Investigation of the immune response following immunization with Immucothel/Alhydrogel with or without tetanus. Per efficacy endpoint, the following parameters will be explored:(a) Response size;(b) Inter-individual variability of the response;(c)…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy endpoints
* KLH-specific and tetanus toxoid-specific IgG and IgM titers (ELISA);
* OX40 and OX40L expression by flow cytometric analysis, on T-cells, B-cells
and monocytes;
* Ex vivo lymphocyte proliferation upon Immucothel challenge of isolated PBMCs.
Response quantification by flow cytometry (OX40, OX40L), proliferation (by
CellTrace Violet), and (optionally) cytokine release (e.g. IL-2, IL-6, IL10,
IL-17 and IFNy);
* mRNA analysis of lymphocyte populations (T-helper cells, cytotoxic T-cells
and T-regulatory cells) sorted by immunomagnetic selection. Readouts may entail
OX40, OX40L, and optionally other cell activation markers;
* Erythema, swelling and redness at the sites of intradermal KLH (Delayed Type
Hypersensitivity [DTH] upon intradermal injection of 1 *g Immucothel in 10*L,
on the flexor aspect of the forearm).
Tolerability / safety endpoints
- Treatment-emergent (serious) adverse events ((S)AEs).
- Concomitant medication
- Clinical laboratory tests
o Haematology
o Chemistry
o Urinalysis
- Vital signs
o Pulse Rate (bpm)
o Systolic blood pressure (mmHg)
o Diastolic blood pressure (mmHg)
- Electrocardiogram (ECG)
o Heart Rate (HR) (bpm), PR, QRS, QT, QTcF
- Immucothel intramuscular injection site responses.
Secondary outcome
Not applicable
Background summary
Keyhole limpet hemocyanin (KLH) is derived from the keyhole limpet, a type of
mollusc. KLH is regarded as an ideal immunization antigen for studying T-cell
dependent immune response to a neoantigen. KLH is available as a pure
homogeneous substance, as a clinical grade product (KLH subunits), it has been
used widely in patients and the injected form appears to be associated with
mild local reactions and perhaps mild pyrexia (Immucothel SmPC). It appears to
be immunogenic for the entire population, it has no cross-reacting antibody,
and it elicits predictable primary T-cell dependent immune responses following
one or two administrations.
For a future FIH trial investigating the effects of OX40/OX40L interaction
blocking, a model that allows direct pharmacodynamics (PD) assessment of the
compound is desirable. In this future study, both the influence of the compound
on the immune response following presentation of a novel antigen and of a
recall antigen needs to be assessed. KLH will be the novel antigen that will be
administered. Tetanus toxoid will be the recall antigen that is presented,
since the entire population of the Netherlands born after 1957 has been
vaccinated against tetanus.
The aim of the present study is to characterize the humoral and cellular
response after novel antigen presentation (KLH) and recall antigen presentation
(tetanus), and evaluate if the T cell response to one antigen is substantially
modulated by the response to the other antigen. Characterization and
quantification of the immune response to these immunizations will allow
rational design of the future OX40/OX40L blocking study, and allow application
of KLH and tetanus immunizations in other future clinical studies.
Study objective
Investigation of the immune response following immunization with
Immucothel/Alhydrogel with or without tetanus. Per efficacy endpoint, the
following parameters will be explored:
(a) Response size;
(b) Inter-individual variability of the response;
(c) Time course of the response.
Moreover, for each efficacy endpoint, it will be confirmed that a simultaneous
administration of tetanus toxoid does not interfere (or only minimally) with
the KLH response. This is valuable information to support simultaneous
KLH/tetanus toxoid immunizations in the future intervention trial targeting
OX40/OX40L. The data generated in the current study will allow selection of the
most robust readout measures for quantification of the
Immucothel/Alhydrogel-induced immune response in the future OX40/OX40L study
and allow for a power analysis of studies using this model
Study design
A randomized, double-blind, placebo-controlled study investigating the effects
of immunization with Immucothel, adsorbed to Alhydrogel, administered to
healthy male volunteers on its own or administered simultaneously with tetanus
toxoid into the contralateral deltoid muscle. Each participant will receive two
KLH injections in the deltoid muscle, separated by one week and a single
tetanus immunization at day 0.
Intervention
Six volunteers will receive Immucothel/Alhydrogel, six will receive
Immucothel/Alhydrogel and tetanus toxoid, and three volunteers will receive
placebo (saline).
Study burden and risks
Burden: measurements, blood and urine sampling, lifestyle restrictions and time
investment.
Risks: potential adverse events caused by the vaccin
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
Eligible subjects must meet all of the following inclusion criteria at screening:
1. Healthy male subjects, 18 to 45 years of age (inclusive). The health status is verified by absence of evidence of any clinical significant active or uncontrolled chronic disease following a detailed medical history and a complete physical examination including vital signs, laboratory measurements and 12-lead ECG;
2. Body mass index (BMI) between 18 and 30 kg/m2, inclusive, and with a minimum bodyweight of 50 kg;
3. Previous immunization with tetanus toxoid as reported by the subject;
4. Willing to give written informed consent and willing and able to comply with the study protocol.
Exclusion criteria
Eligible subjects must meet none of the following exclusion criteria at screening:
1. Any disease associated with immune system impairment, including auto-immune diseases, HIV, any confirmed history of severe allergic reaction and transplantation patients;
2. Known infection requiring antibiotic therapy within the last three months prior to the study
3. Previous known exposure to Immucothel® or KLH;
4. Any adverse immune reaction following immunization with tetanus toxoid;
5. Known allergy against Thiomersal®, which is a stabilizer in the tetanus toxoid immunization;
6. Received immunosuppressive or immunomodulatory medication within 30 days prior to enrollment or planned to use during the course of the study;
7. Use of medication (prescription or over-the-counter) within 21 days of the first study day, or less than 5 half-lives (whichever is longer), and during the course of the study;
8. Participation in an investigational drug or device study within 3 months prior to screening or more than 4 times a year;
9. Previous participation in an investigational drug or device study involving the dosing of a biological targeted at any immune pathway within one year prior to screening;
10. Loss or donation of blood over 500 mL within three months prior to screening;
11. Any (medical) condition that would, in the opinion of the investigator, potentially compromise the safety or compliance of the subject or may preclude the subjects* successful completion of the clinical trial.
12. History of Schistosomiasis (infection with Schistosoma parasite).
13. History or current nicotine use in access of 5 cigarettes per day, or unable not to smoke during the course of the study, defined as between the screening visit and the final visit.
14. Tetanus toxoid immunization within the last 10 years before study participation
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 | EUCTR2017-000084-32-NL |
| CCMO | NL60489.056.17 |