- To determine the safety, - To investigate the pharmacokinetics (PK), and- To obtain pilot efficacy data
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Intracraniële laesies verwezen voor contrastverbeterde MRI van de hersenen
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- To determine the safety,
- To investigate the pharmacokinetics (PK), and
- To obtain pilot efficacy data
Secondary outcome
N/A
Background summary
The process of MRI is based upon the ability to induce and detect the resonance
of small magnetic fields, or moments, of some atomic nuclei which have the
inherent properties of spin and charge. The most abundant of the naturally
occurring spinning nuclei in the human body is the hydrogen nucleus, or proton,
found in water and lipids. As is true for any charge in motion, protons
generate a moment, which behaves with all the characteristics of a magnet. When
placed into an external, strong magnetic field (in clinical practice, ranging
from 1.5 T to 3.0 T), these small magnets align with the axes of the applied
field. If a pulse of specific radiofrequency energy is then introduced, the
protons will absorb this energy and re-orient themselves against the external
magnetic field. When the radiofrequency pulse is then discontinued, the
*excited* nuclei re-align themselves with the axes of the external magnetic
field and, in doing so, release the absorbed energy as a detectable
characteristic radiofrequency signal. This process of relaxation can be
measured as relaxation times, termed T1 (spin-lattice relaxation) and T2
(spin-spin relaxation), which characterize the rate of relaxation of the
excited protons.
Gadolinium-based contrast agents (GBCAs) are most commonly used to shorten the
T1 relaxation time of tissues for T1-weighted images in traditional MR imaging
causing signal intensity (SI) enhancement in the areas where contrast agents
distribute. Differential SI enhancement between abnormal and normal
structures, or contrast enhancement, is used to detect and characterize disease
in several regions of the body.
In the central nervous system (CNS), contrast enhancement produced by
intravenous (IV) injection of GBCAs is a combination of two primary processes:
intravascular (vascular) enhancement and interstitial (extravascular)
enhancement. Intravascular enhancement may reflect abnormal vascularity, i.e.,
neovascularity, vasodilatation or hyperemia, and shortened transit time or
shunting through the vasculature. The blood vessels that vascularize the CNS
possess unique properties, termed the blood-brain barrier (BBB), which allow
these vessels to tightly regulate the movement of ions, molecules, and cells
between the blood and the brain.
The intact BBB prevents leakage of GBCAs into these tissues. Interstitial
enhancement is related to enhancement resulting from alterations in the BBB
permeability, whereas intravascular enhancement results from and is
proportional to increases in blood flow or blood volume.
Therefore, the primary reasons for the use of GBCAs in MRI of the CNS are to
increase the difference in SI between areas with BBB breakdown or with abnormal
vascularity and normal areas, in order to detect/exclude presence of brain or
spine lesions, determine lesion location and size, characterize lesions through
assessment of internal morphologic features, to delineate lesion borders and
distinguish them from surrounding edema or normal tissues, and/or to define
their extent and relationship with adjacent structures in patients with
suspected primary or secondary tumors, focal neurologic deficits, endocrinology
disorders, or other conditions.
The degree of contrast enhancement produced by GBCAs depends on their
concentration in the tissues or blood, and on their relaxivity. Relaxivity
reflects the capability to shorten water proton relaxation rates T1 and T2/T2*
and is a measure of the potency of GBCAs to increase the relaxation rates (R1
and R2) of surrounding water protons. Proton relaxation rate is the property
that provides MRI signal: the higher the relaxation rate, the higher the SI on
T1-weighted images and the higher the contrast enhancing efficacy of a GBCA.
Stability, the strength with which the GBCA chelate holds on to the gadolinium
(Gd) ion, is another differentiator of the GBCAs: those with a macrocyclic
chelate bind most tightly to the gadolinium and thus are characterized by a
higher stability than linear GBCAs. The higher the stability of a GBCA, the
lower the propensity of the chelate to undergo transmetallation, which is the
replacement of Gd by other metal ions like zinc, iron, or copper in the
chelate, and subsequent release of Gd, which immediately binds to a number of
substrates in blood and tissues (endogenous anions like phosphates, carbonates
and citrates, or macromolecules) and forms Gd-compounds that may be retained in
tissues. Lower-stability GBCAs are associated with a higher level of retention
of Gd-compounds in brain and body tissues.
The first contrast agent approved for MRI of the CNS was the linear GBCA
Magnevist® (gadopentetate dimeglumine). This was followed by: i) the
macrocyclic GBCAs Dotarem® and Clariscan* (gadoterate meglumine),
ProHance®(gadoteridol) and Gadovist® (gadobutrol); ii) and by the linear GBCAs
Omniscan® (gadodiamide), MultiHance® (gadobenate dimeglumine), and OptiMARK®
(gadoversetamide). All these GBCAs are characterized by similar relaxivity,
with the only exception of the linear GBCA MultiHance, whose relaxivity is
higher at all field strengths of MRI scanners. The higher relaxivity of
MultiHance was repeatedly shown to provide a significantly better contrast
enhancement, measured as contrast-to-noise ratio (CNR) and lesion-to-brain
ratio (LBR), and significantly better conspicuity and delineation of CNS
lesions, better definition of extent of brain and spine disease, and better
depiction of the internal architecture/morphology of CNS lesions when compared
with the same dose of lower-relaxivity GBCAs. Additionally, half dose of
MultiHance was shown to produce comparable morphologic and morphometric
assessment of intracranial lesions when compared with the full dose of the
lower-relaxivity GBCA Dotarem®.
However, the stability of MultiHance is lower than that of the macrocyclic
GBCAs. Currently there are no approved GBCAs that are characterized by both a
high relaxivity and a high stability. Therefore, Bracco has designed and is
developing B26826, a new macrocyclic GBCA characterized by both an elevated in
vivo stability and a very high relaxivity in blood, markedly higher than that
of all the currently GBCAs, MultiHance included.
Study objective
- To determine the safety,
- To investigate the pharmacokinetics (PK), and
- To obtain pilot efficacy data
Study design
Study B26826-101 is the FIH study of the new GBCA B26826, designed as a
multicenter (5 investigational centers, but additional centers may be added
based on the complexity of the study), open-label, dose-escalation study of
four ascending single intravenous doses of this MR contrast agent, and as a
blinded, within-patient comparison of the contrast enhancement efficacy
obtained with B26826 and a validated comparator, Gadovist®, in MRI of the brain.
Patients providing informed consent to participate in this study, scheduled for
contrast-enhanced MRI of the brain and meeting the inclusion and exclusion
criteria set forth in this protocol will be sequentially allocated to one of
four dose cohorts, starting from the lowest B26826 dose to be tested.
Intervention
All patients will have their scheduled contrast enhanced MRI with Gadovist®.
Gadovist® will be injected at the dose of 0.1 mmol Gd/Kg corresponding to 0.1
mL/Kg as per prescribing information.
At least 48 hours later and no later than 4 days the patients will be asked to
return to the hospital to undergo the contrast enhanced MRI with B26826
(followed by an hospitalization of 48 hours).
There are 4 dose cohorts with a different dose of B26826. Patients will receive
their allocated dose of B26826 and immediately undergo the magnetic resonance
procedure.
B26826 and Gadovist® will be administered by intravenous injection as a bolus
using sterile syringes and aseptic techniques at a rate of 1 mL/sec manually or
using a power injector. If a power injector is used, a commercially available
injector in place at the investigational site will be used for product
administrations. All injections will be followed by at least 20 mL saline flush.
The same administration procedure must be used for both products within the
same patient. B26826 will be administered in an escalating manner; the study
will start with the lowest dose group (i.e., 0.025 mmol Gd/kg). Between each
consecutive dose group there will be an interval of time sufficient for
reviewing the safety data. The volume of B26826 to be administered is
calculated based on the weight of patient and on the belonging group of the
patient.
Study burden and risks
The aim of this study is to evaluate the safety and diagnostic efficacy of a
new contrast medium (B26826) for Magnetic Resonance.
This is a diagnostic trial not a therapeutic one, for this reason there are no
expected benefits about the management of the disease.
However, the new compound has such properties to result in a better efficacy
compared to other contrast media currently used in Magnetic Resonance in terms
of signal enhancement of the affected areas of the brain, allowing a more
accurate evaluation of the pathology.
The information obtain from this study will be useful in the future for people
suffering from the brain lesions, when they will have to undergo Magnetic
Resonance examinations.
Disadvantages of participation in the study may be:
- possible side effects
- possible side effects/discomforts of the evaluations in the study
Participation in the study also means:
- could cost you extra time.
-You need to be hospitalized. Or longer than usual.
-You have to comply with the study agreements.
Via Caduti di Marcinelle 13
Milaan 20134
IT
Via Caduti di Marcinelle 13
Milaan 20134
IT
Listed location countries
Age
Inclusion criteria
• Provides written Informed Consent and is willing to comply with protocol
requirements;
• Male and female between 18 and 75 years of age inclusive;
• Is referred for and has been scheduled to undergo a contrast-enhanced MRI
examination of the brain;
• Has a Karnofsky Performance Score >=70.
Exclusion criteria
• Is a pregnant or lactating female. Exclude the possibility of pregnancy: • by
testing on site at the institution (serum βHCG) within 24 hours prior to the
start of Gadovist(r) administration, • by surgical history (e.g., tubal
ligation or hysterectomy), • post-menopausal with a minimum 1 year without
menses; • Has any known allergy to GBCAs; • Have congestive heart failure
(class IV according to the classification of the New York Heart Association;);
• Have suffered a stroke within a year; • Have received or are scheduled to
receive any other contrast medium in the 24 hours preceding Gadovist(r)
injection through 7 days following B26826 administration; • Have received or
are scheduled to receive an investigational compound and/or medical device
within 30 days before admission into the present study, through the 7 days
post-administration of B26826; • Suffers from mild-to-severe chronic kidney
disease (estimated glomerular filtration rate < 60 mL/min/1.73 m2
calculating using the abbreviated MDRD formula); • Has, in the previous 7 days
before the first MRI with Gadovist® (0.1 mmolGd/kg) through B26826
administration, received prescription or non-prescription systemic medications
(e.g., anticancer drugs, barbiturates, or phenothiazines) which, in the opinion
of the Investigator, may interfere with the study procedure or affect safety
and efficacy assessments; • Has received or are scheduled for one of the
following: • Surgical, radiation or chemotherapeutic treatment within one weeks
prior to the first examination or between the two examinations; • initiation of
steroid therapy between the two examinations; • Has any contraindications to
MRI such as a pacemaker, magnetic material (i.e., surgical clips) or any other
conditions that would preclude proximity to a strong magnetic field • Are
suffering from severe claustrophobia; • Has participated in a clinical trial of
an investigational drug and/or medical device within 3 months before admission
into this study; • Has any medical condition or other circumstances which would
significantly decrease the chances of obtaining reliable data, achieving study
objectives, or completing the study and/or post-dose follow-up examinations; •
Cannot reliably communicate with the Investigator or is not likely to
co-operate with the requirements of the study.
Design
Recruitment
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 | EUCTR2020-003386-20-NL |
| CCMO | NL75814.078.20 |