Table 2

Principal phase 2 or phase 3 head-to-head placebo-controlled RCTs (published in the last 10 years) testing the efficacy and safety of non-antihyperglycaemic drug treatments on NAFLD or NASH (assessed either by liver biopsy or by MRI) in overweight or obese adult individuals

First author, year*RCT’s characteristicsIntervention (group sizes), DurationMain resultsMain adverse effectsCardiometabolic effects of the ‘active’ drug treatment
Younossi ZM et al, 2019156 Multicentre, phase 3 RCT of overweight or obese adults with definite NASH and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity (REGENERATE trial)
  1. Obeticholic acid 10 mg/day (n=312), an agonist of the farnesoid X nuclear receptor

  2. Obeticholic acid 25 mg/day (n=308)

  3. Placebo (n=311)

Duration: 18 months (planed analysis ad interim)
Fibrosis improvement (≥1 stage) was achieved by 12% of patients in the placebo group, 18% in the obeticholic acid 10 mg group (p=0.045), and 23% in the obeticholic acid 25 mg group (p=0.0002). The NASH resolution endpoint was not met (p=0.13)Most common adverse event was mild-to moderate pruritus (19% in the placebo group, 28% in the obeticholic acid 10 mg group, and 51% in the obeticholic acid 25 mg group)Mild decrease in body weight. Marked increase in plasma LDL-cholesterol levels (nearly+40 mg/dL) after 1 month of treatment (more than half of patients treated with obeticholic acid started statin therapy over the trial). In patients with established diabetes, obeticholic acid was also associated with an early transient increase in plasma glucose and haemoglobin A1c levels
Harrison et al, 2019Multicentre, phase 2 RCT of US overweight or obese adults with biopsy-confirmed NASH (fibrosis stages 1–3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction
  1. Resmetirom (MGL-3196) 80 mg/day (n=84)

  2. Placebo (n=41)

Duration: 36 weeks
Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat content compared with placebo (n=38) both at week 12 (−32.9% resmetirom vs −10.4% placebo; least squares mean difference −22.5%, 95% CI −32.9 to −12.2; p<0.001) and at week 36 (−37.3% resmetirom(n=74) vs −8.5 placebo (n=34); −28.8%, −42 to −15.7; p<0.001)Adverse events were mild or moderate and were well balanced between the groups, except for a higher incidence of transient mild diarrhoea and nausea in the resmetirom groupSignificant reductions in plasma LDL-cholesterol, triglycerides, apolipoprotein CIII and lipoprotein (a) levels. No significant effects on body weight and other metabolic parameters
Sanyal et al, 2018Multicentre, phase 2 RCT of US overweight or obese adults with biopsy-confirmed NASH (fibrosis stage 1–3), and a hepatic fat fraction of at least 10% when assessed by magnetic resonance imaging-proton density fat fraction
  1. Pegbelfermin (BMS-986036) 10 mg once a day subcutaneoulsy (n=25)

  2. Pegbelfermin 20 mg once a week subcutaneoulsy (n=24)

  3. Placebo (n=26)

Duration: 16 weeks
Significant decrease in absolute hepatic fat fraction in the group receiving 10 mg pegbelfermin daily (−6.8% vs −1.3%; p=0.0004) and in the group receiving 20 mg pegbelfermin weekly (−5.2% vs −1.3%; p=0.008) compared with the placebo groupMost adverse events were mild; the most common events were diarrhoea in 16% of patients treated with pegbelfermin and 8% of patients treated with placebo and nausea in 14% patients treated with pegbelfermin and 8% patients treated with placeboNo significant changes in body weight and plasma lipid profile (although plasma LDL-cholesterol levels tended to improve in those treated with pegbelfermin 10 mg/day) between treatment arms. Significant increase in plasma adiponection levels in those treated with pegbelfermin
Loomba et al, 2018Multicentre, phase 2 study of US overweight or obese adults with biopsy-confirmed NASH (fibrosis stage 1–3), and a hepatic fat fraction of at least 8% when assessed by magnetic resonance imaging-proton density fat fraction and liver stiffness of at least 2.5 kPa, based on MRI elastography measurement or historical biopsy result consistent with NASH and F1-F3 fibrosis
  1. GS-0976 5 mg/day (an inhibitor of acetyl-coenzyme A carboxylase) (n=46)

  2. GS-0976 20 mg/day (n=46)

  3. Placebo (n=26)

Duration: 12 weeks
A relative decrease of at least 30% from baseline in MRI-PDFF occurred in 48% of patients given GS-0976 20 mg (p=0.004 vs placebo), 23% given GS-0976 5 mg (p=0.43 vs placebo), and 15% given placebo. Changes in MRI elastography-measured stiffness did not significantly differ among the groups, but a dose-dependent decrease in the fibrosis marker tissue inhibitor of metalloproteinase-1 (TIMP-1) levels was observed in patients given GS-0976 20 mgGS-0976 was safe; the most common adverse events were nausea and diarrhoea as well as increase in serum alkaline phosphatase levelsSignificant increases in plasma triglyceride and glucose levels were observed (16% of GS-0976-treated patients showed hypertriglyceridemia >500 mg/dL and started treatment with fibrates over the trial)
Harrison et al, 2018Multicentre, phase 2 RCT of overweight or obese adults with biopsy-confirmed NASH (stage 1–3 fibrosis), and at least 8% liver fat content when assessed by magnetic resonance imaging-proton density fat fraction
  1. NGM282 3 mg once a day subcutaneoulsy (n=27), an engineered FGF19 analogue,

  2. NGM282 6 mg once a day subcutaneoulsy (n=28)

  3. Placebo (n=27)

Duration: 12 weeks
At 12 weeks, 74% patients in the 3 mg dose group and 79% in the 6 mg dose group achieved at least a 5% reduction in absolute liver fat content measured by MRI-PDFF from baseline (relative risk 10% (95% CI 2.6 to 38.7] vs 11.4% (95% CI 3.0 to 43.8), respectively; p<0.001 for both comparisons) vs 7% in the placebo groupThe most commonly (≥10%) reported adverse events were injection site reactions, diarrhoea, abdominal pain and nauseaMarked increases in plasma LDL-cholesterol levels in both the 3 mg NGM282 group and the 6 mg NGM282 group. No significant effects on body weight and other metabolic parameters (plasma glucose, insulin and haemoglobin A1c)
Loomba et al, 2018Multinational, phase 2 RCT of overweight or obese adults with biopsy-confirmed NASH (fibrosis stage 2 or 3)
  1. Selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, 6 mg/day plus once-weekly injections of 125 mg of Simtuzumab (n=30)

  2. Selonsertib 18 mg/day plus once-weekly injections of 125 mg of Simtuzumab (n=32)

  3. Once-weekly injections of 125 mg of Simtuzumab, a monoclonal antibody against lysyl oxidase-like 2, (n=10)

Duration: 24 weeks
After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in liver fibrosis in the 18 mg selonsertib group was 13 of 30 (43%); in the 6 mg selonsertib group, 8 of 27 (30%); and in the simtuzumab-alone group, 2 of 10 (20%). Fibrosis improvement was associated with reductions in liver stiffness on MRI elastography, collagen content and lobular inflammation on liver biopsyNo significant differences in adverse events between the treatment groups; the most common adverse events were headache, nausea and sinusitisSignificant increases in plasma glucose levels (>250 mg/dL) were observed in nearly 10% of treated patients. Marked increases in plasma triglycerides (>500 mg/dL) were also observed in nearly 5% of treated patients. No significant effects on body weight or haemoglobin A1c levels
Friedman et al, 2018Multinational, phase 2b RCT of overweight or obese adults with biopsy-confirmed NASH (stage 1–3 fibrosis) (CENTAUR trial)
  1. Cenicriviroc, 150 mg/day (n=126), a dual antagonist of C-C chemokine receptor types 2 and 5

  2. Placebo (n=126)

Duration: 1 year
The improvement in fibrosis endpoint was met in significantly more subjects on cenicriviroc than placebo (20% vs 10%; p=0.02). In contrast, NAS improvement in the intent-to-treat population and resolution of NASH was achieved in a similar proportion of subjects on cenicriviroc and placebo (16% vs 19% and 8% vs 6%, respectively)Safety and tolerability of cenicriviroc were comparable to placebo; the most common adverse events were headache, diarrhoea and fatigueNo significant effects on body weight and fasting metabolic parameters (plasma lipids, glucose and haemoglobin A1c levels) were observed between the two group treatments
Kim et al, 2017Multicentre, phase 2 RCT of Korean overweight or obese adults with imaging-defined NAFLD (with at least 20% liver fat content when assessed by magnetic resonance spectroscopy) and elevated serum transaminase levels
  1. Oltipraz 60 mg twice daily (n=21), a synthetic dithiolethione with an anti-steatotic effect by inhibiting the activity of liver X receptor alpha

  2. Oltipraz 120 mg twice daily (n=22),

  3. Placebo (n=21)

Duration: 24 weeks
Compared with the placebo group (−3.2±11%), absolute reduction in liver fat content increased in a dose-dependent manner: −7.7±7% and −13.9±11% for the low-dose and high-dose groups (p=0.13 and p<0.01). Percent reduction in liver fat content was also greater in the high-dose group than in the placebo group (−34.6±29% vs −0.6±63%, p=0.046)Adverse events were comparable among the groups; the most common adverse events were gastrointestinal symptomsBody weight significantly decreased in the high-dose group compared with the placebo group. However, absolute changes in HOMA-insulin resistance and plasma lipids were not different among the groups
Ratziu et al,159 2016Multinational, phase 2 RCT of overweight or obese adults with biopsy-confirmed NASH without cirrhosis
  1. Elafibranor 80 mg/day (n=93), an agonist of PPAR-α and PPAR-δ

  2. Elafibranor 120 mg/day (n=91)

  3. Placebo (n=92)

Duration: 52 weeks
In intention-to-treat analysis, there was no significant difference between the two elafibranor groups and placebo in the resolution of NASH without fibrosis worsening. However, NASH resolved without fibrosis worsening in a higher proportion of patients in the 120 mg elafibranor group vs the placebo group (19% vs 12%; p=0.045), based on a post-hoc analysis for the modified definition. Patients with NASH resolution after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resolutionElafibranor was safe and well tolerated, but did produce a mild, reversible increase in serum creatinine levelsElafibranor did not cause weight gain. Plasma lipids (including LDL-cholesterol and triglycerides) and glucose levels were significantly reduced in the elafibranor 120 mg group vs the placebo group
Neuschwander-Tetri et al,155 2015Multicentre, phase 2b RCT of US overweight or obese adults with biopsy-confirmed NASH without cirrhosis (FLINT trial)
  1. Obeticholic acid 25 mg/day (n=110)

  2. Placebo (n=109)

Duration: 72 weeks
45% of patients in the obeticholic acid group had improved liver histology (ie, decrease in NAS score by at least two points without worsening of fibrosis) compared with 21% of patients in the placebo group (p=0.0002). The NASH resolution endpoint was not met (p=0.08)Adverse events were generally mild to moderate and were similar for the two groups, except for pruritus; 23% of patients in the obeticholic acid had pruritus compared with 6% in the placebo groupMild decrease in body weight. Improvement in fasting insulin and HOMA-IR values, but no significant changes in plasma glucose and haemoglobin A1c levels. Marked increase in plasma LDL-cholesterol and decrease in HDL-cholesterol (already within 3 months of treatment with obeticholic acid). Significant increases in platelet count and serum creatinine levels were also observed
Zein et al,160 2011Multicentre, phase 2 RCT of US overweight or obese adults with biopsy-confirmed NASH
  1. Pentoxifylline 400 mg three times a day (n=26)

  2. Placebo (n=29)

Duration: 12 months
After 1 year, intention-to-treat analysis showed a decrease of ≥2 points in the NAS in 38.5% of patients on pentoxifylline vs 13.8% of those on placebo (p=0.036). Pentoxifylline significantly improved steatosis (mean change in score −0.9 vs −0.04 with placebo) and lobular inflammation (median change −1 vs 0 with placebo). Although not statistically significant, improvement in fibrosis was observed in a greater proportion (35%) of patients on pentoxifylline compared with those on placebo (15%)Nausea and vomiting were more frequently among those treated with pentoxifyllineMild decrease in body weight. No significant changes in HOMA-insulin resistance, plasma glucose, lipids and cytokines (ie, plasma adiponectin and tumour necrosis factor-alpha levels)
Van Wagner et al,161 2011Single-centre, phase 2 RCT of US overweight or obese adults with biopsy-confirmed NASH
  1. Pentoxifylline 400 mg three times a day (n=21)

  2. Placebo (n=9)

Duration: 12 months
After 12 months, liver steatosis and cellular ballooning improved in the pentoxifylline group (p<0.05), whereas no histological feature of NASH improved with placeboAdverse events were mild, most frequently headache and abdominal cramps, and did not differ between the groupsNo significant changes in body weight, HOMA-insulin resistance, plasma glucose, lipids and cytokines
Sanyal et al,126 2010Multicentre, phase 3 RCT of US overweight or obese adults with biopsy-confirmed NASH without diabetes (PIVENS trial)
  1. Pioglitazone 30 mg/day (n=80)

  2. Vitamin E 800 IU/day (n=84)

  3. Placebo (n=83)

Duration: 96 weeks
Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in NASH (43% vs 19%, p=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; p=0.04). Both agents were associated with significant reductions in hepatic steatosis and lobular inflammation but not with improvement in fibrosis scores compared with placeboAdverse effects were similar among the three groups (except for weight gain in the pioglitazone group)Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo. Pioglitazone also significantly increased plasma HDL-cholesterol levels, improved HOMA-insulin resistance, decreased plasma glucose levels and tended to decrease plasma triglycerides compared with placebo. No significant changes in body weight, plasma lipids and metabolic parameters were observed between the vitamin E and the placebo groups
  • NB: We did not include in the table phase 3 RCTs (ie, the Safety and Efficacy of Selonsertib in Adults with Nonalcoholic Steatohepatitis and Brindging F3 Fibrosis [STELLAR 3] and STELLAR 4 trials) with selonsertib in patients with advanced fibrosis or compensated cirrhosis that were early stopped for lack of any efficacy. We did not also include in the table phase 2 RCTs that used probiotic/synbiotic supplementations, vitamin D supplementations or high-dose n-3 polyunsaturated fatty acids.

  • *The complete list of references that are included in the table are reported in the online supplementary material.

  • HOMA, homoeostasis model assessment; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; RCT, randomised controlled trial.