Trial record 1 of 2 for:    CEROID LIPOFUSCINOSIS, NEURONAL, 10
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AAVRh.10 Administered to Children With Late Infantile Neuronal Ceroid Lipofuscinosis With Uncommon Genotypes or Moderate/Severe Impairment

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by Weill Medical College of Cornell University
Sponsor:
Information provided by (Responsible Party):
Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:
NCT01414985
First received: December 13, 2010
Last updated: September 5, 2013
Last verified: September 2013
  Purpose

The investigators propose to assess the safety and efficacy of a new administration method to deliver a biologic to children with a form of Batten disease using an experimental gene transfer procedure. This gene transfer procedure consists of delivering a good copy of the mutated gene to the nerve cells via a virus. These children are born with genetic changes called mutations that result in the inability of the brain to properly recycle proteins. The recycling failure leads to death of the nerve cells in the brain and progressive loss of brain function. Children with Batten disease are normal at birth but by age 2 to 4 have motor and vision problems which progress rapidly to death at age approximately 10 years old. There are no therapies available to treat the disease.

The investigators previous clinical trial used a virus called adeno-associated virus 2 (AAV2) as the gene delivery system. That study showed that viral delivery of the gene was safe and showed small, but significant benefits to the recipient. The investigators currently have an IRB approved protocol which uses a slightly different virus called AAVrh.10 as the gene delivery system. This 3rd protocol proposes to use the same virus AAVrh.10 as the gene delivery system and has expanded the eligibility criteria.


Condition Intervention Phase
Late Infantile Neuronal Ceroid Lipofuscinosis
Batten Disease
Biological: AAVrh.10CUCLN2
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Direct CNS Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human CLN2 cDNA to Children With LINCL With Uncommon Genotypes and/or Moderate to Severe Impairment

Resource links provided by NLM:


Further study details as provided by Weill Medical College of Cornell University:

Primary Outcome Measures:
  • Weill Cornell LINCL Scale [ Time Frame: Month 1, 6, 12 and 18 ] [ Designated as safety issue: No ]
    The Weill Cornell LINCL scale, a 12 point scale which combines assessment of feeding, gait, motor and language to give an overall assessment of various CNS functions (Appendix II for the paper describing the scale and Appendix VI for the scale)27. This rating scale evaluation will be performed by 2 independent pediatricians, on the basis of a videotaped evaluation. If the 2 independent scores differ by 1 or less they will be averaged and if they differ by greater than 1 point, a consensus will be obtained by a 3rd pediatrician.This outcome measure will look at changes over time.

  • MRI [ Time Frame: Month 6, 12 and 18 ] [ Designated as safety issue: Yes ]
    3 imaging parameters (% gray matter volume, % ventricular volume and cortical apparent diffusion coefficient) correlate with age and the Weill Cornell LINCL scale. These 3 imaging parameters will be used to assess disease progression (control protocol) and safety of the gene transfer vector (vector protocol) over time. In addition to these imaging parameters we will also perform magnetic resonance spectroscopy (MRS) but the data obtained from this will be for information only for method development. This outcome measure will look at changes over time.


Secondary Outcome Measures:
  • Child Health Questionnaire [ Time Frame: Month 1, 6, 12 and 18 ] [ Designated as safety issue: No ]
    The CHQ or ITQoL, a quality of life questionnaire which will be completed by at least one parent/legal guardian at the time of the LINCL patients' visits to Weill Cornell28,29; we will administer this survey independently to each parent to minimize observer bias if both parents are present. This outcome measure looks at a change over time.

  • Mullen Scale [ Time Frame: Month 1, 6, 12 and 18 ] [ Designated as safety issue: No ]
    The Mullen scale, a pediatric developmental psychological rating scale; will be administered by a developmental psychologist, and be videotaped. This outcome measure will look at changes over time.


Estimated Enrollment: 8
Study Start Date: December 2010
Estimated Study Completion Date: December 2022
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A
Group A consists of 2 subjects who received 9x10^11 molecules of AAVrh.10CUCLN2, the gene transfer vector carrying the CLN2 gene. This is equal to 900,000,000,000 molecules of the study drug. The drug will be administered only once in the study.
Biological: AAVrh.10CUCLN2
There will be 2 dose cohorts in this study. Group A consists of 2 subjects who have received 9.0x10^11 genome copies (900,000,000,000 molecules) of the study drug, AAVrh.10CUCLN2. Group B will consist of 6 subjects who will receive a lower dose of 2.85x10^11 genome copies (285,000,000,000 molecules) of the study drug, AAVrh.10CUCLN2.
Other Name: AAVrh.10
Experimental: Group B
Group B will consist of 6 subjects who will receive 2.85x10^11 molecules of AAVrh.10CUCLN2, the gene transfer vector carrying the CLN2 gene. This is equal to 285,000,000,000 molecules of the drug. The drug will be administered only once in the study.
Biological: AAVrh.10CUCLN2
There will be 2 dose cohorts in this study. Group A consists of 2 subjects who have received 9.0x10^11 genome copies (900,000,000,000 molecules) of the study drug, AAVrh.10CUCLN2. Group B will consist of 6 subjects who will receive a lower dose of 2.85x10^11 genome copies (285,000,000,000 molecules) of the study drug, AAVrh.10CUCLN2.
Other Name: AAVrh.10

Detailed Description:

This study is designed to run parallel to our currently IRB approved protocol #0810010013 entitled "Direct CNS Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human CLN2 cDNA to Children with Late Infantile Neuronal Ceroid Lipofuscinosis," which will assess the safety and efficacy of the virus AAVrh.10 to deliver the CLN2 gene to children in the early stages of the disease. This current study proposes to assess the safety and efficacy of the administration of the same biologic to children who do not fit the criteria for IRB protocol #0810010013.

The differences between protocol #0810010013 and the proposed "parallel" protocol is that inclusion criteria have been modified to include children with any genotype (not only the 5 most common genotypes as in the currently approved protocol) and/or those who score below a 6 but at least a 1 on the Weill Cornell LINCL scale. The reason for expanding the eligibility criteria is to obtain a range of safety data for all children with LINCL, not only those with limited genotype and/or severity. Only 8 subjects will be administered the gene transfer vector in this "parallel" protocol. Subjects will be accrued through IRB approved protocol #0901010186 entitled, "Genotype-Phenotype Correlations of Late Infantile Neuronal Ceroid Lipofuscinosis (2)." Those who do not fit all criteria for the already approved gene transfer protocol (#0810010013) may have the opportunity to be enrolled in this proposed "parallel protocol" (Figure 1). The subjects in the new protocol will be compared to the 16 treated and 16 untreated children enrolled in IRB protocol #0810010013 and #0901010186, respectively.

  Eligibility

Ages Eligible for Study:   3 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria.

  1. Definitive diagnosis of LINCL, based on clinical phenotype and genotype. The study does not limit to one specific genotype (genetic constitution).
  2. The subject must be between the age of 3 and 18 years.
  3. Subjects will have an average total score of less than 6 but at least 1, and/or an uncommon genotype defined as any genotype that does not include at least one of the 5 most common mutant CLN2 genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron8), and G4655A. The total LINCL score should not be outside the 95th percentile confidence limits for age based on our historic data.
  4. The subject will not previously have participated in a gene transfer or stem cell study.
  5. Parents of study participants must agree to comply in good faith with the conditions of the study, including attending all of the required baseline and follow-up assessments, and both parents or legal guardians must give consent for their child's participation.
  6. Sexually active subjects will have to use contraception during the treatment and for 2 months after completion of the treatment.

Exclusion criteria.

  1. Presence of other significant medical or neurological conditions may disqualify the subject from participation in this study, particularly those which would create an unacceptable operative risk or risk to receiving the AAVrh.10CUhCLN2 vector, e.g., malignancy, congenital heart disease, liver or renal failure.
  2. Subjects without adequate control of seizures.
  3. Subjects with heart disease that would be a risk for anesthesia or a history of major risk factors for hemorrhage.
  4. Subjects who cannot participate in MRI studies.
  5. Concurrent participation in any other FDA approved Investigational New Drug.
  6. Subjects with history of prolonged bleeding or abnormal platelet function or taking aspirin.
  7. Renal disease or altered renal function as defined by serum creatinine > 1.5 mg/dl at admission.
  8. Abnormal serum sodium, potassium calcium, magnesium, phosphate at grade III or IV by Division of AIDS Toxicity Scale
  9. Hepatic disease or altered liver function as defined by SGPT > 150 U/L, and or T.Bilirubin> 1.3 mg/dL
  10. Immunosuppression as defined by WBC < 3,000 at admission
  11. Uncorrected coagulopathy during the baseline period defined as INR > 1.4; PTT > 35 sec; PLT < 150,000/mm3
  12. Anemia (hemoglobin < 11.0 mg/dl at > 2 years of age, with normal serum iron studies)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01414985

Contacts
Contact: Charleen Hollmann, PhD 646.962.2672 chollman@med.cornell.edu
Contact: Denesy Mancenido, BA 646.962.4537 dem2026@med.cornell.edu

Locations
United States, New York
Weill Cornell Medical College Recruiting
New York, New York, United States, 10065
Contact: Charleen Hollmann, PhD    646-962-2672    chollman@med.cornell.edu   
Contact: Denesy Mancenido, BA    646-962-4537    dem2026@med.cornell.edu   
Sponsors and Collaborators
Weill Medical College of Cornell University
Investigators
Principal Investigator: Ronald Crystal, MD Weill Medical College of Cornell University
  More Information

No publications provided

Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT01414985     History of Changes
Other Study ID Numbers: 1005011054, IND 13951
Study First Received: December 13, 2010
Last Updated: September 5, 2013
Health Authority: United States: Food and Drug Administration
United States: Federal Government
United States: Institutional Review Board

Keywords provided by Weill Medical College of Cornell University:
Batten Disease

Additional relevant MeSH terms:
Neuronal Ceroid-Lipofuscinoses
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Lipid Metabolism Disorders
Metabolic Diseases

ClinicalTrials.gov processed this record on July 31, 2014