Table 3.
Clinical studies with cell death based interventions in liver disease
| Treatment | Cell death Intervention | Study Design | Results | Year of completion | Phase | Patient number | NCT Identifier or reference |
|---|---|---|---|---|---|---|---|
| Acute liver failure | |||||||
| N-acetylcysteine in acetaminophen-induced liver failure | Replenishment of hepatic GSH and reduction of oxidative stress | Non-randomized | Reduction of mortality, early treatment more effective than late treatment | 1985 | 2540 | 187 | |
| Late N-acetylcysteine in acetaminophen-induced liver failure (10–36h after intoxication) | Replenishment of hepatic GSH and reduction of oxidative stress | Randomized | Improved survival, and less edema in patients receiving N-acetylcysteine | Not described. | 50 | 189 | |
| N-acetylcysteine in acute liver failure (not acetaminophen induced) | Replenishment of hepatic GSH and reduction of oxidative stress | Randomized | Improved transplant-free survival | 2009 | 3 | 173 | NCT00004467 239 |
| N-acetylcysteine in acute liver failure (not acetaminophen induced) in pediatric patients | Replenishment of hepatic GSH and reduction of oxidative stress | Randomized | No improvement in 1-year survival, 1-year transplant-free survival significantly lower than placebo (!) | 2011 | 3 | 184 | NCT00248625 240. |
| Emricasan (PF-03491390 / IDN-6556) in patients with acute on chronic liver failure | Caspase-Inhibition, anti-apoptotic | Randomized | pending | 2014 | 2 | 60 | NCT01937130 |
| ALF-5755 in patients with severe acute hepatitis and early acute liver failure (not acetaminophen) | Prevents apoptosis and oxidative stress, promotes regeneration | Randomized | Not fully published | 2013 | 2 | 60 | NCT01318525 |
| Viral Hepatitis | |||||||
| Combined oral and i.v. antioxidants in chronic HCV patients after failure of interferon | Reduction of oxidative stress | Randomized | Decline in ALT levels | 2007 | 2 | 100 | 241 |
| Vitamin E for children with chronic Hepatitis B | Reduction of oxidative stress | Randomized | Non-significant trend to higher HBeAg-seroconversion | 2008 | 2 | 76 | 242 |
| Mitoquinone mesylate in patients with chronic HCV | Caspase-inhibition, mitochondria-targeted antioxidant, anti-apoptotic | Randomized | Reduction in ALT and AST levels | 2010 | 2 | 30 | NCT00433108 243 |
| GS-9450 in patients with chronic HCV | Caspase-inhibition, anti-apoptotic | Randomized | Reduction in ALT levels | 2010** | 2 | 32 | NCT00725803 244 |
| Emricasan (PF-03491390 / IDN-6556) in chronic HCV | Caspase-Inhibition, anti-apoptotic | Randomized | Reduction in ALT and AST levels | 2010 | 2 | 204 | NCT00088140 245 |
| Pentoxifylline added to PEG-Interferon and Ribavirin in chronic HCV | Inhibition of TNF, protection of hepatocytes | Randomized | Increased SVR rates | 2013 | 2 | 72 | 246 |
| Peginterferon Alfa-2b (SCH 054031) vs Glycyrrhizin in Interferon (IFN)-Treated Patients With Chronic Hepatitis C | Glycyrrhizin is a natural compound of licorice with HMGB1 inhibitory activity | Randomized | Significantly higher ALT reduction by glyzyrrhizin compared to placebo after 12 weeks and improved necroinflammation and fibrosis after 52-weeks | NCT00686881 247 | |||
| Alcoholic liver disease | |||||||
| Pentoxifylline in severe alcoholic hepatitis | Inhibition of tumor necrosis factor (TNF) | Randomized | Improved 1-month-survival, reduced fraction of patients with hepatorenal syndrome | 2000 | 101 | 248 | |
| Pentoxifylline vs. prednisolone in severe alcoholic hepatitis | Inhibition of TNF | Randomized | Improved 3-month-survival and lower 1-month-MELD-score | 2009 | 2 | 68 | 249 |
| Pentoxifylline plus Anakinra plus zink (vs. methylprednisolone) in alcoholic hepatitis | Inhibition of TNF and Interleukin-receptor signaling | Randomized | pending | 2015 | 2/3 | 130 | NCT01809132 |
| Combined antioxidant treatment (alone or with corticosteroids) | Reduction of oxidative stress | Randomized | No improvement in 6-month-survival | 2007 | 2 | 70 | 250 |
| Eternacept in moderate to severe alcoholic hepatitis | TNF inhibition | Randomized | Increased mortality and increased infections in eternacept group | 2007 | 48 | 230 | |
| N-acetylcysteine in severe alcoholic hepatitis | Replenishment of hepatic GSH and reduction of oxidative stres | Randomized | No benefits in survival and biological parameters | 2010 | 3 | 52 | NCT00962442 251 |
| N-acetylcysteine plus (plus corticoids) in severe alcoholic hepatitis | Replenishment of hepatic GSH and reduction of oxidative stress (anti-inflammatory) | Randomized | Combination did not improve 6 months-survival compared to corticoids alone (primary endpoint), improved 1-months-survival | 2011 | 3 | 174 | NCT00863785 231 |
| Emricasan (PF-03491390 / IDN-6556) in patients with alcoholic hepatitis and contraindications to steroids | Caspase-Inhibition, anti-apoptotic | Randomized | pending | 2018 | 2 | 60 | NCT01912404 |
| Pentoxifylline and prednisolone versus prednisolone in severe alcoholic hepatitis | Randomized | No improvement in survival by the combination of pentoxifylline and prednisolone vs. prednisolone alone | 2010 | 3 | 270 | NCT01214226. 252 | |
| NAFLD | |||||||
| Pentoxifylline in NASH | Inhibition of TNF | Randomized | Improved NAFLD activity score | 2011 | 3 | 55 | NCT00590161 253 |
| Vitamin E (or Pioglitazone) in non-diabetic NASH patients (PIVENS) | Reduction of oxidative stress | Randomized | Histological improvement in NASH (not Pioglitazone), Reduction in AST/ALT, Reduced steatosis, no improvement in fibrosis score | 2010 | 3 | 247 | NCT00063622 219 |
| Vitamin E (or Metformin) in children and adolescents with NAFLD (TONIC) | Reduction of oxidative stress | Randomized | No benefit of Vit. E and Metformin on ALT/AST; improved hepatocyte ballooning score, NAFLD activity score and proportion of NASH resolution with Vit. E | 2011 | 3 | 173 | 218 |
| Vitamin E in NASH: Effects of Dose reduction (200mg, 400mg, 800mg) | Reduction of oxidative stress | Randomized | pending | 2018 | 2 | 90 | NCT01792115 |
| Obeticholic acid in patients with NASH and type II diabetes | FXR agonism | Randomized | Improved insulin sensitivity, ALT, GGT, and liver fibrosis markers in 20 mg OCA dose group; improved GGT in 50 mg OCA dose group | 2009 | 2 | 64 | 220 |
| Phyllanthus urinaria (Hepaguard®) in NASH | Reduction of oxidative stress | Randomized | No significant histological or serological improvement compared to placebo | 2013 | Not provided | 60 | NCT01210989 254 |
| Anthocyanin in non-diabetic NAFLD patients | Reduction of oxidative stress | Randomized | pending | 2014 | 0 | Not indicated | NCT01940263 |
| Metadoxin (and Metformin) in prediabetic NAFLD patients | Reduction in oxidative stress | Randomized | pending | 2015 | 4 | 100 | NCT02051842 |
| GS-9450 in patients with NASH | Caspase-inhibition, anti-apoptotic | Randomized | Reduction in ALT levels | 2012 | 2 | 124 | NCT00740610 216. |
| Emricasan (PF-03491390 / IDN-6556) in NAFLD patients with elevated ALT | Caspase-Inhibition, anti-apoptotic | Randomized | pending | 2014 | 2 | 40 | NCT02077374 |
| HCC | |||||||
| AEG35156 in combination with Sorafenib in HCC | XIAP antisense to promote apoptosis of HCC cells | randomized | PFS 4.0 months (combination) vs. 2.4 months (Sorafenib alone) Higher benefit for patients needing dose reductions | 2012 | 2 | 51 | NCT00882869 255 |
| Resminostat (4SC-201) alone or in combination with Sorafenib in 2nd Line HCC Treatment | Histone -Deacetylase inhibition to induce apoptosis and growth arrest | Open label, two arms | Median OS 8.1 Months in patients treated with Resminostat and Sorafenib in 2nd line | 2013 | 2 | 45 | NCT00943449 256 |
| Panobinostat (LBH589) in combination with Sorafenib in HCC | Histone-Deacetylase inhibition to induce apoptosis | Non-randomized | pending | Not reported | 1 | 18 | NCT00823290 |
| JX-594 in low or high dose | Oncolytic and immunotherapeutic vaccinia virus | Randomized | Median survival of 14.1 months compared to 6.7 months on the high and low dose | 2013 | 2 | 30 | 238 |
| JX-594 in combination with sorafenib | Oncolytic and immunotherapeutic vaccinia virus followed by treatment with mulitkinasse | Non-randomized | Pending | 2014 | 2 | 25 | NCT01171651 |