Clinical trial NCT02413255: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Ascending Single- and Multiple-Doses of TAK-020 in Healthy Volunteers
Official title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential-Panel, Ascending Single- and Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TAK-020 in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2015-04-09
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of ascending single- and multiple-doses of TAK-020 in healthy participants.

Detailed description: The drug being tested in this study is called TAK-020. TAK-020 is being tested to evaluate safety and tolerability of single doses and 7 days multiple doses of TAK-020 in healthy volunteers. This study will look at the PK characteristics (how the drug acts throughout the body) of the drug and safety and tolerability (lab results, vital signs, ECG, and side effects) in healthy participants who take TAK-020.

The study will enroll a total of approximately 120 participants. This study is designed to consist of 2 sequential parts: Part 1-a SRD, and Part 2-a MRD. Healthy participants for Part 1 will be enrolled into 9 cohorts. Each cohort will have 8 randomized participants with receiving a single dose of TAK-020, and 2 receiving matching placebo under fasted conditions. In Cohorts 1-9 doses of 0.1, 0.5, 2.5, 4.4, 8.8, 17.5, 35, 70 and 105 mg will be evaluated.

Healthy participants for Part 2 will be enrolled into 7 cohorts. Each cohort will have 8 randomized participants, with participants receiving one dose of TAK-020 on Day 1, followed by a washout on Day 2, then daily dosing on Days 3-9 of TAK-020 with 2 participants receiving matching placebo under fasted conditions. In Cohorts 1-4 doses of 3.75, 5.75, 13 and 25 mg will be evaluated. For Cohorts 5-7, the subsequent dose level is to be determined based on data from Part 1 and review of safety, tolerability and PK data from Part 2 Cohorts 1-4.

This single-center trial will be conducted in the United States. The overall time to participate in this study is up to 45 days. Participants in Part 1 will make multiple visits to the clinic including a period of confinement to the clinic and will be contacted by telephone 14 days after the last dose of study drug for a follow-up assessment. Participants in Part 2 will make multiple visits to the clinic including a period of confinement to the clinic and will be observed at the clinic 17 days after the last dose of study drug for a follow-up assessment.

Eligibility criteria: Inclusion Criteria

Participant eligibility is determined according to the following criteria prior to entry into the study:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. Participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures including requesting that a participant fast for any laboratory evaluations.
3. Participant is a healthy adult male or female.
4. The participant is a health adult male or female aged 18 to 55 years, inclusive, at the time of informed consent and first study medication dose.
5. The participant weighs at least 45 kilogram (kg) and has a body mass index (BMI) between 18.0 and 32.0 kilogram per square meter (kg/m\^2), inclusive at Screening and Day -1.
6. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose.
7. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use adequate contraception from signing of informed consent throughout the duration of the study and until the next menstrual period or 30 days after last dose, whichever is first. If the next menstrual period is delayed, a pregnancy test will be required for exclusion of pregnancy.

Exclusion Criteria

Any participant who meets any of the following criteria will not qualify for entry into the study:

1. The participant has received any investigational compound within 30 days prior to Screening.
2. The participant is an immediate family member, study site employee, or in a dependent relationship with a study site employee who is involved in the conduct of this study (example, spouse, parent, child, sibling) or may consent under duress.
3. Participant has a known hypersensitivity to any component of the formulation of TAK-020, Captisol or related compounds.
4. The participant has a positive urine drug result for drugs of abuse at Screening or Check-in (Day -1).
5. The participant has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as 4 or more alcoholic beverages per day) within 1 year prior to the Screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. One unit is equivalent to a half-pint of beer or 1 measure of spirits or 1 glass of wine.
6. Participant has taken any excluded medication, supplements, or food products, Prohibited Medications and Dietary Products.
7. If female, the participant is pregnant or lactating or intending to become pregnant before, during or within 1 month after exit from this study (30 days post last dose); or intending to donate ova during such time period.
8. If male, the participant intends to donate sperm during the course of this study or for 12 weeks thereafter.
9. Participant has evidence of current cardiovascular, central nervous system, hepatic, hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the participant's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking TAK-020, or a similar drug in the same class, or that might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias.
10. Participant has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (that is, a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis frequent \[more than once per week\] occurrence of heartburn, or any surgical intervention \[example, cholecystectomy\]).
11. Participant has a history of cancer, except basal cell carcinoma which has been in remission for at least 5 years prior to Day 1.
12. Participant has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in Day -1. Cotinine test is positive at Screening or Check-in (Day -1).
13. The participant has poor peripheral venous access.
14. Participant has donated or lost 450 milliliter (mL) or more of his or her blood volume (including plasmapheresis), or had a transfusion of any blood product within 30 days prior to Day 1.
15. Vaccination with any live vaccine within 4 weeks of study drug administration.
16. Participant has a Screening or Check-in (Day -1) abnormal (clinically significant) ECG. Entry of any participant with an abnormal (not clinically significant) ECG must be approved, and documented by signature by the principal investigator medically qualified sub investigator.
17. Participant has QT interval with Fridericia correction method (QTcF) greater than (\>) 450 millisecond (msec) for men and women or PR outside the range of 120 to 220 msec confirmed upon repeat testing within a maximum of 30 minutes, at the Screening Visit or Check-in (Day -1).
18. Participant has abnormal Screening or Day -1 laboratory values that suggest a clinically significant underlying disease or participant with the following lab abnormalities:

    1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>1.2\* the upper limit of normal (ULN).
    2. Positive screen test for drugs of abuse.
    3. Positive blood screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), or human immunodeficiency virus-1 or -2 antibodies.
    4. A positive test for tuberculosis (TB) (QuantiFERON).

Primary outcomes:
measure: Percentage of Participants Who Experience at Least One Treatment-emergent Adverse Event (TEAE) in Part 1 Single-rising Dose (SRD)
timeFrame: First dose of study drug up to and including 30 days after last dose of study drug (Up to 31 days) for Part 1
measure: Percentage of Participants With Markedly Abnormal Values (MAV) for Safety Laboratory Findings at Least Once Post-dose in Part 1 (SRD)
timeFrame: From Day 1 to Day 14 of Part 1
measure: Percentage of Participants With MAV for Vital Sign Measurements at Least Once Post-dose in Part 1 (SRD)
timeFrame: From Day 1 to Day 14 of Part 1
measure: Percentage of Participants With MAV for Safety Electrocardiogram (ECG) Parameters at Least Once Post-dose in Part 1 (SRD)
timeFrame: From Day 1 to Day 14 in Part 1
measure: Percentage of Participants Who Experience at Least One Treatment-emergent Adverse Event (TEAE) in Part 2 Multiple-rising Dose (MRD)
timeFrame: First dose of study drug up to and including 30 days after last dose of study drug (Up to 39 days) in Part 2
measure: Percentage of Participants With MAV for Safety Laboratory Findings at Least Once Post-dose in Part 2 (MRD)
timeFrame: From Day 1 to Day 17 in Part 2
measure: Percentage of Participants With MAV for Vital Sign Measurements at Least Once Post-dose in Part 2 (MRD)
timeFrame: From Day 1 to Day 17 in Part 2
measure: Percentage of Participants With MAV for Safety ECG Parameters at Least Once Post-dose in Part 2 (MRD)
timeFrame: From Day 1 to Day 17 in Part 2
Secondary outcomes:
measure: Cmax: Maximum Observed Plasma Concentration for TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: Cmax: Maximum Observed Plasma Concentration for TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 48 hours) post-dose on Day 1 and pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 48 hours) post-dose on Day 1 and pre-dose and multiple time-points (up to 24 hours) post dose on Day 9 in Part 2
measure: AUC24: Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 24 hours) post-dose in Part 1
measure: AUC24: Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours for TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 1 and pre-dose and multiple timepoints (up to 24 hours) post dose on Day 9 in Part 2
measure: AUC24/D: Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours Divided by TAK-020 Dose for TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 24 hours) post-dose in Part 1
measure: AUC24/D: Area Under the Plasma Concentration-time Curve From Time 0 to Time 24 Hours Divided by TAK-020 Dose for TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 24 Hours) post-dose on Day 1 and pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
measure: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-020 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 48 hours) post-dose on Day 1 and pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
measure: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity Calculated Using the Observed Value for the Last Quantifiable Concentration for TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: AUC∞:Area Under the Plasma Concentration-time Curve From Time 0 to Infinity Calculated Using the Observed Value for the Last Quantifiable Concentration for TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 48 hours) post-dose on Day 1 in Part 2
measure: Rac(AUC): Accumulation Ratio Based on AUC Calculated as AUC24 at Steady State/AUC24 After a Single Dose for TAK-020 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
measure: Rac(Cmax): Accumulation Ratio Based on Cmax Calculated as Cmax at Steady State/Cmax After a Single Dose for TAK-020 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
measure: Cmax/D: Maximum Observed Plasma Concentration Divided by TAK-020 Dose for TAK-020 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: Cmax/D: Maximum Observed Plasma Concentration Divided by TAK-020 Dose for TAK-020 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 48 hours) post-dose on Day 1 and pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
measure: Terminal Disposition Phase Half-life for TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: T1/2z : Terminal Disposition Phase Half-life (T1/2z) for TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 48 hours) post-dose on Day 1 and pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
measure: Lambda z (Λz): Terminal Disposition Phase Rate Constant for TAK-020 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: Lamda z (Λz):Terminal Disposition Phase Rate Constant for TAK-020 (MRD)
timeFrame: From pre-dose to 96 hours post-dose in Part 1 and pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
measure: Tlag: Lag Time to First Quantifiable Concentration for TAK-020 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: Tlag: Lag Time to First Quantifiable Concentration for TAK-020 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 48 hours) post-dose on Day 1 and pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
measure: CL/F: Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration of TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: CL/F: Apparent Clearance After Extravascular Administration Calculated Using the Observed Value of the Last Quantifiable Concentration of TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 48 hours) post-dose on Day 1 and pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
measure: Apparent Volume of Distribution (Vz/F) During the Terminal Disposition Phase After Extravascular Administration Calculated Using the Observed Value for the Last Quantifiable Concentration for TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: Apparent Volume of Distribution (Vz/F) During the Terminal Disposition Phase After Extravascular Administration Calculated Using the Observed Value for the Last Quantifiable Concentration for TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 48 hours) post-dose on Day 1 and pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
measure: Ae(0-24) : Amount of Drug Excreted in Urine During a 24-hour Dosing Interval for TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 24 hours) post-dose in Part 1
measure: Ae(0-24): Amount of Drug Excreted in Urine During a 24-hour Dosing Interval for TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 1 and Day 9 in Part 2
measure: Ae(0-96): Amount of Drug Excreted in Urine From Time 0 to Time 96 Hours for TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: Fe(0-24): Fraction of Drug Excreted in Urine for TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 24 hours) post-dose in Part 1
measure: Fe(0-24): Fraction of Drug Excreted in Urine for TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 1 and Day 9 in Part 2
measure: Fe(0-96): Fraction of Drug Excreted in Urine for TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: Renal Clearance (CLr) for TAK-020 in Part 1 (SRD)
timeFrame: Pre-dose and multiple timepoints (up to 96 hours) post-dose in Part 1
measure: Renal Clearance (CLr) for TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (up to 48 hours) post-dose on Day 1 and pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
measure: R: Linearity Index Calculated as AUC24 at Steady State/AUC∞ After a Single Dose for TAK-020 in Part 2 (MRD)
timeFrame: Pre-dose and multiple timepoints (Up to 48 hours) post-dose on Day 1 and pre-dose and multiple timepoints (up to 24 hours) post-dose on Day 9 in Part 2
Other outcomes:
Locations:
city: Glendale
country: United States
state: California
Study officials:
affiliation: Takeda
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References: