Clinical trial NCT03264079: Effect of Itraconazole on the Pharmacokinetics of Bardoxolone Methyl in Healthy Adults
Official title: An Open-Label Study of the Effect of a Strong CYP3A4 Inhibitor (Itraconazole) on the Pharmacokinetics of Bardoxolone Methyl in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: RTA 402
Bardoxolone methyl
Itraconazole
Sporanox
CYP3A4
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2017-08-28
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: All participants are placed into a one group to receive two interventions: one intervention during Period 1 and a second intervention during Period 2.

For Period 1, all qualified subjects shall receive a single oral dose of bardoxolone methyl (10 mg) on Day 1.

For Period 2, following a washout of 14 days, itraconazole (SPORANOX®) capsules (100 mg) will be administered as a 200-mg single daily dose on Study Days 15 through 27, with bardoxolone methyl (10 mg) administered on Day 18 (1 hour after itraconazole administration)
Primary purpose: TREATMENT

Brief summary: This trial will study the impact of a strong CYP3A4 inhibitor (itraconazole) on the pharmacokinetics of bardoxolone methyl (RTA 402) in healthy adult subjects.

This is an open-label, fixed-sequence crossover pharmacokinetic (PK) study in healthy volunteers.

Subjects will complete a screening visit within 28 days of Study Day 1. Subjects must qualify for the study based on inclusion/exclusion criteria. For Period 1, all qualified subjects shall receive a single oral dose of bardoxolone methyl (10 mg) on Day 1. For Period 2, following a washout of 14 days, itraconazole (SPORANOX®) capsules (100 mg) will be administered as a 200-mg single daily dose on Study Days 15 through 27, with bardoxolone methyl (10 mg) administered on Day 18 (1 hour after itraconazole administration).

Bardoxolone methyl doses will be administered under fasted conditions. Itraconazole will be administered under fed conditions on Study Days 15-17, and Study Days 19-27.

On study Day 18, itraconazole will be administered under fasted conditions. Subjects will be confined beginning on Study Day -1 through the last blood sample collection on Study Day 9 during Period 1, and from Study Day 14 through the last PK blood draw on Study Day 28 during Period 2.


Eligibility criteria: Inclusion Criteria:

* Male or female and age is between 18 and 55 years, inclusive;
* Female subjects of childbearing potential must not be planning a pregnancy, pregnant, or lactating, and must have a negative serum pregnancy test result before enrollment into the study, and must be willing to use contraception as specified or abstain from sexual activity for the duration of the study;
* If male, subject must be surgically sterile or practicing an approved method of contraception, from initial study drug administration through 90 days after administration of the last dose of study drug;
* If male, subject agrees to abstain from sperm donation through 90 days after administration of the last dose of study drug;
* Body Mass Index (BMI) is ≥ 18 to ≤31 kg/m2, inclusive;
* A condition of general good health, based upon the results of a medical history, physical examination, vital signs, laboratory profile, and a 12-lead electrocardiogram (ECG), as judged by the investigator;
* Must voluntarily sign and date each informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.

Exclusion Criteria:

* History of clinically significant drug allergies, including allergies to any of the components of the investigational product and/or clinically significant food allergies as determined by the investigator;
* Presence or history of any significant cardiovascular, gastrointestinal, hepatic, renal, pulmonary, hematologic, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease, as determined by the investigator;
* Presence of any other condition (including surgery) known to interfere with the absorption, distribution, metabolism, or excretion of medicines;
* Known hypersensitivity to any component in the formulations of bardoxolone methyl, or SPORANOX®;
* Requirement for any over-the-counter and/or prescription medication, vitamins, and/or herbal supplements on a regular basis;
* Use of any medications (over-the-counter and/or prescription medication), vitamins, and/or herbal supplements, within the 30-day period prior to study drug administration or within 5 half-lives (if known), whichever is longer;
* Recent (6-month) history of drug or alcohol abuse;
* B-type natriuretic peptide (BNP) level \>200 pg/mL at screening;
* Positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), or HIV antibodies (HIV Ab) at screening;
* Donation or loss of 550 mL or more blood volume (including plasmapheresis) or receipt of a transfusion of any blood product within 8 weeks prior to study drug administration;
* Receipt of any investigational product within a time period equal to 10 half-lives of the product, if known, or a minimum of 30 days prior to study drug administration;
* Positive screen results for drugs of abuse, alcohol, or cotinine at screening or Day -1;
* Consumption of alcohol within 72 hours prior to study drug administration;
* Consumption of grapefruit, grapefruit products, star fruit, star fruit products, or Seville oranges within the 72-hour period prior to study drug administration;
* Use of tobacco or nicotine-containing products within the 6-month period preceding study drug administration;
* Current enrollment in another clinical study;
* Screening laboratory analyses that show any of the following abnormal laboratory results:

  1. Alanine transaminase (ALT) or aspartate aminotransferase (AST) levels above the upper limit of normal (ULN);
  2. Clinically significant abnormal ECG; ECG with QTc using Fridericia's correction formula (QTcF) \> 450 msec is exclusionary;
  3. Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive either bardoxolone methyl or itraconazole.

Primary outcomes:
measure: Area under the plasma concentration-time curve of bardoxolone methyl from time 0 to the last measurable time point (AUC0-t).
timeFrame: 28 days
measure: Area under the plasma concentration-time curve of bardoxolone methyl extrapolated to infinity (AUC0-inf)
timeFrame: 28 days
measure: Maximum observed drug concentration (Cmax) in plasma of bardoxolone methyl
timeFrame: 28 days
Secondary outcomes:
Other outcomes:
Locations:
city: Cincinnati
country: United States
facility: Medpace Clinical Pharmacology Unit
state: Ohio
Study officials:
References: