Primary objectives- To evaluate the feasibility of leukapheresis and the production of human clinical-grade proinsulin-peptideC19-A3-pulsed TolDCs (PIpepTolDCs) in type 1 Diabetes Mellitus patients.- To evaluate the safety of clinical use of…
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
a. Primary safety endpoints
Occurrence of any of the following safety and feasibility concerns:
- hypersensitivity reaction grade >= 3 to PIpepTolDC product upon intradermal
injections
- any infectious complications requiring systemic medical treatment
- diagnosis of any new disease associated with autoimmunity
- diagnosis of new malignancy
- any other serious adverse event
b. Primary feasibility endpoints
- failure to complete a successful leukapheresis procedure
- failure to isolate sufficient numbers of mononuclear cells by leukapheresis
for PIpepTolDC production
- failure to generate the required dose of PIpepTolDCs
- any event that prevents the protocol or follow up to be executed as planned.
Secondary outcome
Secondary endpoints
- Improved or decreased stimulated C-peptide production compared to baseline at
12 and 24 weeks
- Change in the level or quality of T-cell specific immune responses at 4, 8,
12, and 24 weeks versus baseline.
Long term follow up (amendment):
- General medical history taking at least one time >1 year after vaccination
and if consented by the patient yearly thereafter .
- Assessment of remaining changes in the level or quality of T-cell specific
immune responses at least one time > 1 year after vaccination and if consented
by the patient yearly thereafter versus baseline as defined by:
o Change in responsiveness to proinsulin peptide or protein from IFNg- into
IL-10-producing as detected by ELISPOT;
o Disappearance of T cell responsiveness to autoantigens (GAD, IA-2), as
determined by lymphocyte stimulation test (LST);
o Disappearance of autoreactive CD8+ T cells as determined by Q-DOT.
Background summary
Type 1 Diabetes is a T-cell mediated autoimmune disease in which the insulin
producing pancreatic beta-cells are destroyed. Patients suffering from type 1
Diabetes Mellitus are faced with huge and unmet medical needs. Therapy is
usually limited to controlling collateral damage and symptoms, rather than
curing the disease. Studies in animal models indicate that the modulation of
immune responses may prevent or attenuate autoimmune diseases. Therefore, there
is a growing interest to induce tissue specific immunomodulation in a clinical
setting. In man, the use of T-cell inhibition or autoantigen vaccination
strategies are safe but of temporary or limited clinical efficacy. Tolerogenic
DCs (TolDCs), which selectively inhibit autoreactive effector T-cells and
induce immune tolerance against tissue and disease specific autoantigens are
attractive targets for investigation as an alternative to general immune
suppression to treat autoimmune diseases including type 1 Diabetes Mellitus.
Study objective
Primary objectives
- To evaluate the feasibility of leukapheresis and the production of human
clinical-grade proinsulin-peptideC19-A3-pulsed TolDCs (PIpepTolDCs) in type 1
Diabetes Mellitus patients.
- To evaluate the safety of clinical use of intradermally administered
increasing doses PIpepTolDCs in patients with type 1 Diabetes Mellitus as
measured by appropriate biomarkers listed in paragraph 10 and appendix D
Secondary objectives
- To examine beneficial effects of intradermal administration of PIpepTolDCs
such as improved stimulated C-peptide production and /or the level and quality
of T-cell specific immune responses listed in paragraph 10 and appendix D of
the protocol
Study design
This is a prospective, single-center, phase I, open label dose escalation
safety and feasibility study.
Intervention
Two intradermal injections of PIpepTolDCs (5x 10e6, 10x 10e6 or 20 x 10e6/
injection in 3 patients each) with a 28-day interval.
Patienten worden behandeld met 2 series van intradermale injecties met
PIpepTolDC met een interval van 4 weken, in 3 dosis-cohorten van elk 3
patienten.
- 1e dosiscohort: 2x 5 injecties, overeenkomend met 2x 0.5*10e7 PIpepTolDC
- 2e dosiscohort: 2x 10 injecties, overeenkomend met 2x 1*10e7 PIpepTolDC
- 3e dosiscohort: 2x 20 injecties, overeenkomend met 2x 2*10e7 PIpepTolDC
De eerste patient van elk nieuw dosis-cohort ontvangt initieel 1 serie met
placebo-injecties. Deze patienten zullen in 2e instantie alsnog worden
behandeld met PIpepTolDC in hetzelfde of in een hoger dosiscohort.
Study burden and risks
• Burden: an approximately 2.5 hour leukapheresis procedure, 2 intradermal
injections of PIpepTolDCs (or 3 for three patients receiving initially also one
set of saline injections), 4x stimulated C-peptide Mixed Meal Tolerance
Testing (or 5x for the patients also receiving the saline injection as
metabolic controls) and additional blood samplings during for clinical and
immunomonitoring.
• Risks: (a) possible: inflammatory/allergic reactions both local or at
injection site; (b) small: accelerated loss of stimulated beta-cell function;
(c) negligible: general immunosuppression
Belasting: De belasting voor de deelnemende proefpersonen bestaat uit 8-12
extra ziekenhuisbezoeken met steeds een extra bloedafname van gemiddeld 45 ml,
1 leukaferese-procedure met voorafgaande keuring, 2-3x een serie intradermale
injecties, en 4-5x een vloeibare maaltijd-tolerantie test.
For longer follow up amendment: at least one (yearly) visit and blood sampling
Albinusdreef 2
Leiden 2333ZA
NL
Albinusdreef 2
Leiden 2333ZA
NL
Listed location countries
Age
Inclusion criteria
• Age 18-45 years;
• Diagnosis of T1D at least 18 months dated from the first insulin injection
• Adequate self-assessment of blood glucose values, and recording of glucose
values and administered insuline doses as deemed sufficient by the patient*s
physician
• Stable glycemic control according to the patient*s physician
• Possession of *0401 allele at the HLA-DRB1 gene locus;
• Written informed consent.
Pregnancies during the study must be prevented both by female participant and
in case of male participants by them or their partners.
Exclusion criteria
• Use of immunosuppressive or immunomodulatory therapies, including systemic
steroids within 1 month prior to enrolment and/or prior monoclonal antibody
therapy of any type given for any indication at any time;
• Use of beta-cell stimulants (e.g. sulphonylureas), glucagon-like peptide-1
agonists, dipeptidyl peptidase-IV inhibitors, insulin sensitizers (e.g.
metformin, thiazolidinediones)
• Immunisation with live or killed vaccines or allergic desensitization
procedures less than 1 month prior to enrolment;
• History of disease associated with autoimmunity or inflammatory disorders
other than T1D;
• History of malignancy;
• Male or female patients who are fertile and are unwilling to use adequate
contraception at least 3 months prior to the first administration of
PIpepTolDCs until at least 60 days following the last administration of
PIpepTolDCs;
• Recent (< 3 months) HbA1c > 64 mmol/ mol.
• Lack of beta-cell autoantibodies (eligible autoantibodies: GADA or dIA-2A)
• Low vitamin D25 (OH) (<50 nmol/l) and/or 1,25 (OH)2 Vitamin D levels (< 40
pmol/l) at PIpepTolDCs injections
• Female patients who are pregnant or breastfeeding;
• Recent patient*s involvement in other studies which in the opinion of the
investigators could affect the safety of the patient or the result of the study;
• Any other medical condition, which in the opinion of the investigators could
affect the safety of the patient*s participation;
• Medically unable (like positive viral serology) or otherwise unwilling to
undergo a leukapheresis procedure.
• Any psychological, familial, sociological and /or geographical condition
potentially hampering compliance with the study protocol and follow-up
schedule.
Design
Recruitment
Medical products/devices used
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 | EUCTR2013-005476-18-NL |
CCMO | NL48984.000.14 |