To prospectively assess the potential effect of repeated exposure to either a linear or amacrocyclic gadolinium-based contrast agent (GBCA) on change from baseline to Year 5 inmotor and cognitive function among neurologically normal adults in…
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Source
Brief title
after repeated CE-MRI
Condition
- Other condition
Synonym
Health condition
motorische en cognitieve functie bij neurologisch normale volwassenen
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
o-Primary Endpoint to Assess Motor Function
One co-primary endpoint is the change from baseline to year 5 in motor function
as expressed
by composite z score, defined as the weighted sum of the z scores of the
individual tests.
Since each of these tests is considered equally important, each test will be
assigned an equal
weight.
The 4 tests to assess motor functions for the specific motor function domains
(described in
detail in Appendix 1) are the Nine Hole Peg Test (NHPT), the Finger Tapping
Test (FTT), the
Single Leg Stance Test (SLST), and the Timed Up and Go (TUG) test.
3.3.2 Co-Primary Endpoint to Assess Cognitive Function
The other co-primary endpoint is the change from baseline to year 5 in
cognitive function as
expressed by the composite z score, defined as the weighted sum of the z scores
of the
individual tests. Since each of the tests is considered equally important, each
test will be
assigned an equal weight.
The 3 tests to assess cognitive functions for the specific 5 cognitive function
domains
(described in detail in the separate Motor Function and Cognitive Testing
Appendix) are the
Secondary outcome
Changes from baseline in the composite endpoints (Years 1 to 4) and in each
individual test of
motor and cognitive function (Years 1 to 5) will be assessed.
Additional secondary endpoints include:
• Evaluation of adverse events. The recording of AEs that occur after signing
of the
informed consent form (ICF) at Screening will be done at baseline and at each
annual
visit. Signs/symptoms, onset and end date, severity, causality, seriousness,
treatment,
and outcome, will be recorded.
• Total gadolinium concentrations in blood plasma and urine samples collected at
baseline and at each annual visit will be determined. If the CE-MRI is obtained
at the
same visit, the blood and urine samples will be obtained prior to imaging.
Background summary
Gadolinium-based contrast agents have been used worldwide for about 30 years
and have
been used in more than 450 million patients. For a broad spectrum of diseases,
GBCAs are
indispensable adjuncts to MRI for detection and therapeutic guidance. Their
accumulated
safety record is positive, with an extremely low rate of serious adverse
reactions.1, 2,3,4,5,6,7
Until 2006, it was generally assumed that any GBCA administered to patients was
excreted
shortly thereafter or that whatever amount might be retained by the body long
term was so
small as to be clinically inconsequential.8 But in 2006, two European
groups9,10 suggested that
the use of GBCAs could be the cause of nephrogenic systemic fibrosis (NSF),
which is a rare
fibrosing disorder that occurs in patients with advanced kidney disease,
including end-stage
renal disease requiring dialysis. The possibility that GBCA administration
could trigger NSF
in patients with severe kidney disease rapidly led to permanent changes and
restrictions in the
GBCA labeling and new standards of care that incorporated renal function
testing before
administration, adherence to approved dosing regimens, and restrictions in the
use of certain
agents in patients with severe renal dysfunction. This redefined the
understanding of, and
approach to, the safety of GBCAs as a class.11 These studies also resulted in
clear distinctions
in the relative safety of individual GBCAs within the clinically approved
class. Although the
pathogenesis of NSF has not been fully elucidated, its etiology is likely to be
multifactorial.
Nevertheless, swift actions and risk minimization measures by the
manufacturers, the
radiologic community, and the regulators resulted in a dramatic decrease in the
number of
new NSF cases.
In 2013, researchers in Japan noted increased signal intensity in certain
regions (globus
pallidus [GP] and dentate nuclei [DN]) of the brain on the unenhanced scans of
participants
who had received multiple administrations of linear GBCAs.12 It was only after
the
publication of 3 investigations of autopsy specimens that gadolinium deposition
in the areas
of T1 signal intensity (SI) increase could be confirmed.3,4,5 The McDonald
group evaluated 13
autopsy specimens from individuals (all of whom had had an estimated glomerular
filtration
rate [eGFR] >=49 mL/min/1.73 m2) who had undergone >=4 MR examinations with
Omniscan
and 10 autopsy specimens from individuals who had never received a GBCA.3
Compared
with neuronal tissues of control patients, all of whom demonstrated
undetectable levels of
gadolinium, neuronal tissues of patients exposed to Omniscan contained 0.1-58.8
µg
gadolinium per gram of tissue, in a significant dose-dependent relationship
that correlated
with signal intensity changes on precontrast T1-weighted MR images. Gadolinium
deposition
in the capillary endothelium and neural interstitium was observed only in the
contrast group.3
The Kanda group evaluated autopsy specimens from 5 patients who had eGFRs
>45 mL/min/1.73 m2 and who had received >=2 total doses of Magnevist
(gadopentetate
dimeglumine) and either Omniscan (gadodiamide) or ProHance (gadoteridol) and
compared
them to the findings from 5 autopsy specimens from patients who had not
received GBCAs.
Using inductively coupled plasma mass spectrometry (ICP-MS), the Kanda group
also found
the presence of gadolinium, not only in the GP and DN but also in frontal lobe
cortex, frontal
lobe white matter, and cerebellar white matter, at concentrations that far
exceeded those seen
in the control group.5
Murata et al4 also performed a postmortem Gd deposition study of 9 decedents
who had
single-agent exposures to 1 or more doses of a GBCA (including Gadavist
[gadobutrol, 2
cases], ProHance [gadoteridol, 5 cases], MultiHance [gadobenate dimeglumine, 1
case] and
Eovist [gadoxetate disodium, 1 case]). They also found 9 control decedents who
had had no
MRI or no CE-MRI during their lifetime. Tissue samples from GP, the head of the
caudate
(CA), the white matter from the centrum semiovale (CSor WMCS), the putamen
(PU), the
DN, and the pons (PO) were collected and analyzed with ICP-MS. None of the
decedents had
severe renal failure. Importantly, none had primary brain tumors or cerebral
metastases, and
none had received cerebral radiation therapy. Results of the study revealed
that Gd is also
deposited in human brain tissues with the macrocyclic agents Gadavist and
ProHance and
with the 2 linear protein-interacting agents MultiHance and Eovist. As in
previous
postmortem studies of brain tissue,3,5 the levels of Gd in brain tissue were
highest in GP and
DN but Gd was also present in all other brain tissues sampled, including CA,
CSor WMCS,
PU, and PO, although at much lower concentrations.4 It was not possible to draw
any firm
conclusions from these data about differences seen between different agents
since for some
GBCAs measurements were available from only a single case and, as the authors
acknowledged, previous GBCA administrations could not be excluded. However, a
number of
studies that used ICP-MS to measure Gd in brain tissue of rats exposed to GBCAs
showed
clear differences in the content of Gd between macrocyclic and linear
GBCAs,13,14,15,16 and
also within each class of linear and macrocyclic GBCAs.16,17
The detection of retained Gd in human brain parenchyma following repeated
intravenous
administration was unexpected for several reasons, not the least of which is
that the
administered GBCA molecules were considered unable to pass through an intact
blood-brain
barrier (BBB). Thus, the question of how the retained Gd could be found on the
other side of
the BBB within the human brain parenchyma remained another aspect of the puzzle
that had
to be solved.
A recent publication by McDonald et al verified the presence of
intraparenchymally retained
Gd in the complete absence of known perturbations of the BBB.6 This observation
contributes
to the growing body of evidence that the cerebrospinal fluid (CSF) and the
glymphatic system
play a role in the normal biodistribution of intravenously administered GBCAs,
even in the
absence of significant renal disease. These findings tend to support those of
an animal study
by Jost et al18 and those of clinical studies by Öner et al,19 Iliff et al,20
Naganawa et al,21 and
others 22, 23 who have documented the normal role that the CSF and the
glymphatic system
play in the biodistribution of intravenously administered GBCAs and the likely
role in
providing a pathway to the brain parenchyma that bypasses the otherwise intact
BBB. This
brings up the intriguing possibility that although the 1- to 2-hour biologic
half-lives typically
reported for GBCAs are well known, a smaller component of the administered dose
may well
experience a longer effective biologic half-life during its glymphatic
transition stage.
No histological abnormalities were detected in the brain after multiple
administrations of
either linear or macrocyclic GBCAs in animals.14,16 Moreover, no study showed
any
morphological changes or obvious tissue reactions such as degeneration or
inflammation.
These findings are consistent with the few available clinical data reporting
the lack of
apparent histological changes in sections of DN from patients, including
children,7 who
received Omniscan up to a total cumulative dose of 500 mL3,6 and other agents
including
linear and macrocyclic GBCAs.24
Finally, to date, no neurological symptoms or conditions have been associated
with abnormal
T1 signal intensity increase in deep brain areas. In addition, Welk et al
conducted a
population-based study and found no statistical evidence for an association
between exposure
to GBCAs and development of Parkinsonism in elderly patients.25 Studies aimed
at detecting
and measuring elemental Gd in brain tissues following exposure to GBCAs showed
that the
highest levels were in the DN and in the GP.3, 4, 5, 24 Given that GP lesions
are typically
associated with motor deficits, including parkinsonism, tremor, and
dystonia,26, 27, 28 the
results of the Welk study do not support the hypothesis that GBCA
administration is
associated with parkinsonism at the dosing regimen reported.
Study objective
To prospectively assess the potential effect of repeated exposure to either a
linear or a
macrocyclic gadolinium-based contrast agent (GBCA) on change from baseline to
Year 5 in
motor and cognitive function among neurologically normal adults in comparison
to a matched
non-GBCA-exposed control group.
Secondary Objectives
• To assess the change from baseline in the composite endpoints (motor and
cognitive)
at each of the post-baseline time points (Years 1 to 4) in GBCA-exposed
participants
as compared to controls.
• To assess the change from baseline for each of the individual tests (motor and
cognitive) at each of the post-baseline time points (Years 1 to 5) in
GBCA-exposed
participants as compared to controls.
• To evaluate safety through collection of adverse events.
• To assess total Gd concentrations (as measured in a central laboratory) in
blood and
urine samples taken from exposed and control participants at the time of the
annual
visit.
Study design
This study will be conducted as a prospective, multinational, multicenter,
longitudinal cohort
study in 2 groups of participants exposed to GBCAs (either linear or
macrocyclic no generics
permitted in this study) and a matched control group of participants not
exposed to any
GBCA. Assignment to GBCA will be non-randomized and will be based on medical
need and
usual institutional practice.
All participants must be neurologically normal adults. Participants in the GBCA
arms are
expected to undergo >=5 CE-MRIs in order to evaluate the association of repeated
administration of GBCAs. Each GBCA participant will receive the same GBCA
throughout
the study. Participants in the control group should have never been exposed to
any GBCA in
the past and should not receive GBCAs during the study; however, they will
continue to
receive any clinically indicated imaging required (including, but not limited
to, UE-MRI,
and/or unenhanced/enhanced computed tomography [CT], ultrasound [US] and/or
X-ray).
All participants will undergo neurologic function assessment using a
comprehensive battery
of motor and cognitive tests administered annually over the course of >=5 years.
Intervention
N/A
Study burden and risks
N/A
Al. Stamboliiski blvd 103
Sofia 1303
BG
Al. Stamboliiski blvd 103
Sofia 1303
BG
Listed location countries
Age
Inclusion criteria
1. Participant must be an adult having reached legal majority age and less than
65 years
old.
2. Participant must be neurologically normal, defined as free of unstable
neurologic and
psychiatric disease as confirmed by a normal neurologic examination at
screening.
3. Participant agrees to be tested as per protocol for 5 consecutive years
4. Participant (GBCA-exposed or controls) agrees to undergo UE-MRI of the brain
at
enrollment and at the end of the observation period (5 years).
5. Patient affiliated to national health insurance according to local regulatory
requirements, where applicable.
6. Participants should have at least 1 of the following indications:
• Medium to high risk for breast cancer or with dense breasts undergoing breast
cancer screening with MRI
• Elevated PSA under active diagnostic surveillance of prostate cancer
• Chronic liver disease (eg. liver cirrhosis limited to Child Class A,
post-hepatitis
chronic hepatopathy, or primary sclerosing cholangitis) for surveillance of
hepatocellular carcinoma development
• Low-grade colorectal cancer or neuroendocrine tumor undergoing surveillance
for
liver metastases
• Branch-duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas
(maximum size <= 2 cm) undergoing imaging surveillance.
Exclusion criteria
1. As evidenced by history or determined in the neurologic exam at screening,
concurrent
neurological and/or psychiatric disease (or treatments) that could influence
the results
of the study*s motor and cognitive tests. Examples include but are not limited
to:
• Cerebrovascular disease.
• Multiple sclerosis.
• Neurodegenerative disease.
• Malignant disease other than listed in indications.• Carcinoid tumors.
• Epilepsy.
• Prior neurosurgery.
• Psychotic disorders or any prior psychotic episode not otherwise specified
(NOS)*any documented prior history of chronic schizophrenia.
• Remittent or current medically confirmed major depressive disorder or bipolar
disorder. History of long-term major depression or bipolar affective disorder
with
an active episode in the past 2 to 5 years.
• Neurodevelopmental disorders (eg, trisomy 21).
• Uncontrolled severe migraine.
• Uncontrolled or controlled anxiety or depression within 6 months before
enrollment.
• Screening scores of <=24 on the MMSE and/or >=11 on the HADS.
2. Prior, planned, or ongoing chemotherapy or brain irradiation.
3. Use of concomitant medication(s) affecting neuro-cognitive or motor function
(an
authorized exception is a single intake before the study MRI because of anxiety
if
administered after the motor and cognitive test evaluation):
• Regular use of benzodiazepines or non-benzodiazepine hypnotics. Long-acting
benzodiazepines (eg, diazepam) should not be administered within 24 hours prior
to cognitive testing.
• Short/medium-acting benzodiazepines (eg, alprazolam, lorazepam, oxazepam,
temazepam), except if used chronically for sleep and on a stable dose for 8
weeks
prior to Screening Visit 1 or 12 hours prior to cognitive testing.
• Regular use of anticholinergic drugs (anticholinergics for bladder control
with
limited cognitive effects are permitted).
• Long-term use of corticosteroids or methotrexate, cladribine.
• Regular use of antidepressants (eg, anticholinergics, tricyclics, monoamine
oxidase
inhibitors [MAOIs], norepinephrine-dopamine reuptake inhibitors [NDRIs],
selective serotonin reuptake inhibitors [SSRIs], serotonin and norepinephrine
reuptake inhibitors [SNRIs], or lithium, anti-epileptics, and/or antipsychotic
drugs:
Use of antidepressants is allowed if at stable doses for 8 weeks prior to
Screening
Visit. Antipsychotics used on a regular basis, except for low doses of atypical
antipsychotics (e.g., risperidone, aripiprazole, or quetiapine),
anticonvulsants with
limited cognitive effects, such as lamotrigine, pregabalin, levetiracetam for
treatment of pain, and other non-epilepsy indications, are allowed as-needed
basis
or if used at a stable dose for 8 weeks prior to Screening Visit
• CNS stimulants (eg, for ADHD).
4. Substance or alcohol abuse as determined by the investigator.
5. Alcoholic cirrhosis.
6. Any history or presence of other relevant chronic disease that prevents
participation in
the study or that may confound neurofunction testing.
7. Renal disease, defined as estimated glomerular filtration rate (eGFR)
< 60 mL/min/1.73 m2, calculated by using the Modification of Diet in Renal
Disease
(MDRD) formula or the Kidney Disease Epidemiology Collaboration (CKD-EPI)
equation.
8. History of environmental/occupational/other exposure to one or more
chemicals that
may affect cognitive and/or motor function, including, but not limited to,
heavy metals
(arsenic [As], cadmium [Cd], lead [Pb], manganese [Mn], and mercury [Hg]),
pesticides, solvents, or carbon monoxide.
9. Anticipated, current, or past conditions (medical, psychological, social, or
geographical) that, in the opinion of the investigator, would compromise the
participant*s safety or her/his ability to participate in the study (eg,
clinically
significant vitamin B12 deficiency, folic acid deficiency, uncontrolled thyroid
dysfunction from medical history).
10. Clinical indications requiring >1 CE-MRI every 6 months.
11. Receipt of any investigational product or participation in any other
clinical trial within
30 days prior to enrolling in this study or while enrolled in this trial.
12. Previous enrollment in this study.
13. Pregnant or nursing (lactating) women.
14. Presence of any metal-containing joint implants/prostheses.
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 | EUCTR2019-004730-42-NL |
| CCMO | NL78113.099.21 |