CMV-Specific Immunotherapy for Congenital Cytomegalovirus Disease

Recruiting at 5 trial locations

Overseen By Mitchell S Cairo, MD

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: New York Medical College

Must be taking: Valganciclovir, Ganciclovir

Must not be taking: Steroids

Disqualifiers: HIV in mother, others

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

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

23 Participants Needed

Trial Summary

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 be on steroids at a dose higher than 0.5 mg/kg on the same day as the CMV CTL infusion.

What data supports the effectiveness of the drug Valcyte (valganciclovir) for congenital cytomegalovirus disease?

Research indicates that treatment with valganciclovir, an oral form of ganciclovir, may prevent hearing deterioration in children with symptomatic congenital CMV infection and central nervous system involvement, providing similar plasma concentrations to intravenous ganciclovir. ^{1 2 3 4 5}

Is CMV-specific immunotherapy generally safe for humans?

Valganciclovir, a treatment for CMV, can cause blood-related side effects like low white blood cell counts, which can be serious, especially in people with kidney problems. It should be used carefully in these patients to avoid severe complications. ^{6 7 8 9 10}

How is the drug Valganciclovir unique for treating congenital cytomegalovirus?

Valganciclovir is unique because it is an oral medication that provides similar blood levels to intravenous ganciclovir, making it a more convenient option for treating congenital cytomegalovirus, especially in children with central nervous system involvement. ^{1 5 6 11 12}

What is the purpose of this trial?

Patients with moderate or severe CMV disease less than 21 days old who have a maternal donor who has a CMV response to the peptivators will be screened. All patients will receive treatment with valganciclovir or ganciclovir. There is a safety run in with treatment with CMV CTLs in cohort 1 and if found to be safe, will proceed to cohort 2 for randomization to receive antiviral therapy with or without CMV CTLs. Funding source: FDA OOPD

Research Team

Mitchell S Cairo, MD

Principal Investigator

New York Medical College

Eligibility Criteria

This trial is for newborns under 21 days old with moderate to severe CMV disease, weighing at least 2500 grams and born after at least 34 weeks of gestation. They must have a maternal donor with an immune response to CMV. Babies on high-dose steroids, in other CMV trials, or with certain medical conditions can't participate.

Inclusion Criteria

I have inflammation in the back of my eye.

My white blood cell count is high for my age in my central nervous system.

My blood, kidney, and liver tests meet the required levels.

Exclusion Criteria

I am taking steroids equivalent to more than 0.5 mg/kg of prednisone on the day of my treatment.

Any medical condition that could compromise participation in the study according to the investigator's assessment

My legal representative cannot follow the study rules or give consent for me.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-in

The first 3 patients enrolled will receive both anti-viral medication and CMV CTLs, with treatment staggered every 28 days from the last dose of CMV CTLs from the prior patient.

28 days per patient

Randomized Treatment

Patients are randomized 1:1 to either anti-viral treatment alone or anti-viral treatment plus CMV CTLs. CMV CTL infusions may occur every 2 weeks up to 5 times if no adverse events are observed.

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including the incidence and severity of Grade I-IV acute GVHD within 8 weeks after the last CMV CTL infusion.

8 weeks

Treatment Details

Interventions

• Anti-viral Therapy
• CMV Cytotoxic T-Lymphocytes

Trial Overview The study tests the safety and effectiveness of adding CMV-specific T-cells (CMV CTLs) from the mother to standard antiviral therapy (valganciclovir or ganciclovir) in treating congenital CMV infection in neonates.

Participant Groups

Group I: Cohort 2 Antiviral medication + CMV CTLs Experimental Treatment 2 Interventions

Patients will receive both anti-viral medication and CMV CTLs

Group II: Cohort 1 Safety Run-in Experimental Treatment 2 Interventions

The first 3 patients enrolled will receive both anti-viral medication and CMV CTLs, and treatment will be staggered every 28 days from the last dose of CMV CTLs from the prior patient.

Group III: Cohort 2 Antiviral medication only Active Control 1 Intervention

Patients will only receive anti-viral therapy

Anti-viral Therapy is already approved in European Union, United States for the following indications:

Approved in European Union as Valcyte for:

• Cytomegalovirus (CMV) retinitis
• CMV prophylaxis in organ transplant recipients

Approved in United States as Valcyte for:

• CMV retinitis
• CMV prophylaxis in organ transplant recipients

Who Is Running the Clinical Trial?

New York Medical College

Lead Sponsor

Trials

73

Recruited

8,700+

Findings from Research

Cytomegalovirus (CMV) is a significant cause of congenital infection, affecting 0.3 to 0.6% of live births in Europe, with a notable risk of long-term complications such as hearing loss and mental retardation in infected infants.

Treatment with intravenous ganciclovir for six weeks can help prevent hearing deterioration in symptomatic congenital CMV cases, and valganciclovir offers a promising alternative due to its effective oral bioavailability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Consensus document from the Spanish Society of Paediatric Infectious Diseases (SEIP) on the diagnosis and treatment of congenital cytomegalovirus infection]. Baquero-Artigao, F.[2009]

A recent study found that using oral valaciclovir after a mother's primary cytomegalovirus (CMV) infection during early pregnancy can reduce the risk of passing the virus to the fetus by 71%.

Preventing congenital CMV infection is feasible, but effective implementation requires early and widespread screening of pregnant women to identify asymptomatic infections, which poses a significant challenge in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention strategies for congenital cytomegalovirus infection. Tol, I., Heath, PT., Khalil, A.[2021]

In a case series of 8 pregnancies with fetal cytomegalovirus (CMV), high-dose maternal valacyclovir was well-tolerated and helped stabilize fetal lesions without worsening symptoms.

Despite treatment, the newborns' viral load remained unchanged, indicating that while valacyclovir may not significantly alter viral levels, it can prevent progression of fetal CMV lesions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maternal high-dose valacyclovir and its correlation with newborn blood viral load and outcome in congenital cytomegalovirus infection. Goncé, A., Hawkins-Villarreal, A., Salazar, L., et al.[2022]

Valacyclovir is the only medication proven to lower the risk of congenital CMV infection when a mother has a primary infection during pregnancy, based on randomized clinical trial data.

There is currently no information on the long-term outcomes for children born with congenital CMV infection after their mothers received valacyclovir, highlighting the need for thorough neurocognitive follow-up for these children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Asymptomatic CMV infection at birth following maternal primary infection despite valacyclovir treatment and a subsequent negative amniocentesis. Case report. Toti, MS., Zammarchi, L., Pasquini, L., et al.[2023]

Ganciclovir therapy has shown promise in a controlled clinical trial for reducing sensorineural hearing loss caused by congenital CMV infection, indicating its potential efficacy in preventing neurodevelopmental injuries in newborns.

Current antiviral treatments for CMV, including ganciclovir, foscarnet, and cidofovir, work by targeting the viral DNA polymerase, but there is a need for further research and the development of vaccines to effectively control congenital and perinatal CMV infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview of congenitally and perinatally acquired cytomegalovirus infections: recent advances in antiviral therapy. Schleiss, MR., McVoy, MA.[2019]

Valganciclovir (Valcyte) provides significantly higher exposure to ganciclovir compared to oral ganciclovir, with an average increase of 1.65-fold, making it an effective option for preventing cytomegalovirus (CMV) disease in high-risk solid organ transplant recipients.

The pharmacokinetic analysis showed that oral valganciclovir achieves ganciclovir levels comparable to those obtained from intravenous administration, indicating its suitability for convenient prophylactic use in patients at risk of CMV disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients. Wiltshire, H., Hirankarn, S., Farrell, C., et al.[2018]

In a study of 67 solid organ transplant recipients undergoing CMV preemptive therapy, severe neutropenia occurred in 21.8% of patients, but it did not increase the risk of infections, suggesting that neutropenia may not have significant clinical consequences in this context.

Liver transplant recipients were found to be 6.7 times more likely to experience neutropenia compared to kidney transplant recipients, indicating that certain patient groups may require closer monitoring during antiviral therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical impact of neutropenia related with the preemptive therapy of CMV infection in solid organ transplant recipients. Martín-Gandul, C., Pérez-Romero, P., González-Roncero, FM., et al.[2018]

In a study of 19 patients who underwent allogeneic hematopoietic stem cell transplantation, valganciclovir demonstrated a high efficacy rate of 94.7% in treating cytomegalovirus (CMV) viremia, with many patients showing negative CMV-DNA results within 7 to 14 days of treatment.

The treatment was found to be safe, as no severe adverse effects were reported and there were no occurrences of CMV-related disease, making valganciclovir a promising option for managing CMV viremia in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Valganciclovir for treatment of cytomegalovirus viremia in patients following allogeneic hematopoietic stem cell transplantation]. Wang, Y., Huang, XJ., Xu, LP., et al.[2018]

Valganciclovir, used for preventing CMV disease in organ transplant patients, can cause severe bone marrow failure in patients with end-stage renal disease, especially when given at standard doses despite renal impairment.

In a study of 4 patients who received valganciclovir after kidney transplantation, all experienced severe hematologic adverse effects within 18 to 20 days, leading to fatal infections in 2 cases, highlighting the need for cautious use in those with renal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe bone marrow failure due to valganciclovir overdose after renal transplantation from cadaveric donors: four consecutive cases. Ar, MC., Ozbalak, M., Tuzuner, N., et al.[2018]

A study involving 143 pregnant women showed that treatment with valacyclovir (VCV) significantly reduced the risk of congenital cytomegalovirus (CMV) transmission from mother to fetus, with an odds ratio of 0.40, indicating a 60% reduction in transmission risk.

The treatment was associated with mild and non-specific side effects, suggesting that VCV is a safe option for pregnant women with primary CMV infection, particularly effective during the first and second trimesters.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New data on efficacy of valacyclovir in secondary prevention of maternal-fetal transmission of cytomegalovirus. Egloff, C., Sibiude, J., Vauloup-Fellous, C., et al.[2023]

Prophylactic treatment with valacyclovir significantly reduced the incidence of CMV disease in both CMV-negative and CMV-positive kidney transplant recipients, with a dramatic drop from 45% to 3% in seronegative patients and from 6% to 0% in seropositive patients within 90 days after transplantation.

Valacyclovir treatment also lowered the rate of acute graft rejection from 52% to 26% in seronegative recipients, indicating not only its efficacy in preventing CMV disease but also its potential benefits in improving transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. Lowance, D., Neumayer, HH., Legendre, CM., et al.[2018]

A large analysis of over 3 million reports found no increased risk of adverse pregnancy outcomes, such as miscarriage or birth defects, associated with the use of valganciclovir compared to aciclovir during pregnancy.

The findings suggest that valganciclovir may be a potential treatment option for severe maternal or fetal CMV infections, although further studies are needed to confirm these results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing the risk of adverse pregnancy outcomes and birth defects reporting in women exposed to ganciclovir or valganciclovir during pregnancy: a pharmacovigilance study. Contejean, A., Leruez-Ville, M., Treluyer, JM., et al.[2023]

References

1. Spain pubmed.ncbi.nlm.nih.gov

[Consensus document from the Spanish Society of Paediatric Infectious Diseases (SEIP) on the diagnosis and treatment of congenital cytomegalovirus infection]. [2009]

2. United States pubmed.ncbi.nlm.nih.gov

Prevention strategies for congenital cytomegalovirus infection. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Maternal high-dose valacyclovir and its correlation with newborn blood viral load and outcome in congenital cytomegalovirus infection. [2022]

4. Ireland pubmed.ncbi.nlm.nih.gov

Asymptomatic CMV infection at birth following maternal primary infection despite valacyclovir treatment and a subsequent negative amniocentesis. Case report. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Overview of congenitally and perinatally acquired cytomegalovirus infections: recent advances in antiviral therapy. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Clinical impact of neutropenia related with the preemptive therapy of CMV infection in solid organ transplant recipients. [2018]

8. China pubmed.ncbi.nlm.nih.gov

[Valganciclovir for treatment of cytomegalovirus viremia in patients following allogeneic hematopoietic stem cell transplantation]. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Severe bone marrow failure due to valganciclovir overdose after renal transplantation from cadaveric donors: four consecutive cases. [2018]

10. England pubmed.ncbi.nlm.nih.gov

New data on efficacy of valacyclovir in secondary prevention of maternal-fetal transmission of cytomegalovirus. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Assessing the risk of adverse pregnancy outcomes and birth defects reporting in women exposed to ganciclovir or valganciclovir during pregnancy: a pharmacovigilance study. [2023]