Celiac Disease
Conditions
Keywords
celiac, gluten, Interleukin 15 (IL-15), AMG 714, gluten challenge
Brief summary
This study is designed to evaluate the efficacy and safety of AMG 714 for the attenuation of the effects of gluten exposure in adult patients with celiac disease during a gluten challenge.
Interventions
BIOLOGICALAMG 714
AMG 714 administered by subcutaneous injection
BIOLOGICALPlacebo
Matching placebo to AMG 714 administered by subcutaneous injection
OTHERPlacebo Gluten Challenge
Gluten-free cookies (Finnish rusks)
OTHERGluten Challenge
Gluten-containing cookies (Finnish rusks), 1-2 g gluten per serving
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of celiac disease by intestinal biopsy at least 12 months prior to screening * On a gluten-free diet for at least 12 months * Negative celiac serology * Avoidance of pregnancy
Exclusion criteria
* Severe complications of celiac disease, such as refractory celiac disease * Celiac symptoms * Other concomitant autoimmune disease * Chronic, active gastrointestinal disease * Infections, concomitant diseases * Prohibited medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Villous Height to Crypt Depth Ratio (VH:CD) at Week 12 | Baseline and week 12 | Attenuation of the effects of gluten exposure was assessed by measuring the percent change from baseline in villous height to crypt depth ratio after 10 weeks of gluten challenge. Villi are the small fingerlike projections that line the small intestine and promote nutrient absorption and are often shortened in patients with celiac disease. Crypts are grooves between the villi that are often elongated in patients with celiac disease. A decreased VH:CD ratio indicates worsening disease. Small bowel biopsies were performed at baseline and week 12; histological assessments were performed by a blinded central pathologist. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Improvement in Marsh Score at Week 12 | Baseline and week 12 | The Marsh classification system describes the stages of damage in the small intestine as seen under a microscope, with possible values of 0, 1, 2, 3a, 3b, or 3c. A score of 0 (best score) indicates that the intestinal lining is normal and celiac disease highly unlikely, a score of 3c (worst score) indicates increased intraepithelial lymphocytes, increased crypt hyperplasia and complete villi atrophy. Improvement is defined as a lower grade on the Marsh score scale compared to baseline. |
| Percent Change From Baseline in Anti-Tissue Transglutaminase (tTG) Immunoglobulin A (IgA) Antibodies at Week 12 | Baseline and week 12 | Levels of anti-tTG IgA antibodies in serum were determined using an enzyme-linked immunosorbent assay (ELISA) immunoassay. |
| Change From Baseline in Anti-Deamidated Gliadin Peptide (DGP) Antibodies at Week 12 | Baseline and week 12 | Levels of serum anti-DGP antibodies (immunoglobulin A \[IgA\] and immunoglobulin G \[IgG\]) were determined using ELISA immunoassay. |
| Percent Change From Baseline in Intraepithelial Lymphocyte Density at Week 12 | Baseline and week 12 | Intraepithelial lymphocytes (IELS) are white blood cells interspersed between epithelial cells of the small and large intestine where they function to preserve the integrity of the mucosal barrier by protecting the epithelium against pathogen or immune-induced pathology. Increased intraepithelial lymphocytes is associated with celiac disease. Small bowel biopsies were performed at baseline and week 12; histological assessments were performed by a blinded central pathologist. |
| Number of Participants With Diarrhoea at Baseline and Week 12 | Baseline and week 12 | The Bristol Stool Form Scale (BSFS) is a pictorial aid to help study participants identify the shape and consistency of their bowel movements. Participants were asked to complete this form daily using an electronic diary at the time of each bowel movement. The BSFS categorizes bowel movements into 7 types, from Type 1 (separate hard lumps, like nuts; hard to pass) to Type 7 (watery, no solid pieces, entirely liquid). Diarrhoea was defined as at least one BSFS score \>= 6 for the given week. |
| Percent Change From Baseline in Total Weekly Gastrointestinal Symptom Rating Scale (GSRS) Score at Week 12 | Baseline and 12 weeks | The GSRS is a 15-question 7-scale questionnaire used to assess 5 dimensions of gastrointestinal syndromes: diarrhea, indigestion, constipation, abdominal pain, and reflux. Questions are scored between 1 (no discomfort at all) and 7 (very severe discomfort). The total GSRS score is calculated as the sum of the scores of all 15 questions, and ranges from 15 (no discomfort at all) to 105 (very severe discomfort in all 5 dimensions of gastrointestinal syndromes). |
| Change From Baseline in Total Celiac Disease GSRS (CeD-GSRS) Score at Week 12 | Baseline and 12 weeks | The CeD-GSRS score is derived from a subset of questions from the GSRS questionnaire, including the diarrhea, indigestion, and abdominal pain domains (a total of 10 questions), which are each assessed on a scale of 1 (no discomfort at all) to 7 (very severe discomfort). The total CeD-GSRS score is calculated as the sum of the scores of all 10 questions, and ranges from 10 (no discomfort at all) to 70 (very severe discomfort in all celiac syndromes). |
| Number of Weekly Bowel Movements at Baseline and Week 12 | Baseline and week 12 | Participants were asked to record every bowel movement during the study using an electronic diary. If no bowel movements were experienced on any given day, the participant was required to document this using the electronic diary. |
Countries
Finland
Participant flow
Recruitment details
This study was conducted at three sites in Finland.
Pre-assignment details
Participants who met the study entry criteria were randomized at a 1:1:1 ratio to receive 150 mg or 300 mg AMG 714 or placebo once every 2 weeks for a total of 6 administrations over a period of 10 weeks. Randomization was stratified by study site and sex.
Participants by arm
| Arm | Count |
|---|---|
| AMG 714 150 mg Participants received 150 mg AMG 714 via subcutaneous injection once every 2 weeks for a total of 6 doses over 10 weeks from day 0. Participants received gluten-free cookies twice a day for the first 2 weeks and gluten-containing cookies twice a day from weeks 2 to 12 (gluten-challenge). | 22 |
| AMG 714 300 mg Participants received 300 mg AMG 714 via subcutaneous injection once every 2 weeks for a total of 6 doses over 10 weeks from day 0. Participants received gluten-free cookies twice a day for the first 2 weeks and gluten-containing cookies twice a day from weeks 2 to 12 (gluten-challenge). | 22 |
| Placebo Participants received placebo subcutaneous injection once every 2 weeks for a total of 6 doses over 10 weeks from day 0. Participants received gluten-free cookies twice a day for the first 2 weeks and gluten-containing cookies twice a day from weeks 2 to 12 (gluten-challenge). | 20 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | AMG 714 150 mg | AMG 714 300 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 51.0 years STANDARD_DEVIATION 15.5 | 47.8 years STANDARD_DEVIATION 15.1 | 54.7 years STANDARD_DEVIATION 14.9 | 51.0 years STANDARD_DEVIATION 15.2 |
| Age, Customized 18 - 64 years | 17 Participants | 20 Participants | 12 Participants | 49 Participants |
| Age, Customized ≥ 65 years | 5 Participants | 2 Participants | 8 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 22 Participants | 20 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 22 Participants | 22 Participants | 20 Participants | 64 Participants |
| Sex: Female, Male Female | 16 Participants | 17 Participants | 14 Participants | 47 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 6 Participants | 17 Participants |
| Small Intestinal Villous Height to Crypt Depth Ratio | 2.12 ratio STANDARD_DEVIATION 0.251 | 2.19 ratio STANDARD_DEVIATION 0.343 | 2.19 ratio STANDARD_DEVIATION 0.426 | 2.17 ratio STANDARD_DEVIATION 0.341 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 21 | 0 / 19 |
| other Total, other adverse events | 21 / 22 | 20 / 21 | 19 / 19 |
| serious Total, serious adverse events | 0 / 22 | 0 / 21 | 0 / 19 |
Outcome results
Primary
Percent Change From Baseline in Villous Height to Crypt Depth Ratio (VH:CD) at Week 12
Attenuation of the effects of gluten exposure was assessed by measuring the percent change from baseline in villous height to crypt depth ratio after 10 weeks of gluten challenge. Villi are the small fingerlike projections that line the small intestine and promote nutrient absorption and are often shortened in patients with celiac disease. Crypts are grooves between the villi that are often elongated in patients with celiac disease. A decreased VH:CD ratio indicates worsening disease. Small bowel biopsies were performed at baseline and week 12; histological assessments were performed by a blinded central pathologist.
Time frame: Baseline and week 12
Population: The per protocol 1 (PP1) population included randomized participants who received at least 1 dose of study drug, were histologically evaluable (provided a post-treatment biopsy sample) and received gluten challenge for at least 1 week.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AMG 714 150 mg | Percent Change From Baseline in Villous Height to Crypt Depth Ratio (VH:CD) at Week 12 | -62.66 percent change | Standard Error 5.39 |
| AMG 714 300 mg | Percent Change From Baseline in Villous Height to Crypt Depth Ratio (VH:CD) at Week 12 | -53.78 percent change | Standard Error 4.83 |
| Placebo | Percent Change From Baseline in Villous Height to Crypt Depth Ratio (VH:CD) at Week 12 | -60.17 percent change | Standard Error 5.22 |
p-value: 0.727195% CI: [-16.82, 11.83]ANCOVA
p-value: 0.343895% CI: [-7.07, 19.85]ANCOVA
Secondary
Change From Baseline in Anti-Deamidated Gliadin Peptide (DGP) Antibodies at Week 12
Levels of serum anti-DGP antibodies (immunoglobulin A \[IgA\] and immunoglobulin G \[IgG\]) were determined using ELISA immunoassay.
Time frame: Baseline and week 12
Population: Per protocol 1 population with available data
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| AMG 714 150 mg | Change From Baseline in Anti-Deamidated Gliadin Peptide (DGP) Antibodies at Week 12 | Immunoglobulin A | 43.19 kU/L | Standard Error 12.85 |
| AMG 714 150 mg | Change From Baseline in Anti-Deamidated Gliadin Peptide (DGP) Antibodies at Week 12 | Immunoglobulin G | 28.29 kU/L | Standard Error 21.45 |
| AMG 714 300 mg | Change From Baseline in Anti-Deamidated Gliadin Peptide (DGP) Antibodies at Week 12 | Immunoglobulin A | 18.47 kU/L | Standard Error 10.7 |
| AMG 714 300 mg | Change From Baseline in Anti-Deamidated Gliadin Peptide (DGP) Antibodies at Week 12 | Immunoglobulin G | 17.98 kU/L | Standard Error 14.57 |
| Placebo | Change From Baseline in Anti-Deamidated Gliadin Peptide (DGP) Antibodies at Week 12 | Immunoglobulin A | 25.38 kU/L | Standard Error 11.44 |
| Placebo | Change From Baseline in Anti-Deamidated Gliadin Peptide (DGP) Antibodies at Week 12 | Immunoglobulin G | 15.12 kU/L | Standard Error 16.02 |
Comparison: Analysis of Change From Baseline in Anti-DGP-IgAp-value: 0.303495% CI: [-16.68, 52.29]Mixed-effect Model Repeat Measurement
Comparison: Analysis of Change From Baseline in Anti-DGP-IgAp-value: 0.656995% CI: [-38.11, 24.28]Mixed-effect Model Repeat Measurement
Comparison: Analysis of Change From Baseline in Anti-DGP-IgGp-value: 0.625495% CI: [-40.86, 67.2]Mixed-effect Model Repeat Measurement
Comparison: Analysis of Change From Baseline in Anti-DGP IgGp-value: 0.895595% CI: [-40.84, 46.57]Mixed-effect Model Repeat Measurement
Secondary
Change From Baseline in Total Celiac Disease GSRS (CeD-GSRS) Score at Week 12
The CeD-GSRS score is derived from a subset of questions from the GSRS questionnaire, including the diarrhea, indigestion, and abdominal pain domains (a total of 10 questions), which are each assessed on a scale of 1 (no discomfort at all) to 7 (very severe discomfort). The total CeD-GSRS score is calculated as the sum of the scores of all 10 questions, and ranges from 10 (no discomfort at all) to 70 (very severe discomfort in all celiac syndromes).
Time frame: Baseline and 12 weeks
Population: Per protocol 1 population with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AMG 714 150 mg | Change From Baseline in Total Celiac Disease GSRS (CeD-GSRS) Score at Week 12 | 0.65 units on a scale | Standard Error 1.52 |
| AMG 714 300 mg | Change From Baseline in Total Celiac Disease GSRS (CeD-GSRS) Score at Week 12 | 1.77 units on a scale | Standard Error 1.37 |
| Placebo | Change From Baseline in Total Celiac Disease GSRS (CeD-GSRS) Score at Week 12 | 3.41 units on a scale | Standard Error 1.52 |
p-value: 0.190895% CI: [-6.89, 1.3]Mixed-effect Model Repeat Measurement
p-value: 0.408895% CI: [-5.53, 2.25]Mixed-effect Model Repeat Measurement
Secondary
Number of Participants With Diarrhoea at Baseline and Week 12
The Bristol Stool Form Scale (BSFS) is a pictorial aid to help study participants identify the shape and consistency of their bowel movements. Participants were asked to complete this form daily using an electronic diary at the time of each bowel movement. The BSFS categorizes bowel movements into 7 types, from Type 1 (separate hard lumps, like nuts; hard to pass) to Type 7 (watery, no solid pieces, entirely liquid). Diarrhoea was defined as at least one BSFS score \>= 6 for the given week.
Time frame: Baseline and week 12
Population: Per protocol 1 population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AMG 714 150 mg | Number of Participants With Diarrhoea at Baseline and Week 12 | Baseline | 4 Participants |
| AMG 714 150 mg | Number of Participants With Diarrhoea at Baseline and Week 12 | Week 12 | 1 Participants |
| AMG 714 300 mg | Number of Participants With Diarrhoea at Baseline and Week 12 | Baseline | 9 Participants |
| AMG 714 300 mg | Number of Participants With Diarrhoea at Baseline and Week 12 | Week 12 | 5 Participants |
| Placebo | Number of Participants With Diarrhoea at Baseline and Week 12 | Baseline | 7 Participants |
| Placebo | Number of Participants With Diarrhoea at Baseline and Week 12 | Week 12 | 6 Participants |
Secondary
Number of Participants With Improvement in Marsh Score at Week 12
The Marsh classification system describes the stages of damage in the small intestine as seen under a microscope, with possible values of 0, 1, 2, 3a, 3b, or 3c. A score of 0 (best score) indicates that the intestinal lining is normal and celiac disease highly unlikely, a score of 3c (worst score) indicates increased intraepithelial lymphocytes, increased crypt hyperplasia and complete villi atrophy. Improvement is defined as a lower grade on the Marsh score scale compared to baseline.
Time frame: Baseline and week 12
Population: The per protocol 1 (PP1) population included randomized participants who received at least 1 dose of study drug, were histologically evaluable (provided a post-treatment biopsy sample) and received gluten challenge for at least 1 week.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMG 714 150 mg | Number of Participants With Improvement in Marsh Score at Week 12 | 0 Participants |
| AMG 714 300 mg | Number of Participants With Improvement in Marsh Score at Week 12 | 0 Participants |
| Placebo | Number of Participants With Improvement in Marsh Score at Week 12 | 0 Participants |
Secondary
Number of Weekly Bowel Movements at Baseline and Week 12
Participants were asked to record every bowel movement during the study using an electronic diary. If no bowel movements were experienced on any given day, the participant was required to document this using the electronic diary.
Time frame: Baseline and week 12
Population: Per protocol 1 population with available data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AMG 714 150 mg | Number of Weekly Bowel Movements at Baseline and Week 12 | Baseline | 8.9 bowel movements per week | Standard Deviation 3.66 |
| AMG 714 150 mg | Number of Weekly Bowel Movements at Baseline and Week 12 | Week 12 | 9.3 bowel movements per week | Standard Deviation 2.58 |
| AMG 714 300 mg | Number of Weekly Bowel Movements at Baseline and Week 12 | Baseline | 10.2 bowel movements per week | Standard Deviation 3.96 |
| AMG 714 300 mg | Number of Weekly Bowel Movements at Baseline and Week 12 | Week 12 | 11.5 bowel movements per week | Standard Deviation 5.25 |
| Placebo | Number of Weekly Bowel Movements at Baseline and Week 12 | Baseline | 9.6 bowel movements per week | Standard Deviation 2.92 |
| Placebo | Number of Weekly Bowel Movements at Baseline and Week 12 | Week 12 | 11.6 bowel movements per week | Standard Deviation 3.99 |
Comparison: Analysis of Total Weekly Bowel Movements at Week 12p-value: 0.16195% CI: [0.63, 1.08]Generalized Linear Mixed Model
p-value: 0.78195% CI: [0.81, 1.32]Generalized Linear Mixed Model
Secondary
Percent Change From Baseline in Anti-Tissue Transglutaminase (tTG) Immunoglobulin A (IgA) Antibodies at Week 12
Levels of anti-tTG IgA antibodies in serum were determined using an enzyme-linked immunosorbent assay (ELISA) immunoassay.
Time frame: Baseline and week 12
Population: Per protocol 1 population with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AMG 714 150 mg | Percent Change From Baseline in Anti-Tissue Transglutaminase (tTG) Immunoglobulin A (IgA) Antibodies at Week 12 | 5019.77 percent change | Standard Error 1482.59 |
| AMG 714 300 mg | Percent Change From Baseline in Anti-Tissue Transglutaminase (tTG) Immunoglobulin A (IgA) Antibodies at Week 12 | 1562.42 percent change | Standard Error 784.83 |
| Placebo | Percent Change From Baseline in Anti-Tissue Transglutaminase (tTG) Immunoglobulin A (IgA) Antibodies at Week 12 | 617.53 percent change | Standard Error 866.44 |
p-value: 0.01495% CI: [936.39, 7868.1]Mixed-effect Model Repeat Measurement
p-value: 0.422895% CI: [-1410.65, 3300.44]Mixed-effect Model Repeat Measurement
Secondary
Percent Change From Baseline in Intraepithelial Lymphocyte Density at Week 12
Intraepithelial lymphocytes (IELS) are white blood cells interspersed between epithelial cells of the small and large intestine where they function to preserve the integrity of the mucosal barrier by protecting the epithelium against pathogen or immune-induced pathology. Increased intraepithelial lymphocytes is associated with celiac disease. Small bowel biopsies were performed at baseline and week 12; histological assessments were performed by a blinded central pathologist.
Time frame: Baseline and week 12
Population: The per protocol 1 (PP1) population included randomized participants who received at least 1 dose of study drug, were histologically evaluable (provided a post-treatment biopsy sample) and received gluten challenge for at least 1 week.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AMG 714 150 mg | Percent Change From Baseline in Intraepithelial Lymphocyte Density at Week 12 | 95.14 percent change | Standard Error 15.06 |
| AMG 714 300 mg | Percent Change From Baseline in Intraepithelial Lymphocyte Density at Week 12 | 68.22 percent change | Standard Error 13.64 |
| Placebo | Percent Change From Baseline in Intraepithelial Lymphocyte Density at Week 12 | 109.46 percent change | Standard Error 14.65 |
p-value: 0.474695% CI: [-54.39, 25.74]ANCOVA
p-value: 0.034395% CI: [-79.28, -3.2]ANCOVA
Secondary
Percent Change From Baseline in Total Weekly Gastrointestinal Symptom Rating Scale (GSRS) Score at Week 12
The GSRS is a 15-question 7-scale questionnaire used to assess 5 dimensions of gastrointestinal syndromes: diarrhea, indigestion, constipation, abdominal pain, and reflux. Questions are scored between 1 (no discomfort at all) and 7 (very severe discomfort). The total GSRS score is calculated as the sum of the scores of all 15 questions, and ranges from 15 (no discomfort at all) to 105 (very severe discomfort in all 5 dimensions of gastrointestinal syndromes).
Time frame: Baseline and 12 weeks
Population: Per protocol 1 population with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AMG 714 150 mg | Percent Change From Baseline in Total Weekly Gastrointestinal Symptom Rating Scale (GSRS) Score at Week 12 | 4.14 percent change | Standard Error 9.01 |
| AMG 714 300 mg | Percent Change From Baseline in Total Weekly Gastrointestinal Symptom Rating Scale (GSRS) Score at Week 12 | 14.96 percent change | Standard Error 8.17 |
| Placebo | Percent Change From Baseline in Total Weekly Gastrointestinal Symptom Rating Scale (GSRS) Score at Week 12 | 17.58 percent change | Standard Error 8.93 |
p-value: 0.276195% CI: [-37.66, 10.77]Mixed-effect Model Repeat Measurement
p-value: 0.822195% CI: [-25.51, 20.27]Mixed-effect Model Repeat Measurement