Safety, Tolerability and Pharmacokinetics of Escalating Single Doses of TAK-137 in Healthy Participants

Phase 1

Completed

• Conditions: Dose Finding Study
• Interventions: Drug: TAK-137; Drug: Placebo

• Registration Number: NCT02334982
• Lead Sponsor: Takeda

Brief Summary

The purpose of this study is to characterize the safety and tolerability profile of TAK-137 when administered as a single dose of tablets at escalating dose levels in healthy participants.

Detailed Description

The drug being tested in this study is called TAK-137. TAK-137 is being tested to find a safe and well-tolerated dose. This study looked at safety (lab results and side effects) and pharmacokinetic properties (drug absorption, distribution, metabolism, and excretion) in people who took TAK-137. This study was designed as a single ascending 6 Cohort dose study with planned doses of 2, 5, 15, 50, and 100 mg and Cohort 6 dose to be determined if the maximum tolerated dose (MTD) was not reached. Anticipated enrollment was 48.

This study enrolled 47 participants and consisted of 6 Cohorts. Participants in Cohorts 1, 2, 3, 5 and 6 were randomized to receive a single dose of TAK-137 or placebo after a 10-hour fast. Participants in Cohort 4 were randomized to receive a single dose of TAK-137 or placebo under fasted conditions, followed by a single dose of TAK-137 or placebo under fed conditions 14 days later. Participants in cohort 4 will receive the same dose in both fasted and fed conditions. The starting dose was 2 mg followed by administrations of 5, 10, 0.5 and 20 mg.

This single-center trial was conducted in the United States. For Cohorts 1, 2, 3, 5, and 6 the overall time to participate in this study was up to 42 days. Participants made 4 visits to the clinic including one 5-day period of confinement to the clinic, and were contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

For Cohort 4 the overall time to participate in this study was up to 56 days. Participants made 7 visits to the clinic including two 5-day periods of confinement to the clinic, and were contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

Study Timeline

• Study Start: 2013-06
• Primary Completion: 2014-01
• Study Completion: 2014-01
• Status Verified: 2015-01
• Study First Submitted: 2015-01-06
• Study First Submitted QC: 2015-01-08
• Study First Posted: 2015-01-09
• Results First Submitted: 2015-01-29
• Results First Submitted QC: 2015-01-29
• Last Update Submitted: 2015-01-29
• Results First Posted: 2015-02-10
• Last Update Posted: 2015-02-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 47

Inclusion Criteria

1. Is a healthy male or non-pregnant, non-lactating female adult who is 18 to 55 years of age inclusive at the time of informed consent and first study medication dose.
2. Weighs at least 45 kg and has a body mass index (BMI) between 18 and 30.0 kg/m^2, inclusive at Screening.
3. Is able to comply with the protocol and is willing to sign the informed consent prior to undergoing any study-related procedures.

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Exclusion Criteria

1. Has a known hypersensitivity to any component of the formulation of TAK-137.
2. Has a medical condition such as mental retardation that can cause cognitive impairment.
3. Has a risk of suicide according to the Investigator's clinical judgment (eg, per Columbia-Suicide Severity Rating Scale [C-SSRS] or has made a suicide attempt in the previous 6 months).
4. 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.
5. There is any finding in the participant's medical history, physical examination, or safety laboratory tests (including safety electroencephalogram [EEG]) giving reasonable suspicion of a disease that would contraindicate taking TAK-137, 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.
6. Has taken any excluded medication, supplements, or food products listed in the Excluded Medications and Dietary Products table.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 3: TAK-137 10 mg	TAK-137	TAK-137 10 mg, tablets, orally, once on Day 1.
Cohorts 1-6: Placebo	Placebo	TAK-137 placebo-matching tablets, orally, once on Day 1.
Cohort 4: TAK-137 5 mg Food Effect	TAK-137	TAK-137 5 mg, tablets, orally, under fasted conditions, once on Day 1 of Period 1, followed by 14 days of follow-up, followed by TAK-137 5 mg, tablets, orally, under fed conditions, once on Day 1 of Period 2.
Cohort 1: TAK-137 2 mg	TAK-137	TAK-137 2 mg, tablets, orally, once on Day 1.
Cohort 2: TAK-137 5 mg	TAK-137	TAK-137 5 mg, tablets, orally, once on Day 1.
Cohort 5: TAK-137 0.5 mg	TAK-137	TAK-137 0.5 mg, tablets, orally, once on Day 1.
Cohort 6: TAK-137 20 mg	TAK-137	TAK-137 20 mg, tablets, orally, once on Day 1.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Abnormal Safety Laboratory Findings	Day 1 to 14 days after the last dose of study medication (Up to 30 Days)	The percentage of participants with any markedly abnormal standard safety laboratory values was collected throughout study.
Percentage of Participants With Markedly Abnormal Vital Sign Measurements	Day 1 to 14 days after the last dose of study medication	The percentage of participants with any markedly abnormal standard vital sign measurements was collected throughout study.
Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event	Day 1 to 14 days after the last dose of study medication(Up to 30 days)	An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event is defined as an adverse event with an onset that occurs after receiving study drug.

Secondary Outcome Measures

Name	Time	Method
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-137	Day 1	Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
Cmax: Maximum Observed Plasma Concentration for TAK-137	Day 1	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-137	Day 1	(AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC\[0-tlqc\]).
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-137	Day 1	AUC(0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.
Terminal Elimination Half-life (T1/2) for TAK-137_101	Day 1	Terminal Phase Elimination Half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Apparent Volume of Distribution (Vz/F) for TAK-137_101	Day 1	Vz/F is the distribution of a drug between plasma and the rest of the body following oral administration, calculated as CL/F divided by λz.
Renal Clearance (CLr) for TAK-137	Day 1	CLr is a measure of apparent clearance of the drug from the urine, calculated as CLr=Ae(0-t)/AUC(0-96).
Apparent Clearance (CL/F) for TAK-137_101	Day 1	CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC(0-inf), expressed in liters per hour (L/hr).
Total Amount of Drug (TAK-137) Excreted in Urine From Time 0 to Time t (Ae[0-t])	Day 1	Total amount of drug excreted in urine from time 0 to time t, calculated as Sum (Cu\*Vu), where Cu is the concentration of drug excreted in urine and Vu is the volume of urine excreted.
Fraction of TAK-137 Excreted in Urine (Fe)	Day 1	Fraction of drug excreted in urine, calculated as Fe=(Ae\[0-t\]/dose)×100.