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, Khurram; Basile, Anna; Behrend, C.; Bercík, P; Bressler, Brian; Byrnes, Valerie; Chandan, Vishal S.; Cheekati, V.; Chipps, Bradley E.; Coates, Allan G.; Collatrella, A.; Condemi, John J.; Corder, Clinton N.; Corren, Jonathan; Curtis, Craig; DeMeo, Mark T.; Desta, Taddese; Devereaux, Christopher E.; DiMarino, Anthony J.; DuPree, M.; Ennis, Craig; Fedorak, Richard N.; Fogel, Ronald; Freeman, Stefanie; Freilich, B.; Friedenberg, Keith; Geenen, Daniel J.; Gill, Kiren; Goldsobel, Alan B.; Goldstein, J.; Goldstein, Michael J.; Gordon, Glenn; Hardi, Robert; Harris, Lucinda A.; Holmes, R.; Jagarlamundi, K.; James, G.; Kaplan, Mustafa; Kirstein, J.; Knoll, Anette; Kotfila, Ronald; Krause, Richard A.; Kravitz, Alexxai V.; Kreines, Michael; Lähdeaho, Marja–Leena; Lamet, Mark; Laskin, Keith J.; Lebwohl, Benjamin; Leffler, Daniel A.; Lewis, Suzanne K.; Liakos, S; Lundin, Knut E.A.; Marks, Keith H; Merkes, K.; Minton, Susan; Moussa, Sam; Narayen, V.; Nehra, Vandana; Newton, Eric; Nyberg, Anders; Oosthuizen, Jean; Otrok, T; Patel, Dilip D.; Pepin, Craig; Phillips, R A; Pyle, Gail G.; Reichelderfer, Mark; Reid, Barbara S.; Ritter, Timothy E.; Saini, Sharanjot; Sanders, David S.; Schulman, Matthew R.; Semrad, Carol E.; Shah, Sveta; Stockwell, David H.; Strout, Cynthia; Suez, Daniel; Tatum, H.; Torbenson, M. S.; Turner, Mark S.; Varunok, Peter; Vázquez-Roque, María I.; Vento, Anna Rita; Welton, Thomas A.; Wohlman, Robert; Wood, Mariah; Woods, Simon; Yousef, Khalil

doi:10.1053/j.gastro.2016.11.004

Cited by 106 publications

(59 citation statements)

References 34 publications

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“…We conducted a nested cross‐sectional study on a pre‐randomisation cohort of 1345 patients from CeliAction (clinicaltrials.gov identifier NCT01917630), a multicenter, randomised clinical trial evaluating the effect of latiglutenase (formerly ALV003, Alvine Pharmaceuticals, San Carlos, CA, USA), a gluten‐specific enzyme therapeutic agent . The trial recruited adults with coeliac disease from North America, the United Kingdom, Ireland, Norway and Finland.…”

Section: Methodsmentioning

confidence: 99%

Factors associated with villus atrophy in symptomatic coeliac disease patients on a gluten‐free diet

Mahadev

Murray

et al. 2017

Aliment Pharmacol Ther

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Of 1345 symptomatic patients, 511 (38%, 95% CI, 35-41%) were found to have active coeliac disease with persistent villus atrophy, defined as average villus height to crypt depth ratio ≤2.0. On multivariable analysis, older age (OR, 5.1 for ≥70 vs. 18-29 years, 95% CI, 2.5-10.4) was a risk factor while longer duration on gluten-free diet was protective (OR, 0.37, 95% CI, 0.24-0.55 for 4-5.9 vs. 1-1.9 years). Villus atrophy was associated with use of proton-pump inhibitors (PPIs; OR, 1.6, 95% CI, 1.1-2.3), non-steroidal anti-inflammatory drugs (NSAIDs; OR, 1.64, 95% CI, 1.2-2.2), and selective serotonin reuptake inhibitors (SSRIs; OR, 1.74, 95% CI, 1.2-2.5). Symptoms were not associated with villus atrophy after adjusting for covariates. Conclusions A majority of symptomatic coeliac disease patients did not have active disease on follow-up histology. Symptoms were poorly predictive of persistent mucosal injury. The impact of NSAIDs, PPIs, and SSRIs on mucosal healing in coeliac disease warrants further study.

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Section: Methodsmentioning

confidence: 99%

Factors associated with villus atrophy in symptomatic coeliac disease patients on a gluten‐free diet

Mahadev

Murray

et al. 2017

Aliment Pharmacol Ther

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“…Quantitative histology provides accurate assessment of duodenal mucosal injury in coeliac disease by using highly reproducible measurements of villous height, crypt depth and intraepithelial lymphocyte density in well‐oriented distal duodenal biopsies . With implementation of rigorous standard operating procedures, quantitative duodenal histology outperforms conventional qualitative histology using grouped classifications such as Marsh score, and is emerging as a preferred measure of efficacy in therapeutics trials for coeliac disease . Perhaps surprisingly, quantitative histology has not yet, to our knowledge, been used to evaluate disease activity/duodenal injury in patients with coeliac disease who appear clinically ‘well controlled’ and are in serological remission.…”

Section: Introductionmentioning

confidence: 99%

Baseline quantitative histology in therapeutics trials reveals villus atrophy in most patients with coeliac disease who appear well controlled on gluten‐free diet

et al. 2020

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Summary Background The prevalence and severity of duodenal injury in coeliac disease patients controlled on a gluten‐free diet is unclear. Aims To use quantitative histology to assess duodenal injury in treated coeliac disease. Methods Quantitative histology in pre‐treatment duodenal biopsies collected in clinical trials assessing an investigational immunotherapy for coeliac disease was analysed. Morphometric readings were converted to Marsh classifications. Results Ninety‐three patients had duodenal biopsies. For well‐oriented sections of second part biopsies, six (6%) patients were classified as Marsh 0 or 1, 30 (33%) as Marsh 2 and 56 (60%) as Marsh 3a or 3b. In second part biopsies from 78 seronegative patients on gluten‐free diet >2 years, 27 (35%) were Marsh 2 and 45 (58%) were Marsh 3a or 3b. Distal compared to proximal duodenal biopsies had significantly higher villus height to crypt depth ratios (median, third part: 2.1 vs bulb: 1.4; P < 0.0001) and higher intraepithelial lymphocyte density (44 vs 30; P = 0.0002). The sum of paired villus height and adjacent crypt depth measurements was correlated strongly with villus height (rs = 0.82, P < 10−10). At least one biopsy was graded Marsh 3a or worse in all 26 patients who had serial biopsies from the bulb, first, second and third part, but was overlooked in 20 patients by subjective histology. Conclusions Quantitative histology in well‐oriented biopsy sections reveals villus atrophy in the majority of patients with coeliac disease who appear well controlled on gluten‐free diet. Standardisation of biopsy collection, processing and evaluation could substantially improve the value of follow‐up biopsies in coeliac disease.

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“…To address the latter question, a double-blind, placebo controlled study was performed to evaluate the effects of varying doses of latiglutenase in symptomatic CD patients who reported following a gluten-free diet for at least one year prior to randomization. In all study groups, including the placebo group, a comparable improvement in histological scores was observed and therefore the primary endpoint for histologic improvement was not met [10]. The published manuscript focused on the reasons for the failed endpoint, but did note indication of statistically significant improvement for certain symptoms that were particularly pronounced in seropositive patients.…”

Section: Introductionmentioning

confidence: 99%

Latiglutenase Improves Symptoms in Seropositive Celiac Disease Patients While on a Gluten-Free Diet

et al. 2017

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Background and Aims Celiac disease (CD) is a widespread condition triggered by dietary gluten and treated with a lifelong gluten-free diet (GFD); however, inadvertent exposure to gluten can result in episodic symptoms. A previous trial of latiglutenase (clinicaltrials.gov; NCT01917630), an orally administered mixture of two recombinant gluten-specific proteases, was undertaken in symptomatic subjects with persistent injury. The primary endpoint for histologic improvement was not met, presumably due to a trial effect. In this post hoc analysis we investigated the efficacy of latiglutenase for reducing symptoms in subgroups of the study participants based on their seropositivity. Methods The study involved symptomatic CD patients following a GFD for at least one year prior to randomization. Patients were treated for 12 weeks with latiglutenase or placebo. Of 398 completed patients 173 (43%) were seropositive at baseline. Symptoms were recorded daily and weekly symptom scores were compiled. P-values were calculated by analysis of covariance (ANCOVA). Results A statistically significant, dose-dependent reduction was detected in the severity and frequency of symptoms in seropositive but not seronegative patients. The severity of abdominal pain and bloating was reduced by 58% and 44%, respectively, in the cohort receiving the highest latiglutenase dose (900 mg, n=14) relative to placebo (n=54). Symptom improvement increased from week 6 to week 12. There was also a trend toward greater symptom improvement with greater baseline symptom severity. Conclusions Seropositive CD patients show symptomatic improvement from latiglutenase taken with meals and would benefit from the availability of this treatment.

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

Cited by 106 publications

References 34 publications

Factors associated with villus atrophy in symptomatic coeliac disease patients on a gluten‐free diet

Factors associated with villus atrophy in symptomatic coeliac disease patients on a gluten‐free diet

Baseline quantitative histology in therapeutics trials reveals villus atrophy in most patients with coeliac disease who appear well controlled on gluten‐free diet

Latiglutenase Improves Symptoms in Seropositive Celiac Disease Patients While on a Gluten-Free Diet

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