Primary Objectives* To evaluate the safety and tolerability of repeated intradermal LPS challenges in healthy volunteers* To evaluate the local response in healthy volunteers after repeated intradermal LPS challenges performed 14 days apartSecondary…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Challenge model development
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
>Safety:
* Treatment-emergent (serious) adverse events ((S)AEs)
* Safety labs tests (acute phase proteins (CRP), leukocyte differentiation)
* Vital signs (HR, BP)
* NRS pain score
>Dermal imaging/scoring:
* Perfusion by Laser speckle contrast imaging (LSCI)
* Erythema by Antera 3D camera
* Erythema grading score
>Blister exudate analysis
* Neutrophils and monocyte subsets
Secondary outcome
>Dermal imaging/scoring
* Perfusion
* Erythema
Background summary
Lipopolysaccharide (LPS) is a pro-inflammatory substance found on the outer
cell membranes of Gram-negative bacteria. It protects these bacteria from
phagocytosis and lysis. LPS is recognized by Toll-like receptor (TLR) 4 in a
normally functioning immune system. Administration of LPS into healthy human
volunteers creates a model in which immune responses can be monitored and
influenced. LPS can be administered via intravenous, inhaled, nasal and
intradermal routes. Intradermal administration creates a rapid, limited local
inflammatory reaction which allows detailed insights into the local immune
response (CHDR1752A, CHDR1752B, CHDR1912B, CHDR2136). In previous intradermal
LPS studies at CHDR, LPS was applied on the lower forearm.
To date, intradermal LPS studies testing the ability of investigational
medicinal products (IMPs) to reduce inflammation at the challenge site have
used a parallel control group, with each subject challenged with LPS only at a
single time point after dosing of placebo or active drug. Consequently, to
generate dose response information for the pharmacodynamic effect of an IMP on
the LPS induced inflammation, different subjects must be used for the placebo
and each different dose level. An alternative design would be to challenge
subjects with LPS at baseline before administration of the IMP, and then repeat
the LPS challenge at a different skin site after dosing the IMP, such that each
subject becomes its own control. It can be envisaged that subsequent to the
second LPS challenge, a subject would be dosed again with a higher dose level
of IMP and then after a defined time period rechallenged with LPS to again
measure pharmacodynamic effects. This uptitration design would enable a single
subject to be used as a control, low IMP dose and high IMP dose to measure the
effects on LPS-induced inflammation, potentially reducing the number of
subjects for a study by a factor of 3. An additional potential benefit of the
uptitration design is reduced overall variability.
In this study, we aim to assess the safety of repeated local LPS challenges and
to investigate if immune tolerance to LPS occurs in the skin. The latter will
be assessed by the recruitment of monocytes and neutrophils to sites of an
intradermal LPS challenge performed at D1, D15 and D29. Additionally, to enable
the proposed follow-up study design with uptitration of an IMP, the response
will need to be assessed at six different administration sites. Therefore, in
this study, participants will receive multiple intradermal LPS injections on
the upper back over time. Subjects will receive one additional injection in the
lower arm, to assess the difference in clinical response between the lower arm
and the upper back. This design permits studying the response to repeated
intradermal LPS within one participant, as well as comparison of the response
between intradermal LPS applied on the lower arm and the upper back. If a
similar immune response is seen at the D1, D15 and D29 timepoints, future IMP
studies would then be able to implement this design such that each subject
would act as its own control and could also be used to ascertain dose-response
relationship.
Study objective
Primary Objectives
* To evaluate the safety and tolerability of repeated intradermal LPS
challenges in healthy volunteers
* To evaluate the local response in healthy volunteers after repeated
intradermal LPS challenges performed 14 days apart
Secondary Objectives
* To compare local inflammatory responses to LPS in skin on volar forearm and
the back
Study design
This is a single-centre, repeated LPS challenge study to explore the effects of
local intradermal LPS challenges over time in healthy volunteers. A total of 8
subjects receive 7 intradermal LPS injections each (1 on the volar forearm and
6 on the upper back) for non-invasive imaging and to measure monocyte
infiltration via suction blistering on the back.
Intervention
LPS, purified lipopolysaccharide prepared from Escherichia Coli: 113: H10:K
negative (U.S. Standard Reference Endotoxin)
Study burden and risks
Although subjects do not have any direct medical benefit from participating in
the study, LPS has been administered safely to humans over 30 years, and is
generally well tolerated. This study, however, may provide futures studies with
an investigational medicinal product (IMP) an uptitration design to enable a
single subject to be used as a control, low IMP dose and high IMP dose to
measure the effects on LPS-induced inflammation. Consequently reducing the
number of subjects for a study potentially. An additional benefit of the
uptitration design is reduced overall variability.
In this study, all subjects will receive 7 intradermal LPS injections (5 ng per
injection) in total with a maximum of 3 injections per study day. LPS has been
widely used as a challenge agent to induce mild and reversible inflammation. In
the study of Basran et al. (2013), subjects received intradermal LPS injections
with a dose up to 15 ng per injection (maximum dose of 45 ng per subject in
total). This led to a small skin reaction with mild erythema and edema. No
significant adverse effects of intradermal LPS administration were observed.
CHDR has conducted several studies (CHDR1752A, CHDR1752B, CHDR1912B, CHDR2124,
CHDR2136, and CHDR2149) using the intradermal LPS challenge model to induce a
local, mild, and transient skin reaction. Subjects received up to 4 injections
in total with a dose of 5 ng per injection. No systemic side effects were
observed. However, a slight transient rise in circulating leukocytes (mainly
neutrophils) following intradermal LPS administration was observed in some of
the subjects, but declined to baseline levels with-in 48h. Administration of
intradermal LPS has shown to be safe and well-tolerated. Although the total LPS
dose administered in this study will be higher than in previous studies
conducted at CHDR (35 ng in total, divided over 3 dosing days), it is expected
that repeated exposure to LPS will not result in additional safety issues, as
the LPS response is local and transient, and there will be no repeated exposure
on the same application site. Additionally, the maximum dose administered per
day will be lower than in the previous CHDR study5, with a total of 15 ng LPS
on day 1, and 10 ng LPS on day 15 and 29. Additionally, the LPS dose injected
(5 ng per injection) is much lower than the dose used in i.v. LPS challenge
studies6,7
The invasive measurement in this study consists of blister formation. This will
be limited to 6 blisters per subject. To minimize the risk of post inflammatory
hyperpigmentation, Fitzpatrick skin types 4-6 are excluded.
Grenzacherstrasse .
Basel 1244070
CH
Grenzacherstrasse .
Basel 1244070
CH
Listed location countries
Age
Inclusion criteria
1. Healthy male and female subjects, 18 to 45 years of age, inclusive. Healthy
status is defined by absence of evidence of any active or chronic disease
following a detailed medical and surgical history, a complete physical
examination including vital signs, 12-lead ECG, haematology, blood chemistry,
blood serology and urinalysis. In the case of uncertain or questionable
results, tests performed during screening may be repeated before enrollment to
confirm eligibility or judged to be clinically irrelevant for healthy subjects;
2. Body mass index (BMI) between 18 and 30 kg/m2 and a minimum weight of 50 kg,
inclusive;
3. Fitzpatrick skin type I-III (Caucasian);
4. Subjects of childbearing potential must use effective contraception for the
duration of the study;
5. Able and willing to give written informed consent and to comply with the
study restrictions.
Exclusion criteria
1. History of pathological scar formation (keloid, hypertrophic scar) or
keloids or surgical scars in the target treatment area (lower arm and upper
back) that in the opinion of the investigator, would limit or interfere with
dosing and/or measurement in the trial;
2. Have any current and / or recurrent pathologically, clinical significant
skin condition at the treatment area (lower arm and upper back, i.e. atopic
dermatitis); including tattoos;
3. Requirement of immunosuppressive or immunomodulatory medication within 30
days prior to enrolment or planned to use during the course of the study;
4. Known immunodeficiency
5. Use of topical medication (prescription or over-the-counter [OTC]) in local
treatment area or any medication that may interfere with the study objectives
as judged by the investigator within 30 days of study drug administration, or
less than 5 half-lives (whichever is longer)
6. Participation in an investigational drug or device study within 3 months, or
5 half-lives whichever is longer, prior to screening or more than 4 times in
the past year.
7. Loss or donation of blood over 500 mL within three months prior to screening
or donation of plasma within 14 days of screening
8. Any (medical) condition that would, in the opinion of the investigator,
potentially compromise the safety or compliance of the patient or may preclude
the patient*s successful completion of the clinical trial.
9. Pregnant, a positive pregnancy test, intending to become pregnant during the
study conduct, or breastfeeding.
10. Positive hepatitis B surface antigen (HbsAg), hepatitis C antibody (HCV
ab), or human immunodeficiency virus antibody (HIV ab) at screening.
11. A history of ongoing, chronic or recurrent infectious disease
12. Hypersensitivity for dermatological marker at screening
13. Current smoker and/or regular user of other nicotine-containing products
(e.g., patches)
14. History of or current drug or substance abuse considered significant by the
PI (or medically qualified designee), including a positive urine drug screen.
15. Presence of current, clinically relevant infections
16. Any vaccination within the last 4 weeks before day 1. Intention to receive
any vaccination(s) before the last day of follow-up.
17.Prolonged exposure of the investigational skin (lower arm, back) to sunlight
(including artificial tanning)
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 |
|---|---|
| CCMO | NL84863.056.23 |