Study of SHP620 (Maribavir) in Healthy Adults

Study Overview
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Brief Summary
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The purpose of this study is to determine how an investigational treatment (maribavir) is handled by the body when administered with two already approved drugs (digoxin and dextromethorphan). The study will also look at the safety and tolerability when maribavir is coadministered with digoxin and dextromethorphan versus digoxin and dextromethorphan alone.

Official Title
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A Phase 1, Open-label, 2-period Fixed-sequence Study to Evaluate the Effect of Multiple Doses of SHP620 (Maribavir) on the Pharmacokinetics of Digoxin and Dextromethorphan in Healthy Adult Subjects

Conditions
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Cytomegalovirus (CMV)

Intervention / Treatment
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* Drug: Digoxin
* Drug: Maribavir
* Drug: Dextromethorphan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: An understanding, ability, and willingness to fully comply with study procedures and restrictions. Ability to provide written, personally signed, and dated informed consent to participate in the study, before completing any study-related procedures. Age 18-50 years, inclusive at the time of consent. Subjects must be willing to consent to and provide blood samples for pharmacogenomics analysis. Willingness to comply with any applicable contraceptive requirements of the protocol and is: Male, or Female of non-childbearing potential Non-pregnant, non-lactating female Females must be at least 90 days postpartum or nulliparous. Must be considered healthy. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, hematology, blood chemistry (includes T3, T4, and TSH at screening only), and urinalysis. Body mass index (BMI) between 18.5 and 30.0 kg/m2 inclusive. Hemoglobin is equal to or greater than 12.0g/dL. Ability to swallow a dose of investigational product (which may be multiple tablets at one time or consecutively 1 tablet at a time) Exclusion Criteria: Subject has a clinically significant history or a disorder detected during the medical interview/physical examination such as any cardiovascular, broncho-pulmonary, gastrointestinal (eg, inflammatory bowel disease, chronic diarrhea), hepatic, biliary (including gallbladder removal), renal, hematological, endocrine, autoimmune, neurological, or psychiatric disease (including depression) or any other medical condition that is capable of altering the absorption, metabolism, or elimination of drugs; or of constituting a risk factor when taking the investigational product in the judgment of the investigator. Known or suspected intolerance or hypersensitivity to the investigational product(s), closely related compounds, or any of the stated ingredients. Significant illness, as judged by the investigator, within 2 weeks of the first dose of investigational product. Known history of alcohol or other substance abuse within the last year. Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to receiving the first dose of investigational product. Within 30 days prior to the first dose of investigational product: Have used an investigational product (if elimination half-life is <6 days, otherwise 5 half-lives). Have been enrolled in a clinical study (including vaccine studies) that, in the investigator's opinion, may impact this study. Have had any substantial changes in eating habits, as assessed by the investigator. Confirmed systolic blood pressure >139 mmHg or <89 mmHg and diastolic blood pressure >89 mmHg or <49 mmHg. Twelve-lead ECG demonstrating QTcB >450 msec at screening. A positive screen for alcohol or drugs of abuse at screening or Day -1, Period 1. Male subjects who consume more than 21 units of alcohol per week or 3 units per day; female subjects who consume more than 14 units of alcohol per week or 2 units per day (1 alcohol unit=1 beer or 1 wine [5 oz/150 mL] or 1 liquor [1.5 oz/40 mL] or 0.75 oz alcohol). A positive human immunodeficiency virus, hepatitis B surface antibody, or hepatitis C virus antibody screen. Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing products in any form (eg, gum, patch). Ex-users must report that they have stopped using tobacco for at least 30 days prior to receiving the first dose of investigational product. Routine consumption of more than 2 units of caffeine per day or subjects who experience caffeine withdrawal headaches. (One caffeine unit is contained in the following items: one 6 oz [180 mL] cup of coffee, two 12 oz [360 mL] cans of cola, one 12 oz cup of tea, or three 1 oz [85 g] chocolate bars. Decaffeinated coffee, tea, or cola are not considered to contain caffeine.) Prior screen failure, randomization, participation, or enrollment in this study or prior enrollment in a clinical study investigating maribavir. Current use (defined as use within 14 days prior to the first dose of investigational product) of any medication (including over-the-counter, herbal, or homeopathic preparations [eg, St. John's wort, ginkgo biloba]) with the exception of hormonal replacement therapy and occasional use of ibuprofen and acetaminophen. History of sensitivity to heparin or heparin-induced thrombocytopenia. Ingestion of known CYP3A modulators within 7 days of Day 1, Period 1 (includes grapefruit or grapefruit juice, oranges, Seville oranges, apples or apple juice, vegetables from the mustard green family [eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard], charbroiled meats, and products containing these ingredients).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Digoxin<br>On Day 1, subjects will receive a single 0.5 mg (2 x 0.25 mg) oral dose of digoxin. | Drug: Digoxin<br>* 0.5 mg (2 x 0.25 mg) Digoxin oral dose<br>|
| Experimental: Maribavir<br>On Day 8 through Day 15, subjects will receive a 400 mg (2 x 200 mg) BID oral dose of maribavir. Subjects will be given the second dose of maribavir approximately 12 hours after the first dose. On Day 13, subjects will receive a coadministration of a single 0.5 mg (2 x 0.25 mg) oral dose of digoxin and a single 30 mg oral dose of dextromethorphan given with the morning dose of maribavir. | Drug: Digoxin<br>* 0.5 mg (2 x 0.25 mg) Digoxin oral dose<br>Drug: Maribavir<br>* 200mg twice a day for 8 days<br>Drug: Dextromethorphan<br>* 30 mg oral dose<br>|
| Active Comparator: Dextromethorphan<br>On Day 1, subjects will receive a single 30 mg oral dose of dextromethorphan. | Drug: Dextromethorphan<br>* 30 mg oral dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Digoxin | Cmax is the maximum observed plasma concentration of digoxin. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Maximum Observed Plasma Concentration (Cmax) of Dextromethorphan | Cmax is the maximum observed plasma concentration of dextromethorphan. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Maximum Observed Plasma Concentration (Cmax) of Dextrorphan | Cmax is the maximum observed plasma concentration of dextrorphan, the metabolite of dextromethorphan. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Maximum Observed Plasma Concentration (Cmax) of Maribavir | Cmax is the maximum observed plasma concentration of maribavir. | Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Digoxin | Tmax is the time to reach the maximum observed drug concentration in plasma during a dosing interval. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Dextromethorphan | Tmax is the time to reach the maximum observed drug concentration in plasma during a dosing interval. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Dextrorphan | Tmax is the time to reach the maximum observed drug concentration in plasma during a dosing interval. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Maribavir | Tmax is the time to reach the maximum observed drug concentration in plasma during a dosing interval. | Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13 | 
| Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-infinity) of Digoxin | AUC0-infinity is the area under the plasma concentration versus time curve extrapolated to infinity, calculated using the observed value of the last non-zero concentration. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-infinity) of Dextromethorphan | AUC0-infinity is the area under the plasma concentration versus time curve extrapolated to infinity, calculated using the observed value of the last non-zero concentration. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-infinity) of Dextrorphan | AUC0-infinity is the area under the plasma concentration versus time curve extrapolated to infinity, calculated using the observed value of the last non-zero concentration. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Area Under the Plasma Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Digoxin | AUClast is the area under the plasma concentration versus time curve from the time of dosing to the last measurable concentration. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Area Under the Plasma Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Dextromethorphan | AUClast is the area under the plasma concentration versus time curve from the time of dosing to the last measurable concentration. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Area Under the Plasma Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Dextrorphan | AUClast is the area under the plasma concentration versus time curve from the time of dosing to the last measurable concentration. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Parent/Metabolite Ratio of Area Under the Plasma Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) for Dextromethorphan Over AUClast for Dextrorphan (AUClast Parent/Metabolite Ratio) | AUClast parent/metabolite ratio is the ratio of AUClast for dextromethorphan over AUClast for dextrorphan. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Parent/Metabolite Ratio of Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-infinity) for Dextromethorphan Over AUC0-infinity for Dextrorphan (AUC0-infinity Parent/Metabolite Ratio) | AUC0-infinity parent/metabolite ratio is the ratio of AUC0-infinity for dextromethorphan over AUC0-infinity for dextrorphan. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Area Under the Plasma Concentration Versus Time Curve From Time Zero to the End of the Dosing Interval at Steady-State (AUCtau) of Maribavir | AUCtau is the area under the plasma concentration versus time curve from the time zero to the end of the dosing interval at steady-state. | Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13 | 
| First-order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve of Digoxin | Lambda z is the first-order rate constant associated with the terminal (log-linear) portion of the plasma concentration versus time curve, determined as the negative slope of the terminal log-linear phase of the curve. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| First-order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve of Dextromethorphan | Lambda z is the first-order rate constant associated with the terminal (log-linear) portion of the plasma concentration versus time curve, determined as the negative slope of the terminal log-linear phase of the curve. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| First-order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve of Dextrorphan | Lambda z is the first-order rate constant associated with the terminal (log-linear) portion of the plasma concentration versus time curve, determined as the negative slope of the terminal log-linear phase of the curve. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Terminal Half-life (t1/2) of Digoxin | Terminal half-life (t1/2) is the time in hours required for the concentration of the drug to reach half of its original value. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Terminal Half-life (t1/2) of Dextromethorphan | Terminal half-life (t1/2) is the time in hours required for the concentration of the drug to reach half of its original value. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Terminal Half-life (t1/2) of Dextrorphan | Terminal half-life (t1/2) is the time in hours required for the concentration of the drug to reach half of its original value. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Terminal Half-life (t1/2) of Maribavir | Terminal half-life (t1/2) is the time in hours required for the concentration of the drug to reach half of its original value. | Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13 | 
| Apparent Oral Clearance (CL/F) of Digoxin | CL/F is equal to dose/AUC0-infinity (dose divided by area under the plasma concentration versus time curve extrapolated to infinity [AUC0-infinity]). | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Apparent Oral Clearance (CL/F) of Dextromethorphan | CL/F is equal to dose/AUC0-infinity (dose divided by area under the plasma concentration versus time curve extrapolated to infinity [AUC0-infinity]) | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Apparent Oral Clearance (CL/F) of Maribavir | CL/F is equal to dose/AUCtau (dose divided by area under the curve from time 0 to the end of the dosing interval at steady state [AUCtau]) | Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13 | 
| Concentration at the End of Dosing Interval (Ctau) of Maribavir | Ctau is the concentration of maribavir at the end of the dosing interval. | Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13 | 
| Volume of Distribution Divided by the Fraction of Dose Absorbed (Vz/F) of Digoxin | Vz/F is the volume of distribution associated with the terminal slope following extravascular administration divided by the fraction of dose absorbed. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Volume of Distribution Divided by the Fraction of Dose Absorbed (Vz/F) of Dextromethorphan | Vz/F is the volume of distribution associated with the terminal slope following extravascular administration divided by the fraction of dose absorbed. | Pre-dose,0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,48,72 hours post-dose on Day 1 for Treatment A and Day 13 for Treatment B | 
| Pre-dose Concentration (C0) of Maribavir | C0 is the lowest concentration reached by a drug before the next dose is administered. | Pre-dose on Day 13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Study-related Adverse Events (AEs), Serious Adverse Events (SAEs) and Treatment-emergent Adverse Events (TEAEs) | An AE was any untoward medical occurrence in a participant administered an investigational product (IP) and that did not necessarily have a causal relationship with this treatment. AE was considered to be study-related if there was any valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect relationship between the IP and the occurrence of the AE. An AE was considered a TEAE if it had a start date on or after the first dose of IP or if it had a start date before the date of the first dose of IP, but increased in intensity on or after the date of the first dose of IP. A serious adverse event (SAE) was any untoward medical occurrence (related either to the test product or to the other IP or not) that at any dose resulted in death; was life-threatening; required or prolongation of hospitalization; resulted in persistent or significant disability/incapacity; was a congenital abnormality/birth defect; was an important medical event. | From start of study drug administration up to follow-up (up to 25 days) | 
| Number of Participants With Clinically Significant Changes Reported as TEAE in Physical Examination, Vital Signs, 12-lead ECGs, Hematology, Blood Chemistry and Urinalysis | Clinical significance of the changes observed in the safety parameters to be reported as TEAE was interpreted by the investigator. | Baseline up to Day 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Maribavir