8603: A Phase I, Adaptive, Escalating Single-Dose and Multiple-Dose Pharmacokinetic and Safety Assessment of Letermovir in Infants with Symptomatic Congenital Cytomegalovirus Disease (DMID 21-0027)

Background

Congenital CMV infection is the leading non-genetic cause of sensorineural hearing loss (SNHL) and the most frequent known viral cause of mental retardation, affecting 0.5% to 0.7% of live births. Overall, congenital CMV is a rare infection but accounts for 21% of hearing loss at birth and 24% of hearing loss by four years of age.

The Congenital and Perinatal Infectious Consortium (CPIC) (previously know as the Collaborative Antiviral Study Group [CASG]), conducted a series of studies over 30 years evaluating the antiviral treatment of infants with symptoms of congenital CMV disease, first with intravenous (IV) ganciclovir and then with valganciclovir by mouth. These trials have documented that treating infants with these medications improve hearing and development, although only to a modest degree. Patients with symptoms of congenital CMV disease whose virus levels drop by day 14 of receiving valganciclovir and then continue taking it for an additional 4 months are more likely to have improved hearing across the first two years of life. Combination therapy with the addition of another antiviral drug with CMV activity, a different mode of action, and a good safety profile has the potential to greatly advance the treatment options of babies with symptoms from congenital CMV disease.

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 levels of Letermovir in this Phase 1 study will identify the dose of Letermovir to use in future studies of Letermovir in combination with valganciclovir to treat babies with symptoms of congenital CMV diseases. The combination of these two antiviral drugs with different modes of action may improve the benefit on both hearing and development. As such, this study is foundational for what may be the next major advancement in the treatment of babies with symptoms from congenital CMV disease.

What Happens During This Study?

Two groups will be enrolled in this study. The study drug, Letermovir will be given by mouth for 14 days for both groups. All babies will receive valganciclovir by mouth as standard of care. Group 1 (4 newborns) will be given a single dose of Letermovir (based on weight) on Study Day 0, with 5 small blood samples collected over the next 24 hours to see if the dose given is the correct dose of medication. Blood specimens will be shipped within approximately 24 hours to the study lab in order to get the results back to the study site within 7 days.

If the drug levels are good, the baby will begin a 14-day course of once a day by mouth Letermovir at the same dose as given on Study Day 0. The first dose of the 14-day course will be given on Study Day 1. If the blood levels of Letermovir on Study Day 0 is too high, the once a day by mouth dose of Letermovir will be lowered.

• Labs will be collected to see if the drug has made any changes in the kidney and cells that fight infection.
• We will also draw blood to determine the amount of virus in the body.
• On study day 10, we will draw a small amount of blood at 6 different times to determine the amount of medication in your baby’s body.
• We will ask you if your baby had any issues taking the medication.

Following enrollment of the first 4 subjects in Group 1, a special safety committee will review all safety and drug level data. If no concerns are identified, then 8 additional babies will be enrolled in Group 2. Babies in Group 2 will start a 14-day course of once a day Letermovir by mouth. The dose selected for Group 2 will be based on the dose determined from Group 1. Blood will be drawn on study Days 1, 5, 10 and 14 to determine the amount of both Letermovir and ganciclovir in your baby’s body. We will ask you to keep a record of any problems your baby has after starting the medication. Babies enrolled will continue on valganciclovir as part of routine clinical care to complete 6 months of treatment.

The total number of babies for Group 1 and Group 2 combined is at least 12 (maximum of 18) babies.

To be eligible to participate, you must:

• Have a signed informed consent from parent(s) or legal guardian(s)
• Have CMV confirmed from urine/throat swab
• Have symptoms of congenital CMV disease, by one or more of the following: thrombocytopenia (elevated platelets); Petechia (fine rash on the body); hepatomegaly (enlarged liver); splenomegaly (enlarged spleen); intrauterine growth restriction (small growth while in the mom’s belly); hepatitis; or microcephaly (small head for age), radiographic abnormalities indicating that the CMV is in the brain, abnormal cerebral spinal fluid findings for age, chorioretinitis (inflammation of the retina in the eye), decreased hearing, and/or positive CMV results from the spinal fluid
• Age at study enrollment:
  • ≤ 21 days for Group 1 subjects
  • ≤ 28 days for Group 2 subjects
• Weight at study enrollment 2.6 kg to < 8.0 kg
• Age between conception and birth of ≥ 32 weeks at birth
• Plans by baby’s doctor to prescribe valganciclovir for 6 months for congenital CMV disease

* Group 1 subjects must enroll and receive the Study Day 0 dose of Letermovir on or before 21 days of life so that valganciclovir can be started prior to day 30 of life, as is standard of care.

You are not eligible to participate if your baby has/is:

• Born to women who are HIV positive (but HIV testing is not required for study entry).
• Currently receiving any other investigational drugs.
• Elevated liver function labs.
• Stomach and intestine issues which might prevent the absorption of a medication by mouth.
• Anticipated receiving carbamazepine (Tegretol), nafcillin, pheynobarbital, or phenytoin (Dilantin) during the period that study drug is being given.

How to participate?

In order to participate in this study, you must contact the study coordinator or investigator of any of the participating institutions by phone or by email.