Phase I study on the safety and preliminary efficacy of allogeneic mesenchymal stem cells in hypoxic-ischemic encephalopathy

Table 1 Enrollment criteria

Inclusion criteria
Age ≥ 18
HIE ≥ 6 mo prior, radiologically confirmed at initial diagnosis and at study enrollment
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
Life expectancy > 12 mo
No substiantial improvement despite of a treatment in neurological/functional status for the 3 mo before study enrollment
Severe disability defined as subject confined to a wheelchair/required to have home nursing care/needing assistance with activities of daily living
Expectation that the patient will receive standard post-treatment care and attend all visits
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
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
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
History of uncontrolled seizure disorder
History of cerebral neoplasm, or cancer within the past 5 yr, with the exception of localized basal or squamous cell carcinoma
Having clinic symptoms that formation of white sphere number ≥ 15000/µL or platelet count ≤ 100.000/µL
Serum aspartate aminotransferase and serum alanine aminotransferase > 3 × upper limit of normal/creatinine > 1.5 × upper limit of normal
Pregnant/lactating/expectation to become pregnant during the study
Participation in an another investigational stem cell study before treatment
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	20.00	1	11.1
	25.00	1	11.1
	27.00	1	11.1
	29.00	1	11.1
	34.00	1	11.1
	37.00	1	11.1
	43.00	1	11.1
	51.00	1	11.1
Sex	M	8	100.0
	F	0	0
Cause of hypoxia	Cardiac arrest	1	12.5
	Cardiac arrest due to acute myocard infarction	3	37.5
	Cardiac arrest due to explosive devices injury	1	12.5
	Cardiac arrest due to multi-trauma	1	12.5
	Cardiac arrest, unkown ethiology	2	25.0
Duration of hypoxia	25.00	1	12.5
	30.00	1	12.5
	40.00	1	12.5
	45.00	3	37.5
	60.00	1	12.5
	75.00	1	12.5
Previous treatment	No	8	100.0
	Yes	0	0
Comorbidity	Atrial fibrilation	1	12.5
	No	7	87.5
Duration between hypoxia and first SCT	6.00	3	37.5
	10.00	1	12.5
	11.00	1	12.5
	18.00	2	25.0
	96.00	1	12.5

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				Patient No: 7				Patient No: 8
		Administration				Administration				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	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 functional independence measure motor scores of the patients before and after the operation

	n	Mean	SD	Mean rank	χ2	df	P value
Pre-test	8	13.00	0.00	2.69	24.583	5	0.000
Post-test 1 wk	8	13.00	0.00	2.69
Post-test 1 mo	8	13.38	1.06	2.88
Post-test 2 mo	8	14.00	2.45	3.25
Post-test 4 mo	8	16.25	7.23	4.19
Post-test 12 mo	8	17.63	9.10	5.31

Table 6 Friedman test results regarding the change in the functional independence measure cognitive scores of the patients before and after the operation

	n	Mean	SD	Mean rank	χ2	df	P value
Pre-test	8	5.38	1.06	1.63	37.500	5	0.000
Post-test 1 wk	8	5.50	1.41	1.75
Post-test 1 mo	8	7.50	2.45	2.88
Post-test 2 mo	8	9.13	3.83	3.88
Post-test 4 mo	8	11.00	5.68	5.00
Post-test 12 mo	8	13.75	6.23	5.88

Table 7 Friedman test results regarding the change in the modified Ashworth scale right scores of the patients before and after the operation

	n	Mean	SD	Mean rank	χ2	df	P value
Pre-test	8	21.88	2.17	5.81	38.875	5	0.000
Post-test 1 wk	8	19.75	3.28	5.06
Post-test 1 mo	8	18.25	3.24	3.94
Post-test 2 mo	8	17.00	3.59	3.19
Post-test 4 mo	8	14.75	3.69	1.94
Post-test 12 mo	8	13.00	4.24	1.06

Table 8 Friedman test results regarding the change in the modified Ashworth scale left scores of the patients before and after the operation

	n	Mean	SD	Mean rank	χ2	df	P value
Pre-test	8	21.63	2.83	5.75	38.741	5	0.000
Post-test 1 wk	8	19.50	3.21	5.066
Post-test 1 mo	8	17.75	2.96	4.06
Post-test 2 mo	8	16.38	3.02	3.13
Post-test 4 mo	8	13.88	3.40	1.94
Post-test 12 mo	8	12.13	3.64	1.06

Table 9 Wilcoxon signed ranks test results regarding the change in the Karnofsky scale scores of the patients before and after the operation

Karnofsky scale	Ranks	n	Mean rank	Sum of ranks	z	P value
Pre-test-Post-test 12 mo	Negative ranks	0	0.00	0.00	-2.565	0.010
	Positive ranks	8	4.50	36.00
	Ties	0
	Total	8