Combination strategies for pharmacologic treatment of non-alcoholic steatohepatitis

Table 3 Multidrug regimens for the treatment of non-alcoholic steatohepatitis

Trial name/NCT number	Phase	Manufacturer	Drugs	Mechanism of action	Enrollment (targeted)	Study arms	Duration (weeks)	Primary or relevant end point(s)
NCT02781584 (Proof of Concept)	1	Gilead Sciences	Selonsertib, firsocostat, cilofexor, fenofibrate, icosapent ethyl	(1) Selonsertib-selective ASK1 inhibitor; (2) Firsocostat-ACC inhibitor; (3) Cilofexor-FXR agonist; (4) Fenofibrate-PPAR agonist; and (5) Icosapent ethyl-under investigation	220	(1) Selonsertib; (2) Firsocostat; (3) Cilofexor; (4) Selonsertib + cilofexor; (5) Selonsertib + firsocostat; (6) Firsocostat + cilofexor; (7) Firsocostat (cirrhotic patients); (8) Cilofexor (cirrhotic patients); (9) Selonsertib + firsocostat + cilofexor; (10) Firsocostat + fenofibrate 48 mg; (11) Firsocostat + fenofibrate 145 mg; and (12) Icosapent ethyl + firsocostat + cilofexor	12	(1) Adverse events; (2) Serious adverse events; and (3) Lab abnormalities
ATLAS/NCT03449446	2	Gilead Sciences	Selonsertib, firsocostat, cilofexor	(1) Selonsertib-selective ASK1 inhibitor; (2) Firsocostat-ACC inhibitor; and (3) Cilofexor-FXR agonist	395	(1) Selonsertib + firsocostat + placebo; (2) Selonsertib + cilofexor + placebo; (3) Firsocostat + cilofexor + placebo; (4) Selonsertib + placebo + placebo; (5) Firsocostat + placebo + placebo; (6) Cilofexor + placebo + placebo; and (7) 3 placebos	48	(1) Adverse events; (2) Lab abnormalities; and (3) Improvement of ≥ 1-stage in fibrosis without worsening of NASH
NCT03987074	2	Gilead Sciences, Novo Nordisk	Cilofexor, semaglutide, firsocostat	(1) Semaglutide-GLP-1 agonist; (2) Firsocostat-ACC inhibitor; and (3) Cilofexor-FXR agonist	109	(1) Semaglutide; (2) Firsocostat + semaglutide; (3) Semaglutide + cilofexor 30 mg; (4) Semaglutide + cilofexor 100 mg; and (5) Semaglutide + firsocostat + cilofexor	24	(1) Adverse events; (2) Serious adverse events; and (3) Lab abnormalities
ELIVATE/NCT04065841	2	Novartis	Tropifexor, licogliflozin	(1) Tropifexor-FXR agonist; and (2) Licogliflozin-SGLT1/2 inhibitor	380	(1) Tropifexor + licogliflozin; (2) Tropifexor + placebo; (3) Licogliflozin + placebo; and (4) 2 placebos	48	(1) Improvement of ≥ 1-stage in fibrosis without worsening of NASH; and (2) Resolution of NASH without worsening fibrosis
NCT03776175	2A	Pfizer	PF-05221304, PF-06865571	(1) PF-05221304-ACC inhibitor; and (2) PF-06865571 - DGAT 2 inhibitor	99	(1) ACC inhibitor + placebo; (2) DGAT2 inhibitor + placebo; (3) ACC inhibitor + DGAT2 inhibitor; and (4) 2 placebos	6	Improvement in fat fraction
TANDEM/NCT03517540	2	Novartis, Allergan	Tropifexor, cenicriviroc	(1) Tropifexor-FXR agonist; and (2) Cenicriviroc-CCR2/CCR5 inhibitor	193	(1) Tropifexor; (2) Cenicriviroc; (3) Tropifexor dose 1 + cenicriviroc; and (4) Tropifexor dose 2 + cenicriviroc	48	(1) improvement in fibrosis; and (2) Resolution of steatohepatitis
CONTROL/NCT02633956	2	Intercept Pharmaceuticals	Obeticholic acid, atorvastatin	(1) Obeticholic acid-FXR agonist; and (2) Atorvastatin-HMG-CoA reductase inhibitor	84	(1) Obeticholic acid 5 mg/10 mg/25 mg + atorvastatin 10 mg/20 mg; and (2) Placebo + atorvastatin 10 mg/20 mg	16	(1) Change in LDL concentration; (2) Change in LDL particle size; and (3) Change in LDL particle concentration
NCT04235205	2	Albireo Pharma	Elobixibat, cholestyramine	(1) Elobixibat-IBAT inhibitor; and (2) Cholestyramine-bile acid binding resin	100	(1) Elobixibat + cholestyramine; (2) Elobixibat + placebo; (3) Placebo + cholestyramine; and (4) 2 placebos	16	(1) Change in liver fat fraction measured by MRI-PDFF; and (2) Change in fibrosis measured by MRE
PUVENAFLD/NCT04198805	2	DSM Nutritional Products	Vitamin E, omega-3 fatty acid	(1) Vitamin E-scavenging reactive oxidation species; and (2) Omega 3 FA-competing with omega 6 for cyclooxgenase and lipoxygenase-mediated inflammatory eicosanoid production, forming anti-inflammatory compounds	200	(1) Vitamin E + placebo; (2) Omega-3 fatty acid + placebo; (3) Omega 3-fatty acid + vitamin E; and (4) 2 placebos	24	(1) Change in liver fat fraction measured by MRI-PDFF; (2) Change in liver enzymes; and (3) FIB-4 scores
NEXSCOT/NCT04147195	2	Novartis	LYS006, tropifexor	(1) Tropifexor-FXR agonist; and (2) LYS006-leukotriene A4 hydrolase inhibitor	250	(1) LYS006; and (2) LYS006 + tropifexor	21	(1) Change in ELF score; and (2) Change in liver fat fraction measured by MRI-PDFF
NCT02466516	2	Gilead Sciences	Selonsertib, simtuzumab	(1) Selonsertib-selective ASK1 inhibitor; and (2) Simtuzumab-lysyl oxidase-like 2 inhibitor	72	(1) Selonsertib 6 mg; (2) Selonsertib 18 mg; (3) Selonsertib 6 mg + simtuzumab; (4) Selonsertib 18 mg + simtuzumab; and (5) Simtuzumab	24	(1) Adverse events; (2) Serious adverse events; (3) Lab abnormalities; and (4) Number of participants who prematurely discontinued study due to adverse events
NCT01703260	2	AstraZeneca	Roflumilast, pioglitazone	(1) Roflumilast-phosphodiesterase 4 inhibitor; and (2) Pioglitazone-PPAR agonist	16	(1) Roflumilast + pioglitazone; (2) Roflumilast + placebo; and (3) Pioglitazone + placebo	20	(1) Change in liver enzymes; and (2) Change in liver fat fraction measured by MRI-PDFF

ASK1: Apoptosis signal-regulating kinase-1; ACC: Acetyl-coenzyme A carboxylase; FXR: Farnesoid X receptor; PPAR: Peroxisome proliferator-activated receptor; GLP-1: Glucagon-like peptide-1; SGLT: Sodium/glucose transport protein; DGAT: Diacylglycerol acyltransferase; CCR: C-C motif chemokine receptor; IBAT: Ileal bile acid transporter.