Clinical Trial Summary
CMV infection is the most prevalent infection after heart transplantation (HTX), occurring in
up to 40-60% of the recipients. It most frequently occurs within the first 6 months after
transplantation and commonly presents as an asymptomatic viral replication. Viral syndrome or
tissue-invasive disease (gastroenteritis, pneumonitis, myocarditis or meningitis) are much
less common. Even though CMV infection is generally treatable with virostatic therapy and/or
CMV-specific immunoglobulins, direct effects of CMV infection (viral syndrome and
tissue-invasive disease) and general and transplant-specific indirect effects of CMV
infection have been associated with significant morbidity and mortality in HTX patient
population, mainly due to graft loss, development of malignancies, or opportunistic
infections. According to the latest consensus paper on CMV prophylaxis and treatment in solid
organ transplant recipients, valgancyclovir (or its active form gancyclovir) represents a
virostatic therapy of choice for CMV prophylaxis and treatment after HTX. However,
valgancyclovir has an array of side effects including hematological (leukopenia, neutropenia,
anemia, thrombocytopenia), neurologic (headache, insomnia), gastrointestinal (decreased
appetite, diarrhea, vomiting and dyspepsia) and psychiatric (depression) disorders. These can
either expose HTX patients to additional complications (e.g. leukopenia and/or neutropenia
can result in systemic fungal infections), decrease patients' quality of life, or mandate a
decrease in valgancyclovir dose, which exposes patients to an increased risk for CMV
reactivation. Recently, letermovir (a novel CMV viral terminase inhibitor), was approved for
CMV prophylaxis in allogeneic bone marrow transplant recipients as the placebo-controlled
study showed that significantly less patients, treated with letermovir, developed CMV disease
(37% vs. 60%; P<0.001) and there was also a trend towards lower all-cause mortality. Data on
bone marrow transplant recipients additionally suggest that letermovir is generally well
tolerated with side effects limited to mild gastrointestinal symptoms (diarrhea, nausea).
Importantly, myelosuppresive side effects of letermovir occur very rarely. Some encouraging
data does exist on the use of letermovir in kidney transplant recipients, where a recently
published proof-of-concept trial (N=27) suggested comparable safety and efficacy of
leteremovir (N=18) and valgancyclovir (N=9): both treatment regimens resulted in similar
time-course of viral load reduction and viral clearance and were well tolerated in terms of
adverse events. Currently, a Phase III clinical trial is ongoing in renal transplant
recipients (Clinicaltrials.gov: NCT03443869) to confirm this pilot data. However, to date,
there is no published data on the use of letermovir in patients after HTX.
Based on the results in kidney transplantation, the aim of this pilot study is thus to
evaluate the effects of letermovir-based CMV prophylaxis in heart transplant recipients.
The primary objective of the study is to investigate the efficacy of letermovir-based CMV
prophylaxis in patients after heart transplantation.
The secondary objectives of the study are:
- to investigate the tolerability of letermovir-based CMV prophylaxis in patients after
heart transplantation.
- to explore the potential correlation between letermovir-based CMV prophylaxis and
restitution of cell-regulated immunity in patients after heart transplantation.
This protocol represents a Phase II pilot prospective non-randomized single arm open-label
study design. We aim to enroll 30 patients after heart transplantation (Study Group), who
will meet all of the inclusion and none of the exclusion criteria and 60 propensity-matched
historical controls (Controls; matched for gender, age, CMV serological status, CMV DNA
quantification method, donor and transplant data and immunosuppresion treatment). All
patients in the Study Group will receive virostatic prophylaxis with letermovir 480 mg qd (We
will be utilizing Letermovir oral formulation of 240 mg or 480 mg as available). Patients in
Controls will receive virostatic prophylaxis with valgancyclovir 450 mg bid. In all patients
the virostatic prophylaxis will be initiated between days 4 and 7 after heart transplantation
and the duration of virostatic prophylaxis will be determined by the Quantiferon-CMV assay.
In all patients, initial Quantiferon-CMV assay evaluation will be performed 100 days
post-heart transplant at which time PCR CMV assay will also be made. In patients with
negative PCR CMV and Quantiferon-CMV values ≥ 0,2 IU/mL the virostatic therapy will be
discontinued [10]. In patients with negative PCR CMV and Quantiferon-CMV values < 0,2 IU/mL
the virostatic prophylaxis will continue for additional 30 days at which point
Quantiferon-CMV assay will be re-evaluated. In an event of CMV infection/disease CMV it will
be treated using valgancyclovir (900 mg q12) or gancyclovir (5 mg/kg q12h) per discretion of
the treating heart transplant cardiologist and resistance to virostatic therapy will be
tested at this time point. All patients (Study Group and Controls) will receive
immunosuppresion induction therapy and triple maintenance immunosuppression therapy
(TAC/MMF/steroid), fungal (posaconazole - 6 months), and pneumocystis prophylaxis (TMP/SMX -
lifelong). In the Study Group additional, HSV /VZV viral prophylaxis with valacyclovir (500
mg q12, adjusted for renal function) will be used for 6 months after heart transplantation.
Patients will be followed on an outpatient basis monthly for 12 months after enrollment and
the events will be recorded using the following definitions. The maximum expected duration of
letermovir therapy in the Study Group will be equal to the duration of follow-up - 12 months.
After completion of the study all patients in the Study Group that may still require CMV
virostatic prophylaxis according to our institutional guidelines will be switched to the
current standard of care at our institution - valgancyclovir.
