Cytomegalovirus Prophylaxis With Letermovir in Heart Transplant Recipients

NCT05432778 | Recruiting Phase 2 DMC

• 1 other identifier: 01
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

CMV Viremia

Keywords

CMV reactivation; letermovir; heart transplantation

Outcome Measures

Primary Outcomes (1)

• The rate of early CMV infections/disease during virostatic prophylaxis.

  The rate of early CMV infections/disease during virostatic prophylaxis.

  baseline - 12 months

Secondary Outcomes (5)

• The rate of leukopenia during virostatic prophylaxis

  baseline - 12 months

• The rate of neutropenia during virostatic prophylaxis

  baseline - 12 months

• The rate of late CMV infections/disease between virostatic discontinuation and 6 months thereafter.

  baseline - 12 months

• The time-course of the restitution of cell-mediated immunity during virostatic prophylaxis

  baseline - 12 months

• The rate of CMV resistance to virostatic therapy

  baseline - 12 months

Study Arms (2)

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).

Drug: Letermovir Pill

Control Group

NO INTERVENTION

Patients in Controls will receive standard-of-care virostatic prophylaxis with valgancyclovir 450 mg bid.

Interventions

Letermovir Pill DRUG

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

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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)

Sponsors & Collaborators

• University Medical Centre Ljubljana: lead

Study Sites (1)

University Medical Center Ljubljana

Ljubljana, 1000, Slovenia

RECRUITING

MeSH Terms

Interventions

letermovir

Study Officials

• Bojan Vrtovec, MD, PhD

  Advanced Heart Failure and Transplantation Center, Universtiy Medical Center Ljubljana, Slovenia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bojan Vrtovec, MD, PhD

CONTACT

+38615222844; bojan.vrtovec@kclj.si

Gregor Poglajen, MD, PhD

CONTACT

+38615228671; gregor.poglajen@kclj.si

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 20, 2022
• First Posted: June 27, 2022
• Study Start: May 1, 2023
• Primary Completion: August 1, 2025
• Study Completion (Estimated): August 1, 2026
• Last Updated: November 9, 2023

Record last verified: 2023-11

Locations

SL (1)