Letermovir for Cytomegalovirus Prophylaxis in Kidney Transplant Recipients

Overseen By Gelila Abebe

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Virginia Commonwealth University

Must be taking: Valganciclovir

Must not be taking: Pimozide, Ergot alkaloids

Disqualifiers: Re-transplantation, Pregnancy, Hypersensitivity, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate how effectively the new drug, Letermovir, prevents cytomegalovirus (CMV) infections in African American kidney transplant patients. CMV can cause serious illness after a transplant. The study compares Letermovir to the standard treatment, Valganciclovir. It targets African American kidney recipients at high risk for CMV due to receiving a kidney from a CMV-positive donor. Participants must not have had a previous transplant or certain immune responses, and they must not be allergic to specific medications. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

If you are taking pimozide, ergot alkaloids, or pitavastatin/simvastatin with cyclosporine, you may need to switch to a different medication. The study team will work with your doctor to find a suitable alternative.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Letermovir is generally well tolerated. In a study with adult kidney transplant recipients, Letermovir prevented CMV (cytomegalovirus) infection effectively. The results indicated that patients handled the treatment well, with no major safety issues reported.

Another study examined Valganciclovir in high-risk kidney transplant recipients. This study found Valganciclovir effective and safe for CMV prevention over 200 days.

Both Letermovir and Valganciclovir have been studied for their safety in preventing CMV in kidney transplant recipients. The data suggests that both treatments are well tolerated, meaning they usually don't cause serious side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for cytomegalovirus?

Unlike the standard of care for preventing cytomegalovirus (CMV) in kidney transplant recipients, which typically involves valganciclovir, Letermovir offers a unique approach. Letermovir is exciting because it targets the CMV DNA terminase complex, a novel mechanism of action compared to the traditional drugs that inhibit viral DNA polymerase. This difference may lead to fewer side effects and potentially reduce the risk of drug resistance. Researchers are optimistic that Letermovir could provide a safer and more effective option for preventing CMV in transplant patients.

What evidence suggests that this trial's treatments could be effective for preventing cytomegalovirus in kidney transplant recipients?

Research has shown that Letermovir, which participants in this trial may receive, effectively prevents cytomegalovirus (CMV) in high-risk transplant patients. Studies have found that Letermovir performs as well as Valganciclovir in preventing CMV disease when used for up to 200 days post-transplant. It has significantly reduced CMV-related complications and deaths in transplant recipients. Letermovir is generally well tolerated and has demonstrated positive results in real-world use. For African American kidney transplant recipients, these findings suggest that Letermovir could be a strong option to prevent CMV issues. ^{1 5 6 7 8}

Who Is on the Research Team?

Gaurav Gupta, MD

Principal Investigator

Virginia Commonwealth University

Are You a Good Fit for This Trial?

This trial is for African American adults who've received a kidney transplant and are at high risk for Cytomegalovirus (CMV) because they got the virus from the donor. It's not open to those who have already been treated with valganciclovir for CMV or have certain transplant-related complications.

Inclusion Criteria

Ability to provide informed consent before any trial related activities

I have received a kidney transplant.

I am at high risk for CMV due to donor/recipient status.

Exclusion Criteria

Patients with hypersensitivity to Letermovir or any of its components

I am not taking pimozide, ergot alkaloids, or certain cholesterol medicines with cyclosporine.

Positive cytotoxic cross match at the time of transplant

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive prophylactic Letermovir or are assessed retrospectively for Valganciclovir use for CMV prophylaxis

6 months

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety, effectiveness, and secondary outcomes such as leukopenia and allograft rejection

up to 1 year

Periodic visits for assessment and monitoring

What Are the Treatments Tested in This Trial?

Interventions

• Letermovir

Trial Overview The study is testing if Letermovir, taken once daily, is effective in preventing CMV compared to Valganciclovir, following guidelines by the AST ID COP. Participants will be monitored and treated accordingly if they develop CMV viremia.

How Is the Trial Designed?

Group I: Letermovir group (study group) Experimental Treatment 1 Intervention

Letermovir 480 mg once daily

Group II: Historical Control study group Experimental Treatment 1 Intervention

Historically matched AA kidney transplant recipients who received the standard of care 450mg once a day valganciclovir prophylaxis

Letermovir is already approved in United States, European Union for the following indications:

Approved in United States as Prevymis for:

• Prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT)
• Prophylaxis of cytomegalovirus (CMV) disease in adult kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-])
• Prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT)
• Prophylaxis of cytomegalovirus (CMV) disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-])

Approved in European Union as Prevymis for:

• Prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT)
• Prophylaxis of cytomegalovirus (CMV) disease in adult kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-])

Who Is Running the Clinical Trial?

Virginia Commonwealth University

Lead Sponsor

Trials

732

Recruited

22,900,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

In a retrospective study of 10 abdominal transplant recipients, letermovir was well tolerated and successful in preventing CMV infection when used as primary prophylaxis, with all patients achieving positive outcomes.

However, letermovir was less effective as secondary prophylaxis, failing in 62.5% of cases due to breakthrough CMV infections, highlighting the need for further research on its efficacy in solid organ transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Letermovir for Primary and Secondary Cytomegalovirus Prophylaxis in Abdominal Organ Transplantation: A Single Center Experience. Ibrahim, D., Byrns, J., Maziarz, E., et al.[2023]

Letermovir (Prevymis™) is an effective prophylactic treatment for preventing cytomegalovirus (CMV) infection and disease in adult patients who are CMV-seropositive and have received an allogeneic hematopoietic stem cell transplant, with approvals in Canada and the USA.

The drug works by inhibiting the CMV DNA terminase complex and has received positive regulatory feedback in Europe, indicating its potential for broader international use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir: First Global Approval. Kim, ES.[2019]

Letermovir, an anti-CMV drug, was successfully used to treat ganciclovir-resistant CMV colitis in a heart transplant recipient, demonstrating its potential as a curative option.

In a second case, while letermovir was used as pre-emptive therapy for CMV reactivation, it did not prevent CMV esophagitis, indicating that while effective for secondary prophylaxis, it may not always prevent all forms of CMV-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir use to treat complex cytomegalovirus reactivations in two heart transplant recipients. Boignard, A., Augier, C., Kheng, M., et al.[2022]

Letermovir, approved by the FDA for preventing CMV infection in stem cell transplant recipients, was used off-label for a heart transplant patient with ganciclovir-resistant CMV, showing its potential beyond initial indications.

The patient had previously experienced unacceptable toxicities from other treatments (cidofovir and foscarnet), highlighting letermovir as a safer alternative for managing resistant CMV infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir successfully used for secondary prophylaxis in a heart transplant recipient with ganciclovir-resistant cytomegalovirus syndrome (UL97 mutation). Chong, PP., Teiber, D., Prokesch, BC., et al.[2019]

Letermovir is highly effective in preventing cytomegalovirus (CMV) reactivation and disease in transplant recipients, showing similar efficacy to standard treatments like valganciclovir but with a significantly better safety profile, including reduced myelotoxicity and no need for renal dose adjustments.

Recent studies indicate that letermovir not only prevents CMV effectively but also improves overall clinical outcomes, such as reduced mortality and lower rates of graft versus host disease, making it a promising option for extended prophylaxis in hematopoietic stem cell and solid organ transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new direction for cytomegalovirus prophylaxis among transplant recipients: Benefits and nonviral outcomes of letermovir use as primary CMV prophylaxis. Moore, WJ., Boutin, CA., Tanna, S.[2023]

In a Phase 1 trial with 24 subjects, letermovir was well tolerated and showed increased exposure in patients with moderate to severe renal impairment, indicating that kidney function affects how the drug is processed in the body.

Specifically, renal impairment led to a significant increase in the unbound fraction of letermovir, with exposure levels rising by 192% in moderate impairment and 142% in severe impairment compared to healthy subjects, suggesting careful monitoring may be needed for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment. Kropeit, D., Scheuenpflug, J., Erb-Zohar, K., et al.[2021]

In an observational study of 48 transplant recipients treated with Letermovir (LET) for cytomegalovirus (CMV) infection, patients with a viral load below 1000 IU/ml at the start of treatment showed promising virologic outcomes, with only 2 experiencing a significant increase in viral load by week 12.

For patients who started LET with a viral load above 1000 IU/ml, 60% achieved a lower viral load by the end of therapy, indicating that LET may still be beneficial even in cases of higher initial viral loads, although further research is needed to optimize treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir treatment of cytomegalovirus infection or disease in solid organ and hematopoietic cell transplant recipients. Linder, KA., Kovacs, C., Mullane, KM., et al.[2021]

Letermovir, an antiviral agent typically used for preventing CMV infection in stem cell transplant recipients, was successfully used off-label to treat a patient with resistant CMV disease after renal transplant.

This case report is significant as it demonstrates the effectiveness of combining letermovir with hyperimmune CMV immunoglobulin for treating high viral load CMV infections, providing a potential alternative when standard treatments are inadequate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Viremia in a Renal Transplant Recipient With Letermovir and Adjunct Hyperimmune Cytomegalovirus Immunoglobulin: A Case Report. Pearston, AP., Ingemi, AI., Ripley, K., et al.[2021]

In a study of 48 CMV-seropositive allogeneic stem cell transplant recipients, letermovir prophylaxis significantly reduced the incidence of CMV reactivation to 33.3% compared to 76.2% in the control group, highlighting its efficacy in preventing this serious complication.

Patients receiving letermovir also showed improved overall survival at 180 days (92.6% vs. 80.9% in the control group), suggesting that prolonged use of letermovir may provide additional survival benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir Prophylaxis for CMV Reactivation in Allogeneic Stem Cell Recipients: A Retrospective Single Center Analysis. Koch, K., Osswald, L., Miller, I., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38615067/

a multicenter, open-label, noncomparative Phase 3 study Results: Among 22 participants (12 were D+/R-) who received letermovir prophylaxis, 20 (90.9%) experienced ≥ 1 AE through Week 28. Most AEs were ...

2. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2805945

Letermovir vs Valganciclovir for Prophylaxis of ... Letermovir was noninferior to valganciclovir for prevention of CMV disease when taken for up to 200 days after transplant by adult high-risk CMV ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1053249825022570

Tolerability and Clinical Efficacy of Letermovir for Primary ... Letermovir (LET), a novel antiviral agent, has shown promising results in preventing CMV reactivation in high-risk transplant populations, ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9879759/

Real-World Outcomes Associated With Letermovir Use for ... Letermovir for CMV PP was effective in reducing the risk of CMV-related complications overall and mortality beyond day 200 among adult allo-HCT recipients.

5. merckconnect.com merckconnect.com/prevymis/kidney-transplant-endpoint-results/

Study results in adult kidney transplant patients Review the primary and exploratory endpoint results from a clinical trial studying the efficacy of PREVYMIS® (letermovir) in adult kidney transplant ...

6. link.springer.com link.springer.com/article/10.1007/s10157-024-02471-0

a multicenter, open-label, noncomparative Phase 3 study Letermovir was generally well tolerated, and the data support its use for the prevention of CMV disease/infection in adult Japanese KTRs.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04129398

Study Details | NCT04129398 | MK-8228 (Letermovir) in ... This study aims to evaluate the safety, efficacy and pharmacokinetics (PK) of Letermovir (LET) administered as prevention of cytomegalovirus (CMV) infection and ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1600613525028503

Impact of kidney function on 200 days of antiviral ... The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant.