Primary• To assess the safety and tolerability in healthy volunteers of nizaracianine administered IV in three divided dosesSecondary• To perform pharmacokinetic analyses of blood and urine• To determine if bolus injection of nizaracianine enables…
ID
Source
Brief title
Condition
- Urinary tract signs and symptoms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Treatment-emergent (serious) adverse events ((S)AEs) throughout the study at
every study visit
• Concomitant medication throughout the study at every study visit
• Vital signs (pulse rate (bpm), systolic blood pressure (mmHg), diastolic
blood pressure (mmHg)) as per assessment schedule
• Clinical laboratory tests (hematology, blood chemistry and urinalysis) as per
assessment schedule
• ECG parameters (heart rate (HR) (bpm), PR, QRS, QT, QTcF) as per assessment
schedule
Secondary outcome
• PK- parameters of nizaracianine by multi-compartmental analysis of the plasma
concentration-time data and urine data:
* AUCinf, AUClast, CL/F, Cmax, t1/2, tlag, tmax, Vz/F
* Dose-normalized PK parameters: AUCinf, AUClast, Cmax
* Urine PK parameters: Aelast, Aelast%, CLR
• Analysis of continuous NIR fluorescence imaging of the vascular flush in the
abdominal vasculature from 5 seconds prior to the injection until 1 minute
after the injection. PD-parameters are:
* Fluorescent yes or no
* Signal-to-background ratio (SBR)
* Mean fluorescent intensity in the most prominent artery or vein
* Mean fluorescent intensity in the background
• Fluorescence intensity is reported as:
* Fluorescent yes or no
* Signal-to-background ratio (SBR)
* Mean fluorescent intensity in the Foley tubing
* Mean fluorescent intensity in the background
Background summary
Fluorescence imaging using near-infrared (NIR) light (i.e., 700-900 nm) can
assist surgeons to recognize structures that need to be spared, e.g., blood
vessels and ureters, and structures that need to be resected, e.g., sentinel
lymph nodes and tumors. Currently, the only clinically available NIR
fluorophores are methylene blue, 5-ALA and indocyanine green (ICG). However,
the fluorescence emission intensity (i.e., the product of extinction
coefficient and quantum yield) and peak (600 nm and 700 nm, respectively) of
5-ALA and methylene blue and the clearance route of ICG (primarily hepatic),
are far from optimal. Nizaracianine (formerly ZW800-1) has improved in vivo
properties compared to available NIR fluorophores, including low non-specific
binding and uptake, a high extinction coefficient and quantum yield. Moreover,
nizaracianine has exclusive renal clearance after intravenous administration,
which allows intraoperative imaging of the ureters, and this could prevent
damage to the ureter during surgery. Safety of nizaracianine administered as a
single dose was tested in animal studies and a phase 1 human volunteer study. A
phase 2 study in surgical patients showed that after a single low-dose
intravenous injection, ureters were visible for 1-3 hours during abdominopelvic
surgery. The purpose of this repeat phase 1 clinical trial is to assess the
safety of nizaracianine in healthy volunteers when administered as three
divided doses. Long surgeries are common with abdominopelvic procedures and
repeat dosing of nizaracianine should provide the surgeon with continuous
visualization of the ureters during most common procedures.
Study objective
Primary
• To assess the safety and tolerability in healthy volunteers of nizaracianine
administered IV in three divided doses
Secondary
• To perform pharmacokinetic analyses of blood and urine
• To determine if bolus injection of nizaracianine enables NIR fluorescence
angiography
• To determine the fluorescence intensities in the tubing of the Foley catheter
(a proximal surrogate for fluorescence intensity of the ureters)
Study design
This is an ascending dose, double-blind, randomized, placebo-controlled study
in healthy volunteers.
Intervention
Nizaracianine or placebo
Study burden and risks
Adverse reactions, such as hypersensitivity reactions, may occur. However, the
likelihood of a hypersensitivity reaction is low as no such toxicity was seen
in the earlier studies. Nevertheless, study subjects will be monitored
clinically (observation, vital signs, etc.) before, during, and after IMP
administration in a dedicated research clinic. In the phase 1 and phase 2a
administration of nizaracianine was well tolerated without relevant toxicity.
In the renal transplant patient pilot study unexplained rejection of the renal
transplants were observed in two transplant recipients. A relationship to the
nizaracianine administration cannot be excluded. Therefore, subjects will be
monitored closely to identify potential adverse effects on renal function
Erie Drive 11
Natick MA 01760
US
Erie Drive 11
Natick MA 01760
US
Listed location countries
Age
Inclusion criteria
1. Subject is 18-55 years old at screening (inclusive).
2. Subject is able and willing to comply with study procedures.
3. Subject is in good general health, according to the investigator*s judgement
based on vital signs, medical history, physical examination, and laboratory
tests performed.
4. Body mass index between 18-32 kg/m2 (inclusive) and with a minimum body
weight of 50 kg at screening.
5. An estimated GFR >= 90.
6. Female subjects need to be surgically sterile, post-menopausal or
pre-menopausal with a negative urine pregnancy test at screening and before
administration of nizaracianine. Pre-menopausal female subjects who are not
surgically sterile have to agree to use an effective method of contraception.
7. Subject*s screening ECG and clinical laboratory test results are within
normal limits, or if any are outside of normal limits they are considered to be
clinically insignificant.
8. Subject has negative test results for drug and alcohol screening.
9. Written informed consent must be given prior to any study activities,
according to ICH/GCP and national/local regulations.
Exclusion criteria
1. (A history of) any clinically significant medical condition or
abnormalities, as judged by the investigator, in physical examination,
laboratory test results (including chemistry panel with hepatic and renal
panels, complete blood count, and urine dipstick) or electrocardiography (ECG)
at screening. In the case of uncertain or questionable results, tests performed
during screening may be repeated to confirm eligibility or judged by the
investigator to be clinically irrelevant for healthy subjects.
2. Female subjects that are lactating or pregnant.
3. The subject has a positive screening test for hepatitis B, hepatitis C, and
human immunodeficiency virus.
4. Use of any prescription medication and any other substance that in the
opinion of the investigators may influence the outcome of the study within 7
days prior to study drug administrations, or less than five half-lives
(whichever is longer, and during the course of the study).
5. Previous inclusion in this study.
6. Participation in a clinical trial within 3 months or 5 half-lives, whichever
is longer.
7. Use of alcohol during the 24 hours prior to screening and/or an
unwillingness to abstain from alcohol consumption during the stay at the
clinical unit, and for at least 24 hours prior to each study visit;
8. Positive urine drug screen or alcohol test at screening and/or at first
study day.
9. History of anaphylactic reactions to a prescription drug, over-the-counter
drug, or herbal supplement.
10. Prior organ transplant.
11. Signs of moderate or severe symptoms of prostate hypertrophy
12. Loss or donation of blood over 500 mL within four months prior to
screening.
13. Any other condition that in the opinion of the investigator would
complicate or compromise the study or the well-being of the subject.
14. History of AV blocks or any type of AV block on the ECG at the screening
15. History of syncope
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 | EUCTR202200145723-NL |
| CCMO | NL81211.056.22 |