Table 3.

Terminated and completed phase III clinical trials in NAFLD and NASH

Compound/Company or academic lead	Study design	Mechanism of action	Intervention/control	Key inclusion criteria	Key exclusion criteria	Status
Metadoxine/Hospital General de Mexico	Non-diabetic patients with NAS>3 (NCT02541045). Primary outcome: Improvement of NAS	–↓Oxidative stress – Restoration NADH, ATP and GSH – Prevention increase collagen –↓TNF secretion	–Metaxodine 500 mg/day – Placebo (N total= 108)	– Non-diabetic patients – BMI≥25 – Proof of liver steatosis with ultrasonography – NAS≥3 with at least 1 point on each – Without fibrosis or fibrosis stage ≤ F2 according to NASH CRN classification	– Cirrhosis – Other liver diseases – Uncontrolled chronic disease, hypothyroidism or hyperthyroidism	Suspended due to lack of financial resources
Rimonabant (SR141716)/Sanofi	NASH patients with T2DM (NCT00577148) and without (NCT00576667)	Cannabinoid-1 receptor blocker	– Rimonabant 20 mg/day – Placebo (N total= 89 for NCT00577148and N= 165 for NCT00576667)	NASH patients	– T1DM for NCT00577148 or type I/II diabetes for NCT00576667 – Other chronic liver disease – Previous or current HCC – Previous bariatric surgery	Terminated by company decision taken in light of demands by certain national health authorities
Cenicriviroc (CVC)/AbbVie	AURORA: NASH patients with liver fibrosis (NCT03028740) Primary outcomes: Improvement of ≥1 stage in fibrosis according to NASH CRN System without worsening of NASH (Part 1); and improvement of histopathological progression, liver-related clinical outcomes and all-cause mortality (Part 2)	Chemokine 2 and 5 receptor antagonist	– CVC 150 mg/day – Placebo (N total= 1779)	– Proof NASH based on liver biopsy – Subjects in part 1: F2/F3 per the NASH CRN System based on liver biopsy. Subjects in Part 2: F3 per the NASH CRN System, based on liver biopsy.	– Other liver diseases or serious infections – Liver transplantation – HbA1c>10% at Screening – Weight reduction ≥7% through bariatric surgery in the past 5 years or bariatric surgery planned during study – Malignancy within past 5 years or ongoing, other than basal cell carcinoma or resected noninvasive cutaneous squamous cell carcinoma – GLP-1 agonist, DPP-4 inhibitor, SGLT2 and/or SGLT1 inhibitor, TZD for ¡6 mo. before screening	Terminated due to lack of efficacy in Part I
Elafibranor (GTF505)/Genfit	RESOLVE-IT: NASH patients with fibrosis (NCT02704403). Primary outcomes: NASH resolution without worsening of fibrosis; composite long-term outcome composed of all-cause mortality, cirrhosis, liver-related clinical outcome	Peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-δ agonist	– Elafibranor 120 mg/day – Placebo (N total= 2157)	– BMI≤45 kg/m2 – NASH confirmation by liver biopsy with at least 1 in each component NAS score – NAS score≥4 – Fibrosis stage≥1 or <4 according to the NASH CRN system	– Known heart failure – Bariatric surgery – Uncontrolled hypertension – T1DM patients – HbA1c>9% – Weight loss >5% within last 6 months – Compensated and decompensated cirrhosis – Other chronic liver diseases	Terminated due to failure to meet primary efficacy endpoint
Selonsertib (SEL/GS-4997)/Gilead Sciences	NASH patients and F3 (NCT03053050) Primary outcomes: ≥1 stage improvement in fibrosis according to NASH CRN System and event-free survival	ASK-1 inhibitor	– SEL 6 mg/day – SEL 18 mg/day – Placebo (N total= 808)	– Liver biopsy NASH and F3 according to NASH CRN System – HbA1c≥9.5– ALT ≤ x8 ULN	– MELD score >12 – Other liver diseases – Liver transplantation – HCC	Terminated due to lack of efficacy
Diamel/Catalysis SL	NASH with insulin resistance (NCT00820651). Primary outcome: histological improvement	– Antioxidant – Biocatalyst –↓ Gastrointestinal absorption glucose	–Diamel 660 mg/x2 every 8h – Placebo: hypocaloric diet of 1620 kcal daily (N total= 158)	Histological diagnosis of NASH	– Other liver disease – Decompensated cirrhosis – Fasting glucose levels >250 mg/dL	Completed (no results available)
Pioglitazone or vit. E/National Institute of diabetes and Digestive and Kidney diseases (NIDDK)	PIVENS: NASH (NCT00063622). Primary outcomes: improvement of ≥1 hepatocyte ballooning, NAS≤3 or decrease of 2 points and no worsening of fibrosis	– Vit. E: antioxidant – Pioglitazone: thiazolidinedione that targets insulin resistance and adipose tissue dysfunction	– Pioglitazone 30 mg/day (N= 80) – Vit. E 800 IU/day (N= 84) – Placebo (N= 83)	NASH based on liver biopsy	– Adults with diabetes – Other liver or cardiovascular diseases – Cirrhosis	Completed. Significant difference for vit. E (p= 0.001), but not with pioglitazone (p= 0.04). Improvement in serum ALT and AST (p <0.001), steatosis (p= 0.005/p= 0.001) (vit. E/pioglitazone) and inflammation (p= 0.02/p= 0.004); but not fibrosis scores (p= 0.24/p= 0.12). (Pre-specified level of significance was p= 0.025)
Losartan/Newcastle-upon-Tyme Hospitals NHS Trust	FELINE: NASH patients (NCT01051219). Primary outcome: change in histological fibrosis stage (NASH CRN system)	Angiotensin II receptor type 1 (AT1) antagonist	– Losartan 50 mg/day (N= 15) – Placebo (N= 17)	NASH and fibrosis stage 1–3 NASH CRN System	– Use of ACEI or ARBs in past year – Change in diabetes regimen in last 3 months – Weight loss >50% in last 6 months	Study was terminated early due to slow recruitment, but patients were allowed to complete the study if they wanted to. No significant results
Oltipraz/PharmaKing	NAFLD patients (NCT02068339). Primary outcomes: change in liver fat assessed by MRS	AMP-activated protein kinase (AMPK) activator	–Oltipraz 90 mg/day –Oltipraz 120 mg/day – Placebo (N total= 283)	– NAFLD patients – Abnormal ALT/AST	– Cirrhosis – AST/ALT >2 ratio – T1DM/T2DM – Other liver diseases/cancer – Vit. E consumption – Bariatric surgery within 6 months	Completed. No results available
Pentoxifylline (PO TID)/NortwesternUniversity	NASH patients (NCT00267670). Primary outcomes: Improvement of ALT≥30% change	Non-specific phosphodiesterase inhibitor	– PO TID 400 mg/day (N= 19) – Placebo (N= 7)	– Steatosis score ≥1 – ALT ≥ x1.5 ULN – HgbA1c<7%	– Decompensated cirrhosis – Current anti-diabetic, anti-TNF-α or vit. E medication	Completed. No significant change in ALT (p= 0.08)