Clinical trial NCT02168868: Proteomic Biomarker Tests in Blood Samples from Children with Autism Spectrum Disorder (ASD)
Official title: Proteomic Biomarker Tests in Blood Samples from Children with Autism Spectrum Disorder (ASD)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Autistic Disorder
Keywords: Autoimmune Diseases
Child Development Disorders
Inflammation
Risk Factors
Pervasive
Autism
Autistic Disorder
Lead sponsor: Cell El Ltd
Sponsor class: INDUSTRY
Collaborators: name: Shaare Zedek Medical Center
First posted: 2014-06-20
Enrollment: 900
Sex: ALL
Minimum age (years): 10
Maximum age (years): 19
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 1. Up to a total of 350 male and female children, aged 2-12 years, diagnosed with ASD according to DSM-IV (299.00) or DSM-V (299.00)
2. Up to a total of 350 male and female typically developing (TD) children aged 2-12 years with no signs of ASD or history of ASD in the immediate family who will serve as controls for the main subset of children with ASD
3. Up to 50 infants aged 10-19 months not diagnosed with ASD but with a sibling diagnosed with ASD according to DSM-IV (299.00) or DSM-V (299.00) (herein, high-risk infants)
4. Up to 50 mothers of the high-risk infants participating in the study
5. Up to 50 male and female children, aged 2-12 years, diagnosed with ASD according to DSM-IV (299.00) or DSM-V (299.00) scheduled to undergo stem cell therapy (SCT)
6. Up to 50 male and female children, aged 12-18 years, diagnosed with ASD according to DSM-IV (299.00) or DSM-V (299.00) scheduled to undergo SCT

Brief summary: Behavioral testing is the gold standard for diagnosing autism spectrum disorder (ASD). These tests, including ADOS and ADI-R, are subjective, require trained staff to administer, are time-consuming, and can only be administered at a later age. Blood-, urine- or stool-based diagnostic biomarker test for ASD would enable objective early diagnosis, potentially even before clinical symptoms are present, eliminate the need for trained staff and enable early intervention. Such a test would not only conserve money and time but would also provide clues to ASD pathogenesis.

To date, no definitive treatment exists for ASD. Most therapies are symptom-focused, generally focusing on behavioral, social and communication skills. Recent works have reported on promising outcomes of mesenchymal stem cell (MSC) treatment of children with ASD. MSCs are multipotent, non-hematopoietic, easily isolatable and expandable stem cells involved in tissue repair, immunomodulatory responses and neuromodulation. MSC treatment of children with ASD has reportedly led to improvements in speech, sociability, eye coordination, balance, cognition and overall well-being. At the base of this approach lies the known plasticity of the human brain and immune system in the early childhood years and the ability of MSCs to modulate atypical inflammatory and immune activities. Assessment of ASD biomarker profiles in children with ASD who have undergone one or more SCT sessions may shed light on the mechanism of action, assist in better defining ASD-specific diagnostic markers and monitor treatment outcomes.

Detailed description: There is accumulating evidence that at least a subset of children diagnosed with ASD also have aberrant immune functions. This study will attempt to identify more specifically the nature of the potential immune abnormalities in children.

The study will follow a case-control design, involving the following cohorts:

1. young children (2-12 years) diagnosed with ASD
2. children (12-18 years) diagnosed with ASD
3. age- and sex-matched typically developing children
4. high-risk infants (10-19 months) with at least one sibling with diagnosed ASD
5. mothers of these high-risk infants
6. young children (2-12 years) diagnosed with ASD and scheduled to undergo stem cell transplantation therapy (SCT)

Parents will be asked to complete several questionnaires relating to demographic and anamnestic details and to the child's development.

* A single blood draw from all participants will be performed in the clinic.
* A stool sample will be collected from high-risk infants.
* A stool and urine sample will be collected at home from children due to undergo SCT. For children scheduled to undergo SCT, the blood, stool and urine samples must be collected before therapy.

  * Parents of high-risk infants will be contacted by phone or email when the child reaches diagnosable age (3.5 years) and again at the age of 6 years, to obtain an update on the child's ASD status. If the child has been diagnosed with ASD, an additional blood and stool sample may be collected.
  * Children who underwent SCT will be contacted 2±1 months and 6±1 months after the first treatment session, for collection of additional blood samples. Stool and urine samples will be collected at the 6±1 month post-treatment visit as well. Should the child undergo additional SCT within two years of the first treatment, additional blood, stool and urine samples may be collected. At each subsequent visit, a parent/legal guardian will be asked to complete several short questionnaires.

Adverse events to blood drawing will be reported to the Data Coordinating Center using the appropriate Case Report Form (CRF).

In cases of adverse effects (AE) related to the drawing of blood or performance of examination of patients in the course of standard examination procedures, the investigating team will proceed in accordance with local guidelines (to be inserted by the PI), reporting the incidents which occurred during the course of a clinical trial.

Clinical data will be collected by the investigator, or a person appointed and appropriately trained by the investigator, and shall be entered into standardized CRFs and shared online with the sponsor. Source data will be retained for all data entered in the CRFs. Progress reports and the Final Report at the conclusion of the trial will be submitted to the regulatory authority and the Ethics Committee, as required.

Eligibility criteria: Inclusion Criteria:

1. Male and female children
2. Child aged 2-12 years with diagnosed ASD according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV (299.00) or DSM-V (299.00) OR Child aged 2-18 years diagnosed ASD according to DSM-IV (299.00) or DSM-V (299.00) AND scheduled to undergo stem cell transplantation OR Child aged 10-19 months not diagnosed with ASD but with a sibling diagnosed with ASD according to (DSM)-IV (299.00) or DSM-V (299.00) (herein termed "high-risk infants") OR Mothers of recruited high-risk infants OR A typically developing child aged 2-12 years with no signs of ASD or history of ASD in the immediate family
3. Informed consent signed by the parent/legal guardian

Exclusion Criteria:

1. Child and/or mother completed treatment with systemic steroids or immune suppressants less than 4 weeks before the screening visit
2. Child and/or mother diagnosed with severe infectious diseases or sepsis over the last 6 months
3. Child with ASD treated for a severe convulsive disorder (intractable seizures)
4. Child and/or mother with hematological or malignant disorder
5. For children in the SCT cohort: No new planned immune-modulating treatment (other than SCT) for at least 6 months before or after planned stem cell transplantation date
6. If the PI suspects that the participant will not comply with study requirements, the participant may be excluded.

Primary outcomes:
measure: Identification of discriminating proteomic biomarker profile in blood of children with ASD vs. matched TD children
timeFrame: One day
measure: Identification of discriminating proteomic biomarker profiles in blood of high-risk infants, at recruitment vs. after diagnosis of ASD, if diagnosed
timeFrame: Up to 5 years after initial blood draw
measure: Comparison of blood biomarker profiles in ASD children before versus after SCT
timeFrame: Through study completion, up to 6 months
Secondary outcomes:
measure: ASD severity vs. blood biomarker levels
timeFrame: Through study, up to 5 years, depending on cohort
measure: Blood biomarker levels and SCT outcomes
timeFrame: Through study completion, up to 6 months
Other outcomes:
measure: Identification of ASD-specific proteomic biomarkers and/or microbiome profile in stool samples of children with ASD before vs. after SCT
timeFrame: Up to 6 months
measure: Comparison of urine biomarker profiles in ASD children before versus after SCT
timeFrame: Up to 6 months
measure: Identification of ASD-specific proteomic biomarker and microbiome signature in stool samples of high-risk infants before vs. after ASD diagnosis, if diagnosed
timeFrame: Through study completion, up to 5 years
measure: Identification of discriminating proteomic profiles in blood of the mothers of high-risk infants
timeFrame: One day
measure: Correlative assessment of proteomic biomarker expression in the high-risk infant and his/her mother
timeFrame: 1 day
Locations:
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
Study officials:
affiliation: Cell El Ltd
name: Benjamin Gesundheit, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gesundheit B, Rosenzweig JP, Naor D, Lerer B, Zachor DA, Prochazka V, Melamed M, Kristt DA, Steinberg A, Shulman C, Hwang P, Koren G, Walfisch A, Passweg JR, Snowden JA, Tamouza R, Leboyer M, Farge-Bancel D, Ashwood P. Immunological and autoimmune considerations of Autism Spectrum Disorders. J Autoimmun. 2013 Aug;44:1-7. doi: 10.1016/j.jaut.2013.05.005. Epub 2013 Jul 15.
citation: Gesundheit B, Zisman PD, Hochbaum L, Posen Y, Steinberg A, Friedman G, Ravkin HD, Rubin E, Faktor O, Ellis R. Autism spectrum disorder diagnosis using a new panel of immune- and inflammatory-related serum biomarkers: A case-control multicenter study. Front Pediatr. 2023 Feb 21;11:967954. doi: 10.3389/fped.2023.967954. eCollection 2023.