Autologous BMMNCs Combined With Educational Intervention for ASD

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and effectiveness of autologous bone marrow mononuclear cell infusion combined with educational intervention for children with autism spectrum disorder (ASD). Inclusion criteria: Male/Female patients diagnosed with Autism disorder based on DSM-V scale, the patient is between 3 to 7 years old, a patient has a medium level to server level of autism (CARS score>=30 to <50), VARS-2 >=50, patient's parent or caregiver must have the educational level of high school or above, patient's family has given consent to participate in the study. Exclusion criteria for treatment group: patient above seven years of age and smaller than 3-year old, autistic patients having epilepsy, hydrocephalus with ventricular drain, allergy to anesthetic agents, severe health conditions such as cancer, failure of heart, lung, liver, or kidney, active infections, children with birth defects of the spine.

Detailed Description
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A total of 54 patients with autism spectrum disorder (aged 3-7) will be recruited and divided into two groups: the control group (only intervention education) (n = 27) and the treatment group (bone marrow mononuclear cell transplantation combined intervention education (n =27). The bone marrow mononuclear cell will be applied to 27 patients in the treatment group infuse via the intrathecal administration. The primary outcome is measured by the number of AEs/SAEs during BMMNCs infusion. The secondary outcome was measured by clinical examinations performed at baseline and then at 02, 06, and 12 months after the first infusion. Multiple tools were used to diagnose and determine the severity of ASD, including DSM-5, CARS, the Vineland Adaptive Behavior Scales Second Edition (VABS-II), and the Clinical Global Impression (CGI). DSM-5, which was published in May 2013, provides new diagnostic criteria for ASD

Official Title
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Autologous Bone Marrow Mononuclear Cell Transplantation Combined With Educational Intervention for Autism Spectrum Disorders (ASD): A Phase 2 Randomised Controlled Trial

Conditions
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Autism Spectrum Disorder

Intervention / Treatment
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* Combination Product: Autologous BMMNCs transplantation and educational intervention
* Combination Product: Educational intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is between 3 to 7 years old Male/Female patient diagnosed with Autism disorder according to the diagnostic criteria for Autism Spectrum Disorder in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Patient has a medium level to the most severe level of autism (CARS score >=34 to 50) Patient's parent or caregiver must have an educational level of high school or above Patient's family has given consent to participate in the study Exclusion Criteria: Patient is above seven years of age Autistic patient having epilepsy Patient with coagulation disorders Hydrocephalus with ventricular drain Allergy to anesthetic agents Sever health conditions such as cancer, failure of heart, lung, liver, or kidney Active infections

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 7 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A total of 54 patients with autism spectrum disorder (3-7 years old) will be recruited and divided into two groups: the controlled group (only intervention education) (n = 27) and the treatment group (Bone marrow mononuclear cell infusions combined educational intervention (n =27)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous BMMNCs infusion combined with educational intervention<br>Bone marrows are harvested from the patient's iliac depending on the patient's body weight as follows: 8 ml/kg for patients under 10 kg; [80 ml + (body weight in kg - 10) × 7 ml] for patients above 10 kg. Mononuclear cells from collected bone marrow are infused intrathecally through a space between number vertebrae 4th and 5th. Two transplantations will be conducted at an interval of 6 months. The educational intervention will be developed based on the Early Start Denver Model for 6 months after the first infusion. Evaluation: The efficacy outcomes will be measured using the CARS, Vineland Adaptive Behavior Scales - second Edition (VABS), Autism Behavior Checklists (ABC), and Clinical Global Impression (CGI). In addition, Health-related quality of life (HRQoL) in patients will be evaluated at baseline, two months, six months, and 12 months with those in the control group (educational intervention only) using the Pediatric Quality of Life Inventory (PedsQL) | Combination Product: Autologous BMMNCs transplantation and educational intervention<br>* Biological/ Vaccine: Autologous bone marrow-derived mononuclear cell infusion (BM-MNCs) will be administrated at baseline, and the second infusion will be performed six months after the first administration. For each transplantation, the bone marrow will be harvested through an anterior iliac crest puncture under general anesthesia in the operating theatre. The volume collected depends on the patient's body weight based on our experience from a previous study as follows: 8 ml/kg for patients under 10 kg; [80 ml + (body weight in kg - 10) x 7 ml] for patients above 10 kg but no more than 250 ml in total. Educational intervention: 6 months based on the Early Start Denver Model<br>|
| Active Comparator: Educational intervention (controlled group)<br>The educational intervention will be developed based on the Early Start Denver Model for six months after enrollment. Evaluation: The efficacy outcomes will be measured using the CARS, Vineland Adaptive Behavior Scales - second Edition (VABS), Autism Behavior Checklists (ABC), and Clinical Global Impression (CGI). In addition, Health-related quality of life (HRQoL) in patients will be evaluated at baseline, two months, six months, and 12 months with those in the control group (educational intervention only) using the Pediatric Quality of Life Inventory (PedsQL) | Combination Product: Educational intervention<br>* Educational intervention: 6 months based on the Early Start Denver Model<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of severity of ASD after intervention through the Diagnostic and Statistical Manual of Mental Disorders | The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). DSM-5 describes three levels of increasing severity of ASD.DSM-5 describes three levels of increasing severity of ASD, from (1) (requiring support) to (2) (requiring substantial support), and finally to (3) (requiring very substantial support). | 2 months, 6 months, 12 months after the first BMMNCs infusion | 
| Change of severity of ASD after intervention through the Childhood Autism Rating Scale | The Childhood Autism Rating Scale (CARS) consists of 14 domains assessing behaviors associated with ASD, with a 15th domain rating general impressions of ASD. Each domain is scored on a scale ranging from one to four; higher scores are associated with a higher level of impairment. Total scores can range from a low of 15 to a high of 60; scores below 30 indicate that the individual is in the non-autistic range, scores between 30 and 36.5 indicate mild to moderate autism, and scores from 37 to 60 indicate severe autism. | 2 months, 6 months, 12 months after the first BMMNCs infusion | 
| Changes in social interaction; adaptive behaviour; daily living skills through Vineland Adaptive Behaviour Scale | The Vineland Adaptive Behaviour Scale second version (VABS-2) is a semi-structured interview measuring adaptive behavior with standard scores (M = 100, SD = 15). We define proficiency as a standard score of 85 or above (i.e., 1 SD below the mean). This metric for not impaired is used in other optimal outcome studies and the learning disability literature. We define growth as an improvement of at least 1 SD in standard scores (15 points) from T1 to T2. Improvement of 1 SD in clinical trials is considered a large effect size. | 2 months, 6 months, 12 months after the first BMMNCs infusion | 
| Changes in social interaction; adaptive behaviour; daily living skills through Clinical Global Impression Improvement | The Clinical Global Impression Improvement (CGI) is a rating scale that measures symptom severity and treatment response. The severity is categorized into seven levels: 1) not present (no ASD); 2) barely evident ASD symptoms; 3) mild ASD symptoms; 4) moderate ASD symptoms; 5) moderately severe ASD symptoms; 6) severe ASD symptoms or 7) very severe ASD symptoms. The response of each patient is also divided into seven levels: level 1) very much improved; level 2) much improved; level 3) minimally improved; level 4) no change; level 5) minimally worse; level 6) much worse; level 7) very much worse. | 2 months, 6 months, 12 months after the first BMMNCs infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in health-related quality of life using Pediatric Quality of Life Inventory (PedsQL) | The Pediatric Quality of Life Inventory™ 4.0 Generic Core Scales - Parent Report (PedsQL) is a tool for assessing the HRQoL of children aged 2-18. PedsQL includes four domains (physical functioning, emotional functioning, social functioning, and school functioning) and is scored using three levels: no problems (1), some problems (2), or many problems (3). The PedsQL has 23 items, and scores on the standard portion range from 0 to 100, with 100 representing the best possible quality of life. | 2 months, 6 months, 12 months after the first BMMNCs infusion |