Establishing delivery route-dependent safety and efficacy of living biodrug mesenchymal stem cells in heart failure patients

Table 1 Baseline characteristics of the included trials

Ref.	Trial registry	Study design, phase, blinding	Sample size (n)	Size at each arm (n)		Sex (n)		Age (yr)	Intervention	Source	Cell type	RoD	Dose (million)	NYHA
						M	F							I	II	III	IV
Ascheim et al[21], 2014	NCT01442129	RCT, II, double-blind	30	Exp	20	17	3	55.10 ± 15.40	BM-MSC	NA	Allo	TEPI	25	0	0	3	17
				Ctrl	10	8	12	62.20 ± 7.80	Placebo					0	1	2	7
Perin et al[27], 2015	NCT00721045	RCT, II, double-blind	60	Exp	45	44	1	62.20 ± 10.30	BM-MSC	Iliac crest	Allo	TESI	25, 75, 150	0	31	6	0
				Ctrl	15	11	4	62.70 ± 11.20	Placebo					0	14	9	0
Mathiasen et al[25], 2015	NCT00644410	RCT, II, double-blind	60	Exp	40	36	6	66.10 ± 7.70	BM-MSC	NA	Auto	TESI	NA	0	11	29	0
				Ctrl	20	14	6	64.20 ± 10.60	Placebo					0	5	15	0
Zhao et al[19], 2015	NA	RCT, NA, NA	59	Exp	30	24	6	52.90 ± 16.32	UC-MSC	Fetal UC	Allo	IC	NA	NA	NA	NA	NA
				Ctrl	29	19	10	53.21 ± 11.46	Standard care					NA	NA	NA	NA
Patel et al[23], 2016	NCT01670981	RCT, II, double-blind	109	Exp	58	55	3	65.30 ± 8.49	BM-MSC	Iliac crest	Auto	TESI	NA	0	2	52	4
				Ctrl	51	45	6	64.70 ± 9.94	Placebo					0	2	47	2
Butler et al[22], 2017	NCT02467387	RCT, II, single-blind	22	Exp	10	13	9	47.30 ± 12.80	BM-MSC	NA	Allo	IV	1.5/kg	0	21	1	0
				Ctrl	12				Placebo
Xiao et al[29], 2017	NA	RCT, NA, double-blind	37	Exp	17	12	5	51.60 ± 12.20	BM-MSC	Iliac spine	Auto	IC	NA	NA	NA	NA	NA
				Ctrl	20	14	6	15.40 ± 11.60	Placebo					NA	NA	NA	NA
Florea et al[18], 2017	NCT02013674	RCT, II, double-blind	30	Exp	15	15	0	65.60 ± 9.40	BM-MSC	NA	Allo	TESI	100	6	7	1	1
				Ctrl	15	12	3	66.80 ± 12.20	BM-MSC	NA	Allo	TESI	20	4	8	3	0
Yau et al[20], 2019	NCT02362646	RCT, II, NA	159	Exp	106	94	12	55.50 ± 12.30	BM-MSC	NA	Allo	TEPI	150	0	0	31	75
				Ctrl	53	47	6	56.90 ± 11.70	Placebo					0	0	12	41
Bolli et al[26], 2021	NCT02501811	RCT, II, double-blind	94	Exp	62	58	4	61.35 ± 8.90	BM-MSC ± CPC	NA	Allo	TESI	150	2	46	14	0
				Ctrl	32	31	1	63.10 ± 8.80	Placebo					1	28	3	0
Qayyum et al[28], 2023	NCT03092284	RCT, II, double-blind	81	Exp	54	44	10	67.00 ± 9.00	A-MSC	Abd SC	Allo	TESI	100	NA	NA	NA	NA
				Ctrl	27	24	3	66.60 ± 8.10	Placebo					NA	NA	NA	NA
Qayyum et al[28], 2023	NCT02673164	RCT, II, double-blind	133	Exp	90	84	6	66.40 ± 8.10	A-MSC	Abd SC	Allo	TESI	100	0	62	28	0
				Ctrl	43	38	5	64.00 ± 8.80	Placebo					0	30	13	0

A-MSC: Adipose cell-derived mesenchymal stem cells; Abd SC: Abdominal subcutaneous fat; Allo: Allogenic; Auto: Autologous; BM-MSC: Bone marrow-derived mesenchymal stem cells; CPC: c-kit positive cardiac cells; Ctrl: Control arm; Exp: Exposure arm; IM: Intramyocardial injection; IV: Intravenous infusion; NA: Not applicable; NYHA: New York Heart Association; RCT: Randomized controlled trials; TESI: Transendocardial stem cell injection; UC-MSC: Umbilical cord-derived mesenchymal stem cells.

Table 2 Outcome and follow-up characteristics of included trials

Ref.	Trial registry	Arm	FU		Imaging				SAE/death	LVEF (%)		6MWD (meter)		Pro-BNP (pg/mL)
			For 1° outcome	For LVEF	Echo	CCT	CMR	SPECT		Baseline	FU	Baseline	FU	Baseline	FU
Ascheim et al[21], 2014	NCT01442129	Exp	12	12	Yes	No	No	No	19/0	17.50 ± 3.90	24.00 ± 3.90	NA	883.00 ± 233.00	NA	NA
		Ctrl							9/3	19.30 ± 5.10	22.50 ± 5.10	NA	1080.00 ± 359.50	NA	NA
Perin et al[27], 2015	NCT00721045	Exp	36	12	Yes	No	No	Yes	10/2	31.30 ± 8.58	32.40 ± 8.70	401.60 ± 96.40	427.30 ± 115.10	436.80 ± 563.40	347.30 ± 335.69
		Ctrl							5/3	34.60 ± 6.43	33.10 ± 9.30	319.30 ± 121.40	346.60 ± 121.80	217.70 ± 149.60	319.80 ± 193.02
Mathiasen et al[25], 2015	NCT00644410	Exp	6	6	Yes	Yes	Yes	No	13/1	28.20 ± 9.30	33.20 ± 3.80	401.00 ± 70.00	421.40 ± 76.60	582.69 ± 970.01	NA
		Ctrl							16/1	25.10 ± 8.50	23.80 ± 3.70	385.00 ± 81.00	414.72 ± 79.60	564.08 ± 981.86	NA
Zhao et al[19], 2015	NA	Exp	6	6	No	No	No	No	1/2	30.00 ± 4.50	49.00 ± 5.10	312.17 ± 89.19	466.36 ± 82.90	4376.27 ± 510.71	1648.96 ± 304.54
		Ctrl							0/7	28.00 ± 4.90	39.00 ± 3.50	295.07 ± 46.87	334.27 ± 43.80	4701.76 ± 513.53	2835.09 ± 412.03
Patel et al[23], 2016	NCT01670981	Exp	12	12	Yes	No	No	No	31/2	26.50 ± 5.10	28.10 ± 6.13	313.00 ± 100.00	370.62 ± 114.30	1755.00 ± 1842.00	NA
		Ctrl							41/7	24.40 ± 6.00	25.30 ± 6.10	302.00 ± 105.00	353.43 ± 128.30	2132.00 ± 2021.00	NA
Butler et al[22], 2017	NCT02467387	Exp	6	3	No	No	Yes	No	0/0	34.30 ± 7.91	34.10 ± 9.70	NA	NA	806.27 ± 1387.85	768.25 ± 2945.53
		Ctrl							0/0	34.50 ± 7.49	36.70 ± 5.40	NA	NA	NA	NA
Xiao et al[29], 2017	NA	Exp	12	12	Yes	No	No	Yes	5/0	34.10 ± 3.600	41.00 ± 6.70	309.00 ± 84.70	NA	539.20 ± 213.60	NA
		Ctrl							7/2	33.70 ± 4.00	34.30 ± 5.30	323.30 ± 89.40	NA	575.30 ± 207.60	NA
Florea et al[18], 2017	NCT02013674	Exp	12	12	Yes	Yes	No	No	2/1	30.10 ± 8.80	33.10 ± 7.30	434.90 ± 120.00	463.00 ± 143.10	377.70 ± NA	NA
		Ctrl							3/0	37.60 ± 13.30	37.30 ± 13.00	398.70 ± 111.60	409.70 ± 130.20	532.30 ± NA	NA
Yau et al[20], 2019	NCT02362646	Exp	12	6	Yes	No	No	No	88/15	17.30 ± 5.80	19.00 ± 9.40	NA	NA	NA	NA
		Ctrl							41/8	16.20 ± 6.00	17.60 ± 6.20	NA	NA	NA	NA
Bolli et al[26], 2021	NCT02501811	Exp	12	12	No	No	Yes	No	19/5	29.23 ± 6.30	30.50 ± 6.90	367.72 ± 83.85	398.72 ± 93.10	1026.07 ± 2702.11	640.37 ± 1512.69
		Ctrl							13/4	29.66 ± 6.18	29.40 ± 5.90	367.60 ± 85.60	384.88 ± 101.70	856.72 ± 1364.72	1072.32 ± 2161.64
Qayyum et al[28], 2023	NCT03092284	Exp	12	6	Yes	No	No	No	21/3	34.20 ± 7.90	34.80 ± 5.80	388.00 ± 92.00	400.00 ± 86.10	1382.71 ± 1538.32	1850.22 ± 951.24
		Ctrl							11/0	33.76 ± 2.70	33.80 ± 6.90	416.00 ± 121.00	447.87 ± 120.20	1283.77 ± 1206.81	1589.83 ± 543.70
Qayyum et al[28], 2023	NCT02673164	Exp	12	6	Yes	No	No	No	26/3	31.60 ± 7.20	32.80 ± 7.50	419.00 ± 12.00	432.00 ± 13.00	1495.00 ± 2242.00	1607.00 ± 274.00
		Ctrl							10/2	32.00 ± 8.90	34.70 ± 9.70	423.00 ± 18.00	451.00 ± 19	1828.00 ± 2376.00	1652.00 ± 595.00

6MWD: 6-minute walk distance; CCT: Cardiac computed tomography; CMR: Cardiac magnetic resonance imaging; Ctrl: Control arm; Echo: Echocardiography; Exp: Exposure arm; FU: Follow-up; LVEF: Left ventricular ejection fraction; Pro-BNP: Pro-B-type natriuretic peptide; SAE: Serious adverse events; SPECT: Single-photon emission computed tomography.

Table 3 Jadad scale quality assessment of the included trials (R, randomization; B, blinding; D, dropout)

Ref.	Trial registry	Jadad scale				Quality
		R (0-2)	B (0-2)	D (0-1)	Total
Ascheim et al[21], 2014	NCT01442129	1	1	1	3	High
Perin et al[27], 2015	NCT00721045	2	0	1	3	High
Mathiasen et al[25], 2015	NCT00644410	2	2	1	5	High
Zhao et al[19], 2015	NA	1	0	0	1	Low
Patel et al[23], 2016	NCT01670981	2	2	1	5	High
Butler et al[22], 2017	NCT02467387	1	0	1	2	Low
Xiao et al[29], 2017	NA	1	0	0	1	Low
Florea et al[18], 2017	NCT02013674	2	1	1	4	High
Yau et al[20], 2019	NCT02362646	2	0	1	3	High
Bolli et al[26], 2021	NCT02501811	1	2	1	4	High
Qayyum et al[28], 2023	NCT03092284	1	1	1	3	High
Qayyum et al[28], 2023	NCT02673164	2	2	1	5	High