Clinical trial NCT02775240: Study of SHP620 (Maribavir) in Healthy Adults
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cytomegalovirus (CMV)
Keywords: Maribavir
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2016-05-17
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.


Eligibility criteria: 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:

  1. Male, or
  2. Female of non-childbearing potential
  3. Non-pregnant, non-lactating female
  4. 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:

  1. Have used an investigational product (if elimination half-life is \<6 days, otherwise 5 half-lives).
  2. Have been enrolled in a clinical study (including vaccine studies) that, in the investigator's opinion, may impact this study.
  3. 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).

Primary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Digoxin
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Dextromethorphan
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Dextrorphan
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Maribavir
timeFrame: Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Digoxin
timeFrame: 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
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Dextromethorphan
timeFrame: 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
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Dextrorphan
timeFrame: 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
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Maribavir
timeFrame: Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13
measure: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-infinity) of Digoxin
timeFrame: 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
measure: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-infinity) of Dextromethorphan
timeFrame: 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
measure: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-infinity) of Dextrorphan
timeFrame: 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
measure: Area Under the Plasma Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Digoxin
timeFrame: 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
measure: Area Under the Plasma Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Dextromethorphan
timeFrame: 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
measure: Area Under the Plasma Concentration Versus Time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) of Dextrorphan
timeFrame: 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
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the End of the Dosing Interval at Steady-State (AUCtau) of Maribavir
timeFrame: Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13
measure: First-order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve of Digoxin
timeFrame: 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
measure: First-order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve of Dextromethorphan
timeFrame: 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
measure: First-order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve of Dextrorphan
timeFrame: 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
measure: Terminal Half-life (t1/2) of Digoxin
timeFrame: 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
measure: Terminal Half-life (t1/2) of Dextromethorphan
timeFrame: 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
measure: Terminal Half-life (t1/2) of Dextrorphan
timeFrame: 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
measure: Terminal Half-life (t1/2) of Maribavir
timeFrame: Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13
measure: Apparent Oral Clearance (CL/F) of Digoxin
timeFrame: 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
measure: Apparent Oral Clearance (CL/F) of Dextromethorphan
timeFrame: 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
measure: Apparent Oral Clearance (CL/F) of Maribavir
timeFrame: Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13
measure: Concentration at the End of Dosing Interval (Ctau) of Maribavir
timeFrame: Pre-dose, 0.25,0.5,1,1.5,2,3,4,5,6,8,12 hours post-dose on Day 13
measure: Volume of Distribution Divided by the Fraction of Dose Absorbed (Vz/F) of Digoxin
timeFrame: 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
measure: Volume of Distribution Divided by the Fraction of Dose Absorbed (Vz/F) of Dextromethorphan
timeFrame: 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
measure: Pre-dose Concentration (C0) of Maribavir
timeFrame: Pre-dose on Day 13
Secondary outcomes:
measure: Number of Participants With Study-related Adverse Events (AEs), Serious Adverse Events (SAEs) and Treatment-emergent Adverse Events (TEAEs)
timeFrame: From start of study drug administration up to follow-up (up to 25 days)
measure: Number of Participants With Clinically Significant Changes Reported as TEAE in Physical Examination, Vital Signs, 12-lead ECGs, Hematology, Blood Chemistry and Urinalysis
timeFrame: Baseline up to Day 16
Other outcomes:
Locations:
city: Miami
country: United States
facility: Clinical Pharmacology of Miami, Inc.
state: Florida
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Song IH, Ilic K, Murphy J, Lasseter K, Martin P. Effects of Maribavir on P-Glycoprotein and CYP2D6 in Healthy Volunteers. J Clin Pharmacol. 2020 Jan;60(1):96-106. doi: 10.1002/jcph.1504. Epub 2019 Aug 6.