Letermovir Treatment for Refractory or Resistant Cytomegalovirus Infection
Letermovir Treatment for Refractory or Resistant Cytomegalovirus Infection
The trial will evaluate the safety and efficacy of letermovir antiviral treatment of active
 cytomegalovirus infection or cytomegalovirus disease in patients with infections that are
 refractory or resistant to available treatments or who are experiencing organ dysfunction
 that makes unsafe the use of available antiviral treatments.
This is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness
 of an investigational drug to learn whether the drug works in treating a specific disease.
 "Investigational" means that the drug is being studied.

 The FDA (the U.S. Food and Drug Administration) has not approved letermovir for treatment of
 cytomegalovirus infection, but it has approved letermovir for the prevention of
 cytomegalovirus infection in bone-marrow transplantation patients.

 This is the first time that letermovir will be administered to children in a clinical trial.

 Cytomegalovirus (CMV) is a common virus, which a majority of people acquire at some time in
 their life. CMV remains in your body, but does not cause symptoms in the majority of people.
 Patients with a weakened immune system (a system that protects you from infections) may be
 more at risk for the virus becoming active and causing damage to some of your organs,
 especially in the gut and lungs. If the virus becomes present above a certain quantity, the
 doctor usually prescribes a drug to treat the infection at this stage to avoid damage to the
 organs.

 In this case, the virus is no longer responding to the prescribed drug, and other drug
 options will be harmful to the participant's health. Participants are being invited to take
 part in a research study for an investigational drug called letermovir. The purpose of this
 study is to find out whether letermovir is as effective and as safe in treating CMV infection
 in patients who cannot tolerate standard treatments such as ganciclovir or foscarnet.
Inclusion Criteria:

 -  Age ≥12 years

 -  Weight ≥30 kg

 -  Transplant recipient (HCT, SOT) or other immunocompromised patients including those
 with HIV infection that require antiviral treatment for CMV.

 -  Documented CMV disease or persistent CMV infection (CMV virus load above 500 IU/mL on
 consecutive measurements, at least one day apart).

 -  CMV infection is refractory to treatment (defined as ≥14 days of standard CMV
 treatment without clinical improvement for CMV disease, or failure to achieve >1 log
 reduction in CMV VL after ≥14 days of standard treatment for CMV infection)16,17

 -  Current CMV infection has documented genotypic resistance to ganciclovir or foscarnet.

 -  For patients with any prior CMV infection episode that broke through letermovir
 prophylaxis, but not during the current CMV infection, documentation of letermovir
 susceptibility testing should demonstrate absence of letermovir mutations known to
 confer resistance to letermovir.

 -  Severe myelosuppression (ANC <1000/µL, Hemoglobin <8g/dL, or Platelets <25,000/µL)17
 or renal dysfunction (estimated creatinine clearance <60 mL/min by MDRD in adults or <
 60 ml/min/1.73 m2 by bedside Schwartz equation in < 18 years-old) at baseline or which
 develops during antiviral treatment.

 --Patients who develop severe myelosuppression or renal dysfunction during antiviral
 treatment as defined above are eligible without having to meet the
 refractoriness/antiviral resistance criterion.

 -  Combinations of genotypic antiviral resistance and organ dysfunction that lead to
 eligibility are presented in the full protocol eligibility table.

 -  The effects of letermovir on the developing human fetus are unknown. For this reason,
 women of child-bearing potential and men must agree to use adequate contraception
 (barrier method of birth control; abstinence) prior to study entry, for the duration
 of study participation, and 3 months after completion of letermovir administration.
 Should a woman become pregnant or suspect she is pregnant while she or her partner is
 participating in this study, she should inform her treating physician immediately. Men
 treated or enrolled on this protocol must also agree to use adequate contraception
 prior to the study, for the duration of study participation, and 3 months after
 completion of letermovir administration.

 --Patients of childbearing potential must have a negative serum or urine pregnancy
 test.

 -  Able to understand and the willingness to sign a written informed consent document.

 Exclusion Criteria:

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to letermovir.

 -  Known history of cirrhosis with Child-Pugh Class C hepatic insufficiency at screening.

 -  Acute liver injury at baseline meeting Hy's law.

 -  Current CMV infection broke through letermovir prophylaxis.

 -  Patients with life expectancy of less than a week. Determination of life expectancy
 will be discussed with the patient's primary treatment physician.

 -  Patient taking strong inhibitors or inducers of hepatic CYP enzymes including
 rifampicin, phenytoin, clarithromycin, ritonavir, or cobicistat.

 -  HIV patients who are receiving antiretroviral treatment protease inhibitors
 (darunavir, lopinavir, etc) whether by themselves or boosted with ritonavir or
 cobicistat, or HIV patients receiving cyclosporine treatment due to strong drug-drug
 interactions.

 -  Combinations of genotypic antiviral resistance and organ dysfunction that do not meet
 eligibility criteria are described in the full protocol eligibility table.