Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04311346 |
| Other study ID # |
Helsinki UCH CMR |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 7, 2020 |
| Est. completion date |
March 7, 2024 |
Study information
| Verified date |
March 2020 |
| Source |
Helsinki University Central Hospital |
| Contact |
Tiina H Ojala, MD, PhD |
| Phone |
+358504270558 |
| Email |
tiina.h.ojala[@]hus.fi |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
In this a prospective, blinded, collaboration study between pediatric and adult transplant
departments. Cardiac MRI data on patient with heart transplantations will be collected during
years 2020-2022. Based on sample size calculations, the data has enough power to answer the
question, whether MRI can be used as a noninvasive diagnostic tool for detection of acute
rejection as such or whether it can be used as fist line noninvasive screening tool for
detecting those needing for the more detailed invasive study. A clinical protocol will be
developed to optimize the management and outcome of the patients having cardiac
transplantation aiming to decrease the number of invasive procedures in these patients.
Description:
Background Heart transplantation is a treatment for select patients with end-stage heart
failure. Improvements in immunosuppressive therapies and patient management have increased
the life expectancy of heart transplant patients. One-year survivals are 90% and 80%, with 65
% and 49% of pediatric and adult patients surviving 8 - 15 years after transplantation in
Finland, respectively. Despite this success, rejection remains the "Achilles heel" of heart
transplantation. The early detection of acute rejection and cardiac allograft vasculopathy
(chronic rejection) are paramount to avoiding graft loss. Unlike in kidney and liver
transplantation, there are no clinically validated biomarkers for detecting heart transplant
rejection.
Biopsy and invasive coronary angiography are widely accepted as the gold standard for
diagnosing acute graft rejection and chronic rejection (vasculopathy) in both pediatric and
adult heart transplant recipients, respectively. However, biopsies are invasive, and they
carry a significant risk of complication regarding that majority of endocardial biopsies are
performed in asymptomatic patients. In addition, the histologic assessment of biopsies is
often subjective. Due to the lack of consensus, biopsy protocols are center-specific and
depend on the experience and personal preference of the transplant team. Helsinki pediatric
transplant protocol can be considered as high-intensity biopsy center. At best, the routine
surveillance biopsies can detect late episodes of moderate to severe rejection in children
with an 8% - 10% annual incidence up to 11 years after transplantation. However, there is no
correlation between the intensity of biopsies and the incidence of rejection or 4-year
mortality in the pediatric population, suggesting the need for other monitoring practices for
rejection.
Cardiac MRI. Advanced multimodality imaging techniques, such as cardiac magnetic resonance
imaging (MRI), may provide a future alternative to the monitoring practices for children and
adults following heart transplantation. This has the potential to decrease the frequency of
biopsies and radiation, especially in low-risk patients. Cardiac MRI can assess myocardial
changes over time after transplantation. In heart transplant patients, MRI facilitates the
detection of acute and chronic rejection and allows monitoring of gradual adverse remodeling.
Volumetric assessment of the ventricles can further independently predict hospitalizations
and mortality. The most widely investigated MRI parameters for detecting acute rejection are
the T2 (indicates myocardial edema) and T1 relaxation times (indicates extracellular volume
fraction (ECV) and fibrosis). Further, the assessment of global left ventricular function,
myocardial strain analysis as well as late gadolinium enhancement (LGE) have been used for
detection of chronic myocardial changes. Except for LGE and ECV, all of them can be measured
noninvasively without the need for gadolinium contrast.
Even biopsy results may fail to predict rejection. A retrospective study of adults found that
T2 time of ≥56 ms had a 97% negative predictive value for detecting acute rejection grade >
2. Interestingly, up to 80% of patients with a simultaneous negative biopsy but prolonged T2
relaxation time developed acute rejection in the next 30 days. The study suggested that T2
time measurement may be equal, or even superior to biopsy. However, the use of T2 relaxation
time early after transplantation is limited, as it may be elevated in the first 25 days after
transplantation regardless of the rejection status.
Contrast-enhanced MRI with gadolinium may provide additional information to T2 and T1
relaxation times and further limit the need for biopsies. It can identify areas of myocardial
inflammation, scarring, and diffuse fibrosis, as well as assess myocardial perfusion. The
prevalence of late gadolinium enhancement increases with the severity of rejection, whereas
early gadolinium enhancement reflects extracellular space expansion secondary to acute
necrosis and edema. Both myocardial edema (identified on T2- weighted imaging) and early
myocardial contrast enhancement distinguish patients with International Society for Heart and
Lung Transplantation (ISHLT) grade 2R rejection from those with grades 1R and 0R. Further, it
has been reported that late enhancement in serially assessed transplant patients is
associated with major adverse cardiac events and mortality. A recent study in 20 pediatric
heart transplant patients showed that MRI-derived fibrosis markers correlate with the
severity of fibrosis on biopsy. Although replacement fibrosis is irreversible, other MRI
measurements change over time. Therefore, serial imaging can provide insight not only into
disease progression but also on the efficacy of treatment. This is particularly relevant in
acute rejection where the evaluation of myocardial edema with T2 mapping and interstitial
expansion or fibrosis (T1 mapping ) can be accomplished with and without the administration
of contrast agents and could easily limit the number of biopsies.
Hypothesis
Noninvasive cardiac MRI imaging can replace traditional invasive diagnostic procedures in
detecting allograft rejection in cardiac transplant patients. This novel imaging strategy
will reduce the cumulative stress and radiation and will guide clinical decision-making in
these severely ill patients.
Patients and methods In this prospective blinded study, cardiac MRI data on new heart
transplantations will be collected during years 2020-2021 (N = 72, including pediatric and
adult patients). Estimated total count of invasive biopsies in the pediatric population is
100-150/2y samples, and the adult numbers will be three times higher (300-450/2y). The risk
of the primary endpoint of acute rejection/immunoactivation is the highest during the first
five years after transplantation. The immunoactivation occurs in 18 % and 10 % of samples
taken <3 months and > 3 months after transplantation, respectively. Cardiac MRI
immunoactivation/rejection findings will be blindly compared with the histological analysis
of invasive endocardial biopsy done by one pathologist.
Sample size calculation (statistical consultation Tero Vahlberg, PhD): Clinically acceptable
sensitivity for cardiac MRI to detect an acute rejection is 80%. Assuming an alpha level of
0.05, marginal error (precision) of 10% for sensitivity and 15% prevalence for rejection, the
required total sample size is 410 samples. For specificity of 80% for cardiac MRI using the
same assumptions, the required total sample size is 72 patients.
The required sample size is 410 biopsies and estimated time needed for data collection is two
years. The data has then enough power to answer the question - whether MRI can be used as a
noninvasive diagnostic tool for detection of acute rejection as such or whether it can be
used as a fist line noninvasive screening tool for detecting those needing more detailed
invasive study. MRI measurements published in adults for the detection of rejection or
myocardial inflammation will be used. The detection of the secondary endpoint of
vasculopathy/chronic rejection will be studied similarly to acute rejection. Cardiac MRI
studies focusing on the vasculopathy findings will be carried out during the annual follow-up
visits (two times during the study period/per patients, total n= 200). The MRI phenotype will
be compared with invasive angiography findings. Advanced echocardiographic measurements will
be further used for clinical, echocardiographic studies done in parallel with the cardiac MRI
studies. The advanced echocardiographic methodology is based on the last 20 years research of
group. Shortly, the methods to be used for functional MRI studies are the same as used in
echo modality.
Ethical aspects The studies are designed to comply with the Helsinki Declaration and the
Conventions of the Council of Europe on human rights. The results are reviewed and published
anonymously. All clinical studies fulfill the general ethical requirements for clinical
studies. The investigators have obtained following ethical permits from HUS ethical
committee.
Clinical importance of the study Our project is realistic and timely. This project aims to
promote noninvasive diagnostic strategies to replace traditional invasive procedures reducing
cumulative stress and radiation in this group of severely ill heart transplant patients. This
will be possible by creating a substantial amount of non-invasive research data on the
myocardial mechanisms after transplantation. The investigators acknowledge that this project
is ambitious. Our interdisciplinary research-group has vast experience of working with the
proposed methods facilitating the success of this project. Our study results will build the
foundations for new protocols to optimize the management and outcome of these patients. The
methods the investigators use are validated, and the studies are well designed. The
investigators are convinced that the results of the study will largely improve the clinical
care of these patients. As MRI imaging is less expensive than invasive procedures, this
approach will result in reduced health care costs in the long term.
