Treatment of nonalcoholic fatty liver disease in children: TONIC trial design

Contemporary Clinical Trials

Volumn 31, Issue 1, 2010, Pages 62-70

  Lavine, Joel E ^a   Schwimmer, Jeffrey B ^a   Molleston, Jean P ^b   Scheimann, Ann O ^c,m   Murray, Karen F ^d,o   Abrams, Stephanie H ^e   Rosenthal, Philip ^f   Sanyal, Arun J ^g   Robuck, Patricia R ^h   Brunt, Elizabeth M ^i,n   Ünalp, Aynur ^j   Tonascia, James ^j   Bringman, Diane ^k   Dasarathy, Srinivasan ^k   Feldstein, Ariel ^k   Hawkins, Carol ^k   Liu, Yao Chang ^k   McCullough, Arthur ^k   Sargent, Ruth ^k   Stager, Margaret ^k   Abdelmalek, Manal ^l   DIehl, Anna Mae ^l   Gottfried, Marcia ^l   Guy, Cynthia ^l   Killenberg, Paul ^l   Kwan, Samantha ^l   Pan, Yi Ping ^l   Piercy, Dawn ^l   Smith, Melissa ^l   Pfeifer, Kimberly ^m   Torbenson, Michael ^m   Bhimalli, Prajakta ^b   Byam, Elizabeth ^b   Chalasani, Naga ^b   Cummings, Oscar W ^b   Klipsch, Ann ^b   Lee, Lydia ^b   Ragozzino, Linda ^b   Subbarao, Girish ^b   Vuppalanchi, Raj ^b   Barlow, Sarah ⁿ   Derdoy, Jose ⁿ   Hoffmann, Joyce ⁿ   King, Debra ⁿ   Siegner, Joan ⁿ   Stewart, Susan ⁿ   Neuschwander Tetri, Brent A ⁿ   Thompson, Judy ⁿ   Arceo, Diana ^e   Espinosa, Denise ^e   Fairly, Leanel Angeli ^e   Behling, Cynthia ^a   Clark, Lisa ^a   Durelle, Janis ^a   Hassanein, Tarek ^a   Mendoza, Susana ^a   Parman, Zana ^a   Patton, Heather ^a   Sirlin, Claude ^a   Stein, Tanya ^a   Palomares, Zobeida ^a   Bambha, Kiran ^f   Bass, Nathan M ^f   Ferrell, Linda D ^f   Filipowski, Danuta ^f   Merriman, Raphael ^f   Pabst, Mark ^f   Rosenthal, Monique ^f   Steel, Tessa ^f   Coffey, Melissa ^o   Kowdley, Kris V ^o   Mooney, Jody ^o   Nelson, James ^o   Saunders, Cheryl ^o   Yeh, Matthew ^o   Young, Melissa ^o   Boyett, Sherry ^g   Bryan, Daphne ^g   Contos, Melissa J ^g   Fuchs, Michael ^g   Jones, Amy ^g   Luketic, Velimir A C ^g   Sandhu, Bimalijit ^g   Sargeant, Carol ^g   White, Melanie ^g   Mohan, Parvathi ^p   Nair, Kavita ^p   Kleiner, David E ^q   Doo, Edward ^h   Hoofnagle, Jay ^h   Huang, Terry T K ^r   Belt, Pat ^j   Brancati, Fred ^j   Clark, Jeanne ^j   Colvin, Ryan ^j   Donithan, Michele ^j   Green, Mika ^j   Hollick, Rosemary ^j   Isaacson, Milana ^j   Kim, Wana ^j   Lydecker, Alison ^j   Mann, Pamela ^j   Miriel, Laura ^j   Sternberg, Alice ^j   Ünalp Arida, Aynur ^j   Van Natta, Mark ^j   Wilson, Laura ^j   Yates, Kathie ^j   more..

^a UNIVERSITY OF CALIFORNIA   (United States)

^b INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c JOHNS HOPKINS HOSPITAL   (United States)

^d Seattle Children's   (United States)

^e BAYLOR COLLEGE OF MEDICINE   (United States)

^f UNIVERSITY OF CALIFORNIA   (United States)

^g VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

^h NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES   (United States)

ⁱ WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^j JOHNS HOPKINS BLOOMBERG SCHOOL OF PUBLIC HEALTH   (United States)

^k CASE WESTERN RESERVE UNIVERSITY   (United States)

^l DUKE UNIVERSITY MEDICAL CENTER   (United States)

^m JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

ⁿ SAINT LOUIS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^o UNIVERSITY OF WASHINGTON MEDICAL CENTER   (United States)

^p CHILDREN'S NATIONAL MEDICAL CENTER   (United States)

^q NATIONAL CANCER INSTITUTE   (United States)

^r EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT   (United States)

more..

Author keywords

Children; Metformin; Nonalcoholic fatty liver; Nonalcoholic steatohepatitis; Randomized controlled trial; RRR tocopherol; Vitamin E

Indexed keywords

ALANINE AMINOTRANSFERASE; ALPHA TOCOPHEROL; METFORMIN; NATURE MADE; PLACEBO; UNCLASSIFIED DRUG;

ADOLESCENT; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ARTICLE; CHILD; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; FATTY LIVER; FEMALE; HEPATITIS; HUMAN; LIVER BIOPSY; LIVER CELL DAMAGE; LIVER FIBROSIS; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; NONALCOHOLIC FATTY LIVER; RANDOMIZED CONTROLLED TRIAL; SCHOOL CHILD; TREATMENT DURATION; TREATMENT OUTCOME;

EID: 73049090978     PISSN: 15517144     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.cct.2009.09.001     Document Type: Article

References (52)

1. Ludwig J., Viggiano T.R., McGill D.B., and Oh B.J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55 (1980) 434-438
2. Lavine J.E., and Schwimmer J.B. Pediatric non-alcoholic steatohepatitis. In: Farrell G., George J., Hall P., and McCollough A. (Eds). Non-alcoholic steatohepatitis (2004), Blackwell Publishing, Oxford, England 229-240
3. Schwimmer J.B., Behling C., Newbury R., Deutsch R., Nievergelt C., Schork N.J., et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 42 (2005) 641-648
4. Schwimmer J.B., Deutsch R., Kahen T., Lavine J.E., Stanley C., and Behling C. Prevalence of fatty liver disease in children and adolescents. Pediatrics 118 (2006) 1388-1393
5. Fraser A., Longnecker M.P., and Lawlor D.A. Prevalence of elevated alanine transaminase among US adolescents and associated factors: NHANES 1999-2004. Gastroenterology 133 (2007) 1814-1820
6. Moran J.R., Ghishan F.K., Halter S.A., and Greene H.L. Steatohepatitis in obese children: a cause of chronic liver dysfunction. Am J Gastroenterol 78 (1983) 374-377
7. Kinugasa A., Tsunamoto K., Furukawa N., Sawada T., Kusunoki T., and Shimada N. Fatty liver and its fibrous changes found in simple obesity of children. J Pediatr Gastroenterol Nutr 3 (1984) 408-414
8. Baldridge A.D., Perez-Atayde A.R., Graeme-Cook F., Higgins L., and Lavine J.E. Idiopathic steatohepatitis in childhood: a multicenter retrospective study. J Pediatr 127 (1995) 700-704
9. Schwimmer J.B., Deutsch R., Rauch J.B., Behling C., Newbury R., and Lavine J.E. Obesity, insulin resistance, and other clinicopathological correlations of pediatric nonalcoholic fatty liver disease. J Pediatr 143 (2003) 500-505
10. Rashid M., and Roberts E.A. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 30 (2000) 48-453
11. Manton N.D., Lipsett J., Moore D.J., Davidson G.P., Bourne A.J., and Couper R.T. Non-alcoholic steatohepatitis in children and adolescents. Med J Aust 173 (2000) 476-479
12. Vajro P., Fontanella A., Perna C., Orso G., Pedesco M., and De Vincenzo A. Persistent hyperaminotransferasemia resolving after weight reduction in obese children. J Pediatr 125 (1994) 239-241
13. Molleston J.P., White F., Teckman J., and Fitzgerald J.F. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol 97 (2002) 2460-2462
14. Ogden C.L., Flegal K.M., Carroll M.D., and Johnson C.L. Prevalence and trends in overweight among US children and adolescents, 1999-2000. JAMA 288 (2002) 1728-1732
15. Ogden C.L., Carroll M.D., Curtin L.R., McDowell M.A., Tabak C.J., and Flegal K.M. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 295 (2006) 1549-1555
16. Dunn W., and Schwimmer J.B. The obesity epidemic and nonalcoholic fatty liver disease in children. Curr Gastroenterol Rep 10 (2008) 67-72
17. Mofrad P., Contos M.J., Haque M., Sargeant C., Fisher R.A., Luketic V.A., et al. Clinical and histologic spectrum of non-alcoholic fatty liver disease associated with normal ALT values. Hepatology 37 (2003) 1286-1292
18. Falck-Ytter Y., Younossi Z.M., Marchesini G., and McCullough A.J. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis 21 (2001) 17-26
19. Suzuki D., Hashimoto E., Kaneda K., Tokushige K., and Shiratori K. Liver failure caused by non-alcoholic steatohepatitis in an obese young male. J Gastroenterol Hepatol 20 (2005) 327-329
20. Matteoni C.A., Younossi Z.M., Gramlich T., Boparai N., Liu Y.C., and McCullough A.J. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 116 (1999) 1413-1419
21. Adams L.A., Lymp J.F., and St. Sauver J. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129 (2005) 113-121
22. Dam-Larsen S., Franzmann M., Andersen I.B., Christoffersen P., Jensen L.B., Sørensen T.I., et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 53 (2004) 750-755
23. Day C.P., and James O.F. Steatohepatitis: a tale of two "hits". Gastroenterology 114 (1998) 842-845
24. Chitturi S., and Farrell G.C. Etiopathogenesis of nonalcoholic steatohepatitis. Semin Liver Dis 21 (2001) 27-41
25. Marchesini G., Brizi M., Morselli-Labate A.M., Bianchi G., Bugianesi E., McCullough A.J., et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 107 (1999) 450-455
26. Sanyal A.J., Campbell-Sargeant C., Mirshahi F., Rizzo W.B., Contos M.J., Sterling R.K., et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120 (2001) 1183-1192
27. Willner I.R., Waters B., Patil S.R., Reuben A., Morelli J., and Riely C.A. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 96 (2001) 2957-2961
28. Chitturi S., Abeygunasekera S., Farrell G.C., Holmes-Walker J., Hui J.M., Fung C., et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 35 (2002) 373-379
29. Pagano G., Pacini G., Musso G., Gambino R., Mecca F., Depetris N., et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 35 (2002) 367-372
30. Tilg H., and Diehl A.M. Cytokines in alcoholic and nonalcoholic steatohepatitis. New Engl J Med 343 (2000) 1467-1476
31. Wigg A.J., Robert-Thompson I.C., Dymock R.B., McCarthy P.J., Grose R.H., and Cummins A.G. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumor necrosis factor α in the pathogenesis of non-alcoholic steatohepatitis. Gut 48 (2001) 206-211
32. Weltman M.D., Farrell G.C., Hall P., Ingelman-Sundberg M., and Liddle C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology 27 (1998) 128-133
33. Chalasani N., Gorski J.C., Asghar M.S., Asghar A., Foresman B., Hall S.D., et al. Hepatic cytochrome P450 2E1 activity in non-diabetic patients with non-alcoholic steatohepatitis. Hepatology 37 (2003) 544-550
34. Chalasani N., Deeg M.A., and Crabb D.W. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 99 (2004) 1497-1502
35. Schwimmer J.B., Middleton M.S., Deutsch R., and Lavine J.E. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther 21 (2005) 871-879
36. Lin H.Z., Yang S.Q., Chuckaree C., Kuhajda F., Ronnet G., and Diehl A.M. Metformin reverses the fatty liver disease in obese, leptin deficient mice. Nat Med 6 (2000) 998-1003
37. Lavine J.E. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 136 (2000) 734-738
38. Sanyal A.J., Mofrad P.S., Contos M.J., Sargeant C., Luketic V.A., Sterling R.K., et al. A pilot study of vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2 (2004) 1107-1115
39. Hasegawa T., Yoneda M., Nakamura K., Makino I., and Terano A. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 15 (2001) 1667-1672
40. Harrison S.A., Torgerson S., Hayashi P., Ward J., and Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 98 (2003) 2485-2490
41. Kugelmas M., Hill D.B., Vivian B., Marsano L., and McClain C.J. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 38 (2003) 413-419
42. Phung N., Pera N., Farrell G., Leclercq I., Hou J.Y., and George J. Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis. Int J Mol Med 24 (2009) 171-180
43. Nonalcoholic Steatohepatitis Clinical Research Network. Hepatology 37 (2003) 244-244
44. Lavine J.E., Schwimmer J.B., and for the NASH CRN. Pediatric initiatives within the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). J Pediatr Gastroenterol Nutr 37 (2003) 220-221
45. Kleiner D.E., Brunt E.M., Van Natta M., Behling C., Contos M.J., Cummings O.W., et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41 (2005) 1313-1321
46. Bendich A., and Machlin L.J. Safety of oral intake of vitamin E. Am J Clin Nutr 48 (1988) 612-619
47. Machlin L.J. Use and safety of elevated dosages of vitamin E in adults. Int J Vitam Nutr Res Suppl 30 (1989) 56-68
48. Elashoff J.D. nQuery Advisor 5.0 User's Guide. Los Angeles, CA (2002)
49. Fleming T.R., Harrington D.P., and O'Brien P.C. Designs for group sequential test. Control Clin Trials 5 (1984) 348-361
50. Agresti A. Categorical data analysis. 2nd ed. (2002), John Wiley & Sons, Hoboken, NJ
51. NASH CRN Ancillary Studies Policy can be accessed at http://www.jhucct.com/nash/open/ancillary/ancstudies.htm.
52. TONIC Trial Protocol can be accessed at http://www.jhucct.com/nash/open/studies.htm.