Mechanism of Allogeneic UCB Therapy in Cerebral Palsy

Mechanism of Allogeneic Umbilical Cord Blood Therapy in Cerebral Palsy

In our prior study on the therapeutic mechanism of UCB, changes in cytokine levels were observed but the results are inconclusive and further studies on animal models and changes of protein expression before and after UCB therapy in the clinical settings are required.

The changes in protein expression will be assessed by multiplex RT-PCR mRNA assay. Clinical efficacy of UCB therapy will be evaluated with various functional assessment tools. Factors regarding UCB therapy (number of transplanted cells, HLA matching status, serum level of immunosuppressant, etc.) and patient factors (age, functional status, etc.) will be analyzed for correlation with protein expression after UCB therapy. Several target proteins for analysis are available. Pentraxin and toll-like receptor (TLR) 4 are receptors modulating intrinsic immune reaction and was shown to have a significant correlation with clinical efficacy of stem cell therapy. Ubiquitine is a regulatory protein that combines with the target protein and affects its degradation, interaction, localization and activation. The ubiquitine system controls total protein quantity for homeostasis and can be found in all tissues. Deubiquitination (DUB) enzyme down-regulates this ubiquitine and is known to modulate all cellular changes

Study Overview

• Status: Completed
• Conditions: Cerebral Palsy; Child Development
• Intervention / Treatment: Biological: allogeneic cord blood transplantation

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Gyeonggido
    • Seongnam, Gyeonggido, Korea, Republic of, 13496
      • Cha Bundang Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosed with cerebral palsy
2. Age of ≥10 months and ≤20 years
3. Mismatch in HLA-A, B, and DR ≤3, and total nucleated cell count ≥2x107/kg. If the cell count is less than given values, more than 2 units may be used.
4. Voluntary decision to participation in the study with informed consent agreed and obtained from the subject's representative.
5. Patient and/or representatives are both willing and capable of being hospitalized according to the schedule specified in the protocol and continue the study for 12 months after study entry.
6. If the patient has participated in another clinical trial, at least 3 months should have passed since end of the study.

Exclusion Criteria:

1. Current aspiration pneumonia
2. Known genetic disease
3. History of hypersensitivity reaction to any study drugs pertinent to the study
4. Patient with severe convulsion disease who has clinical convulsion despite combination therapy with 3 or more agents
5. Uncontrolled hypertension defined as systolic blood pressure >115 mmHg and/or diastolic blood pressure >70 mmHg
6. Hepatic impairment defined as asparate aminotransferase (AST) >55 IU/L and/or alanine aminotrasferase (ALT) >45 IU/L
7. Renal impairment defined as creatinine (Cr) ≥1.3 mg/dL
8. Presence of diagnosed or suspected malignant tumor and/or hematologic malignancy
9. Non-compliance with study visits specified in the protocol or poor compliance of care-giver.
10. Any factors not specified above that the principal investigator determines medically inadequate for participation in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: allogeneic cord blood transplantation; Intravenous(IV) infusion will be done by the following method A. After 4 hours of fasting, subjects will be sedated with chloral hydrate (Pocral®) syrup B. Intravenous infusion will be conducted in stem cell center, CHA Bundang Medical Center and the therapy will be performed by the Principal Investigator or a physician delegated from the Principal Investigator. The physician conducting the infusion will not participate in the efficacy and result analysis of this study. C. Oxygen saturation will be monitored during therapy.

Biological: allogeneic cord blood transplantation; UCB with total nucleated cell count ≤ 7x108/kg will be used for this clinical trial. Suitable UCB (i.e., containing total nucleated cell count ≥2x107/kg with three or less mismatch among HLA-A, -B, and -DR) will be selected. This criterion was selected upon the rationale that even though minimal HLA mismatch is preferred, prior studies indicate significant effects of UCB therapy for patients with 3 HLA mismatches.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of GMFM	Gross motor function measure measured at baseline before UCB administration is compared to the score measured at months 3, 6, and 12 after UCB treatment.	Baseline before UCB administration, months 3, 6, and 12 after UCB treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of mRNA assay	Separate peripheral blood mononuclear cell (PBMC) from the patients' blood sample and screen for changes in protein enzymes including those related to DUB at the mRNA level after UCB therapy.	Change between the baseline level before UCB therapy and levels after UCB administration at 2 days, 1 week, 5 weeks, and 12 months
Change of GMPM	Dissociated Movement, Coordination, Alignment, Weight shift, and Stability are rated with GMPM (Gross Motor Performance Measure). Each raw score (1-5 point) and converted percent scores are evaluated. Total score is 100(%), higher scores indicate better function. GMPM measured at baseline before UCB administration is compared to the score measured at months 3, 6, and 12 after UCB treatment.	Baseline before UCB administration, months 3, 6, and 12 after UCB treatment

Collaborators and Investigators

• Sponsor: Bundang CHA Hospital
• Investigators: Principal Investigator: MinYoung Kim, MD, PhD, CHA University

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2015
• Primary Completion (Actual): May 21, 2019
• Study Completion (Actual): May 21, 2019

Study Registration Dates

• First Submitted: April 20, 2017
• First Submitted That Met QC Criteria: April 23, 2017
• First Posted (Actual): April 27, 2017

Study Record Updates

• Last Update Posted (Actual): November 4, 2020
• Last Update Submitted That Met QC Criteria: November 2, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Umbilical cord blood transplantation; Cytokine changes
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Damage, Chronic; Cerebral Palsy
• Other Study ID Numbers: 2015-06-093

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No