Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04623788 |
| Other study ID # |
MR/T029153/1 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
February 20, 2020 |
| Est. completion date |
June 2, 2023 |
Study information
| Verified date |
May 2024 |
| Source |
University of Edinburgh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Manganese is a calcium analogue which actively enters viable cells with intact
calcium-handling mechanisms and its uptake is evident by an increase in MRI-detectable T1
relaxivity of tissues. Mangafodipir is a novel manganese-based magnetic resonance imaging
(MRI) contrast medium with unique biophysical properties that are ideal for application to
cardiac imaging. Recent studies in man have demonstrated the utility of manganese-enhanced
MRI (MEMRI) in assessing infarct size more accurately than with standard cardiac MRI
protocols using gadolinium enhancement and have shown reduced myocardial manganese uptake in
patients with cardiomyopathies suggesting abnormal calcium handling.
Understanding the potential for myocardial recovery is key in guiding revascularisation
therapies in ischaemic cardiomyopathy, in addition to novel therapies used in heart failure.
Being able to monitor calcium handling and therefore myocardial function in different types
of cardiomyopathies has the potential to guide management in these patients. The
investigators here propose an investigational observational study of MEMRI to assess
myocardial calcium handling in reversible causes of cardiomyopathy, namely ischaemic
cardiomyopathy, myocarditis and takotsubo cardiomyopathy.
Description:
BACKGROUND Heart failure (HF) is a global pandemic affecting at least million people
worldwide. Despite the significant advances in therapies and prevention, mortality and
morbidity are still high and quality of life poor.
Cardiomyopathy refers to diseases affecting the myocardium which can lead to heart failure.
Ischaemic heart disease (IHD) is the leading cause of cardiovascular morbidity and mortality
in the United Kingdom (UK) and an important cause of reversible cardiomyopathy.
Takotsubo cardiomyopathy (TTS) is a form of stress cardiomyopathy that is characterised by
acute, transient left ventricular (LV) dysfunction. This typically affects the apex extending
beyond a single epicardial vessel with subsequent angiography revealing non obstructive
coronaries. It accounts for up to 2% of acute coronary syndrome (ACS) admissions and despite
being first described 20 years ago its pathophysiology is poorly understood. Typically
takotsubo resolves over time and is considered to have a benign prognosis however acutely it
can cause serious complications such as severe heart failure, cardiac arrhythmias and cardiac
arrest.
Myocarditis is an inflammatory cardiomyopathy with varying aetiology which comprises a wide
clinical spectrum from sub-clinical disease to severe heart failure. Currently myocardial
biopsy is considered the gold standard in diagnosis, although it is prone to sample error and
clinically indicated in only a few scenarios. Although in some cases cardiac MRI can reveal a
'typical' pattern of myocarditis based on T2 oedema imaging, the sensitivity and specificity
is unclear and not yet established giving a limited diagnostic yield. Myocarditis may resolve
spontaneously, recur or become chronic. In a third of biopsy-proven cases, it can lead to
heart failure, cardiac transplantation or death. As a result, it has significant contribution
to the global burden of cardiovascular disease.
Better understanding of underlying mechanisms and assessment of reversible myocardial injury
is vital in the diagnosis, risk stratification, treatment, and intervention with potential to
change clinical practice.
Delayed-enhancement MRI with Gadolinium Cardiac imaging using delayed-enhancement magnetic
resonance imaging with gadolinium (DEMRI) is the gold-standard method for non-invasive
characterisation of myocardial scar and function, and has become an invaluable tool in the
field.
Gadolinium (Gd) is an excellent blood-pool contrast agent. Despite some active uptake in
hepatocytes, Gd acts as a passive marker of the extracellular space. Chelated to
diethylenetriamine-pentacetic-acid (DTPA), Gd diffuses rapidly into the extra cellular space
but its molecular weight prevents it penetrating intact cell membranes. Many pathological
myocardial states have a greater extra cellular volume (ECV) and as a consequence, a greater
osmotic gradient relative to healthy tissue. These diseased tissues also result in the
delayed wash out of Gd-DTPA resulting in an increased signal seen in pathological areas on
DEMRI. However, the non-specific distribution of Gd within the extracellular space means
direct assessment of viability is not possible with DEMRI.
Manganese-enhanced MRI (MEMRI) Manganese (Mn) was the first clinical MRI contrast agent.
Cardiac, hepatic and renal uptake of Mn causes marked shortening of MRI T1 relaxation times
providing excellent tissue contrast imaging. Mn-based contrast media offer potential for a
wide range of MRI platforms having been applied to the assessment of neuronal activity and
function, detection and tracking of lymphocytes16 and pancreatic beta-cell activation as well
as evaluation of myocardial viability in the setting of ischaemia.
The mechanisms by which Mn provides contrast imaging in the heart depend on calcium (Ca)
handling in myocardial cells. During myocardial contraction, Ca2+ ions are taken up into
myocytes predominantly through voltage-gated L-type Ca2+ channels where they then trigger
further Ca2+ release from the sarcoplasmic reticulum (excitation-contraction coupling). In
diastole, Ca2+ is actively transported into sarcoplasmic reticulum by Ca2+-ATPase (SERCA2a),
in addition to passage into the extracellular space via the Na+/Ca2+ exchanger and uptake
into mitochondria. Alterations in this Ca2+ handling, by protein dysfunction and defective
regulatory mechanisms, impair the ability of the myocyte both to increase and decrease
intracellular Ca2+ concentrations, impacting on systole and diastole respectively.
Calcium plays a central role in excitation-contraction coupling and defective Ca2+cycling is
key in the pathophysiological and adaptive mechanisms of defective contractile function and
impaired relaxation in heart failure. Experimental reports have demonstrated reduced
sarcoplasmic reticulum Ca2+storage and release, with decreased SERCA2a activity and Na+- Ca2+
exchange up regulation. The altered expression and activity of voltage-gated L-type Ca2+
channels both in heart failure and hypertrophy observed in several studies is not yet fully
understood, although clearly highlights the centrality of calcium handling to this issue.
Mn acts as a Ca2+ analogue allowing its uptake by voltage-gated Ca2+ channels therefore cells
with active calcium handling avidly take up Mn ions, in contrast to infarcted tissue which
lack the necessary viable mechanisms. The result is a marked shortening of the T1 relaxation
times in tissue with functioning calcium handling mechanisms. This has particular relevance
to myocardial tissue and mitochondria since it has the potential to identify viable
myocardium and provide a measure of myocardial function. In contrast to DEMRI with Gd, which
effectively functions as a marker for pathological myocardium, MEMRI highlights areas of
viable myocardium, marking non-viable myocardium by its absence of uptake. With its
paramagnetic properties also reducing the T1 relaxation times of water, Mn provides positive
image contrast in the tissues where it accumulates giving excellent anatomical delineation.
T1 Mapping The majority of myocardial pathologies prolong T1 relaxation (infarction,
myositis, hypertrophy, ischaemia, amyloidosis, sarcoidosis), although lipid deposition
(arrhythmogenic right ventricular dysplasia), iron deposition (haemachromatosis) and
lysosomal storage disorders (Fabry disease) shorten it. On account of its potent paramagnetic
properties, Gd shortens T1 in both normal and abnormal myocardium. A T1 map is generated by
combining multiple images obtained during diastole, but with different inversion times, to
assess T1 relaxation time for each voxel within the image. Each voxel intensity value
represents the T1 relaxation time for the voxel and is labelled with colour for ease of
visual differentiation. Different imaging protocols and techniques have been developed to
combine an even sampling of the T1 recovery curve whilst minimising artefact, maximising
precision and avoiding long breath holds. The principal potential advantages of T1 mapping
compared to late gadolinium enhancement relates to its ability to detect diffuse more subtle
forms of myocardial disease and to provide quantification rather than a binary "black versus
white" categorisation. Combined with manganese enhancement, and time-optimised T1 mapping
protocols, this should allow specific tissue characterisation rather than the more
generalised extracellular and intravascular assessment provided by late-gadolinium
enhancement.
Whilst T1 mapping eliminates errors introduced by windowing and variable signal enhancement,
post contrast T1 quantification can be affected by variable contrast kinetics and is heavily
reliant on precise timing of acquisition. The derivation of the partition coefficient and use
of plasma volume to calculate extracellular volume fraction (ECV) have been developed to
correct for these factors. Previous studies have demonstrated the value of ECV in the
assessment of myocardial fibrosis in aortic stenosis, shown excellent reproducibility at
3-Tesla (3T) , and have correlated these values with other important biomarkers.
Mangafodipir In its early development, Mn toxicity occurred in animal studies with
administration of magnesium chloride (MnCl2) because it competed too strongly with Ca2+ entry
into the myocardium. It caused decreased myocardial function, hypotension and cardiac
arrest.1 Two approaches were developed to circumvent these risks whilst maintaining the
desired magnetic and kinetic properties. These are (i) chelation to bind the Mn2+ ions
preventing competition with Ca2+, and (ii) co-administration of Ca2+ ions, effectively
competing with Mn and reducing its cardio-toxic potential.12 Mangafodipir utilises the first
of these two approaches, in a similar way to which Gd contrast agents mitigate against
toxicity.
The principal limitation of Gd-based DEMRI imaging lies in quantifying the heterogeneous
peri-infarct zone, where it results in overestimation of the non-viable infarct region.33 To
date, there is no established imaging strategy to identify the viable and potentially,
salvageable cardiomyocytes within this key area of myocardium. The investigators hypothesize
that Mn-enhanced MRI will provide a method of cellular imaging through specific,
non-perfusion dependent distribution due to active uptake by viable myocardial cells. The
potential clinical application of this novel contrast agent will be to assess manganese
uptake and therefore calcium handling in the myocardium of patients with reversible causes of
myocardial injury such as reversible ischaemia, myocarditis and takotsubo cardiomyopathy.
This will guide therapy and enable prognostication in these patient groups with high unmet
clinical need.
RATIONALE for STUDY Pre-clinical and clinical data Mangafodipir has been used in animal
models where it was compared to a non-chelated Mn-based contrast medium, EVP1001-1. Whilst
the latter agent uses co-administration with calcium to counteract toxicity, Mangafodipir
(Teslascan) employs chelation with dipyridoxyl diphosphate (DPDP) to counteract potential
toxic effects.
The study successfully assessed T1 shortening in the healthy rat myocardium using both Mn
contrast agents and demonstrated reduced T1 shortening (Mn uptake) with the simultaneous
administration of diltiazem by approximately one third.
Spath et al have shown that manganese-enhanced magnetic resonance (MEMRI) is a better measure
of myocardial infarction size than late gadolinium enhancement. Data indicate two important
findings: (i) over-estimation of the scar by DEMRI (Gd) and (ii) quantitative differences in
the scar volume between MEMRI and DEMRI. Moreover, they have shown that MEMRI is superior in
assessment of viability as it gives a direct quantification of viable myocardium.
Furthermore, MEMRI with T1 mapping has shown altered manganese uptake and reduced rate of
extra-cellular re-distribution in patients with dilated cardiomyopathy. In addition to better
quantification of myocardial infarct size and assessing viability, we hypothesise that MEMRI
will also allow the study of myocardial recovery in reversible cardiomyopathy such as
reversible ischaemia, myocarditis and takotsubo cardiomyopathy.
Safety data and clinical use Naturally occurring deficiency is rarely reported but toxic
effects of Mn have historically been recognised with Mn accumulating in the striatum and
globus pallidus, the predominant manifestations being headaches and emotional lability, with
parkinsonian extrapyramidal symptoms and gait-disturbance (manganism) developing with
increasing severity. These concerns have been overcome as described above with chelation and
calcium-competition.
The manganese agent used in this study, Mangafodipir (now a generic product), has been widely
used in humans for the investigation of hepatic and pancreatic lesions. The agent has now
been patented for application to cardiovascular disease and shows great promise.
Extensive animal studies and use in humans have enabled Phase I, II and III trials of
Mangafodipir. In Phase III clinical trials, 624 patients were evaluable for adverse events.
Infusion associated discomfort was reported in 4% of patients (n=24) a feeling of warmth of
mild (n=22) to moderate (n=2) intensity. Six serious adverse events occurred. Of these, two
were considered possibly/likely to be drug related and occurred in one patient. These were
reported as a rash of the left arm in the presence of pre-existing lymphedema followed by a
septicaemia after a superficial cut of the left hand. Vital signs were monitored in 321
patients and clinically important changes in blood pressure were recorded in 2 of these, one
with an increased systolic blood pressure of 70 mmHg the other with increased
systolic/diastolic pressures of 50/40 mmHg respectively. Monitoring of blood chemistry
indicated increases in bilirubin levels in one patient and high total serum iron in 5
patients.
Special populations: No specific interaction, renal impairment or high risk patient studies
were submitted. Subjects less than 18 years old were excluded in the trials. In the phase III
studies, 216 of the 624 patients were over 65. The rate of adverse events was lower in this
sub-group (4% vs. 9.3%). Bilirubin was measured in 257 patients and was abnormal in 30 of
them although severe obstructive hepatobiliary disease was an exclusion criterion. 138
patients were recorded as having cirrhosis. No increased adverse event rate was found in
either sub-group. 86 out of the 624 patients had unspecified cardiovascular disease. No
difference in adverse event rate was observed with this sub-group.
Most common adverse reactions reported were transient and of mild intensity, with headache,
nausea and flushing being most commonly reported (1-10%). Uncommonly reported adverse
reactions were skin reactions, rhinitis, pharyngitis, abdominal discomfort, palpitation,
gastrointestinal disturbance, dizziness, paraesthesia, altered taste sensation, fever and
discomfort at injection site (0.1-1%). Other adverse reactions were very uncommon or rare.
The frequency of reactions was found to be increased with faster infusion rates
(4-6mls/minute).
More recently, clinical studies have focused on the application of Mangafodipir to human
cardiovascular imaging and disease, reinforcing this large body of safety data as applied to
a cardiovascular population as well as demonstrating the potential of the agent to
characterise myocardial function.
Control Data This study is designed to explore the application of this novel cardiac MRI
technique in reversible cardiomyopathy. Participants from the patient cohort will be compared
to a healthy volunteer group.
