Study to Evaluate the Efficacy and Safety of AMG 714 in Adult Patients With Type II Refractory Celiac Disease

Study Overview
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Brief Summary
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Protocol CELIM-RCD-002 is designed to evaluate the efficacy and safety of AMG 714 for the treatment of adult patients with type II refractory celiac disease (RCD-II), an in-situ small bowel T-cell lymphoma.

Official Title
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A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of AMG 714 in Adult Patients With Type II Refractory Celiac Disease, an In Situ Small Bowel T Cell Lymphoma

Conditions
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Type II Refractory Celiac Disease (RCD-II), In-situ Small Bowel T-cell Lymphoma

Intervention / Treatment
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* Biological: AMG 714
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of refractory celiac disease Type II (RCD-II) Greater than 20% aberrant intraepithelial lymphocytes (IEL) as assessed by flow cytometry On a gluten-free diet for at least 6 months Avoid pregnancy Exclusion Criteria: Enteropathy-Associated T cell Lymphoma (EATL) Infections Immune suppression Clinically significant co-morbidities

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMG 714<br>Participants were administered 8 mg/kg AMG 714 via intravenous infusion on day 0, day 7 and every 2 weeks thereafter through week 10. | Biological: AMG 714<br>* Administered via a 120-minute IV infusion for a total of 7 times over 10 weeks.<br>|
| Placebo Comparator: Placebo<br>Participants were administered placebo via intravenous infusion on day 0, day 7 and every 2 weeks thereafter through week 10. | Biological: Placebo<br>* Administered via a 120-minute IV infusion for a total of 7 times over 10 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in the Percentage of Aberrant Intestinal Intraepithelial Lymphocytes With Respect to All Intraepithelial Lymphocytes | The primary endpoint in this study was the change form baseline in the percentage of aberrant intestinal intraepithelial lymphocytes (IELs) with respect to total IELs, as assessed by flow cytometry (Immunological Response 1). 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. In refractory coeliac disease type 2, aberrant intraepithelial lymphocytes make up 20% or more of total intraepithelial lymphocytes. Aberrant IELs were defined by flow cytometry as surface cluster of differentiation (CD)3-negative, intracellular CD3-positive IELs (sCD3-, icCD3+). | Baseline and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in the Percentage of Aberrant Intestinal Intraepithelial Lymphocytes With Respect to All Intestinal Epithelial Cells | Percent change from baseline in the percentage of aberrant intestinal IELs with respect to intestinal epithelial cells (Immunological Response 2) is a composite endpoint calculated by multiplying the percent of aberrant IEL versus total IELs (per flow cytometry) by the percent of total IEL versus intestinal epithelial cells as assessed by immunohistochemistry. | Baseline and week 12 | 
| Percent Change From Baseline in Villous Height to Crypt Depth (VH:CD) Ratio | 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 and increases in the VH:CD ratio indicate an improvement in the histology of intestinal mucosa (Histological Response). Small bowel biopsies were performed at baseline and week 12; histological assessments were performed by a blinded central pathologist. | Baseline and week 12 | 
| Percentage 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. | Baseline and week 12 | 
| Percent Change From Baseline in Total Intraepithelial Lymphocyte Count at Week 12 | Small bowel biopsies were performed at baseline and week 12; histological assessments were performed by a blinded central pathologist. The total IEL count is the density of IELs vs intestinal epithelial cells measured by immunohistochemistry. | Baseline and week 12 | 
| 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 by the participant on any given day, the participant was required to document this in the diary. | Baseline and week 12 | 
| Percentage of Participants With Diarrhea at Baseline and Week 12 | The Bristol Stool Form Scale (BSFS) is a pictorial aid to help 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 at least one BSFS score >= 6 for the given week. | Baseline and week 12 | 
| 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). | Baseline and week 12 | 
| Change From Baseline in Total Celiac Disease GSRS (CeD-GSRS) Score at Week 12 | The CeD-GSRS score is derived from a subset of 10 questions from the GSRS questionnaire (questions 1, 4-9, 11, 12 and 14), which are each assessed on a scale of 1 (no discomfort at all) to 7 (very severe discomfort). The total CeD-GSRS score ranges from 10 (no discomfort at all) to 70 (very severe discomfort in all celiac syndromes). | Baseline and week 12 |