Clinical trial NCT01913093: N-PhenoGENICS: Neurocognitive-Phenome, Genome, Epigenome and Nutriome In Childhood Leukemia Survivors
Official title: N-PhenoGENICS: Neurocognitive-Phenome, Genome, Epigenome and Nutriome In Childhood Leukemia Survivors
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Childhood Leukemia Survivors
Keywords: Childhood leukemia survivors
Acute lymphoblastic leukemia
Leukemia
Late effects
Folate
Blood folate
Neurotoxicity
Methotrexate
Pharmacogenetics
Cognitive
Cognitive late effects
N-PhenoGENICS
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Canadian Cancer Society (CCS)
name: C17 Council
name: Garron Family Cancer Centre
name: Pediatric Oncology Group of Ontario
First posted: 2013-07-31
Enrollment: 204
Sex: ALL
Minimum age (years): 8
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Childhood leukemia survivors

Brief summary: To find possible therapeutic targets to help prevent long-term brain and behavioural side effects in survivors of childhood leukemia that may have been caused by chemotherapy (Treatment-Related late Adverse Neuro-Cognitive Effects: TRANCE). The study hypothesis is that genetic variations of the elements in the folate-related cycles and methotrexate disposition networks are associated with the deficit phenotype (TRANCE) of childhood leukemia survivors.

Detailed description: Hypothesis Genetic variants of the elements in the folate-related cycles and methotrexate disposition networks are associated with the TRANCE phenotype of childhood leukemia survivors.

Objectives

1. To identify TRANCE phenotypes of the childhood leukemia survivors.
2. To characterize the folate and vitamin B12 levels of these children
3. To identify DNA methylation patterns associated with TRANCE trait in the leukemia survivors
4. To identify SNPs associated with the TRANCE trait in the leukemia survivors.
5. To identify the "deficit genotype" associated only with the TRANCE leukemia survivors, but not with general population children who show developmental phenotypes similar to TRANCE: TRANCE-unique deficit variant
6. To replicate the association between the TRANCE-unique deficit variants and the TRANCE trait in a population of childhood leukemia survivors.
7. To evaluate the importance of rare genetic variants in the TRANCE trait in the leukemia survivors.

Study design: A case-control study of leukemia survivors

Analyses

1. Leukemia survivors will be characterized by their status of neurocognitive function, and categorized into the Deficit case and the non-deficit Control case.
2. They will be also characterized by the following attributes

   1. Pathway-based genetic variant status (folate and PK-related genes)
   2. Folate and vitamin B12 status
   3. Epigenetic markers
3. Comparative analyses between neuro-cognitiive deficit phenotype (TRANCE) and Control on those parameters

Eligibility criteria: Inclusion Criteria:

* Past diagnosis of acute lymphoblastic leukemia
* 8 years : 0 months - 20 years : 11 months old at the time of their study visit
* At least 2 years : 0 months from the last treatment for acute lymphoblastic leukemia at the time of their study visit
* Continuous complete remission and undergone no bone marrow transplantation or cranial radiation therapy
* Fluent in English (a subject and one parent) for test completion
* Signed informed consent

Exclusion Criteria:

* Inability to complete the phenotyping tests
* Down Syndrome diagnosis

Primary outcomes:
measure: DIVERGET
timeFrame: Within 6 months from the enrolment
measure: Stop Signal Task (SST)
timeFrame: Within 6 months from the enrolment
measure: CONNERS 3
timeFrame: Within 6 months from the enrolment
measure: Pathway-based gene variant status
timeFrame: Within 3 months from the end of enrolment
Secondary outcomes:
measure: WISC-IV
timeFrame: Within 6 months from the enrolment
measure: WIAT-III numerical operations and math fluency composite score
timeFrame: Within 6 months from the enrolment
measure: Brief Rating Inventory of Executive Function (BRIEF)
timeFrame: Within 6 months from the enrolment
measure: N-Back Task
timeFrame: Within 6 months from the enrolment
measure: Folate, vitamin B12 and iron intake
timeFrame: Within 6 months from the enrolment
measure: Folate status
timeFrame: Within 6 months from the enrolment
measure: Serum vitamin B12
timeFrame: Within 6 months from the enrolment
measure: Iron status
timeFrame: Within 6 months from the enrolment
Other outcomes:
measure: Epigenetics marker
timeFrame: Within 3 months from the end of enrolment
Locations:
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: The Hospital for Sick Children
name: Dr. Shinya Ito, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Hospital for Sick Children
name: Dr. Sharon Guger
role: PRINCIPAL_INVESTIGATOR
affiliation: The Hospital for Sick Children
name: Dr. Johann Hitzler
role: PRINCIPAL_INVESTIGATOR
affiliation: The Hospital for Sick Children
name: Dr. Deborah L O'Connor
role: PRINCIPAL_INVESTIGATOR
affiliation: The Hospital for Sick Children
name: Dr. Russell Schachar
role: PRINCIPAL_INVESTIGATOR
affiliation: The Hospital for Sick Children
name: Dr. Brenda Spiegler
role: PRINCIPAL_INVESTIGATOR
affiliation: The Hospital for Sick Children
name: Dr. Rosanna Weksberg
role: PRINCIPAL_INVESTIGATOR
References: