Supplemental Table 1: Moderate and severe definitions of Celiac Disease Symptom Diary

Transcription

1 Supplemental Table 1: Moderate and severe definitions of Celiac Disease Symptom Diary symptoms CDSD Symptom Diarrhea Constipation Abdominal Pain Bloating Nausea Tiredness Moderate Once or twice between Days or Days Severe Three or more times on a single day between Days or Days One or 2 spontaneous bowel movements between Days or Days Scale score of 4, 5, or 6 Scale score of 7, 8, 9, or 10 between Days between Days Moderate between Days 15 Severe or Very Severe 28 between Days Moderate between Days 15 Severe or Very Severe 28 between Days Moderate between Days 15 Severe or Very Severe 28 with the presence of, between Days with the regardless of severity, presence of, regardless of diarrhea, abdominal pain, severity, diarrhea, abdominal bloating, or nausea on the pain, bloating, or nausea on the same day same day CDSD = Celiac Disease Symptom Diary 1

2 Supplemental Table 2: Inclusion and exclusion criteria Inclusion Criteria 1. Age 18 to 80 years 2. Physician-diagnosed celiac disease patients with documented history of biopsyproven celiac disease; patients previously diagnosed only by positive serology and clinical response to exclusion of dietary gluten require biopsy confirmation of celiac disease prior to randomization 3. Self-reported to be on a gluten-free diet for at least 11 months prior to enrollment 4. Experienced at least one self-reported moderate or severe symptom included in the Celiac Disease Symptom Diary, probably/likely as a result of gluten exposure, during the 28-day period prior to screening 5. Had daily telephone access in order to complete the Celiac Disease Symptom Diary 6. Agree to maintain dosing of approved prescribed and over-the-counter medications throughout the course of the study 7. Willing to take study treatment 3 times each day with each major meal, with minimal ingestion outside of these meals 8. Willing to undergo 2 on-study upper gastrointestinal endoscopies with duodenal biopsies 9. Willing and able to comply with all study procedures 10. Signed informed consent 2

3 a. US and Canada: Must be able to read and understand English; Europe: Must have been able to read and understand the native language of the patient s country Exclusion Criteria 1. History of known Immunoglobulin E -mediated reaction to wheat (i.e., wheat allergy ) 2. Currently untreated or active peptic ulcer disease, esophagitis (Los Angeles Classification Grade C), irritable bowel syndrome, inflammatory bowel disease, or microscopic colitis 3. Active dermatitis herptiformis 4. Patients with known rapid gastric emptying (e.g., post-bariatric surgery, Billroth I or II surgery) 5. Chronic infectious gastrointestinal illness, or acute infectious gastrointestinal illness within the 4 week period prior to enrollment 6. Known Refractory Celiac Disease (RCD1 or RCD2). Refractory celiac disease is characterized by persistent symptoms, severe malabsorption, and intestinal damage despite strict adherence to a gluten-free diet (in patients with RCD1, the intraepithelial lymphocyte phenotype is normal; in RCD2, there is a clonal aberrant phenotype of the intraepithelial lymphocyte) 7. Screening laboratory values a. Elevated liver function tests (alanine aminotransferase, aspartate transaminase, alkaline phosphatase or gamma-glutamyl transferase > 2.5x upper limit of normal 3

4 b. Total bilirubin > 2x upper limits of normal c. Serum creatinine > 1.5x upper limits of normal d. Calcium < 8.0 mg/dl e. Serum potassium < 3.0 meq/l, > 5.5 meq/l f. Hemoglobin < 8.5 g/dl g. Platelet count < 75.0 x 10 9 /L or 75,000/mm 3 h. Total white blood cell count < 2.5 x 10 9 /L or 2500/mm 3 i. Total lymphocyte < 0.8 x 10 9 /L or 800/mm 3 8. For women of childbearing potential, positive pregnancy test at screening, or were planning to become pregnant during the course of the study, or unwilling to practice effective birth control during the study 9. Expected use of anticoagulants or antiplatelet agents (e.g., warfarin, heparin, or clopidogrel or similar class), other than mini-dose aspirin (e.g., 81 mg) during the week prior to intestinal biopsies that, in the opinion of the endoscopist, would affect the safety of obtaining the biopsies 10. Change of dose or frequency of systemic glucocorticosteroid medications, oral budesonide, or mesalamine within 28-days prior to enrollment at Visit 2 and/or expected to change during the study 11. Use of angiotensin II receptor blockers within 28 days prior to enrollment at Visit 2 and during the study 4

5 12. History of alcohol abuse or habitual use of illicit drugs (e.g., amphetamines, barbiturates, benzodiazepines, cocaine, and opiates, including abuse of prescription opiates) within the past 6 months 13. Received any experimental drug within 30 days of enrollment at Visit 2; in the case of experimental protein therapeutics or vaccines, at least 6 months prior to enrollment 14. Other than oral contraceptives, use of prescribed medications or over-the-counter medications that in the opinion of the investigator might interfere with the study 15. Any medical condition, which, in the opinion of the study investigator, could have adversely affected the patient s participation in the trial, including the ability to tolerate 2 upper gastrointestinal endoscopies with duodenal biopsies, or affect the trial integrity 16. Known allergy or hypersensitivity to any of the components of ALV003 (including sulfites), E. coli, or E. coli-derived proteins to 24 Treatment Exclusion Criteria 1. Failed to complete Study Period 2, including the 12-week endoscopy and biopsy 2. Insufficient compliance with study medication of at least 80% during Study Period 2 3. Insufficient compliance with Celiac Disease Symptom Diary completion of at least 75% during Study Period 2 4. Unwilling to undergo an additional endoscopy with duodenal biopsy at Week Failed to maintain gluten-free diet 5

6 6. For women of childbearing potential, positive pregnancy test at Visit 6 7. Clinically significant findings that could affect continued patient safety and/or integrity of the study 8. Did not sign an addendum to informed consent 6

7 Supplemental Table 3: Demographics and baseline characteristics Modified Intent-to- Treat treatment extension population Treatment Group (n = 106) Placebo (n = 30) 100 mg (n = 14) 300 mg (n = 22) 450 mg (n = 12) 600 mg (n = 16) 900 mg (n = 12) Sex (n, %) Male 4 (13.3%) 4 (28.6%) 9 (40.9%) 3 (25.0%) 5 (31.3%) 0 Female 26 (86.7%) 10 (71.4%) 13 (59.1%) 9 (75.0%) 11 (68.8%) 12 (100%) Age (Years) Mean (SD) 49.3 (13.45) 48.8 (17.39) 57.2 (12.41) 47.3 (13.50) 48.9 (12.47) 52.1 (13.70) Median Min, Max 23.3, , , , , , 67.7 Ethnicity (n, %) Hispanic 1 (3.3%) 1 (7.1%) (6.3%) 0 Non-hispanic 29 (96.7%) 13 (92.9%) 22 (100%) 12 (100%) 15 (93.8%) 12 (100%) Race (n, %) White 29 (96.7%) 13 (92.9%) 22 (100%) 11 (91.7%) 16 (100%) 12 (100%) Black or African American 1 (3.3%) American Indian or Alaskan Native Asian (7.1%) 0 1 (8.3%) 0 0 Other Height (cm) Mean (SD) (8.09) (7.40) (8.04) (8.34) (8.33) (4.75) Median Min, Max 144.8, , , , , , Body Mass Index (kg/m 2 ) Mean (SD) 28.1 (5.44) 27.8 (6.30) 27.3 (3.37) 29.4 (7.08) 29.3 (7.50) 25.7 (3.89) Median Min, Max 18.9, , , , , , 30.2 Vh:Cd Eligibility Mean (SD) 1.27 (0.591) 1.40 (0.459) 1.20 (0.552) 1.46 (0.560) 1.16 (0.647) 1.31 (0.474) Median Min, Max 0.00, , , , , , 1.80 Vh:Cd = villous height to crypt depth 7

8 Supplemental Table 4: Summary of villous height to crypt depth in the treatment extension (week 24) Modified Intent-to-Treat population Vh:Cd Baseline Treatment Group (N=106) Placebo (N=30) 100 mg (N=14) 300 mg (N=22) 450 mg (N=12) 600 mg (N=16) Number of Patients mg (N=12) Mean (SD) 1.44 (0.599) 1.48 (0.527) 1.38 (0.600) 1.70 (0.434) 1.31 (0.724) 1.50 (0.561) Median Min, Max 0.00, , , , , , 2.33 Number of Patients Mean (SD) 1.72 (0.660) 1.69 (0.470) 1.67 (0.741) 1.74 (0.631) 1.41 (0.715) 1.85 (0.742) Median Min, Max 0.06, , , , , , 2.81 Change from Baseline at Number of Patients Mean (SD) 0.28 (0.353) 0.21 (0.403) 0.29 (0.297) 0.05 (0.629) 0.10 (0.396) 0.35 (0.488) Median Min, Max -0.36, , , , , , 1.48 p-value Week 24 Number of Patients Mean (SD) 1.85 (0.633) 1.85 (0.487) 1.69 (0.657) 1.89 (0.622) 1.53 (0.877) 1.99 (0.886) Median Min, Max 0.10, , , , , , 3.26 Change from Baseline at Week 24 Number of Patients Mean (SD) 0.41 (0.456) 0.38 (0.527) 0.31 (0.316) 0.19 (0.445) 0.22 (0.481) 0.49 (0.831) Median Min, Max -0.33, , , , , , 1.92 p-value < Vh:Cd = villous height to crypt depth 8

9 Supplemental Table 5: Analysis of covariance of the change from baseline of villous height to crypt depth in the treatment extension (week 24) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 Vh:Cd N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo , mg , mg , mg , mg , mg , 0.66 Treatment Effect 2 600mg + 900mg vs Placebo , mg vs Placebo , mg + 450mg vs Placebo , mg + 450mg vs Placebo , mg vs Placebo , mg + 100mg vs Placebo , Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status Vh:Cd = villous height to crypt depth; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 9

10 Supplemental Table 6: Summary of cluster of differentiation 3 positive intraepithelial lymphocytes in the (week 12) Modified Intent-to-Treat population CD3+ IEL (Cells/100 epithelial cells) Baseline Treatment Group (N=405) Placebo (N=125) 100 mg (N=47) 300 mg (N=77) 450 mg (N=39) 600 mg (N=80) 900 mg (N=37) Number of Patients Mean (SD) 51.3 (20.66) 50.1 (18.52) 57.2 (23.68) 50.9 (23.81) 51.8 (24.08) 52.9 (22.59) Median Min, Max 8.5, , , , , , Number of Patients Mean (SD) 55.5 (22.67) 55.9 (20.75) 65.9 (24.81) 57.8 (20.76) 59.4 (27.06) 59.0 (23.02) Median Min, Max 7.5, , , , , , Change from Baseline at Number of Patients Mean (SD) 4.2 (18.44) 5.8 (18.82) 8.7 (17.96) 6.9 (20.95) 7.6 (21.15) 6.0 (16.15) Median Min, Max -40.0, , , , , , 43.0 p-value < CD3+ = cluster of differentiation 3 positive; IEL = intraepithelial lymphocytes 10

11 Supplemental Table 7: Analysis of covariance of the change from baseline of cluster of differentiation 3 positive intraepithelial lymphocytes in the (week 12) Modified Intent-to- Treat population Baseline Change from Baseline Treatment Difference 1 CD3+ IEL (Cells/100 epithelial cells) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo , mg , mg , mg , mg , mg , 11.4 Treatment Effect 2 600mg + 900mg vs Placebo , mg vs Placebo , mg + 450mg vs Placebo , mg + 450mg vs Placebo , mg vs Placebo , mg + 100mg vs Placebo , Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status CD3+ = cluster of differentiation 3 positive; IEL = intraepithelial lymphocytes; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 11

12 Supplemental Table 8: Summary of cluster of differentiation 3 positive intraepithelial lymphocyte treatment extension (week 24) Modified Intent-to-Treat population CD3+ IEL (Cells/100 epithelial cells) Baseline Treatment Group (N=106) Placebo (N=30) 100 mg (N=14) 300 mg (N=22) 450 mg (N=12) 600 mg (N=16) Number of Patients mg (N=12) Mean (SD) 55.3 (21.58) 44.6 (16.62) 53.7 (24.04) 51.3 (28.14) 55.3 (26.34) 54.0 (26.25) Median Min, Max 15.5, , , , , , Number of Patients Mean (SD) 54.5 (23.42) 54.9 (21.97) 62.3 (25.73) 55.0 (13.14) 54.3 (26.89) 58.8 (21.61) Median Min, Max 14.5, , , , , , Change from Baseline at Number of Patients Mean (SD) -0.8 (16.95) 10.3 (19.68) 8.6 (17.03) 3.8 (24.43) -1.0 (22.70) 4.8 (10.35) Median Min, Max -32.0, , , , , , 17.5 p-value Week 24 Number of Patients Mean (SD) 61.7 (25.90) 62.9 (24.68) 60.0 (28.20) 55.3 (20.26) 59.7 (24.30) 59.0 (30.45) Median Min, Max 19.0, , , , , , Change from Baseline at Week 24 Number of Patients Mean (SD) 6.4 (21.65) 18.3 (19.36) 6.3 (20.14) 4.0 (20.86) 4.4 (19.05) 5.0 (24.70) Median Min, Max -24.5, , , , , , 67.5 p-value CD3+ = cluster of differentiation 3 positive; IEL = intraepithelial lymphocyte 12

13 Supplemental Table 9: Analysis of covariance of the change from baseline of cluster of differentiation 3 positive intraepithelial lymphocytes in the treatment extension (week 24) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 CD3+ IEL (Cells/100 epithelial cells) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo , mg , mg , mg , mg , mg , 11.3 Treatment Effect 2 600mg + 900mg vs Placebo , mg vs Placebo , mg + 450mg vs Placebo , mg + 450mg vs Placebo , mg vs Placebo , mg + 100mg vs Placebo , Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status CD3+ - cluster of differentiation 3 positive; IEL = intraepithelial lymphocyte; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 13

14 Supplemental Table 10: Summary of tissue transglutaminase-2-iga serology in the (week 12) Modified Intent-to-Treat population TG2-IgA (U/mL) Baseline Treatment Group (N=404) Placebo (N=126) 100 mg (N=48) 300 mg (N=76) 450 mg (N=39) 600 mg (N=77) 900 mg (N=38) Number of Patients Mean (SD) 10.5 (22.82) 6.2 (12.35) 9.8 (21.07) 4.5 (8.15) 8.7 (20.09) 11.3 (24.73) Median Min, Max 2, 100 2, 79 2, 100 2, 44 2, 100 2, 100 Number of Patients Mean (SD) 10.7 (22.86) 6.1 (14.43) 9.6 (20.60) 5.9 (13.24) 9.2 (21.98) 10.4 (23.19) Median Min, Max 2, 100 2, 96 2, 100 2, 75 2, 100 2, 100 Change from Baseline at Number of Patients Mean (SD) 0.2 (8.80) -0.1 (4.50) -0.2 (4.26) 1.5 (5.34) 0.4 (6.81) -0.9 (10.46) Median Min, Max -35, 59-13, 17-20, 21-2, 31-27, 48-44, 34 p-value TG2 = tissue transglutaminase-2 14

15 Supplemental Table 11: Analysis of covariance of the change from baseline in tissue transglutaminase-2-iga (week 12) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 TG2-IgA (U/mL) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo , mg , mg , mg , mg , mg , 2.5 Treatment Effect 2 600mg + 900mg vs Placebo , mg vs Placebo , mg + 450mg vs Placebo , mg + 450mg vs Placebo , mg vs Placebo , mg + 100mg vs Placebo , Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status TG2 = tissue transglutaminase-2; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 15

16 Supplemental Table 12: Summary of tissue transglutaminase-2-iga serology in the treatment extension (week 24) Modified Intent-to-Treat population TG2-IgA (U/mL) Baseline Treatment Group (N=107) Placebo (N=30) 100 mg (N=14) 300 mg (N=23) 450 mg (N=12) 600 mg (N=16) Number of Patients mg (N=12) Mean (SD) 8.5 (19.09) 4.6 (8.21) 15.3 (27.80) 3.1 (3.75) 15.8 (33.06) 11.9 (23.21) Median Min, Max 2, 100 2, 33 2, 100 2, 15 2, 100 2, 65 Number of Patients Mean (SD) 12.1 (23.32) 3.7 (4.75) 14.2 (26.66) 4.3 (6.88) 16.6 (33.96) 5.9 (9.08) Median Min, Max 2, 87 2, 20 2, 100 2, 26 2, 100 2, 29 Change from Baseline at Number of Patients Mean (SD) 3.6 (13.50) -0.9 (3.56) -1.1 (5.17) 1.3 (3.19) -0.1 (2.47) -6.0 (14.60) Median Min, Max -13, 59-13, 2-20, 9 0, 11-7, 5-44, 1 p-value [1] Week 24 Number of Patients Mean (SD) 8.5 (18.82) 3.8 (4.23) 12.0 (23.32) 5.1 (8.10) 20.8 (36.76) 7.6 (14.34) Median Min, Max 2, 100 2, 18 2, 100 2, 30 2, 100 2, 51 Change from Baseline at Week 24 Number of Patients Mean (SD) 0.0 (5.91) -0.9 (4.17) -3.3 (9.31) 2.0 (4.55) 4.9 (20.43) -4.3 (18.21) Median Min, Max -17, 20-15, 3-31, 8 0, 15-8, 81-60, 15 p-value TG2 = tissue transglutaminase-2 16

17 Supplemental Table 13: Analysis of covariance of the change from baseline in the tissue transglutaminase-2-iga treatment extension (week 24) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 TG2-IgA (U/mL) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo , mg , mg , mg , mg , mg , 3.3 Treatment Effect 2 600mg + 900mg vs Placebo , mg vs Placebo , mg + 450mg vs Placebo , mg + 450mg vs Placebo , mg vs Placebo , mg + 100mg vs Placebo , Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status TG2 = tissue transglutaminase-2; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 17

18 DGP-IgA (U) Baseline Supplemental Table 14: Summary of deamidated gliadin peptide-iga serology in the (week 12) Modified Intent-to-Treat population Treatment Group (N=404) Placebo (N=126) 100 mg (N=48) 300 mg (N=76) 450 mg (N=39) 600 mg (N=77) Number of Patients mg (N=38) Mean (SD) 25.8 (32.88) 24.5 (28.19) 24.4 (29.42) 20.6 (28.75) 28.3 (33.08) 23.6 (30.47) Median Min, Max 1, 100 1, 100 1, 100 1, 100 1, 100 1, 100 Number of Patients Mean (SD) 24.5 (31.50) 24.3 (27.94) 24.3 (26.15) 24.6 (31.38) 27.1 (31.14) 22.6 (26.94) Median Min, Max 1, 100 1, 100 1, 100 1, 100 1, 100 1, 100 Change from Baseline at Number of Patients Mean (SD) -1.2 (10.91) -0.2 (9.48) -0.1 (8.02) 4.0 (8.80) -1.2 (9.51) -1.0 (17.21) Median Min, Max -60, 41-43, 17-27, 32-8, 30-42, 24-63, 66 p-value DGP = deamidated gliadin peptide 18

19 Supplemental Table 15: Analysis of covariance of the change from baseline in deamidated gliadin peptide-iga (week 12) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 DGP-IgA (U) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo , mg , mg , mg , mg , mg , 4.6 Treatment Effect 2 600mg + 900mg vs Placebo , mg vs Placebo , mg + 450mg vs Placebo , mg + 450mg vs Placebo , mg vs Placebo , mg + 100mg vs Placebo , Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status DGP = deamidated gliadin peptide; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 19

20 DGP-IgA (U) Baseline Supplemental Table 16: Summary of deamidated gliadin peptide-iga serology in the treatment extension (week 24) Modified Intent-to-Treat population Treatment Group (N=107) Placebo (N=30) 100 mg (N=14) 300 mg (N=23) 450 mg (N=12) 600 mg (N=16) Number of Patients mg (N=12) Mean (SD) 25.7 (30.38) 17.2 (21.33) 31.3 (35.29) 21.8 (25.20) 33.2 (36.48) 22.1 (25.25) Median Min, Max 3, 95 4, 87 3, 100 4, 80 3, 100 3, 69 Number of Patients Mean (SD) 26.6 (33.33) 16.9 (24.69) 26.7 (30.80) 25.3 (30.56) 31.3 (34.85) 17.2 (13.95) Median Min, Max 2, 100 3, 100 3, 100 3, 96 3, 100 2, 42 Change from Baseline at Number of Patients Mean (SD) 0.9 (11.30) -0.4 (5.12) -4.6 (8.06) 3.4 (7.82) -3.8 (8.98) -4.9 (13.94) Median Min, Max -32, 41-9, 13-27, 2-8, 16-29, 12-37, 12 p-value Week 24 Number of Patients Mean (SD) 26.0 (30.87) 20.8 (24.77) 32.1 (34.63) 25.8 (28.96) 36.6 (40.66) 23.5 (24.77) Median Min, Max 2, 100 4, 97 3, 100 3, 100 3, 100 4, 69 Change from Baseline at Week 24 Number of Patients Mean (SD) 0.3 (12.19) 3.6 (7.09) 0.8 (18.69) 3.9 (8.64) 3.4 (23.66) 1.4 (23.06) Median Min, Max -23, 41-6, 23-57, 54-6, 20-29, 87-48, 58 p-value DGP = deamidated gliadin peptide 20

21 Supplemental Table 17: Analysis of covariance of the change from baseline in the deamidated gliadin peptide-iga treatment extension (week 24) MITT population Baseline Change from Baseline Treatment Difference 1 DGP-IgA (U) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo , mg , mg , mg , mg , mg , 3.9 Treatment Effect 2 600mg + 900mg vs Placebo , mg vs Placebo , mg + 450mg vs Placebo , mg + 450mg vs Placebo , mg vs Placebo , mg + 100mg vs Placebo , Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status DGP = deamidated gliadin peptide; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 21

22 Supplemental Table 18: Summary of deamidated gliadin peptide-igg serology in the (week 12) Modified Intent-to-Treat population DGP-IgG (U) Baseline Treatment Group (N=419) Placebo (N=128) 100 mg (N=49) 300 mg (N=80) 450 mg (N=42) 600 mg (N=82) 900 mg (N=38) Number of Patients Mean (SD) 25.0 (33.13) 24.9 (33.44) 23.7 (31.37) 17.9 (27.78) 26.4 (34.90) 17.6 (27.94) Median Min, Max 1, 100 1, 100 1, 100 1, 100 1, 100 1, 100 Number of Patients Mean (SD) 25.1 (34.19) 24.7 (32.36) 22.8 (30.23) 16.8 (25.70) 24.7 (33.57) 18.1 (28.37) Median Min, Max 1, 100 2, 100 1, 100 1, 100 1, 100 1, 100 Change from Baseline at Number of Patients Mean (SD) 0.2 (11.08) -0.3 (13.90) -1.0 (6.86) -1.1 (7.47) -1.6 (6.88) 0.5 (4.86) Median Min, Max -31, 83-22, 85-23, 22-37, 12-40, 15-16, 16 p-value DGP = deamidated gliadin peptide 22

23 Supplemental Table 19: Analysis of covariance of the change from baseline in deamidated gliadin peptide-igg (week 12) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 DGP-IgG (U) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo , mg , mg , mg , mg , mg , 2.1 Treatment Effect 2 600mg + 900mg vs Placebo , mg vs Placebo , mg + 450mg vs Placebo , mg + 450mg vs Placebo , mg vs Placebo , mg + 100mg vs Placebo , Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status DGP = deamidated gliadin peptide; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 23

24 DGP-IgG (U) Baseline Supplemental Table 20: Summary of deamidated gliadin peptide-igg serology in the treatment extension (week 24) MITT population Treatment Group (N=107) Placebo (N=30) 100 mg (N=14) 300 mg (N=23) 450 mg (N=12) 600 mg (N=16) Number of Patients mg (N=12) Mean (SD) 25.8 (33.20) 17.0 (29.59) 35.6 (39.98) 10.1 (11.90) 33.0 (40.77) 10.1 (16.97) Median Min, Max 1, 100 2, 100 1, 100 2, 44 1, 100 1, 54 Number of Patients Mean (SD) 27.9 (35.83) 15.5 (27.71) 33.8 (37.69) 11.3 (15.40) 29.5 (39.26) 12.1 (20.61) Median Min, Max 1, 100 2, 100 1, 100 1, 56 1, 100 1, 59 Change from Baseline at Number of Patients Mean (SD) 2.1 (15.60) -1.5 (4.91) -1.7 (7.62) 1.2 (3.76) 0.7 (2.47) 2.0 (4.65) Median Min, Max -10, 83-17, 6-21, 16-2, 12-2, 7-1, 16 p-value Week 24 Number of Patients Mean (SD) 23.5 (29.78) 18.4 (30.31) 33.4 (36.83) 12.7 (18.29) 31.8 (36.55) 10.2 (16.89) Median Min, Max 1, 100 1, 99 1, 100 1, 57 1, 100 1, 55 Change from Baseline at Week 24 Number of Patients Mean (SD) -2.3 (12.86) 1.4 (4.88) -2.2 (13.48) 2.6 (10.11) -1.3 (16.97) 0.1 (1.16) Median Min, Max -34, 38-3, 16-34, 25-8, 31-46, 38-2, 2 p-value DGP = deamidated gliadin peptide 24

25 Supplemental Table 21: Analysis of covariance of the change from baseline in the deamidated gliadin peptide-igg treatment extension (week 24) Modified Intent-to-Treat population Baseline Change from Baseline Treatment Difference 1 DGP-IgG (U) N Mean N Mean 95% CI LS Mean 95% CI P-Value Placebo , mg , mg , mg , mg , mg , 5.0 Treatment Effect 2 600mg + 900mg vs Placebo , mg vs Placebo , mg + 450mg vs Placebo , mg + 450mg vs Placebo , mg vs Placebo , mg + 100mg vs Placebo , Difference between treatments for the least square mean Change from Baseline, obtained from the model. 2 Treatment effect p-value was based on an ANCOVA model: Change = Treatment + Baseline + Baseline Serology Status DGP = deamidated gliadin peptide; LS = least square; CI = confidence interval; ANCOVA = analysis of covariance 25

26 Supplemental Table 22: Analysis of covariance summary of non-stool symptoms by stratum Measure Abdominal pain frequency Change from Baseline to Week 6 Change from Baseline to Overall Sero-Negative Sero-Positive Overall Sero-Negative Sero-Positive A (=0.010) A600 (p=0.039) A900 (p=0.034) Abdominal pain severity A (=0.008) A600 (p=0.026) A900 (p=0.038) Bloating frequency A300 (p=0.049) Bloating severity A (p=0.007) A600 (p=0.040) A900 (p=0.021) A (=0.007) A600 (p=0.040) A900 (p=0.023) Nausea frequency A900 (p=0.022) A100 (p=0.043) Nausea severity Tiredness frequency A600 (P-0.049) A (=0.018) A600 (p=0.038) A300 (p=0.015) A (p=0.022) A600 (p=0.012) Tiredness severity A (p=0.014) A600 (p=0.028) A (p=0.025) A (p=0.026) A300 (p=0.046) A (p=0.037) A (=0.009) A600 (p=0.002) Overall non-stool specific frequency Overall non-stool specific activity A (p=0.007) A600 (p=0.029) A900 (p=0.032) The pattern suggests that higher doses (600 mg and 900 mg) in the most symptomatic patients may be able to overcome the trial effect A (=0.007) A600 (p=0.026) A900 (p=0.034) 26

27 Supplemental Table 23: Responder analysis of change from baseline in Celiac Disease Symptom Diary frequency and severity scores based on Patient Global Impression Symptoms responder definitions at week 12 CDSD Domain Change Mean (SD) Much Deterioration (n=6) Deterioration (n=33) No Change (n=128) Improvement (n=109) Much Improvement (n=98) P value 1 Diarrhea frequency 1.57 (1.60) 0.46 (2.11) (1.95) (1.69) (2.29) <0.001 Diarrhea severity 3.0 (2.7) 1.4 (4.8) -0.7 (5.4) -0.8 (4.1) -2.6 (5.9) <0.001 CSBM frequency (2.18) (2.04) 0.05 (1.48) (1.87) (2.52) CSBM severity (31.3) 1.2 (24.2) 1.1 (16.8) -1.0 (18.0) 0.6 (25.0) Abdominal pain frequency 1.13 (1.24) (1.79) (1.93) (2.08) (2.48) <0.001 Abdominal pain severity 3.9 (4.8) -0.4 (7.0) -2.6 (8.9) -3.6 (9.6) -8.9 (10.7) <0.001 Bloating frequency 0.77 (2.91) (1.89) (1.89) (2.10) (2.61) <0.001 Bloating severity 10.6 (10.1) 1.5 (11.2) -2.8 (11.5) -6.3 (12.1) (15.3) <0.001 Nausea frequency 0.75 (0.52) 0.21 (1.17) (1.58) (1.52) (1.86) <0.001 Nausea severity 3.9 (3.2) 0.6 (6.7) -0.8 (8.0) -3.1 (8.4) -6.5 (10.1) <0.001 Tiredness frequency 0.58 (1.16) (1.65) (1.83) (2.24) (2.87) <0.001 Tiredness severity 3.1 (2.7) -3.2 (9.1) -4.9 (11.8) -6.1 (13.4) (17.6) <0.001 Overall non-stool specific gastrointestinal frequency Overall non-stool specific gastrointestinal activity 0.44 (2.60) (1.78) (2.12) (2.09) (2.52) < (13.7) 1.7 (15.6) -6.2 (20.1) (21.5) (27.4) < p value derived from one-way ANOVA F test. CDSD = Celiac Disease Symptom Diary; CSBM = complete spontaneous bowel movement 27

28 Supplemental Table 24: Analysis of covariance predicting change from baseline to week 12 in Impact of Celiac Disease Symptoms Questionnaire overall score Treatment Group LS-Mean SE 95% CI P value Placebo (-2.62, -1.74) <0.001 ALV mg (A100) (-3.61, -2.16) <0.001 ALV mg (A300) (-3.11, -1.92) <0.001 ALV mg (A450) (-3.55, -1.95) <0.001 ALV mg (A600) (-2.98, -1.88) <0.001 ALV mg (A900) (-3.31, -1.61) <0.001 Seronegative at baseline (-2.75, -2.08) <0.001 Seropositive at baseline (-2.87, -2.12) <0.001 Comparisons: (A600+A900) Placebo (-0.94, 0.40) A600 Placebo (-0.96, 0.45) (A600+A450) Placebo (-1.07, 0.24) (A300+A450) Placebo (-1.12, 0.21) A300 Placebo (-1.08, 0.40) (A300+A100) Placebo (-1.17, 0.12) A900 Placebo (1.24, 0.68) A450 Placebo (-1.49, 0.34) A100 Placebo (-1.56, 0.14) ANCOVA model adjusted for baseline score and serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 28

29 Supplemental Table 25: Analysis of covariance predicting change from baseline to week 24 in Impact of Celiac Disease Symptoms Questionnaire overall score Treatment Group LS-Mean SE 95% CI P value Placebo (-3.34, -1.82) <0.001 ALV mg (A100) (-3.71, -1.55) <0.001 ALV mg (A300) (-3.17, -1.47) <0.001 ALV mg (A450) (-4.56, -2.24) <0.001 ALV mg (A600) (-4.52, -2.51) <0.001 ALV mg (A900) (-3.51, -1.16) <0.001 Seronegative at baseline (-3.27, -2.26) <0.001 Seropositive at baseline (-3.31, -2.06) <0.001 Comparisons: (A600+A900) Placebo (-1.44, 0.74) A600 - Placebo (-2.20, 0.32) (A600+A450) Placebo (-1.96, 0.20) (A300+A450) Placebo (-1.34, 0.77) A300 Placebo (-0.90, 1.41) (A300+A100) Placebo (-0.93, 1.13) A900 Placebo (-1.17, 1.65) A450 Placebo (-2.21, 0.57) A100 Placebo (-1.37, 1.26) ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 29

30 Supplemental Table 26: Analysis of covariance predicting change from week 12 in Short Form SF-12v2 Health Survey: Physical component score Treatment Group LS-Mean SE 95% CI P value Placebo (0.0, 7.8) ALV mg (A100) (1.5, 14.4) ALV mg (A300) (4.3, 14.8) <0.001 ALV mg (A450) (3.3, 17.6) ALV mg (A600) (4.6, 14.4) <0.001 ALV mg (A900) (-3.7, 11.3) Seronegative at baseline (3.6, 9.5) <0.001 Seropositive at baseline (4.6, 11.2) <0.001 Comparisons: (A600+A900) Placebo (-3.2, 8.7) A600 - Placebo (-0.7, 11.9) (A600+A450) Placebo (0.2, 11.9) (A300+A450) Placebo (0.02, 12.0) A300 Placebo (-0.9, 12.2) (A300+A100) Placebo (-0.8, 10.5) A900 Placebo (-8.6, 8.4) A450 Placebo (-1.6, 14.7) A100 Placebo (-3.5, 11.6) ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 30

31 Supplemental Table 27: Analysis of covariance predicting change from baseline to week 24 in Short Form SF-12v2 Health Survey: physical component score Treatment Group LS-Mean SE 95% CI P value Placebo (1.5, 15.0) ALV mg (A100) (-4.5, 14.9) ALV mg (A300) (-2.9, 12.2) ALV mg (A450) (4.7, 25.5) ALV mg (A600) (4.6, 22.7) ALV mg (A900) (-1.5, 19.4) Seronegative at baseline (6.7, 15.8) <0.001 Seropositive at baseline (-0.7, 10.5) Comparisons: (A600+A900) Placebo (-6.6, 12.7) A600+Placebo (-5.9, 16.7) (A600+A450) Placebo (-3.6, 15.8) (A300+A450) Placebo (-7.7, 11.0) A300 Placebo (-13.7, 6.5) (A300+A100) Placebo (-12.4, 5.7) A900 Placebo (-11.8, 13.1) A450 Placebo (-5.6, 19.3) A100 Placebo (-14.8, 8.7) ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 31

32 Supplemental Table 28: Analysis of covariance predicting change from baseline to week 12 in Short Form SF-12v2 Health Survey: mental component score Treatment Group LS-Mean SE 95% CI P value Placebo (3.0, 8.7) <0.001 ALV mg (A100) (4.7, 14.1) <0.001 ALV mg (A300) (3.5, 11.2) <0.001 ALV mg (A450) (4.4, 14.9) <0.001 ALV mg (A600) (6.9, 14.1) <0.001 ALV mg (A900) (4.2, 15.3) <0.001 Seronegative at baseline (4.4, 8.7) <0.001 Seropositive at baseline (7.8, 12.7) <0.001 Comparisons: (A600+A900) Placebo (-0.1, 8.6) A600+Placebo (0.0, 9.2) (A600+A450) Placebo (-0.1, 8.5) (A300+A450) Placebo (-1.7, 7.0) A300 Placebo (-3.3, 6.3) (A300+A100) Placebo (-1.7, 6.7) A900 Placebo (-2.4, 10.1) A450 Placebo (-2.2, 9.8) A100 Placebo (-2o, 9.0) ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 32

33 Supplemental Table 29: Analysis of covariance predicting change from baseline to week 24 in Short Form SF-12v2 Health Survey: mental component score Treatment Group LS-Mean SE 95% CI P value Placebo (5.3, 16.4) <0.001 ALV mg (A100) (1.7, 17.7) ALV mg (A300) (6.2, 18.6) <0.001 ALV mg (A450) (7.1, 24.3) <0.001 ALV mg (A600) (7.9, 23.0) <0.001 ALV mg (A900) (2.0, 19.3) Seronegative at baseline (9.1, 16.6) <0.001 Seropositive at baseline (6.7, 16.0) <0.001 Comparisons: (A600+A900) Placebo (-5.8, 10.1) A600+Placebo (-4.8, 13.8) (A600+A450) Placebo (-3.3, 12.6) (A300+A450) Placebo (-4.5, 10.9) A300 Placebo (-6.8, 9.9) (A300+A100) Placebo (-7.4, 7.7) A900 Placebo (-10.6, 10.1) A450 Placebo (-5.4, 15.1) A100 Placebo (-11.0, 8.6) ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 33

34 Supplemental Table 30: Analysis of covariance predicting change from baseline to week 12 in Short Form SF-6D Health Survey: utility index Treatment Group LS-Mean SE 95% CI P value Placebo (0.025, 0.64) <0.001 ALV mg (A100) (0.032, 0.098) <0.001 ALV mg (A300) (0.042, 0.096) <0.001 ALV mg (A450) (0.061, 0.134) <0.001 ALV mg (A600) (0.050, 0.100) <0.001 ALV mg (A900) (0.011, 0.088) Seronegative at baseline (0.039, 0.069) <0.001 Seropositive at baseline (0.057, 0.091) <0.001 Comparisons: (A600+A900) Placebo (-0.012, 0.048) A600+Placebo (-0.001, 0.062) (A600+A450) Placebo (0.012, 0.071) (A300+A450) Placebo (0.009, 0.069) A300 Placebo (-0.009, 0.058) (A300+A100) Placebo (-0.006, 0.051) A900 Placebo (-0.038, 0.048) A450 Placebo (0.012, 0.094) A100 Placebo (-0.018, 0.059) ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 34

35 Supplemental Table 31: Analysis of covariance predicting change from baseline to week 24 in Short Form SF-6D Health Survey: utility index Treatment Group LS-Mean SE 95% CI P value Placebo (0.040, 0.109) <0.001 ALV mg (A100) (0.053, 0.151) <0.001 ALV mg (A300) (0.007, 0.085) ALV mg (A450) (0.063, 0.170) <0.001 ALV mg (A600) (0.042, 0.135) <0.001 ALV mg (A900) (-0.001, 0.106) Seronegative at baseline (0.042, 0.088) <0.001 Seropositive at baseline (0.066, 0.123) <0.001 Comparisons: (A600+A900) Placebo (-0.053, 0.045) A600+Placebo ( ) (A600+A450) Placebo (-0.021, 0.077) (A300+A450) Placebo (-0.041, 0.054) A300 Placebo (-0.081, 0.024) (A300+A100) Placebo (-0.047, 0.046) A900 Placebo (-0.086, 0.042) A450 Placebo (-0.022, 0.105) A100 Placebo (-0.033, 0.088) ANCOVA model adjusted for baseline score and baseline serologic status LS = least square; SE = standard error; CI confidence interval; ANCOVA = analysis of covariance 35

36 Supplemental Table 32: Summary of frequently reported adverse events by system organ class in the safety (week 12) and treatment extension (week 24) populations Treatment Group Gastrointestinal Disorders (n, %) Placebo 100 mg 300 mg 450 mg 600 mg 900 mg Safety Population 46 (31.1%) 12 (24.0%) 29 (29.9%) 15 (31.3%) 27 (27.3%) 15 (31.9%) Treatment Extension Population Infections (n, %) 12 (36.4%) 2 (14.3%) 6 (24.0%) 1 (8.3%) 7 (36.8%) 4 (30.8%) Safety Population 36 (24.3%) 7 (14.0%) 17 (17.5%) 7 (14.6%) 27 (27.3%) 7 (14.9%) Treatment Extension Population 11 (33.3%) 4 (28.6%) 4 (16.0%) 2 (16.7%) 9 (47.4%) 2 (15.4%) 36