| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective: To assess the efficacy of AMG 714 in attenuating the effects of gluten exposure in adults with celiac disease
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| E.2.2 | Secondary objectives of the trial |
Secondary Objective: To assess the safety and tolerability of AMG 714 when administered to adult patients with celiac disease exposed to a gluten challenge
Exploratory Objective: To assess the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD correlations of AMG 714 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must fulfill all of the following inclusion criteria to be eligible for participation at screening and at Visit 1 (Week 0/Day 0): 1. Adult males or females 18 to 80 years of age, inclusive.
2. Demonstrate willingness to participate in the study as documented by signed informed consent.
3. Subjects must have a diagnosis of celiac disease by intestinal biopsy at least 12 months prior to screening as confirmed by medical records, written physician statement or by the Kela statement, the national social security institution determining the governmental reimbursement for biopsy-proven celiac disease patients.
4. Subjects must have been on a GFD for at least 12 consecutive months prior to screening and must be willing to remain on a GFD for the duration of study participation (apart from the Sponsor-supplied 2g gluten taken BID during the 10-week gluten challenge period of the study).
5. Negative anti-tTG (IgA) at screening.
6. Negative iVYLISA GIP gluten stool test results at screening.
7. Negative H.-pylori test prior to study drug administration.
8. Human leukocyte antigen DQ (HLA-DQ) typing compatible with celiac disease provided or obtained before baseline biopsy.
9. Body mass index (BMI) between 16.0 and 45.0 kg/mPP2PP, inclusive.
10. Screening laboratory values within the following parameters (unless investigator considers an abnormality to be not clinically significant): a) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x the upper limit of normal (ULN). b) Hemoglobin > 10 g/dL (>100 g/L in SI units) c) Platelet count > 125,000 mmPP3PP (>125 /L in SI units). d) White blood cell count > 3,500 cells/mmPP3PP (>3.5 x10PP9PP/L). e) Estimated glomerular filtration rate (eGFR) > 60 ml/min. f) Glycosylated hemoglobin (HbA1C) <7% (<53 mmol/mol) in subjects with a diagnosis of Type 1 or Type 2 Diabetes Mellitus
11. Females of non-childbearing potential defined as postmenopausal (>45 years of age with amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and a serum follicle stimulating hormone [FSH] level >40 IU/L at Screening); or permanently sterilized (eg, bilateral tubal occlusion, hysterectomy, bilateral salpingectomy, oophorectomy); or otherwise incapable of pregnancy OR Females of child bearing potential (FOCBP) or males who agree to practice two highly effective methods of birth control (as determined by the Investigator; one of the methods must be a barrier technique) from Screening through the end of study participation (Visit 8, Week 16/Day 112) and for 6 months after the end of the study.
12. Willingness and ability to comply with study procedures and protocol stipulated concomitant medication guidelines.
13. Willingness to return for all scheduled follow-up visits.
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| E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if there is evidence of any of the following:
1. Current diagnosis of any severe complication of celiac disease, such as Refractory Celiac Disease Type I or Type II (RCD-I or RCD-II), enteropathy-associated T-cell lymphoma (EATL), ulcerative jejunitis or perforation.
2. Diagnosis of any autoimmune disease, other than celiac disease or dermatitis herpetiformis (DH), that might interfere with the conduct of the study or require systemic immunomodulation therapy.
3. Occurrence of celiac disease-related symptoms (CeD-GSRS >2.3) as assessed by screening GSRS.
4. Diagnosis of any chronic, active gastrointestinal (GI) disease other than celiac disease (e.g., active, untreated peptic ulcer, esophagitis, gastroesophageal reflux disease [GERD]; active ulcerative colitis; Crohn’s disease, or irritable bowel syndrome] that might, in the Investigator’s opinion, interfere with assessment of symptoms of abdominal pain, diarrhea, or other components of celiac disease.
5. Any known, symptomatic food allergy, including an allergy to the ingredients of the gluten challenge vehicle that, in the opinion of the Investigator, might interfere with the conduct of the study or result in anaphylaxis.
6. Presence of any of the following related to infection:
a) Active acute infection requiring systemic treatment (antibiotics, antifungal, or antiviral)
b) Active GI infection
c) Persistent or severe infection within the three months prior to randomization
d) History of tuberculosis (TB)
e) Positive Interferon Gamma Release Assay (IGRA) test at screening or known recent exposure (within 6 months prior to screening) to a patient with active TB; subject can be enrolled if he or she has been successfully treated with appropriate chemoprophylaxis.
f) History within 3 years prior to screening of an opportunistic infection typical of those seen in immunocompromised patients (e.g., herpes zoster, systemic candida infection, or systemic fungal infection).
7. Use of systemic immune suppressants (including steroids) within 3 months or 5 half-lives, whichever is longer, prior to randomization.
8. Required use of a prohibited medication at the time of randomization (prohibited medications required for treatment of an AE occurring after randomization are permitted).
9. Current diagnosis or history of cancer within the past 5 years, except successfully treated basal cell or squamous cell carcinoma, cervical carcinoma-in-situ, or early stage prostate cancer.
10. Administration of a live vaccine within 14 days prior to the first administration of study drug.
11. History or presence of clinically significant disease that in the opinion of the Investigator would confound the subject’s participation and follow-up in the clinical trial or put the subject at unnecessary risk, including but not limited to:
a) Cardiovascular disease (e.g., uncontrolled hypertension defined as office systolic blood pressure [BP] equal to or greater than 180 mmHg or office diastolic BP equal or greater than 110 mm/Hg, unstable angina, congestive heart failure worse than New York Heart Association [NYHA] Class II, coronary angioplasty or myocardial infarction within the last 6 months, uncontrolled atrial or ventricular cardiac arrhythmias clinically significant pleural or pericardial effusion or ascites)
b) pulmonary disease (e.g., severe chronic pulmonary disease)
c) renal, hematological, gastrointestinal, endocrine (e.g., poorly controlled diabetes), immunologic, dermatologic, neurological, or psychiatric disease
12. History of significant drug or alcohol abuse during the year prior to study screening as obtained by medical record and/or subject report.
13. History of clinically significant hypersensitivity to the study drug, any related drugs, or to any of the excipients.
14. History of anaphylactic reactions (e.g. IgE-mediated reactions) to wheat or gluten.
15. Positive Hepatitis B (Hep B), Hepatitis C (Hep C), or Human Immunodeficiency Virus (HIV) infection test results at the time of screening.
16. Females who are pregnant or planning to become pregnant during the study participation period, or are currently breastfeeding.
17. Blood donation within 3 months prior to screening.
18. Participation in another investigational drug or device study or treatment with an investigational drug within 3 months or 5 half-lives, whichever is longer, prior to randomization.
19. Any additional reason, which in the opinion of the Investigator, would prevent the subject from safely participating in the study or complying with protocol requirements including the endoscopies and biopsy collections.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint:
-Attenuation of gluten-induced small intestinal mucosal morphological injury, measured morphometrically as villous height to crypt depth (VH:CD) ratio |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
-Attenuation of gluten-induced small intestinal mucosal inflammation measured as intraepithelial lymphocyte (IELs) density
-Attenuation of gluten-induced small intestinal mucosal morphological injury using a grouped classification of Marsh score
-Attenuation of gluten-induced serum antibodies:
-Anti-tissue transglutaminase antibodies (anti-tTG IgA)
-Anti-deamidated gliadin peptide (anti-DGP) IgA and IgG
-Attenuation of gluten-induced clinical symptoms as assessed by:
-Bristol Stool Form Scale (BSFS)
-Gastrointestinal Symptom Rating Scale (GSRS) and
-celiac disease GSRS (CeD-GSRS)
Exploratory endpoints:
-Pharmacokinetics (PK), Pharmacodynamics (PD) and Exposure/Response (PK/PD)
-Physician Global Assessment of Disease (PGA)
-Biomarkers of disease activity
-Celiac Disease Patient-Reported Outcome (CeD PRO)
Safety endpoints:
-Adverse events (AEs)
-Clinical laboratory tests
-Physical examination
-Vital signs
-Immunogenicity
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biomarkers related to celiac disease activity |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
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