Feasibility of allogeneic mesenchymal stem cells in pediatric hypoxic-ischemic encephalopathy: Phase I study

Table 1 Enrollment criteria

No.	Inclusion criteria
1	Age < 18
2	HIE radiologically confirmed at initial diagnosis and at study enrollment
3	The patients who does not have any chronic illness (cancer, kidney, heart/hepatic failure etc.) other than HIE. Adequate systemic organ function confirmed by normal ranged laboratory values
4	Life expectancy > 12 mo
5	No substiantial improvement despite of a treatment in neurological/functional status for the 3 mo before study enrollment
6	Severe disability defined as subject confined to a wheelchair/required to have home nursing care/needing assistance with activities of daily living
7	Expectation that the patient will receive standard post-treatment care and attend all visits
8	Signing in the written informed consent form for confirming to that know the treatment to be applied and to be willing by their parents/a surrogate
	Exclusion criteria
1	Presence of any other clinically significant medical/psychiatric condition, or laboratory abnormality, for which study participation would pose a safety risk in the judgment of the investigator/sponsor or history within the past year of drug/alcohol abuse
2	Recently diagnosed severe infection (meningitis, etc.)/development of liver, kidney/heart failure/sepsis or skin infection at the i.v. infusion site or positive for hepatitis B, C/HIV
3	History of uncontrolled seizure disorder
4	History of cerebral neoplasm, or cancer within the past 5 yr, with the exception of localized basal or squamous cell carcinoma
5	Having clinic symptoms that formation of white sphere number ≥ 15000/μL or platelet count ≤ 100.000/μL
6	Serum aspartate aminotransferase and serum alanine aminotransferase > 3× upper limit of normal/creatinine > 1.5× upper limit of normal
7	Participation in an another investigational stem cell study before treatment
8	The patient/parents decides to abandon the treatment or the patient death

HIE: Hypoxic-ischemic encephalopathy; HIV: Human immunodeficiency virus.

Table 2 Study population

		Frequency	Percent
Age	1.00	1	16.7
	6.00	2	33.3
	7.00	1	16.7
	9.00	1	16.7
	12.00	1	16.7
Sex	F	4	66.7
	M	2	33.3
Cause of hypoxia	Acute meningitis	1	16.7
	Cardiac arrest after an orthopedic surgery	1	16.7
	Cardiac arrest due to long QT syndrome	1	16.7
	Cardiac arrest, unknown etiology	1	16.7
	Drowning in water	1	16.7
	Foreign body aspiration	1	16.7
Duration of Hypoxia	25.00	1	16.7
	30.00	3	50.0
	45.00	1	16.7
	75.00	1	16.7
Comorbidity	Long QT syndrome	1	16.7
	no	4	66.7
	Osteogenesis imperfecta	1	16.7
Duration Between Hypoxia & First SCT	6.00	3	50.0
	9.00	1	16.7
	32.00	1	16.7
	72.00	1	16.7

SCT: Stem cell therapy.

Table 3 Administration schedule

Rounds	Route	WJ-MSC
Round 1	IT	1 × 106/kg in 3 mL
	IV	1 × 106/kg in 30 mL
	IM	1 × 106/kg in 20 mL
Round 2 (2nd week)	IT	1 × 106/kg in 3 mL
	IV	1 × 106/kg in 30 mL
	IM	1 × 106/kg in 20 mL
Round 3 (4th week)	IT	1 × 106/kg in 3 mL
	IV	1 × 106/kg in 30 mL
	IM	1 × 106/kg in 20 mL
Round 4 (6th week)	IT	1 × 106/kg in 3 mL
	IV	1 × 106/kg in 30 mL
	IM	1 × 106/kg in 20 mL

WJ-MSC: Wharton’s jelly-derived mesenchymal stem cells; IT: Intrathecal; IV: Intravenosus; IM: Intramuscular.

Table 4 Early and late complications of the procedures

Complications		Patient No. 1				Patient No. 2				Patient No. 3				Patient No. 4				Patient No. 5				Patient No. 6
		Administration				Administration				Administration				Administration				Administration				Administration
		1st	2nd	3rd	4th	1st	2nd	3rd	4th	1st	2nd	3rd	4th	1st	2nd	3rd	4th	1st	2nd	3rd	4th	1st	2nd	3rd	4th
Early	Infection	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
	Fever	-	-	-	-	-	-	-	-	-	+	-	-	-	+	-	-	+	+	-	-	-	-	-	-
	Pain	-	-	-	-	-	-	-	-	+	-	+	-	+	+	-	-	+	-	-	-	-	-	-	-
	Headache	-	-	-	-	-	-	-	-	-	-	+	-	+	-	-	-	-	-	-	-	-	-	-	-
	Increased level of C-reactive protein	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
	Leukocytosis	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
	Allergic reaction or shock	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
	Perioperative complications	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Late	Secondary infections	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
	Urinary tract infections	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
	Deterioration of neurological status	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
	Neuropathic pain	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
	Carcinogenesis	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-

–: Not present; +: Present.

Table 5 Friedman test results regarding the change in the Wee Functional Independence Measure Motor scores of the patients before and after the operation

	n	Mean	SD	Mean rank	χ2	df	P value
Pre-test	6	8.00	0.00	2.50	23.444	5	0.000
Post-test 1 wk	6	8.00	0.00	2.50
Post-test 1 mo	6	8.00	0.00	2.50
Post-test 2 mo	6	8.33	0.52	3.17
Post-test 4 mo	6	9.67	0.82	4.92
Post-test 12 mo	6	10.50	1.52	5.42

SD: Standard deviation.

Table 6 Friedman test results regarding the change in the Wee Functional Independence Measure cognitive scores of the patients before and after the operation

	n	Mean	SD	Mean rank	χ2	df	P value
Pre-test	6	5.50	0.55	1.67	28.255	5	0.000
Post-test 1 wk	6	5.67	0.82	1.83
Post-test 1 mo	6	7.17	1.60	2.75
Post-test 2 mo	6	8.33	2.25	3.83
Post-test 4 mo	6	10.17	3.06	4.92
Post-test 12 mo	6	13.00	2.83	6.00

SD: Standard deviation.

Table 7 Friedman test results regarding the change in the macrophage activation syndrome right scores of the patients before and after the operation

	n	Mean	SD	Mean rank	χ2	df	P value
Pre-test	6	18.67	4.72	5.83	29.439	5	0.000
Post-test 1 wk	6	16.83	6.15	5.17
Post-test 1 mo	6	14.00	7.62	3.92
Post-test 2 mo	6	12.17	6.94	2.92
Post-test 4 mo	6	10.17	6.65	2.17
Post-test 12 mo	6	7.67	6.12	1.00

SD: Standard deviation.

Table 8 Friedman test results regarding the change in the macrophage activation syndrome left scores of the patients before and after the operation

	n	Mean	SD	Mean rank	χ2	df	P value
Pre-test	6	16.33	5.13	5.58	29.000	5	0.000
Post-test 1 wk	6	15.67	5.89	5.25
Post-test 1 mo	6	13.17	7.33	4.08
Post-test 2 mo	6	11.33	6.31	2.92
Post-test 4 mo	6	9.17	5.74	2.17
Post-test 12 mo	6	7.00	5.33	1.00

SD: Standard deviation.