| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type II Refractory Celiac Disease (RCD-II) |
|
| E.1.1.1 | Medical condition in easily understood language |
| RCD-II is a lymphoma of the gut, which occurs in patients with celiac disease who have malignant immune cells. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Primary Objective: To assess the efficacy of AMG 714 in treating RCD-II in adult patients |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary Objective: To assess the safety and tolerability of AMG 714 when administred to adult patients with RCD-II |
|
| 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 years of age or older.
2. Demonstrated willingness to participate in the study as
documented by signed informed consent.
3. 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 (e.g., 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 9, Week 16/Day 112).
4. Prior confirmed diagnosis of RCD-II defined by the following
criteria: celiac disease confirmed by histology, endoscopy or
serology; with persistent and recurrent symptoms (e.g., diarrhea,
weight loss, abdominal pain); with abnormal small bowel
histology; with aberrant intraepithelial lymphocytosis of > 20
aberrant intraepithelial lymphocytes (IEL) per 100 CD45+ cells
as determined by flow cytometry (or >50% if determined by
immunohistochemistry); despite adherence to a strict GFD for at
least 6 months; and after exclusion of other potential causes of
symptomatic non-response (e.g., microscopic colitis, bacterial
overgrowth, lactose intolerance, exocrine pancreatic
insufficiency, hyperthyroidism, etc.) and intestinal histological
abnormality (autoimmune enteropathy, giardiasis,
immunodeficiency, collagenous sprue, Whipple’s disease,
etc.).
NOTE: Subjects who have been treated for RCD-II must continue to
have increased aberrant IELs (>20% by flow cytometry or 50%
by IHC) and abnormal small bowel histology (Marsh ≥1) and
must have had prior history of symptoms, however symptoms are
not required of previously treated subjects, or subjects being
treated with steroids, at the time of study entry.
5. Total attempted adherence to a GFD for at least 6 consecutive
months prior to screening. Subjects must also agree to make no
changes to their current GFD for the duration of study
participation.
6. Anti-tissue transglutaminase (IgA and IgG) at screening <2 x the
diagnostic level for celiac disease (weak positive or negative).
7. Human leukocyte antigen DQ (HLA-DQ) typing compatible
with celiac disease provided or obtained prior to baseline biopsy.
8. Life expectancy > 4 months.
9. Laboratory values:
a) Estimated creatinine clearance (CCr) > 30
mL/min/1.73m2 using the Cockcroft-Gault equation
b) Serum alkaline phosphatase (AP), alanine transaminase
(ALT/SGPT), and aspartate aminotransferase (AST/SGOT)
less than 3x the upper limits of normal (ULN)
c) Total bilirubin of less than 2.5 x ULN
d) Total white blood cell count (WBC) > 300/mm3
e) Platelet count > 85,000/mm3
f) INR less than 1.5
g) Albumin of more than 10 g/L (i.e., 1 g/dL or 1.45 μmol/L)
10.Subjects receiving systemic steroids must be on a stable dose
for at least 4 weeks prior to randomization, the dose should not
exceed 20 mg of prednisone, prednisolone or equivalent per
day. Oral budesonide will be accepted at a maximum dose of 9
mg per day.
11. Willingness and ability to comply with study procedures and
protocol stipulated concomitant medication guidelines.
12. Willingness to return for all scheduled follow-up visits. |
|
| E.4 | Principal exclusion criteria |
Subjects will be excluded from participation in the study if there is
evidence of any of the following, at screening or Visit 1:
1. Diagnosis of Type I Refractory Celiac Disease (RCD-I) or
enteropathy-associated T cell lymphoma (EATL, excluded by the
site’s standard imaging techniques for this purpose).
2. Presence of any of the following related to infection:
a) Active acute infection requiring systemic antibiotic,
parenteral antifungal, or systemic antiviral treatments
b) Severe infection within the 3 months prior to screening
c) History of tuberculosis (TB)
d) 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; the subject can be
enrolled if he or she has been successfully treated with
appropriate chemoprophylaxis.
e) History within the 3 years prior to screening of an
opportunistic infection typical of those seen in
immunocompromised subjects (e.g., systemic candida
infection, or systemic fungal infection).
3. Current diagnosis or history of cancer within the past 5 years,
except RCD-II, successfully-treated basal cell or squamous cell
carcinoma, cervical carcinoma-in-situ, or early stage prostate
cancer
4. 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 the New York Heart Association 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
5. History of significant immune suppression:
- Bone marrow transplant (BMT) or cladribine therapy less
than 6 months prior to baseline. In other words, cladribine
and bone marrow transplant naïve, primary non-responders
(treatment resistant), secondary non-responders (relapse
after response/remission) and incomplete responders may
be enrolled in the study if cladribine therapy and/or BMT
were not provided within the 6 months prior to
randomization.
- Potent systemic immune suppressants (e.g., azathioprine)
in the 3 months prior to baseline.
6. History of alcohol or drug abuse that would interfere with the
ability to comply with the study protocol.
7. History of clinically significant hypersensitivity to the study drug
or any related drugs or to any of the excipients.
8. Positive hepatitis B (Hep B), hepatitis C (Hep C), or Human
immunodeficiency virus (HIV) infection test results at the time of
screening.
9. Females who are pregnant or are planning to become pregnant
during the study participation period or 6 months after last dose,
or are currently breastfeeding.
10. Participation in another investigational drug or device study or
treatment with an investigational drug within 30 days or 5 halflives,
whichever is longer, prior to randomization
11. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the Immunological Response 1: Reduction from baseline in the % of aberrant intestinal intraepithelial lymphocytes (IELs) vs total IELs as assessed by flow-cytometry |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Immunological Response 2: Reduction from baseline in the % of aberrant IELs vs intestinal epithelial cells
Histological Response: Improvement from baseline in small intestinal villous height to crypt depth (VH:CD) ratio, Marsh score or total IEL counts
Clinical Response: Change from baseline in clinical symptoms
-Bristol Stool Form Scale (BSFS)
-Gastrointestinal Symptom Rating Scale (GSRS), including the celiac disease GSRS (CeD-GSRS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 |
|
| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Finland |
| France |
| Netherlands |
| Spain |
| United States |
|
| 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
|
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 24 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 27 |
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