In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores

Jeffrey B. Schwimmer, Joel E. Lavine, Laura A. Wilson, Brent A. Neuschwander-Tetri, Stavra A. Xanthakos, Rohit Kohli, Sarah E. Barlow, Miriam B. Vos, Saul J. Karpen, Jean P. Molleston, Peter F. Whitington, Philip Rosenthal, Ajay K. Jain, Karen F. Murray, Elizabeth M. Brunt, David E. Kleiner, Mark L. Van Natta, Jeanne M. Clark, James Tonascia, Edward Doo & 106 others Stephanie H. Abrams, Sarah Barlow, Ryan Himes, Rajesh Krisnamurthy, Leanel Maldonado, Rory Mahabir, Kimberlee Bernstein, Kristin Bramlage, Kim Cecil, Stephanie DeVore, Rohit Kohli, Kathleen Lake, Daniel Podberesky, Alex Towbin, Stavra Xanthakos, Gerald Behr, Joel E. Lavine, Jay H. Lefkowitch, Ali Mencin, Elena Reynoso, Adina Alazraki, Rebecca Cleeton, Saul Karpen, Jessica Cruz Munos, Nicholas Raviele, Miriam Vos, Molly Bozic, Oscar W. Cummings, Ann Klipsch, Jean P. Molleston, Sarah Munson, Kumar Sandrasegaran, Girish Subbarao, Kimberly Kafka, Ann Scheimann, Katie Amsden, Mark H. Fishbein, Elizabeth Kirwan, Saeed Mohammad, Cynthia Rigsby, Lisa Sharda, Peter F. Whitington, Sarah Barlow, Jose Derdoy, Ajay Jain, Debra King, Pat Osmack, Joan Siegner, Susan Stewart, Susan Torretta, Kristina Wriston, Susan S. Baker, Lixin Zhu, Jonathon Africa, Jorge Angeles, Sandra Arroyo, Hannah Awai, Cynthia Behling, Craig Bross, Janis Durelle, Michael Middleton, Kimberly Newton, Melissa Paiz, Jennifer Sanford, Jeffrey B. Schwimmer, Claude Sirlin, Patricia Ugalde-Nicalo, Mariana Dominguez Villarreal, Bradley Aouizerat, Jesse Courtier, Linda D. Ferrell, Shannon Fleck, Ryan Gill, Camille Langlois, Emily Rothbaum Perito, Philip Rosenthal, Patrika Tsai, Kara Cooper, Simon Horslen, Evelyn Hsu, Karen Murray, Randolph Otto, Matthew Yeh, Melissa Young, Elizabeth M. Brunt, Kathryn Fowler, David E. Kleiner, Sherry Brown, Edward C. Doo, Jay H. Hoofnagle, Patricia R. Robuck, Averell Sherker, Rebecca Torrance, Patricia Belt, Jeanne M. Clark, Michele Donithan, Erin Hallinan, Milana Isaacson, Kevin P. May, Laura Miriel, Alice Sternberg, James Tonascia, Mark Van Natta, Ivana Vaughn, Laura Wilson, Katherine Yates

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background & Aims No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. Methods We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran–Mantel–Haenszel analysis. Results There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8–2.1; P =.34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P =.02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P =.008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1–2.9; P =.03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3–12.3; P =.005). Conclusions In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.

Original languageEnglish (US)
Pages (from-to)1141-1154.e9
JournalGastroenterology
Volume151
Issue number6
DOIs
StatePublished - Dec 1 2016

Fingerprint

Cysteamine
Placebos
Liver
Enzymes
Confidence Intervals
Transaminases
Non-alcoholic Fatty Liver Disease
Inflammation
Intention to Treat Analysis
Aspartate Aminotransferases
Liver Diseases
Histology
Fibrosis
Randomized Controlled Trials
Biopsy

Keywords

  • ALT
  • AST
  • Obesity
  • Pediatrics

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Schwimmer, J. B., Lavine, J. E., Wilson, L. A., Neuschwander-Tetri, B. A., Xanthakos, S. A., Kohli, R., ... Yates, K. (2016). In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores. Gastroenterology, 151(6), 1141-1154.e9. https://doi.org/10.1053/j.gastro.2016.08.027

In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores. / Schwimmer, Jeffrey B.; Lavine, Joel E.; Wilson, Laura A.; Neuschwander-Tetri, Brent A.; Xanthakos, Stavra A.; Kohli, Rohit; Barlow, Sarah E.; Vos, Miriam B.; Karpen, Saul J.; Molleston, Jean P.; Whitington, Peter F.; Rosenthal, Philip; Jain, Ajay K.; Murray, Karen F.; Brunt, Elizabeth M.; Kleiner, David E.; Van Natta, Mark L.; Clark, Jeanne M.; Tonascia, James; Doo, Edward; Abrams, Stephanie H.; Barlow, Sarah; Himes, Ryan; Krisnamurthy, Rajesh; Maldonado, Leanel; Mahabir, Rory; Bernstein, Kimberlee; Bramlage, Kristin; Cecil, Kim; DeVore, Stephanie; Kohli, Rohit; Lake, Kathleen; Podberesky, Daniel; Towbin, Alex; Xanthakos, Stavra; Behr, Gerald; Lavine, Joel E.; Lefkowitch, Jay H.; Mencin, Ali; Reynoso, Elena; Alazraki, Adina; Cleeton, Rebecca; Karpen, Saul; Cruz Munos, Jessica; Raviele, Nicholas; Vos, Miriam; Bozic, Molly; Cummings, Oscar W.; Klipsch, Ann; Molleston, Jean P.; Munson, Sarah; Sandrasegaran, Kumar; Subbarao, Girish; Kafka, Kimberly; Scheimann, Ann; Amsden, Katie; Fishbein, Mark H.; Kirwan, Elizabeth; Mohammad, Saeed; Rigsby, Cynthia; Sharda, Lisa; Whitington, Peter F.; Barlow, Sarah; Derdoy, Jose; Jain, Ajay; King, Debra; Osmack, Pat; Siegner, Joan; Stewart, Susan; Torretta, Susan; Wriston, Kristina; Baker, Susan S.; Zhu, Lixin; Africa, Jonathon; Angeles, Jorge; Arroyo, Sandra; Awai, Hannah; Behling, Cynthia; Bross, Craig; Durelle, Janis; Middleton, Michael; Newton, Kimberly; Paiz, Melissa; Sanford, Jennifer; Schwimmer, Jeffrey B.; Sirlin, Claude; Ugalde-Nicalo, Patricia; Villarreal, Mariana Dominguez; Aouizerat, Bradley; Courtier, Jesse; Ferrell, Linda D.; Fleck, Shannon; Gill, Ryan; Langlois, Camille; Perito, Emily Rothbaum; Rosenthal, Philip; Tsai, Patrika; Cooper, Kara; Horslen, Simon; Hsu, Evelyn; Murray, Karen; Otto, Randolph; Yeh, Matthew; Young, Melissa; Brunt, Elizabeth M.; Fowler, Kathryn; Kleiner, David E.; Brown, Sherry; Doo, Edward C.; Hoofnagle, Jay H.; Robuck, Patricia R.; Sherker, Averell; Torrance, Rebecca; Belt, Patricia; Clark, Jeanne M.; Donithan, Michele; Hallinan, Erin; Isaacson, Milana; May, Kevin P.; Miriel, Laura; Sternberg, Alice; Tonascia, James; Van Natta, Mark; Vaughn, Ivana; Wilson, Laura; Yates, Katherine.

In: Gastroenterology, Vol. 151, No. 6, 01.12.2016, p. 1141-1154.e9.

Research output: Contribution to journalArticle

Schwimmer, JB, Lavine, JE, Wilson, LA, Neuschwander-Tetri, BA, Xanthakos, SA, Kohli, R, Barlow, SE, Vos, MB, Karpen, SJ, Molleston, JP, Whitington, PF, Rosenthal, P, Jain, AK, Murray, KF, Brunt, EM, Kleiner, DE, Van Natta, ML, Clark, JM, Tonascia, J, Doo, E, Abrams, SH, Barlow, S, Himes, R, Krisnamurthy, R, Maldonado, L, Mahabir, R, Bernstein, K, Bramlage, K, Cecil, K, DeVore, S, Kohli, R, Lake, K, Podberesky, D, Towbin, A, Xanthakos, S, Behr, G, Lavine, JE, Lefkowitch, JH, Mencin, A, Reynoso, E, Alazraki, A, Cleeton, R, Karpen, S, Cruz Munos, J, Raviele, N, Vos, M, Bozic, M, Cummings, OW, Klipsch, A, Molleston, JP, Munson, S, Sandrasegaran, K, Subbarao, G, Kafka, K, Scheimann, A, Amsden, K, Fishbein, MH, Kirwan, E, Mohammad, S, Rigsby, C, Sharda, L, Whitington, PF, Barlow, S, Derdoy, J, Jain, A, King, D, Osmack, P, Siegner, J, Stewart, S, Torretta, S, Wriston, K, Baker, SS, Zhu, L, Africa, J, Angeles, J, Arroyo, S, Awai, H, Behling, C, Bross, C, Durelle, J, Middleton, M, Newton, K, Paiz, M, Sanford, J, Schwimmer, JB, Sirlin, C, Ugalde-Nicalo, P, Villarreal, MD, Aouizerat, B, Courtier, J, Ferrell, LD, Fleck, S, Gill, R, Langlois, C, Perito, ER, Rosenthal, P, Tsai, P, Cooper, K, Horslen, S, Hsu, E, Murray, K, Otto, R, Yeh, M, Young, M, Brunt, EM, Fowler, K, Kleiner, DE, Brown, S, Doo, EC, Hoofnagle, JH, Robuck, PR, Sherker, A, Torrance, R, Belt, P, Clark, JM, Donithan, M, Hallinan, E, Isaacson, M, May, KP, Miriel, L, Sternberg, A, Tonascia, J, Van Natta, M, Vaughn, I, Wilson, L & Yates, K 2016, 'In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores', Gastroenterology, vol. 151, no. 6, pp. 1141-1154.e9. https://doi.org/10.1053/j.gastro.2016.08.027
Schwimmer, Jeffrey B. ; Lavine, Joel E. ; Wilson, Laura A. ; Neuschwander-Tetri, Brent A. ; Xanthakos, Stavra A. ; Kohli, Rohit ; Barlow, Sarah E. ; Vos, Miriam B. ; Karpen, Saul J. ; Molleston, Jean P. ; Whitington, Peter F. ; Rosenthal, Philip ; Jain, Ajay K. ; Murray, Karen F. ; Brunt, Elizabeth M. ; Kleiner, David E. ; Van Natta, Mark L. ; Clark, Jeanne M. ; Tonascia, James ; Doo, Edward ; Abrams, Stephanie H. ; Barlow, Sarah ; Himes, Ryan ; Krisnamurthy, Rajesh ; Maldonado, Leanel ; Mahabir, Rory ; Bernstein, Kimberlee ; Bramlage, Kristin ; Cecil, Kim ; DeVore, Stephanie ; Kohli, Rohit ; Lake, Kathleen ; Podberesky, Daniel ; Towbin, Alex ; Xanthakos, Stavra ; Behr, Gerald ; Lavine, Joel E. ; Lefkowitch, Jay H. ; Mencin, Ali ; Reynoso, Elena ; Alazraki, Adina ; Cleeton, Rebecca ; Karpen, Saul ; Cruz Munos, Jessica ; Raviele, Nicholas ; Vos, Miriam ; Bozic, Molly ; Cummings, Oscar W. ; Klipsch, Ann ; Molleston, Jean P. ; Munson, Sarah ; Sandrasegaran, Kumar ; Subbarao, Girish ; Kafka, Kimberly ; Scheimann, Ann ; Amsden, Katie ; Fishbein, Mark H. ; Kirwan, Elizabeth ; Mohammad, Saeed ; Rigsby, Cynthia ; Sharda, Lisa ; Whitington, Peter F. ; Barlow, Sarah ; Derdoy, Jose ; Jain, Ajay ; King, Debra ; Osmack, Pat ; Siegner, Joan ; Stewart, Susan ; Torretta, Susan ; Wriston, Kristina ; Baker, Susan S. ; Zhu, Lixin ; Africa, Jonathon ; Angeles, Jorge ; Arroyo, Sandra ; Awai, Hannah ; Behling, Cynthia ; Bross, Craig ; Durelle, Janis ; Middleton, Michael ; Newton, Kimberly ; Paiz, Melissa ; Sanford, Jennifer ; Schwimmer, Jeffrey B. ; Sirlin, Claude ; Ugalde-Nicalo, Patricia ; Villarreal, Mariana Dominguez ; Aouizerat, Bradley ; Courtier, Jesse ; Ferrell, Linda D. ; Fleck, Shannon ; Gill, Ryan ; Langlois, Camille ; Perito, Emily Rothbaum ; Rosenthal, Philip ; Tsai, Patrika ; Cooper, Kara ; Horslen, Simon ; Hsu, Evelyn ; Murray, Karen ; Otto, Randolph ; Yeh, Matthew ; Young, Melissa ; Brunt, Elizabeth M. ; Fowler, Kathryn ; Kleiner, David E. ; Brown, Sherry ; Doo, Edward C. ; Hoofnagle, Jay H. ; Robuck, Patricia R. ; Sherker, Averell ; Torrance, Rebecca ; Belt, Patricia ; Clark, Jeanne M. ; Donithan, Michele ; Hallinan, Erin ; Isaacson, Milana ; May, Kevin P. ; Miriel, Laura ; Sternberg, Alice ; Tonascia, James ; Van Natta, Mark ; Vaughn, Ivana ; Wilson, Laura ; Yates, Katherine. / In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores. In: Gastroenterology. 2016 ; Vol. 151, No. 6. pp. 1141-1154.e9.
@article{551c8a08a38345f38ad4c0c32ee4a56b,
title = "In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores",
abstract = "Background & Aims No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. Methods We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran–Mantel–Haenszel analysis. Results There was no significant difference between groups in the primary outcome (28{\%} of children in the CBDR group vs 22{\%} in the placebo group; RR, 1.3; 95{\%} confidence interval [CI], 0.8–2.1; P =.34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P =.02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P =.008), and a larger proportion had reduced lobular inflammation (36{\%} in the CBDR group vs 21{\%} in the placebo group; RR, 1.8; 95{\%} CI, 1.1–2.9; P =.03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50{\%} of children in the CBDR group vs 13{\%} in the placebo group; RR, 4.0; 95{\%} CI, 1.3–12.3; P =.005). Conclusions In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.",
keywords = "ALT, AST, Obesity, Pediatrics",
author = "Schwimmer, {Jeffrey B.} and Lavine, {Joel E.} and Wilson, {Laura A.} and Neuschwander-Tetri, {Brent A.} and Xanthakos, {Stavra A.} and Rohit Kohli and Barlow, {Sarah E.} and Vos, {Miriam B.} and Karpen, {Saul J.} and Molleston, {Jean P.} and Whitington, {Peter F.} and Philip Rosenthal and Jain, {Ajay K.} and Murray, {Karen F.} and Brunt, {Elizabeth M.} and Kleiner, {David E.} and {Van Natta}, {Mark L.} and Clark, {Jeanne M.} and James Tonascia and Edward Doo and Abrams, {Stephanie H.} and Sarah Barlow and Ryan Himes and Rajesh Krisnamurthy and Leanel Maldonado and Rory Mahabir and Kimberlee Bernstein and Kristin Bramlage and Kim Cecil and Stephanie DeVore and Rohit Kohli and Kathleen Lake and Daniel Podberesky and Alex Towbin and Stavra Xanthakos and Gerald Behr and Lavine, {Joel E.} and Lefkowitch, {Jay H.} and Ali Mencin and Elena Reynoso and Adina Alazraki and Rebecca Cleeton and Saul Karpen and {Cruz Munos}, Jessica and Nicholas Raviele and Miriam Vos and Molly Bozic and Cummings, {Oscar W.} and Ann Klipsch and Molleston, {Jean P.} and Sarah Munson and Kumar Sandrasegaran and Girish Subbarao and Kimberly Kafka and Ann Scheimann and Katie Amsden and Fishbein, {Mark H.} and Elizabeth Kirwan and Saeed Mohammad and Cynthia Rigsby and Lisa Sharda and Whitington, {Peter F.} and Sarah Barlow and Jose Derdoy and Ajay Jain and Debra King and Pat Osmack and Joan Siegner and Susan Stewart and Susan Torretta and Kristina Wriston and Baker, {Susan S.} and Lixin Zhu and Jonathon Africa and Jorge Angeles and Sandra Arroyo and Hannah Awai and Cynthia Behling and Craig Bross and Janis Durelle and Michael Middleton and Kimberly Newton and Melissa Paiz and Jennifer Sanford and Schwimmer, {Jeffrey B.} and Claude Sirlin and Patricia Ugalde-Nicalo and Villarreal, {Mariana Dominguez} and Bradley Aouizerat and Jesse Courtier and Ferrell, {Linda D.} and Shannon Fleck and Ryan Gill and Camille Langlois and Perito, {Emily Rothbaum} and Philip Rosenthal and Patrika Tsai and Kara Cooper and Simon Horslen and Evelyn Hsu and Karen Murray and Randolph Otto and Matthew Yeh and Melissa Young and Brunt, {Elizabeth M.} and Kathryn Fowler and Kleiner, {David E.} and Sherry Brown and Doo, {Edward C.} and Hoofnagle, {Jay H.} and Robuck, {Patricia R.} and Averell Sherker and Rebecca Torrance and Patricia Belt and Clark, {Jeanne M.} and Michele Donithan and Erin Hallinan and Milana Isaacson and May, {Kevin P.} and Laura Miriel and Alice Sternberg and James Tonascia and {Van Natta}, Mark and Ivana Vaughn and Laura Wilson and Katherine Yates",
year = "2016",
month = "12",
day = "1",
doi = "10.1053/j.gastro.2016.08.027",
language = "English (US)",
volume = "151",
pages = "1141--1154.e9",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "6",

}

TY - JOUR

T1 - In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores

AU - Schwimmer, Jeffrey B.

AU - Lavine, Joel E.

AU - Wilson, Laura A.

AU - Neuschwander-Tetri, Brent A.

AU - Xanthakos, Stavra A.

AU - Kohli, Rohit

AU - Barlow, Sarah E.

AU - Vos, Miriam B.

AU - Karpen, Saul J.

AU - Molleston, Jean P.

AU - Whitington, Peter F.

AU - Rosenthal, Philip

AU - Jain, Ajay K.

AU - Murray, Karen F.

AU - Brunt, Elizabeth M.

AU - Kleiner, David E.

AU - Van Natta, Mark L.

AU - Clark, Jeanne M.

AU - Tonascia, James

AU - Doo, Edward

AU - Abrams, Stephanie H.

AU - Barlow, Sarah

AU - Himes, Ryan

AU - Krisnamurthy, Rajesh

AU - Maldonado, Leanel

AU - Mahabir, Rory

AU - Bernstein, Kimberlee

AU - Bramlage, Kristin

AU - Cecil, Kim

AU - DeVore, Stephanie

AU - Kohli, Rohit

AU - Lake, Kathleen

AU - Podberesky, Daniel

AU - Towbin, Alex

AU - Xanthakos, Stavra

AU - Behr, Gerald

AU - Lavine, Joel E.

AU - Lefkowitch, Jay H.

AU - Mencin, Ali

AU - Reynoso, Elena

AU - Alazraki, Adina

AU - Cleeton, Rebecca

AU - Karpen, Saul

AU - Cruz Munos, Jessica

AU - Raviele, Nicholas

AU - Vos, Miriam

AU - Bozic, Molly

AU - Cummings, Oscar W.

AU - Klipsch, Ann

AU - Molleston, Jean P.

AU - Munson, Sarah

AU - Sandrasegaran, Kumar

AU - Subbarao, Girish

AU - Kafka, Kimberly

AU - Scheimann, Ann

AU - Amsden, Katie

AU - Fishbein, Mark H.

AU - Kirwan, Elizabeth

AU - Mohammad, Saeed

AU - Rigsby, Cynthia

AU - Sharda, Lisa

AU - Whitington, Peter F.

AU - Barlow, Sarah

AU - Derdoy, Jose

AU - Jain, Ajay

AU - King, Debra

AU - Osmack, Pat

AU - Siegner, Joan

AU - Stewart, Susan

AU - Torretta, Susan

AU - Wriston, Kristina

AU - Baker, Susan S.

AU - Zhu, Lixin

AU - Africa, Jonathon

AU - Angeles, Jorge

AU - Arroyo, Sandra

AU - Awai, Hannah

AU - Behling, Cynthia

AU - Bross, Craig

AU - Durelle, Janis

AU - Middleton, Michael

AU - Newton, Kimberly

AU - Paiz, Melissa

AU - Sanford, Jennifer

AU - Schwimmer, Jeffrey B.

AU - Sirlin, Claude

AU - Ugalde-Nicalo, Patricia

AU - Villarreal, Mariana Dominguez

AU - Aouizerat, Bradley

AU - Courtier, Jesse

AU - Ferrell, Linda D.

AU - Fleck, Shannon

AU - Gill, Ryan

AU - Langlois, Camille

AU - Perito, Emily Rothbaum

AU - Rosenthal, Philip

AU - Tsai, Patrika

AU - Cooper, Kara

AU - Horslen, Simon

AU - Hsu, Evelyn

AU - Murray, Karen

AU - Otto, Randolph

AU - Yeh, Matthew

AU - Young, Melissa

AU - Brunt, Elizabeth M.

AU - Fowler, Kathryn

AU - Kleiner, David E.

AU - Brown, Sherry

AU - Doo, Edward C.

AU - Hoofnagle, Jay H.

AU - Robuck, Patricia R.

AU - Sherker, Averell

AU - Torrance, Rebecca

AU - Belt, Patricia

AU - Clark, Jeanne M.

AU - Donithan, Michele

AU - Hallinan, Erin

AU - Isaacson, Milana

AU - May, Kevin P.

AU - Miriel, Laura

AU - Sternberg, Alice

AU - Tonascia, James

AU - Van Natta, Mark

AU - Vaughn, Ivana

AU - Wilson, Laura

AU - Yates, Katherine

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Background & Aims No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. Methods We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran–Mantel–Haenszel analysis. Results There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8–2.1; P =.34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P =.02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P =.008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1–2.9; P =.03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3–12.3; P =.005). Conclusions In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.

AB - Background & Aims No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. Methods We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran–Mantel–Haenszel analysis. Results There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8–2.1; P =.34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P =.02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P =.008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1–2.9; P =.03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3–12.3; P =.005). Conclusions In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.

KW - ALT

KW - AST

KW - Obesity

KW - Pediatrics

UR - http://www.scopus.com/inward/record.url?scp=84997079995&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84997079995&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2016.08.027

DO - 10.1053/j.gastro.2016.08.027

M3 - Article

VL - 151

SP - 1141-1154.e9

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 6

ER -