CMV ViremiaPhase 2CYPHER-TXPilotNCT05432778
Cytomegalovirus Prophylaxis With Letermovir in Heart Transplant Recipients
A Phase 2 study testing Letermovir Pill in people with CMV Viremia, run by University Medical Centre Ljubljana at 1 site in Slovenia.
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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- CMV Viremia
- What is being tested?
- Letermovir Pill
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 90 participants
- Where
- 1 siteSlovenia
- Study dates
- 1 May 2023to 1 Aug 2026
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- heart transplant recipient (new)
- moderate (D+/R+ and D-/R+) or high (D+/R-) risk CMV serostatus
- signed informed consent for participation in the study
Who cannot join
- short-term mechanical circulatory support prior HTX
- ongoing CMV infection/disease
- D-/R- CMV serostatus
- heart re-transplantation
- need for intensified immunosuppression protocol
- >20% cytolytic alloantibodies prior transplant
Show all 13Show fewer
- perioperative (within 7 days after HTX) allograft rejection > 1R
- immunoinduction with ATG
- pregnancy
- active participation in another interventional clinical trial
- know hypersensitivity to letermovir
- known hypersensitivity to valgancyclovir
- known hematological disorders (apart from anemia)
Trial locations and contacts
1 site in 1 country.
Slovenia1 site, 1 recruiting
- Recruiting
University Medical Center Ljubljana
Ljubljana, 1000
Bojan Vrtovec, MD, PhD, +38615221163, mateja.lani@kclj.si
Gregor Poglajen, MD, PhD
About this study
Official title: Cytomegalovirus Prophylaxis With Letermovir in Heart Transplant Recipients: A Non-randomized Cohort Pilot Study
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.
Read more
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.
Read the detailed description
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.
- Conditions
- CMV Viremia
- Being tested
- Letermovir Pill
- Keywords
- CMV reactivation, letermovir, heart transplantation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Letermovir PillDrug
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). n 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.
| Study group | Role | What they receive |
|---|---|---|
| Study Group | Experimental | 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). Receives: Drug: Letermovir Pill |
| Control Group | No intervention | Patients in Controls will receive standard-of-care virostatic prophylaxis with valgancyclovir 450 mg bid. |
What is being measured
The primary outcome is the main question the study is designed to answer.
The rate of early CMV infections/disease during virostatic prophylaxis.
The rate of early CMV infections/disease during virostatic prophylaxis.
Measured: baseline - 12 months
Secondary outcomes (5)
The rate of leukopenia during virostatic prophylaxis
The rate of leukopenia during virostatic prophylaxis
Measured: baseline - 12 months
The rate of neutropenia during virostatic prophylaxis
The rate of neutropenia during virostatic prophylaxis
Measured: baseline - 12 months
The rate of late CMV infections/disease between virostatic discontinuation and 6 months thereafter.
The rate of late CMV infections/disease between virostatic discontinuation and 6 months thereafter.
Measured: baseline - 12 months
The time-course of the restitution of cell-mediated immunity during virostatic prophylaxis
The time-course of the restitution of cell-mediated immunity during virostatic prophylaxis
Measured: baseline - 12 months
The rate of CMV resistance to virostatic therapy
The rate of CMV resistance to virostatic therapy
Measured: baseline - 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jun 2022
- Study start1 May 2023
- Primary completion1 Aug 2025 (estimated)
- Study completion1 Aug 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for CMV ViremiaStudies of the same condition, open and under way.
- More trials run by University Medical Centre LjubljanaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 90 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Medical Centre Ljubljana
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Bojan Vrtovec, MD, PhD, Principal investigator, Advanced Heart Failure and Transplantation Center, Universtiy Medical Center Ljubljana, Slovenia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05432778
- Sponsor's protocol ID
- 01
- Acronym
- CYPHER-TXPilot
- Status last verified
- Nov 2023
- First submitted
- 20 Jun 2022
- Last updated
- 9 Nov 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 9 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cytomegalovirus Prophylaxis With Letermovir in Heart Transplant Recipients: A Non-randomized Cohort Pilot Study
- ClinicalTrials.gov ID
- NCT05432778
- Acronym / sponsor ID
- CYPHER-TXPilot / 01
- Conditions
- CMV Viremia
- Keywords
- CMV reactivation, letermovir, heart transplantation
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 90 participants (estimated)
- Lead sponsor
- University Medical Centre LjubljanaUniversity, hospital or other
- Study start
- 1 May 2023 (actual)
- Primary completion
- 1 Aug 2025 (estimated)
- Study completion
- 1 Aug 2026 (estimated)
- First posted
- 27 Jun 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Study Group | Experimental | Drug: Letermovir PillAll 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). |
| Control Group | No intervention | –Patients in Controls will receive standard-of-care virostatic prophylaxis with valgancyclovir 450 mg bid. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- heart transplant recipient (new)
- moderate (D+/R+ and D-/R+) or high (D+/R-) risk CMV serostatus
- signed informed consent for participation in the study
Key exclusion criteria (13 listed)
- short-term mechanical circulatory support prior HTX
- ongoing CMV infection/disease
- D-/R- CMV serostatus
- heart re-transplantation
- need for intensified immunosuppression protocol
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Letermovir PillPatients 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). n 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. | Drug | Study Group |
Primary outcome
The rate of early CMV infections/disease during virostatic prophylaxis.
Time frame: baseline - 12 months
The rate of early CMV infections/disease during virostatic prophylaxis.
5 secondary outcomes
The rate of leukopenia during virostatic prophylaxis
Time frame: baseline - 12 months
The rate of neutropenia during virostatic prophylaxis
Time frame: baseline - 12 months
The rate of late CMV infections/disease between virostatic discontinuation and 6 months thereafter.
Time frame: baseline - 12 months
The time-course of the restitution of cell-mediated immunity during virostatic prophylaxis
Time frame: baseline - 12 months
The rate of CMV resistance to virostatic therapy
Time frame: baseline - 12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Nov 2023.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bojan Vrtovec, MD, PhD principal investigator
Advanced Heart Failure and Transplantation Center, Universtiy Medical Center Ljubljana, Slovenia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Letermovir Pill in people with CMV Viremia, run by University Medical Centre Ljubljana at 1 site in Slovenia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 9 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Slovenia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Bojan Vrtovec, MD, PhD (+38615222844, bojan.vrtovec@kclj.si), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The rate of early CMV infections/disease during virostatic prophylaxis. (time frame: baseline - 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Nov 2023.