We will assess the safety of adalimumab-800CW through the evaluation of both vital signs after tracer administration and possible (severe) adverse events (SAE/AE*s). Importantly, we will determine the feasibility of molecular fluorescence imaging…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
- Autoimmune disorders
- Synovial and bursal disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. To determine the safety of adalimumab-800CW in IBD and RA/SpA patients by
monitoring of vital signs during tracer infusion and evaluating possible
(severe) adverse events (SAE & AEs).
2. To determine the feasibility of the (intrinsic) fluorescence signal of
adalimumab-800CW as assessed by fluorescence molecular endoscopy (IBD) /
wide-field imaging (RA/SpA) for elucidating local adalimumab-800CW
concentrations and drug distribution throughout
• The gut mucosa in IBD;
• Synovial joint in RA/SpA.
Secondary outcome
Secondary objectives in the IBD cohort
• To quantify NIR fluorescence signals in vivo and ex vivo using MDSFR/SFF
spectroscopy measurements for an *intrinsic* fluorescence signal;
• To correlate and verify fluorescence signals detected in vivo to the
histopathology of biopsies;
Secondary objectives in RA/SpA
• To quantify NIR fluorescence signals in vivo using multi-diameter
single-fiber reflectance, single-fiber fluorescence (MDSFR/SFF) spectroscopy
measurements;
• Optionally, in patients that give additional informed consent for
intra-articular MDSFR/SFF measurements and synovial biopsies:
o To investigate the correlation between the detected and quantified
intra-articular fluorescent signal and the histopathology analysis of the
inflamed synovium.
Background summary
Inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and Spondyl
Arthritis (SpA) are all auto-immune diseases that are characterized by chronic
relapsing inflammation of respectively the ileocolonic tissue and the synovium.
Pathogenesis of the auto-immune diseases is attributed to the proinflammatory
cytokine tumor necrosis factor α (TNFa). Adalimumab is a human monoclonal
anti-TNF antibody used for treating patients with moderate to severely active
IBD, RA or SpA. However, current rates of therapeutic non-responsiveness to
this antibody are variable and difficult to predict in advance, whereas
patients are potentially exposed to a non-effective treatment and its potential
side effects; while clinical deterioration progresses. A key unmet need is the
development of a predictive tool for assessment of a therapeutic (non-)
response to patients and finding an optimal dose strategy in individual
patients before initiating anti-TNF therapy. Unfortunately, we currently lack
crucial information about drug distribution of the drug of interest throughout
the targeted inflamed tissue itself. Therefore, it remains unknown in
IBD/RA/SpA, if the drug reaches its target (in sufficient amounts) and how
local drug concentrations are related to therapeutic response. Thus, we linked
adalimumab to a fluorescent dye (adalimumab-800CW) in order to create a
fluorescent signal of the labelled drug in the diseased tissue that we can
visualize and quantify with dedicated optical fluorescence imaging systems. We
hypothesize that this tracer will bind to TNFa in the mucosa/synovium and thus
create a map of medicine distribution in vivo due to colocalization of the
fluorescent labelled compound. Therefore, the aim of this study is to assess
the feasibility of fluorescent molecular imaging of adalimumab-800CW in IBD, RA
or SpA patients.
Study objective
We will assess the safety of adalimumab-800CW through the evaluation of both
vital signs after tracer administration and possible (severe) adverse events
(SAE/AE*s). Importantly, we will determine the feasibility of molecular
fluorescence imaging using the GMP-produced near-infrared fluorescent tracer
adalimumab-800CW for visualizing medicine distribution in vivo in RA/IBD/SpA
patients with dedicated fluorescence imaging systems.
Study design
The current study is a non-randomized, non-blinded, prospective, multicenter
safety / feasibility dose-finding study. IBD, RA and SpA patients will receive
an intravenous bolus injection of a microdose of 4.5 mg adalimumab-800CW 2-4
days before imaging. Before and after administration, the vital signs will be
monitored. Imaging will be performed with fluorescence endoscopy (IBD) or
fluorescence wide-field imaging and MSOT (RA/SpA) for fluorescence detection.
The fluorescent signal will be quantified by MDSFR/SFF spectroscopy.
Furthermore, biopsies will be taken from non-inflamed and inflamed mucosa in
IBD patients. In RA/SpA patients, fluorescent imaging with spectroscopy
measurements and MSOT will be done both before and after tracer administration.
Optionally, patients give additional consent for sampling of synovial tissue.
An extensive ex vivo procedure in addition to histopathology analysis of the
biopsies will be conducted for tracer localization in order to precisely
correlate this to the in vivo observed signal. The ex vivo procedure will
comprise MDSFR/SFF spectroscopy, immunohistochemistry, fluorescence imaging and
fluorescence microscopy.
Intervention
Two to four days prior to the imaging procedure, the subject receives an
intravenous injection of the fluorescent tracer adalimumab-IRDye800CW. The
first three patients receive 4.5 mg adalimumab-800CW and the second three
patients will receive 15 mg adalimumab-800CW. After these six patients, an
interim analysis will be conducted based upon safety parameters and
target-to-background ratio (TBR)/contrast-to-noise ratio (CNR) of the
fluorescence signal. If these factors are considered positive for one of these
doses, an additional nine patients will receive the same dose. If not, there
will be a dose escalation to 25 mg adalimumab-800CW in the another three
patients and the best dose group can then be extended with six patients. Groups
and interim analyses will be constructed and performed separately per disease
cohort (IBD/RA/SpA).
Study burden and risks
Risks of adalimumab-IRDye800CW are considered negligible. Before, during and
after administration, the subject will be monitored. Subjects will receive a
dose of either 4.5 mg, 15 mg or 25 mg adalimumab-800CW 2-4 days prior to the
imaging procedure. RA/SpA patients have one or two extra visits to the hospital
for the administration and imaging of the tracer. IBD patients, have an extra
visit to the hospital for tracer administration; fluorescent imaging of the
bowel will be on the same day of their endoscopy, which is a clinical standard
procedure. Extra biopsies will be obtained from IBD patients for study
purposes. RA/SpA patients can opt for synovial biopsies. No direct benefits are
expected for study participants.
Hanzeplein 1
Groningen 9700 RB
NL
Hanzeplein 1
Groningen 9700 RB
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
• Established IBD, RA or SpA diagnosis
• Active disease.
o IBD cohort: clinically active disease of the bowel defined either clinically
as at least mild activity using dedicated scoring indices (for definitions of
disease activity, see below) or biochemically active disease as defined by a
faecal calprotectin > 200 *g/g;
o RA / SpA cohort: clinically active disease of at least one joint of the hand
as assessed by rheumatologist;
• Age of 18 years or older and mentally competent;
• Written informed consent.
IBD patients must already have an ileocolonoscopy scheduled due to a
clinical indication.
For female subjects who are of childbearing potential, are
premenopausal with intact
reproductive organs or are less than 2 years postmenopausal
• A negative pregnancy test must be available (blood or urine)
• Willing to ensure that she uses effective contraception during the study and
for 3 months thereafter.
Disease activity scores
Crohn*s disease Ulcerative colitis
CDAI HBI
SCCAI
Clinical remission <150 0-4 <= 2
Mild activity 150-220 5-7
3-5
Moderate to severe activity 220-450 8-16 6-11
Severe fulminant >450 17-100 >= 12
Exclusion criteria
- A potential female subject that is pregnant or provides breastfeeding will be
excluded from participation in this study;
- RA / SpA patients with a skin type above type 3 according to the Fitzpatrick
scale due to feasibility of the MDSFR/SFF spectroscopy measurements;
- Medical or psychiatric conditions that compromise the patient's ability to
give informed consent.
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 | EUCTR2020-004405-31-NL |
| ClinicalTrials.gov | NCT03938701 |
| CCMO | NL75246.042.20 |