Comparison of extracorporeal cellular therapy (ELAD^®) vs standard of care in a randomized controlled clinical trial in treating Chinese subjects with acute-on-chronic liver failure

Figures & data

Table 1 Key inclusion and exclusion criteria

Inclusion	Exclusion
• Age 16–65 years (15–66 years after Amendment 2) • A clinical diagnosis of ACLF • Obvious GI and/or systemic toxic symptoms • Total bilirubin >5 times upper limit of normal or daily increase >1 mg/dL (17.1 μmol/L) • PTA of 20%–50% (10%–50% after Amendment 2), international normalized ratio 1.6–4.0, or prothrombin time >5 seconds longer than the control but <20 seconds • Hepatoencephalopathy absent or encephalopathy at or below grade II • No or mild ascites/pleural effusion	• Primary or metastatic liver cancer • Slowly progressing hepatic cirrhosis and hepatic failure • Uncontrolled severe infection • Shock • Active GI bleeding or obvious bleeding in other sites within 3 days before screening • Grade III or IV hepatoencephalopathy • Platelet count <50×10^9/L (<40×10^9/L after Amendment 2) • Creatinine >1.5 mg/mL • Severe esophageal varices

Notes: Based on “Guidelines for the treatment and prevention of viral hepatitis.”¹ Age, PTA, and platelet count were changed in Amendment 2 to expand the population and to allow for enrollment of subjects with slightly severe baseline disease characteristics.

Abbreviations: ACLF, acute-on-chronic liver failure; GI, gastrointestinal; PTA, prothrombin time activity.

Figure 1 Clinical trial flowchart.

Table 2 Demographics and screening parameters

Variables	ELAD			Control
		n/N	Percentage		n/N	Percentage	P-valuea
Sex
Male		31/32	96.9		15/17	88.2	0.273
Female		1/32	3.1		2/17	11.8
Main diagnosis
Chronic hepatitis B		23/32	71.9		9/17	52.9	0.219
Chronic hepatitis B+alcohol		4/32	12.5		5/17	29.4	0.244
Alcohol-induced hepatitis		1/32	3.1		1/17	5.9	1.000
Acute/subacute hepatitis		3/32	9.4		0/17	0.0	0.542
Drug-induced hepatitis		0/32	0.0		1/17	5.9	0.347
Autoimmune hepatitis		1/32	3.1		0/17	0.0	1.000
Unknown etiology		0/32	0.0		1/17	5.9	0.347
Variables	N	Mean±SD	Range	N	Mean±SD	Range	P-value^*
Demographics
Age (years)	32	39.5±9.6	15.5–65.1	17	39.2±11.6	19.6–61.2	0.929
Height (cm)b	32	169±5	156–182	16	172±5	163–176	0.067
Weight (kg)c	32	67.3±11.9	45.0–95.0	15	71.1±9.7	58.0–89.0	0.285
Signs/symptoms
Fatigue (0–3)	32	2.31±0.59	1.00–3.00	17	2.29±0.77	0.00–3.00	0.926
Flatulence (0–3)	32	0.69±0.78	0.00–2.00	17	1.29±1.10	0.00–3.00	0.030
MELD score	32	28.0±3.5	21.4–36.7	17	30.8±5.6	22.1–40.5	0.040
Hematology
RBCs (10^12/L)	32	3.53±0.90	1.47–5.30	17	3.77±1.12	1.90–6.10	0.411
Hemoglobin (g/L)	32	117.4±23.7	57.0–168.0	17	118.1±24.9	68.0–158.0	0.925
WBCs (10^9/L)	32	7.76±3.53	3.30–17.60	17	7.15±3.31	3.00–14.50	0.564
Platelets (10^9/L)	32	101.3±37.9	46.0–185.0	17	100.5±47.0	44.0–207.0	0.946
Blood chemistry
Aspartate aminotransferase (U/L)	32	163±1.28	41–644	17	188±1.57	36–523	0.548
Alanine aminotransferase (U/L)	32	229±376	15–1,817	17	164±1.34	16–393	0.495
Total bilirubin (mg/dL)	32	22.9±9.5	8.4–45.6	17	23.7±9.4	7.4–41.1	0.762
Direct bilirubin (mg/dL)	32	13.3±5.1	4.7–23.9	17	13.9±6.2	5.0–26.2	0.743
Albumin (g/L)	32	32.3±4.7	21.3–40.0	17	32.7±4.2	24.9–41.3	0.776
Prealbumin (mg/L)d	31	66.5±29.8	20.0–156.0	16	63.3±38.6	16.0–176.0	0.753
Alkaline phosphatase (U/L)	32	173.8±45.1	95.5–304.0	17	141.6±35.2	73.9–201.0	0.014
Cholinesterase (U/L)	32	2,637±959	1,026–4,231	17	2,619±930	955–4,682	0.951
Creatinine (mg/dL)	32	0.81±0.31	0.34–2.08	17	0.80±0.33	0.25–1.54	0.946
Uric acid (mg/dL)	32	2.16±1.29	0.59–7.27	17	2.08±1.02	0.64–4.47	0.827
Glucose (mmol/L)	32	4.55±3.83	0.92–22.17	17	6.69±4.23	2.07–18.79	0.079
Cholesterol (mg/dL)	32	74±23	43–136	17	58±19	16–84	0.019
Coagulation status
Prothrombin time (s)	32	22.7±4.2	17.4–36.6	17	27.2±8.5	18.3–45.4	0.016
AP thromboplastin time (s)	32	64.9±23.5	38.6–120.0	17	79.3±41.2	50.4–220.5	0.124
Prothrombin activity (%)	32	37.7±8.2	16.8–49.6	17	31.8±12.8	14.1–54.5	0.053
International normalized ratio	32	2.49±0.77	1.64–5.10	17	3.29±1.59	1.78–6.46	0.022

Notes:

a ANOVA (continuous variables) or Fisher’s exact test (categorical variables).

b Height at screening was not available for one control subject.

c Weight at screening was not available for two control subjects.

d Prealbumin measurement at screening was not available for one ELAD subject and one control subject.

Abbreviations: AP, activated partial; MELD, Model for End-Stage Liver Disease; RBCs, red blood cells; WBCs, white blood cells.

Table 3 Concomitant therapies

Variables	ELAD		Control		P-valuea
	n/N	Percentage	n/N	Percentage
Patients receiving therapies
Any concomitant therapy	15/32	46.9	6/17	35.3	0.549
Plasma exchange	11/32	34.4	5/17	29.4	1.000
Plasma bilirubin absorption	5/32	15.6	3/17	17.6	1.000
Continuous blood filtration	3/32	9.4	1/17	5.9	1.000

Note:

a P-values determined using Fisher’s exact test.

Figure 2 Kaplan–Meier analysis of transplant-free survival.

Table 4 Proportion of survivors on days 28 and 84

Treatment	Alive (no transplant)	Liver transplant	Death	Total
Day 28
ELAD	26 (81.2%)	1 (3.1%)	4 (12.5%)	32a
Control	8 (47.1%)	5 (29.4%)	3 (17.6%)	17a
Day 84
ELAD	21 (65.6%)	1 (3.1%)	9 (28.1%)	32a
Control	7 (41.2%)	5 (29.4%)	4 (23.5%)	17a

Note:

a One subject in each group withdrew consent.

Table 5 Proportional hazards regression of treatment group/duration of treatment, MELD score, and food intake on transplant-free survival

Variables	Individual regression (n=49)		Multiple regression (n=49)
	Estimate	P-value	Estimate	P-value
Treatment group	0.809	0.065	1.004	0.031
Food intake	0.834	0.001	0.921	0.001
MELD score	0.132	0.007	0.106	0.038
Duration of treatment	−0.010	0.043	−0.020	0.018
Food intake	0.834	0.001	0.925	0.001
MELD score	0.132	0.007	0.118	0.017

Abbreviation: MELD, Model for End-Stage Liver Disease.

Table 6 Number of subjects who died or had transplants, by food intake and MELD

Variables	ELAD (n=32)	Control (n=17)
Food intake scorea
1–2	0/14 (0.0%)	4/9 (44.4%)
3–4	11/18 (61.1%)	6/8 (75.0%)
MELD score
>30	4/7 (57.1%)	5/7 (71.4%)
<30	7/25 (28.0%)	5/10 (50.0%)

Note:

a Food intake score: 1, decreased by 1/4; 2, decreased by 1/2; 3, decreased by 2/3; 4, decreased by 3/4.

Abbreviation: MELD, Model for End-Stage Liver Disease.

Figure 3 Kaplan–Meier analysis of time to progression.

Table 7 Mean change in serum sodium concentration

Sodium (mmol/L)	N	ELAD		N	Control		P-value
Baseline	32	135.8±4.8	125.9 to 142.8	17	137.0±7.0	125.9 to 150.1	0.451
	Change from baseline
Days 3–5	31a	2.0±3.8	–3.8 to 9.6	10b	–1.3±3.9	–7.9 to 4.4	0.025

Notes:

a One ELAD subject was missing serum sodium measurement.

b Seven control subjects were missing serum sodium measurement.

Chinese Medical Association-Chinese Society of Infectious and Parasitic diseases in conjunction with Chinese Society of Hepatic DiseaseViral hepatitis prevention and treatment programsZhonghua Gan Zang Bing Za Zhi20008324329

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