Main objective:To evaluate the safety and tolerability of two i.v. infusions of escalating doses of TPM502 in CeD patients.Secondary objectives:• To identify PD effects consistent with the induction of antigen-specific immune tolerance following the…
ID
Source
Brief title
Condition
- Gastrointestinal conditions NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence, severity, causality and outcomes of TEAEs (serious and nonserious),
including hypersensitivity reactions, CRS, hepatotoxicity and other AEs
suggestive of these conditions.
Secondary outcome
• Ratio "Interleukin 2 (IL-2) after GC post-TPM502 treatment/IL-2 after GC at
screening" compared to the placebo group
• Modified Celiac disease patient*reported outcome (CeD PRO®) and GloSS (Global
Symptom Survey) 1 hour before and then hourly up to 6 hours post GC/ TPM502
compared to placebo
• Maximum observed plasma concentration after dosing (Cmax), area under the
plasma concentration-time curve from time zero to the time of the last
quantifiable sample (AUC0-last).
Background summary
CeD is an autoimmune chronic inflammatory disease of the small intestine
triggered by gluten ingestion in genetically predisposed individuals, and it is
characterized by a specific serological and histological profile.
Gluten is the general term for alcohol-soluble proteins present in various
cereals, including wheat, rye, barley, spelt, and kamut. The main pathological
intestinal manifestations of CeD are villus atrophy and crypt hyperplasia, as
well as inflammatory lymphocyte infiltration of the gut epithelium. This leads
to diarrhoea, abdominal pain, malabsorption and other - often serious -
clinical manifestations. Up to 30% of patients have severe symptoms and/or
persisting inflammation in spite of adhering to a gluten-free diet (GFD) (3).
CeD may also be associated with intestinal lymphoma and enhanced
extra-intestinal autoimmunity, such as Type 1 diabetes (4-6).
CeD is one of the most common autoimmune disorders, with a reported prevalence
of 0.5-1% of the general population, with the exception of areas showing low
frequency of CeD predisposing genes and low gluten consumption (e.g.,
sub-Saharan Africa and Japan). CeD prevalence is increasing in Western
countries (7).
Despite the high medical need, there are currently no effective non-dietary
therapies available to patients, and the only treatment option is lifelong
strict adherence to a GFD. This poses not only multiple restrictions that
impact the patients* physical and mental health and quality of life, but often
fails to completely prevent inflammatory flares, as undeclared or *hidden*
gluten in food products is often consumed involuntarily.
The inflammatory responses triggered by gluten depend on CD4+ T cell-induced
immunity to certain gluten-derived peptides. These peptides are rendered
strongly antigenic through tissue transglutaminase-mediated deamidation of
certain glutamine residues. The resulting charged glutamates bind with high
affinity into peptide binding pockets of the human major histocompatibility
complex (MHC) class II molecules HLA-DQ2 and DQ8 (8).
The causative genetic link between CeD and HLA-DQ2 and HLA-DQ8, together with
insight into disease-associated immune responses against HLA-DQ2 and
DQ8-restricted antigenic gluten peptides, makes CeD a suitable setting to
investigate novel antigenic peptide-specific immunotherapies aiming at
restoring immunological tolerance. Topas particle mix (TPM) 502, which is the
investigational drug tested in this study, represents a targeted (it addresses
specific epitopes) and a personalized (it is addressed to specific individuals
within the diseased population) approach to the disease. In fact, CeD is one of
the few autoimmune conditions for which the key genetic elements, the
auto-antigen involved (tissue transglutaminase) and the environmental trigger
(gluten) are known and well-defined.
Study objective
Main objective:
To evaluate the safety and tolerability of two i.v. infusions of escalating
doses of TPM502 in CeD patients.
Secondary objectives:
• To identify PD effects consistent with the induction of antigen-specific
immune tolerance following the administration of TPM502
• To describe the severity of gastrointestinal (GI) symptoms following the
administration of TPM502 and a GC
• To determine TPM502 PK
Study design
Multi center, double-blind, randomized, placebo-controlled study
Intervention
TPM502
Study burden and risks
TPM502 has not been administered to humans, therefore there are no clinical
data yet indicating a benefit for CeD patients.
Any potential benefit for the patients in the study is theoretical, based on
the assumed mechanism of action and on preclinical results in relevant animal
models, and may be restricted to some of the study groups only or not be
present at all.
Importantly, the safety, tolerability, and PD data obtained from this study
will form the basis for any further clinical development of TPM502 and are thus
expected to be fundamental for the development of a new treatment approach for
CeD and other autoimmune diseases.
Given all the above, the potential long-term benefit of obtaining a safe and
effective treatment for patients with CeD is considered to outweigh any
potential individual risks, and the benefit/risk of conducting the study is
positive.
This benefit/risk will be regularly monitored by the iDMC, to ensure it remains
positive and the patients in the study are adequately protected.
Falkenried 88, Haus A
Hamburg 20251
DE
Falkenried 88, Haus A
Hamburg 20251
DE
Listed location countries
Age
Inclusion criteria
1. Availability of a documented biopsy-confirmed diagnosis of CeD OR documented
tissue transglutaminase >10x upper limit of normal (ULN) and documented
positive immunoglobulin A (IgA) anti-endomysial antibody (EMA) at time of CeD
diagnosis (as per local guidelines) 2. Serum anti-tissue transglutaminase 2
immunoglobin A antibodies within normal range at screening 3. Serum IL-2 levels
(AUC1-6h) > 2x AUC1-6h at the lower level of quantification (LLOQ) (i.e., 8x
LLOQ) following the GC at screening 4. Patients must have been on gluten-free
diet (GFD) for >= 6 months 5. Patients must have well-controlled CeD, defined as
mild or with no ongoing signs or symptoms felt to be related to active CeD, as
per investigator`s assessment 6. Human leukocyte antigen (HLA)-DQ2.5 positive
(homozygous and heterozygous) but HLA-DQ8 and HLA-DQ2.2 negative
Exclusion criteria
1. Known or suspected refractory CeD (refractory CeD type I or II)
2. Known intolerable symptoms following previous GCs, as per investigator`s
assessment
3. Treatment with systemic immunosuppressants (e.g., glucocorticoids), ongoing
or administered in the 12 weeks preceding the first investigational medicinal
product (IMP) administration
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2022-001656-41-NL |
| CCMO | NL83574.056.23 |