsor:
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Tracking Information
First Submitted Date  ICMJE August 3, 2018
First Posted Date  ICMJE August 16, 2018
Last Update Posted Date November 20, 2019
Actual Study Start Date  ICMJE October 6, 2019
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 13, 2018)
Safety of AAVrh.10hAPOE2 gene therapy, as measured by number of adverse events or serious adverse events [ Time Frame: 2 years ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03634007 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 13, 2018)
Maximum tolerated dose of intracisternal delivery of AAVrh.10hAPOE2 gene therapy to APOE4 homozygotes with Alzheimer's disease [ Time Frame: 2 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Gene Therapy for APOE4 Homozygote of Alzheimer's Disease
Official Title  ICMJE Gene Therapy for APOE4 Homozygote of Alzheimer's Disease
Brief Summary This clinical trial is an open label, dose-ranging study designed to evaluate gene therapy to treat patients who are APOE4 homozygotes with clinical diagnosis varying from subjective or mild cognitive impairment to very mild to severe dementia due to Alzheimer's disease. All subjects will have evidence of amyloid plaque by nuclear PET scan and/or cerebrospinal fluid (CSF) biomarkers consistent with Alzheimer's disease. The study will assess the safety and toxicity of intracisternal administration of AAVrh.10hAPOE2, serotype rh.10 adeno-associated virus (AAV) gene transfer vector expressing the cDNA coding for human apolipoprotein E2 (APOE2), directly to the CNS/ CSF of APOE4 homozygotes with Alzheimer's disease. The study will establish a maximum tolerable dose and generate preliminary evidence regarding whether direct administration of AAVrh.10hPOE2 to the CNS of those Alzheimer's patients will lead to conversion of the APOE protein isoforms in the CSF of APOE4 homozygotes from APOE4 to APOE2-APOE4.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Alzheimer Disease
  • Early Onset Alzheimer Disease
Intervention  ICMJE Biological: AAVrh.10hPOE2 vector
AAVrh.10hAPOE2 is a serotype rh.10 adeno-associated virus (AAV) gene transfer vector expressing the cDNA coding for human apolipoprotein E2 (APOE2).
Study Arms  ICMJE
  • Experimental: Cohort I: 8.0 x 10^10 gc/kg
    Subjects will receive 8.0 x 10^10 gc/kg of AAVrh.10hAPOE2.
    Intervention: Biological: AAVrh.10hPOE2 vector
  • Experimental: Cohort II: 2.5 x 10^11 gc/kg
    Subjects will receive 2.5 x 10^11 gc/kg of AAVrh.10hAPOE2.
    Intervention: Biological: AAVrh.10hPOE2 vector
  • Experimental: Cohort III: 8.0 x 10^11 gc/kg
    Subjects will receive 8.0 x 10^11 gc/kg of AAVrh.10hAPOE2.
    Intervention: Biological: AAVrh.10hPOE2 vector
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: August 13, 2018)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • APOE4 homozygotes
  • Males and females, age 50 or older
  • Willing and able to provide informed consent (or consent provided by legally authorized representative)
  • Mild cognitive impairment due to Alzheimer's disease, or clinical diagnosis of very mild to severe dementia due to Alzheimer's disease
  • Evidence of amyloid plaques by nuclear PET scan and/or cerebrospinal fluid (CSF) biomarkers consistent with Alzheimer's disease
  • Serum neutralizing anti-AAVrh10 titer <10-2
  • No evidence of active infection of any type, including hepatitis virus (A, B or C) or human immunodeficiency virus (HIV-1 and HIV-2)
  • Fertile or infertile individuals; it will be recommended that fertile individuals utilize barrier birth control measures to prevent pregnancy for the duration of the study
  • Individuals not receiving experimental medications or participating in another experimental protocol for at least 4 weeks prior to entry to the study

Exclusion Criteria:

  • Individuals receiving corticosteroids, other immunosuppressive medications, or anti-coagulant medications (other than aspirin)
  • Individuals who do not fit the American Journal of Neuroradiology recommendations for image guided spinal procedures9
  • Presence of other significant medical or neurological conditions may disqualify the subject from participation in this study, particularly those which would create an unacceptable risk to receiving the AAVrh.10APOE2 vector, for example, malignancy, heart failure, liver or renal failure, or HIV positive.
  • Evidence of ongoing infection
  • Elevated white blood cell count, temperature >38.5̊C, infiltrate on chest x-ray
  • Prior or concurrent participation in any gene and/or cell therapy
  • Any condition, disorder, or abnormal laboratory test findings at screening which, in the judgment of the investigator, would interfere with the individual's ability to comply with all study requirements, or would require the administration of treatment during the study that could potentially affect the interpretation of the study data, or would place the individual at an unacceptable risk by his/her participation in the study
  • Individuals who cannot participate in MRI, PET and CSF studies
  • Individuals who cannot undergo study-related procedures without general anesthesia
  • More than 4 cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as "possible" or "definite"), a single area of superficial siderosis, or evidence of a prior macrohemorrhage
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Grace W Mammen, BA, CCRP 646-962-2672 gwm2004@med.cornell.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03634007
Other Study ID Numbers  ICMJE 1806019315
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
Plan to Share IPD: No
Responsible Party Weill Medical College of Cornell University
Study Sponsor  ICMJE Weill Medical College of Cornell University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ronald G Crystal, MD Weill Cornell Medicine
PRS Account Weill Medical College of Cornell University
Verification Date November 2019

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