Safety, Tolerability, Pharmacokinetics, and Pharmacodynam... | NCT02209506

ID	Type	Description	Link
U1111-1156-8528	Other Identifier	World Health Organziation

Description Module

Detailed Description

MLN3126 is being tested to find a safe and well-tolerated dose in healthy people and to assess how MLN3126 is processed by the body. In total, approximately 64 participants will be enrolled in the study.

This study is composed of 2 parts: Part A healthy non-Japanese participants and Part B healthy Japanese participants. Each part will consist of 4 Cohorts with 8 participants in each Cohort. In each Cohort, 6 participants will receive MLN3126 and 2 participants will receive matched placebo within 30 minutes after the start of a standard breakfast. The starting dose will be 100 mg followed by doses of 300 mg, 800 mg, and a dose to be determined during the study. Progression to the next dose level will only occur if the previous dose level was considered to be safe and well tolerated.

This single-center trial will be conducted in the United States. The overall time to participate in this study is up to 20 days. All participants will be contacted by telephone 7 days after the last dose of study drug for a follow-up assessment.

Due to toxicology findings from a long-term animal study, Takeda made the decision to terminate this study. No clinically significant safety and/or tolerability issues have been observed or reported in participants exposed to MLN3126.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cohort 1A: MLN3126 100 mg Non-Japanese Participants	Experimental	MLN3126 100 mg, administered orally as tablets once on Day 1, followed by a 7 day washout period, followed by once daily administration for 7 days (Days 9 through 15) in healthy, non-Japanese participants.	Drug: MLN3126
Cohort 2A: MLN3126 300 mg Non-Japanese Participants	Experimental	MLN3126 300 mg, administered orally as tablets, orally, once on Day 1, followed by a 7 day washout period, followed by once daily administration for 7 days (Days 9 through 15) in healthy, non-Japanese participants.	Drug: MLN3126
Cohort 3A: MLN3126 800 mg Non-Japanese Participants	Experimental	MLN3126 800 mg, administered orally as tablets once on Day 1, followed by a 7 day washout period, followed by once daily administration for 7 days (Days 9 through 15) in healthy, non-Japanese participants.	Drug: MLN3126
Cohort 4A: MLN3126 TBD Non-Japanese Participants	Experimental	The MLN3126 dose for this Cohort will be determined based on data collected from Cohort 3A. MLN3126, tablets, administered orally, once on Day 1, followed by a 7 day washout period, followed by once daily administration for 7 days (Days 9 through 15) in healthy, non-Japanese participants.	Drug: MLN3126
Cohorts 1A - 4A: Matched Placebo Non-Japanese Participants

Interventions

Name	Type	Description	Arm Group Labels	Other Names
MLN3126	Drug	MLN3126 tablets	Cohort 1A: MLN3126 100 mg Non-Japanese Participants Cohort 1B: MLN3126 100 mg Japanese Participants Cohort 2A: MLN3126 300 mg Non-Japanese Participants

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)	A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.	Baseline up to 7 days after last dose of study drug (Day 22)
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Electrocardiogram Measurements at Least Once Post Dose	A standard 12-lead ECG was performed. The percentage of participants with markedly abnormal electrocardiogram (ECG) findings during the study.	Baseline up to 7 days after last dose of study drug (Day 22)
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose	The percentage of participants with any markedly abnormal, according to Takeda criteria, standard safety laboratory values, including hematology, serum chemistry, and urinalysis, during the treatment period.	Baseline up to 7 days after last dose of study drug (Day 22)
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post Dose	The percentage of participants who meet markedly abnormal criteria designated by Takeda Global Research and Development Center, Inc. (TGRD). Criteria for markedly abnormal vital signs included body temperature, systolic blood pressure, diastolic blood pressure and pulse rate.	Baseline up to 7 days after last dose of study drug (Day 22)

Secondary Outcomes

Measure	Description	Time Frame
Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite	M-I is the inactive metabolite of MLN3126.	Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Part A (Healthy non-Japanese participants):

In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
The 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.
Is a male or female adult, 18 to 55 years of age, inclusive, at the time of informed consent and study drug dosing.
Is a healthy adult male or female participant as evidenced by their medical history, complete physical examination, vital signs, electrocardiogram (ECG), and safety laboratory evaluations.
Weighs at least 45 kg and has a body mass index (BMI) between 18 and 30 kg/m^2 inclusive at Screening.
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.
A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of informed consent throughout the duration of the study to their next postconfinement menstruation. In addition, participants must be advised not to donate ova during this period.

Part B (Healthy Japanese participants):

In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
The 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.
Is a male or female adult, 20 to 55 years of age, inclusive, at the time of informed consent and study drug dosing, is of Japanese descent (born to Japanese parents and grandparents and has lived outside Japan for less than 15 years), and maintains a Japanese diet and lifestyle.
Is a healthy adult male or female participant as evidenced by their medical history, complete physical examination, vital signs, ECG, and safety laboratory evaluations.
Weighs at least 45 kg and has a BMI between 18 and 28 kg/m^2 inclusive at Screening.
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 the last dose.
A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of informed consent throughout the duration of the study to their next postconfinement menstruation. In addition, participants must be advised not to donate ova during this period.

Exclusion Criteria:

Part A (Healthy non-Japanese participants) and Part B (Healthy Japanese participants):

Has received any investigational compound within 30 days or 5 half-lives of the investigational compound, whichever is longer, prior to the first dose of study medication.
Has received MLN3126 in a previous clinical study.
Is an immediate family member, study site employee, or in a dependant relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal (GI), or endocrine disease or allergic skin rash or other abnormality which may impact the ability of the participant to participate or potentially confound the study results.
Has a known hypersensitivity to any component of the formulation of MLN3126.
Has a positive urine drug result for drugs of abuse at Screening or Check-in (Day -1).
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.
Has taken any excluded medication, supplements, or food products listed in the Excluded Medications and Dietary Products section of the protocol.
If female, the participant is pregnant or lactating or intending to become pregnant before or during the study, including the timeframe to the participant's next post-confinement menstruation after participating in this study.
If male, the participant intends to donate sperm during the course of this study or for 12 weeks thereafter.
Has current or recent (within 6 months) GI disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, any surgical intervention known to impact absorption [eg, bariatric surgery or bowel resection], esophageal reflux, peptic ulcer disease, erosive esophagitis, or frequent [more than once per week] occurrence of heartburn).
Has Gilbert's syndrome or bilirubin level 1.2x the upper limits of normal (ULN).
Has a history of cancer, except basal cell carcinoma, that has been in remission for at least 5 years prior to Day 1.
Has a positive test result for hepatitis B surface antigen (HBsAg) or antibody to hepatitis C virus (anti-HCV) at Screening or a known history of human immunodeficiency virus infection.
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).
Has poor peripheral venous access.
Has donated or lost 450 mL or more of his or her blood volume (including plasmapheresis) or had a transfusion of any blood product within 45 days prior to Day 1.
Has a Screening or Check-in (Day -1) abnormal (clinically significant) electrocardiogram (ECG). Entry of any participant with an abnormal (not clinically significant) ECG must be approved, and documented by signature by the principal investigator.
Has a QT interval with Fridericia correction method (QTcF) > 430 milliseconds (ms) for men or > 450 ms for women or a PR outside the range of 120 to 210 ms confirmed upon repeat testing within a maximum of 30 minutes, at the Screening Visit or Check-in (Day -1).
Has abnormal Screening or Check-in (Day -1) laboratory values that suggest a clinically significant underlying disease or participant with the following laboratory abnormalities: Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 1.5 ULN.

Name	Affiliation	Role
Medical Director Clinical Science	Takeda	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
		Neptune City	New Jersey	07753	United States

Arm/Group Information

ID	Title	Description
FG000	Part A: Placebo	MLN3126 placebo-matching tablet, orally, once on Day 1 of the single dosing period, followed by 1 week washout period, further followed by MLN3126 placebo-matching tablets, orally, once daily from Day 9 up to Day 15 of the 7 day multiple dosing period.
FG001	Part A: MLN3126 100 mg	MLN3126 100 mg, tablet, orally, once on Day 1 of the single dosing period, followed by 1 week washout period, further followed by MLN3126 100 mg, tablets, orally, once daily from Day 9 up to Day 15 of the 7 day multiple dosing period.
FG002	Part A: MLN3126 300 mg	MLN3126 300 mg, tablet, orally, once on Day 1 of the single dosing period, followed by 1 week washout period, further followed by MLN3126 300 mg, tablets, orally, once daily from Day 9 up to Day 15 of the 7 day multiple dosing period.
FG003	Part B: Placebo	MLN3126 placebo-matching tablet, orally, once on Day 1 of the single dosing period, followed by 1 week washout period, further followed by MLN3126 placebo-matching tablets, orally, once daily from Day 9 up to Day 15 of the 7 day multiple dosing period.
FG004	Part B: MLN3126 100 mg	MLN3126 100 mg, tablet, orally, once on Day 1 of the single dosing period, followed by 1 week washout period, further followed by MLN3126 100 mg, tablets, orally, once daily from Day 9 up to Day 15 of the 7 day multiple dosing period.

ID	Title	Description
BG000	Part A: Placebo	MLN3126 placebo-matching tablet, orally, once on Day 1 of the single dosing period, followed by 1 week washout period, further followed by MLN3126 placebo-matching tablets, orally, once daily from Day 9 up to Day 15 of the 7 day multiple dosing period.
BG001	Part A: MLN3126 100 mg

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Part A: Placebo	MLN3126 placebo-matching tablet, orally, once on Day 1 of the single dosing period, followed by 1 week washout period, further followed by MLN3126 placebo-matching tablets, orally, once daily from Day 9 up to Day 15 of the 7 day multiple dosing period.

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Headache	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (v17.0)	Systematic Assessment