Blinding in Clinical Trials for Chronic Liver Diseases

Abstract

Within the field of randomized clinical trials (RCTs), the randomized double-blind placebo-controlled clinical trial is considered the most efficient means of simultaneously assessing the efficacy and safety of a medical therapy in a single trial. While many RCTs are conducted without blinding (open label), it is rare to encounter a blinded trial that does not randomize its subjects. Clinical trials for chronic liver diseases have adopted many of the practices set forth by RCTs in other chronic diseases, but blinding has often been difficult to properly implement. This review examines the rationale for blinding, common challenges to successful blinding, different mechanisms of unintentional unblinding in clinical trials for viral hepatitis and nonalcoholic steatohepatitis, and recommendations for blinding and design in future trials of treatments for liver disease.

Keywords

blinding - clinical trials - randomization - liver disease

Financial Support

E.M.W. received salary support from the University of Pennsylvania Institute for Translational Medicine and Therapeutics Clinical Trials Fellowship.

Disclosures

E.M.W. is a site coinvestigator for clinical trials involving the following medications discussed in the review: elbasvir-grazoprevir, sofosbuvir-velpatasvir, glecaprevir-pibrentasvir, obeticholic acid, selonsertib, emricasan, pegbelfermin.

V.O.—no conflicts.

S.S.E.—no conflicts.

Publication History

Article published online:
06 May 2021

• References

• 1 Poynard T, Marcellin P, Lee SS. et al; International Hepatitis Interventional Therapy Group (IHIT). Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998; 352 (9138): 1426-1432
• 2 Bothwell LE, Podolsky SH. The emergence of the randomized, controlled trial. N Engl J Med 2016; 375 (06) 501-504
• 3 Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what. Lancet 2002; 359 (9307): 696-700
• 4 Friedman LM, Furberg CD, DeMets D, Reboussin DM, Granger CB. Fundamentals of Clinical Trials. 5th ed.. Springer International Publishing; 2015: 147-163
• 5 Katsagoni CN, Papatheodoridis GV, Ioannidou P. et al. Improvements in clinical characteristics of patients with non-alcoholic fatty liver disease, after an intervention based on the Mediterranean lifestyle: a randomised controlled clinical trial. Br J Nutr 2018; 120 (02) 164-175
• 6 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995; 273 (05) 408-412
• 7 Marušić A, Ferenčić SF. Adoption of the double dummy trial design to reduce observer bias in testing treatments. J R Soc Med 2013; 106 (05) 196-198
• 8 Fried MW, Shiffman ML, Reddy KR. et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347 (13) 975-982
• 9 Manns MP, McHutchison JG, Gordon SC. et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358 (9286): 958-965
• 10 Lindsay KL, Trepo C, Heintges T. et al; Hepatitis Interventional Therapy Group. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 2001; 34 (02) 395-403
• 11 Lawitz E, Mangia A, Wyles D. et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368 (20) 1878-1887
• 12 Jacobson IM, Gordon SC, Kowdley KV. et al; POSITRON Study, FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013; 368 (20) 1867-1877
• 13 Zeuzem S, Andreone P, Pol S. et al; REALIZE Study Team. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364 (25) 2417-2428
• 14 Jacobson IM, McHutchison JG, Dusheiko G. et al; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364 (25) 2405-2416
• 15 Poordad F, McCone Jr J, Bacon BR. et al; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364 (13) 1195-1206
• 16 Bacon BR, Gordon SC, Lawitz E. et al; HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364 (13) 1207-1217
• 17 Sanyal AJ, Chalasani N, Kowdley KV. et al; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362 (18) 1675-1685
• 18 Cusi K, Orsak B, Bril F. et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus a randomized trial. Ann Intern Med 2016; 165 (05) 305-315
• 19 Neuschwander-Tetri BA, Loomba R, Sanyal AJ. et al; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385 (9972): 956-965
• 20 Patel K, Harrison SA, Elkashab M. et al. Cilofexor, a nonsteroidal FXR agonist, in non-cirrhotic patients with nonalcoholic steatohepatitis: a phase 2 randomized controlled trial. Hepatology 2020; 72 (01) 58-71
• 21 Harrison SA, Alkhouri N, Davison BA. et al. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase IIb study. J Hepatol 2020; 72 (04) 613-626
• 22 Jacobson IM, Dore GJ, Foster GR. et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2014; 384 (9941): 403-413
• 23 Manns M, Marcellin P, Poordad F. et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2014; 384 (9941): 414-426
• 24 Chang T-T, Gish RG, de Man R. et al; BEHoLD AI463022 Study Group. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006; 354 (10) 1001-1010
• 25 Lai C-L, Shouval D, Lok AS. et al; BEHoLD AI463027 Study Group. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006; 354 (10) 1011-1020
• 26 Sherman M, Yurdaydin C, Sollano J. et al; AI463026 BEHoLD Study Group. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology 2006; 130 (07) 2039-2049
• 27 Gane E, Lawitz E, Pugatch D. et al. Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment. N Engl J Med 2017; 377 (15) 1448-1455
• 28 Wyles D, Poordad F, Wang S. et al. Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: a partially randomized phase 3 clinical trial. Hepatology 2018; 67 (02) 514-523
• 29 Forns X, Lee SS, Valdes J. et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial. Lancet Infect Dis 2017; 17 (10) 1062-1068
• 30 Zeuzem S, Foster GR, Wang S. et al. Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 Infection. N Engl J Med 2018; 378 (04) 354-369
• 31 Roth D, Nelson DR, Bruchfeld A. et al. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet 2015; 386 (10003): 1537-1545
• 32 Sanyal A, Charles ED, Neuschwander-Tetri BA. et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 2019; 392 (10165): 2705-2717
• 33 Ratziu V, Harrison SA, Francque S. et al; GOLDEN-505 Investigator Study Group. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016; 150 (05) 1147-1159.e5
• 34 Loomba R, Kayali Z, Noureddin M. et al. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology 2018; 155 (05) 1463-1473.e6
• 35 Harrison SA, Goodman Z, Jabbar A. et al. A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. J Hepatol 2020; 72 (05) 816-827
• 36 Kang BK, Yu ES, Lee SS. et al. Hepatic fat quantification: a prospective comparison of magnetic resonance spectroscopy and analysis methods for chemical-shift gradient echo magnetic resonance imaging with histologic assessment as the reference standard. Invest Radiol 2012; 47 (06) 368-375
• 37 Gu J, Liu S, Du S. et al. Diagnostic value of MRI-PDFF for hepatic steatosis in patients with non-alcoholic fatty liver disease: a meta-analysis. Eur Radiol 2019; 29 (07) 3564-3573
• 38 Patel J, Bettencourt R, Cui J. et al. Association of noninvasive quantitative decline in liver fat content on MRI with histologic response in nonalcoholic steatohepatitis. Therap Adv Gastroenterol 2016; 9 (05) 692-701
• 39 Cui J, Philo L, Nguyen P. et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol 2016; 65 (02) 369-376
• 40 Harrison SA, Rinella ME, Abdelmalek MF. et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2018; 391 (10126): 1174-1185
• 41 Lai C-L, Gane E, Liaw Y-F. et al; Globe Study Group. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 2007; 357 (25) 2576-2588
• 42 Marcellin P, Heathcote EJ, Buti M. et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008; 359 (23) 2442-2455
• 43 Buti M, Gane E, Seto WK. et al; GS-US-320-0108 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol 2016; 1 (03) 196-206
• 44 Chan HLY, Fung S, Seto WK. et al; GS-US-320-0110 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol 2016; 1 (03) 185-195
• 45 Loomba R, Lawitz E, Mantry PS. et al; GS-US-384-1497 Investigators. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology 2018; 67 (02) 549-559
• 46 Harrison SA, Abdelmalek MF, Caldwell S. et al; GS-US-321-0105 and GS-US-321-0106 Investigators. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology 2018; 155 (04) 1140-1153
• 47 Harrison SA, Wong VW, Okanoue T. et al; STELLAR-3 and STELLAR-4 Investigators. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials. J Hepatol 2020; 73 (01) 26-39
• 48 Friedman SL, Ratziu V, Harrison SA. et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 2018; 67 (05) 1754-1767
• 49 Safadi R, Konikoff FM, Mahamid M. et al; FLORA Group. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2014; 12 (12) 2085-91.e1
• 50 Chalasani N, Abdelmalek MF, Garcia-Tsao G. et al; Belapectin (GR-MD-02) Study Investigators. Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension. Gastroenterology 2020; 158 (05) 1334-1345.e5
• 51 Regev A, Palmer M, Avigan MI. et al. Consensus: guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2019; 49 (06) 702-713
• 52 Nguyen Pv. Electronic health records may threaten blinding in trials of statins. BMJ 2014; 349 (10) g5239
• 53 Ledford H. How Facebook and Twitter could be the next disruptive force in clinical trials. Nature 2018; 563 (7731): 312-315
• 54 Zeuzem S, Jacobson IM, Baykal T. et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370 (17) 1604-1614
• 55 Zeuzem S, Dusheiko GM, Salupere R. et al; VALENCE Investigators. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014; 370 (21) 1993-2001
• 56 Afdhal N, Reddy KR, Nelson DR. et al; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370 (16) 1483-1493
• 57 Kowdley KV, Gordon SC, Reddy KR. et al; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370 (20) 1879-1888
• 58 Sulkowski MS, Gardiner DF, Rodriguez-Torres M. et al; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370 (03) 211-221
• 59 Feld JJ, Kowdley KV, Coakley E. et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370 (17) 1594-1603
• 60 Sulkowski M, Hezode C, Gerstoft J. et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. Lancet 2015; 385 (9973): 1087-1097
• 61 Rockstroh JK, Nelson M, Katlama C. et al. Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. Lancet HIV 2015; 2 (08) e319-e327
• 62 Feld JJ, Jacobson IM, Hézode C. et al; ASTRAL-1 Investigators. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015; 373 (27) 2599-2607
• 63 Foster GR, Afdhal N, Roberts SK. et al; ASTRAL-2 Investigators, ASTRAL-3 Investigators. Sofosbuvir and velpatasvir for HCV Genotype 2 and 3 infection. N Engl J Med 2015; 373 (27) 2608-2617
• 64 Curry MP, O'Leary JG, Bzowej N. et al; ASTRAL-4 Investigators. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med 2015; 373 (27) 2618-2628
• 65 Lawitz E, Poordad F, Wells J. et al. Sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin in direct-acting antiviral-experienced patients with genotype 1 hepatitis C virus. Hepatology 2017; 65 (06) 1803-1809
• 66 Bourlière M, Gordon SC, Flamm SL. et al; POLARIS-1 and POLARIS-4 Investigators. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 2017; 376 (22) 2134-2146
• 67 Hadziyannis SJ, Tassopoulos NC, Heathcote EJ. et al; Adefovir Dipivoxil 438 Study Group. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 2005; 352 (26) 2673-2681
• 68 Younossi ZM, Ratziu V, Loomba R. et al; REGENERATE Study Investigators. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2019; 394 (10215): 2184-2196
• 69 Armstrong MJ, Gaunt P, Aithal GP. et al; LEAN Trial Team. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016; 387 (10019): 679-690