Valacyclovir for Neonatal Herpes

No longer recruiting at 19 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a treatment for newborns at risk of contracting neonatal herpes. Researchers are testing different doses of valacyclovir, a medication for viral infections, to determine the safest and most effective dose. The trial includes two groups: the first receives a set dose, and if deemed safe, the second group receives an adjusted dose based on initial findings. This trial is suitable for newborns under two days old whose mothers have a history of genital herpes and meet other specific health criteria. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to contribute to groundbreaking medical research.

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.

Is there any evidence suggesting that valacyclovir is likely to be safe for neonates?

Research shows that valacyclovir, a drug for treating herpes infections, has undergone safety studies in newborns. Studies have found that acyclovir, a similar drug, is safe and effective for treating herpes in newborns. Valacyclovir converts into acyclovir in the body, suggesting it could also be well-tolerated.

In past studies, newborns taking valacyclovir did not experience serious side effects. This suggests that valacyclovir might be safe for newborns at risk of herpes. However, since this is an early-stage trial, the main goal is to learn more about the drug's safety and how it works in the body. Therefore, researchers continue to monitor safety closely. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for neonatal herpes involve intravenous administration of acyclovir. However, valacyclovir, the study drug, stands out because it can be given orally, which is potentially more convenient and comfortable for neonates and their caregivers. Researchers are eager to see if valacyclovir can offer similar efficacy and safety compared to the standard intravenous options while providing a simpler administration method. Additionally, if valacyclovir shows favorable results, it could streamline the treatment process and improve the quality of life for affected families.

What evidence suggests that valacyclovir might be an effective treatment for neonatal herpes?

Research has shown that valacyclovir closely resembles acyclovir, a medicine proven to significantly reduce the risk of death and improve health in babies with neonatal herpes. This trial will study valacyclovir in two separate cohorts. Studies suggest that valacyclovir could replace acyclovir because it requires less frequent dosing, making it easier for families to adhere to the treatment plan. Early results indicate that valacyclovir converts into acyclovir in the body, aiding in the fight against the herpes virus. This may help control the infection and reduce symptoms. However, more research is needed to confirm these benefits specifically for newborns at risk of herpes. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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 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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5410863/

Neonatal Herpes Simplex Viral Infections and Acyclovir Early studies established effectiveness of “low-dose” acyclovir (30 mg/kg/day); however, more recent data have demonstrated a lower mortality rate with “large- ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04448392

Valacyclovir in Neonatal Herpes Simplex Virus Disease This is an open-label, single center, pharmacokinetic (PK) study to assess valacyclovir pharmacokinetics and pharmacodynamics in neonates and compare to the ...

3. wmjonline.org wmjonline.org/wp-content/uploads/2024/123/6/589.pdf

Valacyclovir Versus Acyclovir for Herpes Simplex Virus ... Discussion: Valacyclovir may be an alternative to acyclovir for suppression of neonatal HSV, offering less frequent dosing and increased compliance.

4. withpower.com withpower.com/trial/phase-1-herpes-simplex-8-2022-635ae

Valacyclovir for Neonatal Herpes · Info for Participants 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, ...

5. uptodate.com uptodate.com/contents/treatment-and-prevention-of-herpes-simplex-virus-type-1-in-immunocompetent-adolescents-and-adults

Treatment and prevention of herpes simplex virus type 1 in ... Valacyclovir shortened outbreaks by approximately one day compared with placebo; treatment for one day was as effective as treatment for two ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05468619

NCT05468619 | Neonatal Phase 1 Valacyclovir Study A Phase 1, open label multicenter trial to assess the safety and pharmacokinetics (PKs) of oral valacyclovir in neonates who are at risk of acquiring neonatal ...

7. clinicaltrial.be clinicaltrial.be/en/details/15902?per_page=20&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Neonatal Phase 1 Valacyclovir Study A Phase 1, open label multicenter trial to assess the safety and pharmacokinetics (PKs) of oral valacyclovir in neonates who are at risk of ...

8. aafp.org aafp.org/pubs/afp/issues/2002/0315/p1138.html

Neonatal Herpes Simplex Virus Infections Acyclovir has proved safety and efficacy and may prevent neonatal HSV infection. All use of acyclovir during pregnancy should be reported to the ...