Letermovir Treatment for Refractory or Resistant Cytomegalovirus Infection

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 2 Study of Letermovir Treatment for Patients Experiencing Refractory or Resistant Cytomegalovirus Infection or Disease With Concurrent Organ Dysfunction

Conditions
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Cytomegalovirus Infections

Intervention / Treatment
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* Drug: Letermovir


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Letermovir<br>Open label letermovir will be administered daily for up to 12 weeks. The study allows an optional additional 12 weeks of treatment for secondary prophylaxis if clinically indicated. | Drug: Letermovir<br>* Patients will receive intravenous or oral letermovir at a dose of 480mg/day. Patients weighing 40 or more kilograms will receive a second, loading, dose 12 hours after the first dose of letermovir treatment. For patients receiving concomitant cyclosporine treatment, the letermovir dose will be 240mg/day.<br>* Other names: Prevymis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological Response on Treatment Week 6 | The virologic response milestones are defined as: 1) Any decrease in CMV DNA from baseline (Week 0), measured on week 3 and 2) A ≥2 log decrease in CMV DNA from baseline, or an undetectable CMV DNA, measured on week 6. For patients with clinical CMV disease, the clinical response milestones are defined as: 1) Stabilization of clinical disease by week 3 (i.e. no worsening signs or symptoms compared to week 1) as assessed by the site investigator and 2) Improvement or resolution of clinical disease by week 6 (i.e., improvement in signs and symptoms of affected organs [resolution of diarrhea, pneumonia, hepatitis, retinitis, etc.]) 3) Patients with clinical CMV disease should also meet virological response milestones outlined above to support the continuation of letermovir therapy. Patients who enter the study based solely on documented CMV disease by histopathology in the absence of quantifiable CMV virus load should remain nonquantifiable (less than 137 IU/mL). | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | number of patients alive | 6 months | 
| CMV Progression-free Survival | Time from study enrollment to CMV progression or death whichever occurs first | 6 months | 
| Kinetics of Viral Clearance | time to undetectable plasma CMV DNA | 6 months | 
| Percent of Patients With a Clinically Meaningful Treatment Response to Letermovir Treatment | Virological response and a concomitant clinical response in patients with CMV disease by Week 6 of treatment. For patients with clinical CMV disease, the clinical response milestones are defined as: Stabilization of clinical disease by week 3 (i.e. no worsening signs or symptoms compared to week 1) as assessed by the site investigator and Improvement or resolution of clinical disease by week 6 (i.e., improvement in signs and symptoms of affected organs [resolution of diarrhea, pneumonia, hepatitis, retinitis, etc.]) Patients with clinical CMV disease should also meet virological response milestones outlined above to support the continuation of letermovir therapy. Patients who enter the study based solely on documented CMV disease by histopathology in the absence of quantifiable CMV virus load should remain nonquantifiable (less than 137 IU/mL). | 6 Weeks | 
| Emergence of Letermovir-resistant CMV Virus in Patients Treated in This Setting | Number of participants with breakthrough letermovir-resistant CMV infection in patients receiving letermovir treatment who experienced an initial virological response. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cytomegalovirus Infections, CMV