Letermovir for Congenital CMV Infection

Recruiting at 12 trial locations

Overseen By David W. Kimberlin

Age: < 18

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Valganciclovir

Must not be taking: Carbamazepine, Nafcillin, Phenobarbital, Phenytoin

Disqualifiers: HIV exposure, Imminent demise, others

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

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

Compensation: Varies

Number of Visits: 7

Duration: 2 weeks

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests letermovir (Prevymis), a new medicine, to evaluate its effects on newborns with congenital Cytomegalovirus (CMV) disease, a condition where babies are born with symptoms like hearing loss or growth problems. The goal is to understand how the drug is processed in the body and determine if it can reduce the virus in these infants. The trial includes two groups of babies who will receive the drug in different doses based on their weight. It seeks newborns diagnosed with symptomatic CMV within their first 30 days of life and whose doctors plan to treat them with another standard medicine, valganciclovir. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering a unique opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take certain drugs like carbamazepine, nafcillin, phenobarbital, or phenytoin during the study.

Is there any evidence suggesting that letermovir is likely to be safe for humans?

Research has shown that letermovir is safe for preventing CMV (Cytomegalovirus) infections in children. Studies have found it effective and well-tolerated, even in those under 18. This finding is encouraging for its use in babies with congenital CMV, like those in the current study. Although this study is in an early phase, earlier research suggests that letermovir is safe for young patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Letermovir is unique because, unlike the standard treatment for congenital Cytomegalovirus (CMV) infection, which typically includes antivirals like ganciclovir or valganciclovir, it specifically inhibits the CMV terminase complex. This new mechanism of action targets a different part of the virus's lifecycle, which could potentially make it more effective or reduce side effects associated with current treatments. Researchers are excited because letermovir's ability to be taken orally and its targeted approach could offer a safer and more convenient option for treating this condition in newborns.

What evidence suggests that letermovir might be an effective treatment for congenital CMV?

Research has shown that letermovir effectively prevents cytomegalovirus (CMV) infections in various groups. Studies involving children undergoing certain transplants demonstrated that letermovir can prevent serious CMV infections, and the treatment proved safe and effective in these cases. In this trial, neonates with symptomatic congenital CMV disease will receive letermovir to assess its potential to lower virus levels in these young patients. Although data specifically for newborns is limited, the drug’s success in similar situations offers hope for its effectiveness here. ^{1 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for infants with symptomatic congenital CMV disease who are planned to be treated with oral valganciclovir for 6 months. Eligible infants must have confirmed CMV, weigh between 2.6 kg and <8.0 kg, be at least 32 weeks gestational age at birth, and show symptoms like thrombocytopenia or CNS involvement.

Inclusion Criteria

My doctor plans to treat my infant's CMV with oral medication for 6 months.

For Group 1 participants, the time lag is no longer than 21 days.

I have symptoms like easy bruising, liver enlargement, or hearing loss due to CMV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

Dose Finding

Participants receive one dose of oral letermovir and undergo pharmacokinetic profiling

1 day

1 visit (in-person)

Treatment

Participants receive a 14-day course of once-daily oral letermovir with concurrent valganciclovir

2 weeks

4 visits (in-person) on Study Days 1, 5, 10, and 14

Follow-up

Participants are monitored for safety and effectiveness after treatment, including viral load assessments

4 weeks

2 visits (in-person) on Study Days 21 and 42

Long-term Follow-up

Participants continue on oral valganciclovir as routine clinical care to complete an anticipated 6-month duration of total therapy

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Letermovir

Trial Overview

The study tests the safety of oral Letermovir in newborns with symptomatic congenital Cytomegalovirus (CMV). It's a Phase 1 trial where subjects receive one dose followed by a pharmacokinetics profile assessment over 24 hours to determine appropriate dosing for a subsequent 14-day treatment course.

How Is the Trial Designed?

Group I: Group 2 Experimental Treatment 1 Intervention

Neonates (\</= 90 days) with symptomatic congenital Cytomegalovirus (CMV) disease will initiate a 14-day course of once-daily oral letermovir, using weight dose banding. All subjects also will receive valganciclovir as standard of care. A dose escalation safety evaluation will occur to ensure the safety data support subjects proceeding. If the median of observed letermovir exposures of subjects in Group 1 is below 34,400 ngxhr/mL (or above 100,000 ngxhr/mL), then the subjects enrolled in Group 2 will receive once-daily oral letermovir at a dose that has been adjusted upward (or downward) in 2.5 mg increments. N=8

Group II: Group 1 Experimental Treatment 1 Intervention

Neonates (\</= 83 days) with symptomatic congenital Cytomegalovirus (CMV) disease will receive one dose of oral letermovir, using weight dose banding. All subjects also will receive valganciclovir as standard of care. A dose safety evaluation will occur to ensure the safety data support subjects proceeding. If the observed letermovir exposure is \</= 100,000 ngxhr/mL, the subject will initiate a 14-day course of once-daily oral letermovir at the same dose as utilized on the Dose Finding Day. If the observed letermovir exposure of the subject is \> 100,000 ngxhr/mL, the once-daily oral letermovir dose that will be used will be adjusted down in 2.5 mg increments from the dose utilized on the Dose Finding Day. N = 4

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?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

In a study of 204 adult CMV-seropositive allo-SCT recipients treated with letermovir for CMV prophylaxis, the cumulative incidence of clinically significant CMV infection was low, at 5.4% by day +100 and 18.1% by day +168, indicating letermovir's efficacy in a real-world setting.

The treatment was generally safe, with low to mild adverse events reported in 40.7% of patients, primarily gastrointestinal issues and skin rashes, suggesting that letermovir is a well-tolerated option for CMV prevention in high-risk transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letermovir Prophylaxis for Cytomegalovirus Infection in Allogeneic Stem Cell Transplantation: A Real-World Experience. Martino, M., Pitino, A., Gori, M., et al.[2021]

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]

In a phase III trial, letermovir significantly reduced the rate of clinically significant CMV infection in adult CMV-seropositive patients after hematopoietic stem cell transplantation, demonstrating its efficacy as a prophylactic treatment.

The study found no significant relationship between letermovir exposure and the incidence of adverse events or the timing of CMV infection onset, supporting the current dosing recommendations for the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients. Prohn, M., Cho, CR., Viberg, A., et al.[2022]

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]

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]

Letermovir (LMV) is effective for preventing cytomegalovirus (CMV) infection in patients receiving hematopoietic stem cell transplants, but resistance can develop quickly, as shown in a case where a patient developed a mutation associated with high-level LMV resistance after secondary prophylaxis.

Monitoring viral loads and conducting genotyping for resistance mutations is crucial when using LMV, especially in patients with detectable CMV, to prevent the rapid selection of resistant strains.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient. Jung, S., Michel, M., Stamminger, T., et al.[2020]

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, a new anti-CMV drug with fewer side effects, was successfully used off-label to treat a heart transplant recipient with ganciclovir-resistant CMV colitis, highlighting its potential as an alternative treatment.

The case suggests that monitoring CMV-pp65 antigenemia levels could be a useful additional marker for assessing the efficacy of letermovir treatment, alongside traditional CMV-DNA PCR levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment with Letermovir in a Heart Transplant Recipient with UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Colitis and Viremia. Yanase, T., Hatano, M., Bujo, C., et al.[2023]

Letermovir (LMV) and Maribavir (MBV) can effectively cross the placenta, achieving fetal concentrations significantly higher than the levels needed to inhibit cytomegalovirus (CMV), suggesting their potential for treating congenital CMV infection.

The study demonstrated that both drugs have favorable transfer rates and retention in the placenta, indicating they could be viable options for maternal treatment to benefit infected fetuses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placental transfer of Letermovir & Maribavir in the ex vivo human cotyledon perfusion model. New perspectives for in utero treatment of congenital cytomegalovirus infection. Faure Bardon, V., Peytavin, G., Lê, MP., et al.[2020]

Citations

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pubmed.ncbi.nlm.nih.gov

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The hypothesis being tested was that MK-8228 is superior to placebo in the prevention of clinically-significant CMV infection through Week 24 post-transplant.

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12170442/

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Letermovir prophylaxis has effectively reduced the incidence of clinically significant CMV infection (csCMVi) in adult HCT recipients.

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The investigators' hypothesis is that maternal treatment with Letermovir will inhibit fetal CMV replication better than Valaciclovir in infected fetuses and ...

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merckconnect.com

merckconnect.com/prevymis/hsct-primary-endpoint-results/

Primary Endpoint Results in Clinical Trials For HSCT Adult ...

PREVYMIS® (letermovir) is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and ...

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pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40949906/

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clinicaltrials.gov

clinicaltrials.gov/study/NCT06118515

NCT06118515 | A Safety Assessment of Oral Letermovir in ...

This is a Phase 1 single-arm open-label study of letermovir in neonates with symptomatic congenital Cytomegalovirus (CMV) disease.

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academic.oup.com

academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaf410/8211939?searchresult=1

Letermovir Prophylaxis Guided by Cytomegalovirus Cell ...

This study aimed to assess whether CMV-CMI–guided letermovir prophylaxis is more effective than a fixed-duration approach in reducing the ...

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cpic.rarediseasesnetwork.org

cpic.rarediseasesnetwork.org/research-study/8603

Research Study | Congenital and Perinatal Infections ...

Letermovir is the first newly licensed antiviral medication with CMV activity in over 20 years and has been shown to be safe to take. Determining the drug ...