Valacyclovir for Neonatal Herpes

Recruiting at 15 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 not be taking: Acyclovir, Ganciclovir, Famciclovir, others

Disqualifiers: Neonatal HSV, Sepsis, Renal anomalies, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 5 days

16 Participants Needed

Trial Summary

What is the purpose of this trial?

A Phase 1 study that will determine the valacyclovir dose that results in a systemic acyclovir exposure comparable to 10 mg/kg of parenterally administered acyclovir, which is an AUC0-12 of 24,000 ngxhr/mL to 48,000 ngxhr/mL. Neonates at risk of acquiring neonatal HSV will be enrolled in one of 2 cohorts. Cohort 1 will be comprised of eight subjects who will receive an initial dose of 10ml/kg of oral valacyclovir. Samples for PK assessments will be obtained to assess the exposure concentration. If the safety profile and the drug exposure concentrations in Cohort 1 are acceptable, eight new subjects will be enrolled in Cohort 2. The dose that these subjects will receive will be predicated upon the pharmacokinetic data from Cohort 1.

Will I have to stop taking my current medications?

The trial does not specify if participants must stop taking their current medications, but neonates currently receiving acyclovir, ganciclovir, famciclovir, or any investigational drugs are excluded from participating.

What data supports the effectiveness of the drug Valacyclovir for treating neonatal herpes?

Valacyclovir is related to acyclovir, a drug that has been shown to significantly reduce the risk of death and improve outcomes in babies with neonatal herpes, especially when the infection involves the brain or multiple organs. Valacyclovir offers better absorption in the body, which may enhance its effectiveness. ^{1 2 3 4 5}

Is valacyclovir generally safe for humans?

Valacyclovir has been shown to have an acceptable safety profile in treating herpes infections, with clinical trials involving around 10,000 patients. However, it can cause kidney issues in some cases, as reported in a Japanese database of adverse drug reactions. ^{1 6 7 8 9}

How does the drug Valacyclovir differ from other treatments for neonatal herpes?

Valacyclovir is unique because it is an oral pro-drug of acyclovir, offering better oral bioavailability, which means it can be taken less frequently compared to acyclovir. This can be particularly beneficial for long-term management and suppression of herpes infections. ^{1 10 11 12 13}

Eligibility Criteria

This trial is for newborns at risk of herpes who are born to mothers with a history of genital HSV infection. The babies must be full-term, weigh at least 2,000 grams, and be no older than 2 days. They can't participate if they have signs of herpes or sepsis, known kidney issues, or were born to HIV-positive mothers.

Inclusion Criteria

I am at least 2 days old.

Your mother has a history of genital herpes.

My baby was born at or after 38 weeks of pregnancy.

Exclusion Criteria

There is proof that the baby has a herpes infection.

I have known kidney issues.

My newborn is currently receiving treatment with acyclovir, ganciclovir, famciclovir, or any experimental drugs.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Neonates receive oral valacyclovir to assess pharmacokinetics and safety

5 days

Daily visits for dosing and PK assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

42 days

Regular monitoring for adverse events

Treatment Details

Interventions

• Valacyclovir

Trial Overview The study tests oral Valacyclovir in two groups (cohorts) of eight newborns each to find the right dose that matches the effect of an existing treatment for herpes. The second group's dose will depend on results from the first group.

Participant Groups

Group I: Cohort 2 Experimental Treatment 1 Intervention

If the safety profile and the drug exposure concentrations in Cohort 1 are acceptable, eight new subjects will be enrolled in Cohort 2. If the mean of observed acyclovir exposures of subjects in Cohort 1 are below 24,000 ngxhr/mL, AND if no Grade 3 or Grade 4 AEs or SAEs are detected in any of the study subjects, then the 8 subjects enrolled in Cohort 2 will receive oral valacyclovir at a dose of 20 mg/kg administered two times daily for 5 days. Alternatively, if the mean of observed acyclovir exposures of subjects in Cohort 1 are above 48,000 ngxhr/mL AND if no Grade 3 or Grade 4 AEs or SAEs are detected in any of the study subjects, then the 8 subjects enrolled in Cohort 2 will receive oral valacyclovir at a dose that has been linearly adjusted downward to target 36,000 ngxh/mL area-under-the-concentration-time curve from 0 to 12 hours (AUC12).

Group II: Cohort 1 Experimental Treatment 1 Intervention

A cohort of neonates who are at risk of acquiring neonatal herpes simplex virus disease will receive 10 mg/kg of valacyclovir will be administered orally two times daily for 5 days. N=8

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

Neonatal herpes simplex virus (HSV) infection, primarily acquired during delivery, poses significant risks including mortality and long-term neurodevelopmental disabilities, especially from primary infections.

High-dose intravenous acyclovir has been shown to dramatically improve clinical outcomes in neonates with HSV, significantly reducing morbidity and mortality, and is now the standard treatment for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neonatal Herpes Simplex Virus: The Long Road to Improved Outcomes. McPherson, CC.[2021]

Neonatal herpes simplex virus infections occur in about 1 in 3,500 deliveries in the U.S., and without antiviral treatment, they can lead to severe complications, including high mortality rates.

Antiviral therapies like acyclovir and vidarabine have significantly improved outcomes, reducing mortality from skin, eye, and mouth infections to nearly zero, and decreasing mortality from encephalitis to about 15%, with many survivors developing normally after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neonatal herpes simplex virus infections. Whitley, RJ.[2019]

In a study of 202 infants with confirmed neonatal herpes simplex virus (HSV) infection, mortality rates were significantly higher in those with disseminated infection (57%) compared to those with encephalitis (15%), highlighting the severity of disseminated disease.

Factors such as being in or near coma at entry, having disseminated intravascular coagulopathy, or being premature significantly increased the risk of death, while survivors with encephalitis or disseminated infection faced higher rates of morbidity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of morbidity and mortality in neonates with herpes simplex virus infections. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Whitley, R., Arvin, A., Prober, C., et al.[2010]

In a study involving 112 children aged 1 month to 11 years, valacyclovir oral suspension was found to produce favorable blood concentrations of acyclovir, particularly at a dose of 20 mg/kg, which was well tolerated across the age groups.

Infants aged 1 to 2 months showed higher blood levels of acyclovir when given 25 mg/kg, but a specific dosing recommendation for infants under 3 months could not be made due to their decreased clearance of the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of extemporaneously compounded valacyclovir oral suspension in pediatric patients from 1 month through 11 years of age. Kimberlin, DW., Jacobs, RF., Weller, S., et al.[2018]

In a study of 1086 neonates with herpes simplex virus (HSV) infection, delayed initiation of acyclovir therapy (more than 1 day after hospital admission) was linked to a significantly higher risk of death, with an adjusted odds ratio of 2.63.

The overall mortality rate was 7.3%, with 9.5% of those receiving delayed treatment dying compared to 6.6% of those treated early, highlighting the importance of prompt acyclovir administration for improving survival in affected neonates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delayed acyclovir therapy and death among neonates with herpes simplex virus infection. Shah, SS., Aronson, PL., Mohamad, Z., et al.[2021]

Valacyclovir is an effective antiviral treatment for genital herpes, showing similar efficacy to acyclovir and is the only drug approved for once-daily suppressive therapy, making it easier for patients to adhere to their treatment.

In treating herpes zoster, valacyclovir is more effective than acyclovir and equally effective as famciclovir in reducing pain duration and severity, while maintaining a good safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valacyclovir for the treatment of genital herpes. Brantley, JS., Hicks, L., Sra, K., et al.[2018]

In a clinical trial involving 260 pediatric patients, hydrochloride valacyclovir demonstrated significantly higher efficacy in treating uncomplicated varicella compared to ribavirin, with an efficacy index of 0.86 versus 0.70 at the end of treatment.

The treatment with hydrochloride valacyclovir was found to be safe, with no severe adverse drug reactions reported, making it a reliable option for managing varicella in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Randomized controlled multi-center trial for treatment of varicella in pediatric patients with hydrochloride valacyclovir]. Yu, H., Zhu, QR., Wang, ZL., et al.[2018]

High-dose (60 mg/kg/d) intravenous acyclovir is safe and effective for treating neonatal herpes simplex virus (HSV) disease, significantly improving survival rates in infants with disseminated HSV compared to standard-dose therapy, with an odds ratio of 3.3.

While some infants experienced transient neutropenia, all cases recovered without lasting effects, indicating that monitoring blood counts during treatment is essential for safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Kimberlin, DW., Lin, CY., Jacobs, RF., et al.[2019]

A study analyzing the PMDA database from 2004 to 2011 found that valacyclovir is associated with a significant number of acute kidney injury (AKI) cases, particularly affecting women and individuals aged 70 to 79.

Out of 344 AKI cases linked to valacyclovir, 74.1% of patients were only using this drug, indicating a strong correlation between valacyclovir use and the development of AKI, especially in patients with hypertension and diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valacyclovir-Induced Acute Kidney Injury in Japanese Patients Based on the PMDA Adverse Drug Reactions Reporting Database. Kitano, A., Motohashi, H., Takayama, A., et al.[2020]

Acyclovir is the preferred treatment for neonatal herpes simplex virus (HSV) infections, having replaced vidarabine since the early 1980s, indicating its established efficacy in this critical area.

Ganciclovir is effective for treating congenital cytomegalovirus (CMV) infections that affect the central nervous system, highlighting its importance in managing serious viral infections in newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of antiviral drugs during the neonatal period. Whitley, RJ.[2021]

Neonatal herpes simplex virus (HSV) infections can lead to serious health issues, and effective management strategies are crucial to reduce transmission and improve outcomes for affected infants.

Parenteral acyclovir is the preferred treatment for neonatal HSV infections, but the dosage and duration of therapy must be tailored to the severity of the infection; despite treatment, the mortality rate remains high.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neonatal Herpes Simplex Viral Infections and Acyclovir: An Update. Harris, JB., Holmes, AP.[2020]

Valaciclovir is an effective treatment for suppressing recurrent genital herpes in both immunocompetent and immunocompromised individuals, with dosages of 500 to 1000 mg daily recommended for optimal efficacy.

While generally well tolerated, high-dose valaciclovir (8 g/day) can lead to serious side effects like thrombotic microangiopathy (TMA) in immunocompromised patients, necessitating careful monitoring for symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valaciclovir: a review of its long term utility in the management of genital herpes simplex virus and cytomegalovirus infections. Ormrod, D., Scott, LJ., Perry, CM.[2018]

In a study of 37 immunocompromised children, valacyclovir was found to have a mean bioavailability of 64% when converted to acyclovir, indicating effective absorption and potential for oral treatment.

Valacyclovir (15 mg/kg) was well tolerated with minimal side effects, and in a small group of patients with herpes zoster, two out of three showed significant improvement with complete scabbing of lesions by day 9.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valacyclovir and acyclovir pharmacokinetics in immunocompromised children. Bomgaars, L., Thompson, P., Berg, S., et al.[2021]

References

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

Neonatal Herpes Simplex Virus: The Long Road to Improved Outcomes. [2021]

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

Neonatal herpes simplex virus infections. [2019]

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

Predictors of morbidity and mortality in neonates with herpes simplex virus infections. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. [2010]

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

Pharmacokinetics and safety of extemporaneously compounded valacyclovir oral suspension in pediatric patients from 1 month through 11 years of age. [2018]

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

Delayed acyclovir therapy and death among neonates with herpes simplex virus infection. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Valacyclovir for the treatment of genital herpes. [2018]

7. China pubmed.ncbi.nlm.nih.gov

[Randomized controlled multi-center trial for treatment of varicella in pediatric patients with hydrochloride valacyclovir]. [2018]

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

Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Valacyclovir-Induced Acute Kidney Injury in Japanese Patients Based on the PMDA Adverse Drug Reactions Reporting Database. [2020]

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

The use of antiviral drugs during the neonatal period. [2021]

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

Neonatal Herpes Simplex Viral Infections and Acyclovir: An Update. [2020]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Valaciclovir: a review of its long term utility in the management of genital herpes simplex virus and cytomegalovirus infections. [2018]

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

Valacyclovir and acyclovir pharmacokinetics in immunocompromised children. [2021]