No Difference Between Latiglutenase and Placebo in Reducing Villous Atrophy or Improving Symptoms in Patients With Symptomatic Celiac Disease

Joseph A Murray, Ciarán P. Kelly, Peter H R Green, Annette Marcantonio, Tsung-Teh Wu, Markku Mäki, Daniel C. Adelman, S. Ansari, K. Ayub, A. Basile, C. Behrend, P. Bercik, B. Bressler, V. Byrnes, V. S. Chandan, V. Cheekati, B. Chipps, A. Coates, A. Collatrella, J. CondemiC. Corder, J. Corren, C. Curtis, M. DeMeo, T. Desta, C. Devereaux, A. DiMarino, M. DuPree, C. Ennis, R. Fedorak, R. Fogel, S. Freeman, B. Freilich, K. Friedenberg, D. Geenen, K. Gill, A. Goldsobel, J. Goldstein, M. Goldstein, G. Gordon, R. Hardi, L. Harris, R. Holmes, K. Jagarlamundi, G. James, M. Kaplan, J. Kirstein, A. Knoll, R. Kotfila, R. Krause, A. Kravitz, M. Kreines, M. L. Lähdeaho, M. Lamet, K. Laskin, B. Lebwohl, D. Leffler, S. Lewis, S. Liakos, K. Lundin, K. Marks, K. Merkes, S. Minton, S. Moussa, V. Narayen, V. Nehra, E. Newton, A. Nyberg, J. Oosthuizen, T. Otrok, D. Patel, C. Pepin, R. Phillips, G. Pyle, M. Reichelderfer, B. Reid, T. Ritter, S. Saini, D. Sanders, M. Schulman, C. Semrad, S. Shah, D. Stockwell, C. Strout, D. Suez, H. Tatum, Michael Torbenson, M. Turner, P. Varunok, Maria I Vazquez Roque, A. Vento, T. Welton, R. Wohlman, M. Wood, S. Woods, K. Yousef

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background & Aims Gluten ingestion leads to symptoms and small intestinal mucosal injury in patients with celiac disease. The only option is the strict lifelong exclusion of dietary gluten, which is difficult to accomplish. Many patients following a gluten-free diet continue to have symptoms and have small intestinal mucosal injury. Nondietary therapies are needed. We performed a phase 2 study of the ability of latiglutenase, an orally administered mixture of 2 recombinant gluten-targeting proteases, to reduce mucosal morphometric measures in biopsy specimens from patients with celiac disease. Methods We performed a double-blind, placebo-controlled, dose-ranging study to assess the efficacy and safety of latiglutenase in 494 patients with celiac disease (with moderate or severe symptoms) in North America and Europe, from August 2013 until December 2014. Participants reported following a gluten-free diet for at least 1 year before the study began. Patients with documented moderate or severe symptoms and villous atrophy (villous height:crypt depth ratio of ≤2.0) were assigned randomly to groups given placebo or 100, 300, 450, 600, or 900 mg latiglutenase daily for 12 or 24 weeks. Subjects completed the Celiac Disease Symptom Diary each day for 28 days and underwent an upper gastrointestinal endoscopy with duodenal biopsy of the distal duodenum at baseline and at weeks 12 and 24. The primary end point was a change in the villous height:crypt depth ratio. Secondary end points included numbers of intraepithelial lymphocytes, serology test results (for levels of antibodies against tissue transglutaminase-2 and deamidated gliadin peptide), symptom frequencies, and safety. Results In a modified intent-to-treat population, there were no differences between latiglutenase and placebo groups in change from baseline in villous height:crypt depth ratio, numbers of intraepithelial lymphocytes, or serologic markers of celiac disease. All groups had significant improvements in histologic and symptom scores. Conclusions In a phase 2 study of patients with symptomatic celiac disease and histologic evidence of significant duodenal mucosal injury, latiglutenase did not improve histologic and symptom scores when compared with placebo. There were no significant differences in change from baseline between groups. ClinicalTrials.gov no: NCT01917630.

Original languageEnglish (US)
Pages (from-to)787-798
Number of pages12
JournalGastroenterology
Volume152
Issue number4
DOIs
StatePublished - Mar 1 2017

Fingerprint

Celiac Disease
Atrophy
Placebos
Glutens
Gluten-Free Diet
Lymphocyte Count
Wounds and Injuries
Biopsy
Safety
Gliadin
Gastrointestinal Endoscopy
Serology
North America
Duodenum
Peptide Hydrolases
Eating
Peptides
Antibodies
Population

Keywords

  • Healing
  • Inflammation
  • Pathology
  • Treatment

ASJC Scopus subject areas

  • Gastroenterology

Cite this

No Difference Between Latiglutenase and Placebo in Reducing Villous Atrophy or Improving Symptoms in Patients With Symptomatic Celiac Disease. / Murray, Joseph A; Kelly, Ciarán P.; Green, Peter H R; Marcantonio, Annette; Wu, Tsung-Teh; Mäki, Markku; Adelman, Daniel C.; Ansari, S.; Ayub, K.; Basile, A.; Behrend, C.; Bercik, P.; Bressler, B.; Byrnes, V.; Chandan, V. S.; Cheekati, V.; Chipps, B.; Coates, A.; Collatrella, A.; Condemi, J.; Corder, C.; Corren, J.; Curtis, C.; DeMeo, M.; Desta, T.; Devereaux, C.; DiMarino, A.; DuPree, M.; Ennis, C.; Fedorak, R.; Fogel, R.; Freeman, S.; Freilich, B.; Friedenberg, K.; Geenen, D.; Gill, K.; Goldsobel, A.; Goldstein, J.; Goldstein, M.; Gordon, G.; Hardi, R.; Harris, L.; Holmes, R.; Jagarlamundi, K.; James, G.; Kaplan, M.; Kirstein, J.; Knoll, A.; Kotfila, R.; Krause, R.; Kravitz, A.; Kreines, M.; Lähdeaho, M. L.; Lamet, M.; Laskin, K.; Lebwohl, B.; Leffler, D.; Lewis, S.; Liakos, S.; Lundin, K.; Marks, K.; Merkes, K.; Minton, S.; Moussa, S.; Narayen, V.; Nehra, V.; Newton, E.; Nyberg, A.; Oosthuizen, J.; Otrok, T.; Patel, D.; Pepin, C.; Phillips, R.; Pyle, G.; Reichelderfer, M.; Reid, B.; Ritter, T.; Saini, S.; Sanders, D.; Schulman, M.; Semrad, C.; Shah, S.; Stockwell, D.; Strout, C.; Suez, D.; Tatum, H.; Torbenson, Michael; Turner, M.; Varunok, P.; Vazquez Roque, Maria I; Vento, A.; Welton, T.; Wohlman, R.; Wood, M.; Woods, S.; Yousef, K.

In: Gastroenterology, Vol. 152, No. 4, 01.03.2017, p. 787-798.

Research output: Contribution to journalArticle

Murray, JA, Kelly, CP, Green, PHR, Marcantonio, A, Wu, T-T, Mäki, M, Adelman, DC, Ansari, S, Ayub, K, Basile, A, Behrend, C, Bercik, P, Bressler, B, Byrnes, V, Chandan, VS, Cheekati, V, Chipps, B, Coates, A, Collatrella, A, Condemi, J, Corder, C, Corren, J, Curtis, C, DeMeo, M, Desta, T, Devereaux, C, DiMarino, A, DuPree, M, Ennis, C, Fedorak, R, Fogel, R, Freeman, S, Freilich, B, Friedenberg, K, Geenen, D, Gill, K, Goldsobel, A, Goldstein, J, Goldstein, M, Gordon, G, Hardi, R, Harris, L, Holmes, R, Jagarlamundi, K, James, G, Kaplan, M, Kirstein, J, Knoll, A, Kotfila, R, Krause, R, Kravitz, A, Kreines, M, Lähdeaho, ML, Lamet, M, Laskin, K, Lebwohl, B, Leffler, D, Lewis, S, Liakos, S, Lundin, K, Marks, K, Merkes, K, Minton, S, Moussa, S, Narayen, V, Nehra, V, Newton, E, Nyberg, A, Oosthuizen, J, Otrok, T, Patel, D, Pepin, C, Phillips, R, Pyle, G, Reichelderfer, M, Reid, B, Ritter, T, Saini, S, Sanders, D, Schulman, M, Semrad, C, Shah, S, Stockwell, D, Strout, C, Suez, D, Tatum, H, Torbenson, M, Turner, M, Varunok, P, Vazquez Roque, MI, Vento, A, Welton, T, Wohlman, R, Wood, M, Woods, S & Yousef, K 2017, 'No Difference Between Latiglutenase and Placebo in Reducing Villous Atrophy or Improving Symptoms in Patients With Symptomatic Celiac Disease', Gastroenterology, vol. 152, no. 4, pp. 787-798. https://doi.org/10.1053/j.gastro.2016.11.004
Murray, Joseph A ; Kelly, Ciarán P. ; Green, Peter H R ; Marcantonio, Annette ; Wu, Tsung-Teh ; Mäki, Markku ; Adelman, Daniel C. ; Ansari, S. ; Ayub, K. ; Basile, A. ; Behrend, C. ; Bercik, P. ; Bressler, B. ; Byrnes, V. ; Chandan, V. S. ; Cheekati, V. ; Chipps, B. ; Coates, A. ; Collatrella, A. ; Condemi, J. ; Corder, C. ; Corren, J. ; Curtis, C. ; DeMeo, M. ; Desta, T. ; Devereaux, C. ; DiMarino, A. ; DuPree, M. ; Ennis, C. ; Fedorak, R. ; Fogel, R. ; Freeman, S. ; Freilich, B. ; Friedenberg, K. ; Geenen, D. ; Gill, K. ; Goldsobel, A. ; Goldstein, J. ; Goldstein, M. ; Gordon, G. ; Hardi, R. ; Harris, L. ; Holmes, R. ; Jagarlamundi, K. ; James, G. ; Kaplan, M. ; Kirstein, J. ; Knoll, A. ; Kotfila, R. ; Krause, R. ; Kravitz, A. ; Kreines, M. ; Lähdeaho, M. L. ; Lamet, M. ; Laskin, K. ; Lebwohl, B. ; Leffler, D. ; Lewis, S. ; Liakos, S. ; Lundin, K. ; Marks, K. ; Merkes, K. ; Minton, S. ; Moussa, S. ; Narayen, V. ; Nehra, V. ; Newton, E. ; Nyberg, A. ; Oosthuizen, J. ; Otrok, T. ; Patel, D. ; Pepin, C. ; Phillips, R. ; Pyle, G. ; Reichelderfer, M. ; Reid, B. ; Ritter, T. ; Saini, S. ; Sanders, D. ; Schulman, M. ; Semrad, C. ; Shah, S. ; Stockwell, D. ; Strout, C. ; Suez, D. ; Tatum, H. ; Torbenson, Michael ; Turner, M. ; Varunok, P. ; Vazquez Roque, Maria I ; Vento, A. ; Welton, T. ; Wohlman, R. ; Wood, M. ; Woods, S. ; Yousef, K. / No Difference Between Latiglutenase and Placebo in Reducing Villous Atrophy or Improving Symptoms in Patients With Symptomatic Celiac Disease. In: Gastroenterology. 2017 ; Vol. 152, No. 4. pp. 787-798.
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abstract = "Background & Aims Gluten ingestion leads to symptoms and small intestinal mucosal injury in patients with celiac disease. The only option is the strict lifelong exclusion of dietary gluten, which is difficult to accomplish. Many patients following a gluten-free diet continue to have symptoms and have small intestinal mucosal injury. Nondietary therapies are needed. We performed a phase 2 study of the ability of latiglutenase, an orally administered mixture of 2 recombinant gluten-targeting proteases, to reduce mucosal morphometric measures in biopsy specimens from patients with celiac disease. Methods We performed a double-blind, placebo-controlled, dose-ranging study to assess the efficacy and safety of latiglutenase in 494 patients with celiac disease (with moderate or severe symptoms) in North America and Europe, from August 2013 until December 2014. Participants reported following a gluten-free diet for at least 1 year before the study began. Patients with documented moderate or severe symptoms and villous atrophy (villous height:crypt depth ratio of ≤2.0) were assigned randomly to groups given placebo or 100, 300, 450, 600, or 900 mg latiglutenase daily for 12 or 24 weeks. Subjects completed the Celiac Disease Symptom Diary each day for 28 days and underwent an upper gastrointestinal endoscopy with duodenal biopsy of the distal duodenum at baseline and at weeks 12 and 24. The primary end point was a change in the villous height:crypt depth ratio. Secondary end points included numbers of intraepithelial lymphocytes, serology test results (for levels of antibodies against tissue transglutaminase-2 and deamidated gliadin peptide), symptom frequencies, and safety. Results In a modified intent-to-treat population, there were no differences between latiglutenase and placebo groups in change from baseline in villous height:crypt depth ratio, numbers of intraepithelial lymphocytes, or serologic markers of celiac disease. All groups had significant improvements in histologic and symptom scores. Conclusions In a phase 2 study of patients with symptomatic celiac disease and histologic evidence of significant duodenal mucosal injury, latiglutenase did not improve histologic and symptom scores when compared with placebo. There were no significant differences in change from baseline between groups. ClinicalTrials.gov no: NCT01917630.",
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TY - JOUR

T1 - No Difference Between Latiglutenase and Placebo in Reducing Villous Atrophy or Improving Symptoms in Patients With Symptomatic Celiac Disease

AU - Murray, Joseph A

AU - Kelly, Ciarán P.

AU - Green, Peter H R

AU - Marcantonio, Annette

AU - Wu, Tsung-Teh

AU - Mäki, Markku

AU - Adelman, Daniel C.

AU - Ansari, S.

AU - Ayub, K.

AU - Basile, A.

AU - Behrend, C.

AU - Bercik, P.

AU - Bressler, B.

AU - Byrnes, V.

AU - Chandan, V. S.

AU - Cheekati, V.

AU - Chipps, B.

AU - Coates, A.

AU - Collatrella, A.

AU - Condemi, J.

AU - Corder, C.

AU - Corren, J.

AU - Curtis, C.

AU - DeMeo, M.

AU - Desta, T.

AU - Devereaux, C.

AU - DiMarino, A.

AU - DuPree, M.

AU - Ennis, C.

AU - Fedorak, R.

AU - Fogel, R.

AU - Freeman, S.

AU - Freilich, B.

AU - Friedenberg, K.

AU - Geenen, D.

AU - Gill, K.

AU - Goldsobel, A.

AU - Goldstein, J.

AU - Goldstein, M.

AU - Gordon, G.

AU - Hardi, R.

AU - Harris, L.

AU - Holmes, R.

AU - Jagarlamundi, K.

AU - James, G.

AU - Kaplan, M.

AU - Kirstein, J.

AU - Knoll, A.

AU - Kotfila, R.

AU - Krause, R.

AU - Kravitz, A.

AU - Kreines, M.

AU - Lähdeaho, M. L.

AU - Lamet, M.

AU - Laskin, K.

AU - Lebwohl, B.

AU - Leffler, D.

AU - Lewis, S.

AU - Liakos, S.

AU - Lundin, K.

AU - Marks, K.

AU - Merkes, K.

AU - Minton, S.

AU - Moussa, S.

AU - Narayen, V.

AU - Nehra, V.

AU - Newton, E.

AU - Nyberg, A.

AU - Oosthuizen, J.

AU - Otrok, T.

AU - Patel, D.

AU - Pepin, C.

AU - Phillips, R.

AU - Pyle, G.

AU - Reichelderfer, M.

AU - Reid, B.

AU - Ritter, T.

AU - Saini, S.

AU - Sanders, D.

AU - Schulman, M.

AU - Semrad, C.

AU - Shah, S.

AU - Stockwell, D.

AU - Strout, C.

AU - Suez, D.

AU - Tatum, H.

AU - Torbenson, Michael

AU - Turner, M.

AU - Varunok, P.

AU - Vazquez Roque, Maria I

AU - Vento, A.

AU - Welton, T.

AU - Wohlman, R.

AU - Wood, M.

AU - Woods, S.

AU - Yousef, K.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Background & Aims Gluten ingestion leads to symptoms and small intestinal mucosal injury in patients with celiac disease. The only option is the strict lifelong exclusion of dietary gluten, which is difficult to accomplish. Many patients following a gluten-free diet continue to have symptoms and have small intestinal mucosal injury. Nondietary therapies are needed. We performed a phase 2 study of the ability of latiglutenase, an orally administered mixture of 2 recombinant gluten-targeting proteases, to reduce mucosal morphometric measures in biopsy specimens from patients with celiac disease. Methods We performed a double-blind, placebo-controlled, dose-ranging study to assess the efficacy and safety of latiglutenase in 494 patients with celiac disease (with moderate or severe symptoms) in North America and Europe, from August 2013 until December 2014. Participants reported following a gluten-free diet for at least 1 year before the study began. Patients with documented moderate or severe symptoms and villous atrophy (villous height:crypt depth ratio of ≤2.0) were assigned randomly to groups given placebo or 100, 300, 450, 600, or 900 mg latiglutenase daily for 12 or 24 weeks. Subjects completed the Celiac Disease Symptom Diary each day for 28 days and underwent an upper gastrointestinal endoscopy with duodenal biopsy of the distal duodenum at baseline and at weeks 12 and 24. The primary end point was a change in the villous height:crypt depth ratio. Secondary end points included numbers of intraepithelial lymphocytes, serology test results (for levels of antibodies against tissue transglutaminase-2 and deamidated gliadin peptide), symptom frequencies, and safety. Results In a modified intent-to-treat population, there were no differences between latiglutenase and placebo groups in change from baseline in villous height:crypt depth ratio, numbers of intraepithelial lymphocytes, or serologic markers of celiac disease. All groups had significant improvements in histologic and symptom scores. Conclusions In a phase 2 study of patients with symptomatic celiac disease and histologic evidence of significant duodenal mucosal injury, latiglutenase did not improve histologic and symptom scores when compared with placebo. There were no significant differences in change from baseline between groups. ClinicalTrials.gov no: NCT01917630.

AB - Background & Aims Gluten ingestion leads to symptoms and small intestinal mucosal injury in patients with celiac disease. The only option is the strict lifelong exclusion of dietary gluten, which is difficult to accomplish. Many patients following a gluten-free diet continue to have symptoms and have small intestinal mucosal injury. Nondietary therapies are needed. We performed a phase 2 study of the ability of latiglutenase, an orally administered mixture of 2 recombinant gluten-targeting proteases, to reduce mucosal morphometric measures in biopsy specimens from patients with celiac disease. Methods We performed a double-blind, placebo-controlled, dose-ranging study to assess the efficacy and safety of latiglutenase in 494 patients with celiac disease (with moderate or severe symptoms) in North America and Europe, from August 2013 until December 2014. Participants reported following a gluten-free diet for at least 1 year before the study began. Patients with documented moderate or severe symptoms and villous atrophy (villous height:crypt depth ratio of ≤2.0) were assigned randomly to groups given placebo or 100, 300, 450, 600, or 900 mg latiglutenase daily for 12 or 24 weeks. Subjects completed the Celiac Disease Symptom Diary each day for 28 days and underwent an upper gastrointestinal endoscopy with duodenal biopsy of the distal duodenum at baseline and at weeks 12 and 24. The primary end point was a change in the villous height:crypt depth ratio. Secondary end points included numbers of intraepithelial lymphocytes, serology test results (for levels of antibodies against tissue transglutaminase-2 and deamidated gliadin peptide), symptom frequencies, and safety. Results In a modified intent-to-treat population, there were no differences between latiglutenase and placebo groups in change from baseline in villous height:crypt depth ratio, numbers of intraepithelial lymphocytes, or serologic markers of celiac disease. All groups had significant improvements in histologic and symptom scores. Conclusions In a phase 2 study of patients with symptomatic celiac disease and histologic evidence of significant duodenal mucosal injury, latiglutenase did not improve histologic and symptom scores when compared with placebo. There were no significant differences in change from baseline between groups. ClinicalTrials.gov no: NCT01917630.

KW - Healing

KW - Inflammation

KW - Pathology

KW - Treatment

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U2 - 10.1053/j.gastro.2016.11.004

DO - 10.1053/j.gastro.2016.11.004

M3 - Article

C2 - 27864127

AN - SCOPUS:85014349931

VL - 152

SP - 787

EP - 798

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 4

ER -