TAK-648 Multiple-Rising Dose Study in Healthy Japanese Participants and Non-Japanese Participants With Type 2 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
This is a phase 1, randomized, double-blind, placebo-controlled, 2-center, multiple-dose study in healthy participants and participants with type 2 diabetes mellitus (T2DM). This study will evaluate the safety, tolerability and pharmacokinetics (PK) of TAK-648 when administered as multiple oral doses of TAK-648 solution at escalating dose levels in healthy participants of Japanese decent and participants with T2DM.

Detailed Description
-----------------
The drug being evaluated in this study is TAK-648 for the treatment of T2DM. This study will consist of 2 parts: (1) multiple ascending doses in participants with T2DM treated with a stable dose of metformin, (2) multiple ascending doses in healthy participants of Japanese descent. Part 1 of this study will consist of 2 multiple dose treatment cohorts (Cohorts 1-2 designated as P1C1 and P1C2) dosed sequentially in escalating order. The projected doses of TAK-648 for Part 1 are 0.15 and 0.35 mg of TAK-648, but may be adjusted higher or lower, and additional cohorts may be added, based on available safety and pharmacokinetic (PK) data. All cohorts in Part 1 will consist of 8 (2 placebo) T2DM participants. Part 2 of this study will consist of 3 multiple dose treatment cohorts (Cohorts 1-3 designated as P2C1, P2C2 and P2C3) in healthy participants of Japanese descent dosed sequentially in escalating order. The projected doses of TAK-648 chosen for Part 2 are 0.05, 0.15 and 0.35 mg of TAK-648, but may be adjusted higher or lower based on available safety and PK data. All cohorts in Part 2 will consist of 8 (2 placebo) healthy participants of Japanese descent. Additional cohorts may be recruited and studied as necessary to better evaluate safety, tolerability, PK, and/or PD parameters.

Official Title
-----------------
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability, and Pharmacokinetic Study of Escalating Multiple Oral TAK-648 Doses in Healthy Japanese Subjects and Subjects With Type 2 Diabetes Mellitus

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: TAK-648
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Part 1: Is an adult male or female and has a historical diagnosis of type 2 diabetes mellitus (T2DM) disease. Is aged 18 to 65 years, inclusive, at the time of informed consent and first study medication dose. Weighs at least 55 kg and has a body mass index (BMI) ≥23.0 kg/m^2 and ≤35.0 kg/m^2 at Screening. Has a systolic blood pressure >90 and ≤150 mm Hg and a diastolic blood pressure of >60 and ≤90 mm Hg at Screening and at Check-in (Day -2). If out of range, may be repeated once for eligibility determination within a maximum of5 minutes. Has a calculated creatinine clearance >60 mL/min at Screening and Check-in (Day -2). Has been treated for inadequate glycemic control with a stable dose of metformin for the least 8 weeks prior to Screening. Has a glycosylated hemoglobin (HbA1c) level between 6.5% and 10.0%, inclusive at Check-in (Day -2). Has a fasting C-peptide concentration ≥0.8 ng/mL at Screening. Has no medical history of type 1 diabetes mellitus (T1DM), hypoglycemia unawareness, diabetic ketoacidosis or hyperosmolar coma. Part 2: Is a healthy adult male or female of Japanese descent (born to Japanese parents and grandparents) and have lived outside of Japan for less than 5 years, inclusive. Is aged 20 to 55 years, inclusive, at the time of informed consent and first study medication dose. Weighs at least 45 kg and has a BMI from 17.0 to 25.0 kg/m^2, inclusive at Screening. Has a systolic blood pressure >90 and ≤150 mm Hg and a diastolic blood pressure of >60 and ≤90 mm Hg at Screening and at Check-in (Day -2). If out of range, may be repeated once for eligibility determination within a maximum of 5 minutes. Has a calculated creatinine clearance >60 mL/min at Screening and Check-in (Day -2). Exclusion Criteria: Part 1: Has Screening or Check-in (Day -2) laboratory values of serum creatinine ≥1.5 mg/dL for males or ≥1.4 mg/dL [females] or abnormal creatinine clearance. Has a history of T1DM, hypoglycemia unawareness, diabetic ketoacidosis, or hyperosmolar coma. Has a history of any clinically significant retinopathy, which is defined as more than moderate nonproliferative diabetic retinopathy or any stage of proliferative diabetic retinopathy or any history of laser-treated retinopathy. Has received any antihyperglycemic medication with the exception of metformin within the previous 12 weeks of Check-in (Day -2) or the subject has changed the dose of metformin within the previous 8 weeks of Screening. Is expecting to receive, receiving or has received systemic glucocorticoid therapy for a duration longer than 5 days within the previous 12 weeks of Check-in (Day -2). Parts 1 and 2: Has received any investigational compound within 30 days prior to the first dose of study medication. Has received TAK-648 in a previous clinical study or as a therapeutic agent. Has any significant medical histories or currently uncontrolled clinical conditions, which may not be safe for participants to participate in the study, may impact the ability of the participant to participate in the study, or may potentially confound the study results. The concerned significant medical histories and uncontrolled clinical conditions include (may not be limited to) cardiovascular (such as ischemic heart disease, heart failure, cardiomyopathy, clinically significant arrhythmia, uncontrolled or unstable blood pressure), central nervous system, hepatic or hematopoietic disease(s), renal dysfunction, metabolic or endocrine dysfunction, pulmonary diseases including serious allergy and asthma hypoxemia, seizures, or allergic skin rash. Has a history of significant GI disorders manifested with persistent, chronic or intermittent nausea, vomiting or diarrhea, or has a current or recent (within 6 months) GI disease that would influence the absorption of drugs (eg, a history or malabsorption, severe esophageal reflux, peptic ulcer disease or erosive esophagitis with frequent [more than once per week] occurrence of heartburn). Has diagnosis of major depression, bipolar disorder or anxiety disorders, or has a risk of anxiety, depression, or insomnia according to the investigator's clinical judgment per HAM-D17 at Screening or has received any medication to treat any psychological disorders within 1 year. Has a risk of suicide according to the investigator's clinical judgment per C-SSRS at Screening or has made a suicide attempt in the past 6 months prior to Screening. Has a known hypersensitivity to any component of the formulation ofTAK-648, or to a PDE4 inhibitor (eg, roflumilast) or Listerine strips. Has a positive urine drug result for drugs of abuse at Screening or Check-in (Day -2). Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse 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. If female, is pregnant or lactating or intending to become pregnant before, during, or within 12 weeks after participating in this study; or intending to donate ova during such time period. If male, intends to donate sperm during the course of this study or for 12 weeks thereafter. 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 HBsAg, 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 6 weeks prior to Check-in (Day -2). Cotinine test is positive at Screening or Check-in (Day -2). 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 30 days prior to Day 1. Has a Screening or Check-in (Day -2) abnormal (clinically significant) ECG, including but not limited to those with evidence of prolonged QT/QTc interval at Baseline (eg, QTc interval >450 milliseconds) or those at risk for QT prolongation (eg with a family history of long QT syndrome). Entry of any subject with an abnormal (not clinically significant) ECG must be approved, and documented by signature by the principal investigator or medically qualified subinvestigator. Has abnormal Screening or Check-in (Day -2) laboratory values that suggest a clinically significant underlying disease or participant with the following laboratory abnormalities: ALT and/or AST >2.5×ULN.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Cohort 1: TAK-648 0.35 mg<br>Participants with T2DM on a stable dose of metformin in study Part 1, Cohort 1 received TAK-648 0.35 mg, solution, orally, single dose on Day 1, no drug administration on Days 2 to 3, followed by once daily (QD) doses starting on Day 4 and continuing through Day 17 (14 days). | Drug: TAK-648<br>* TAK-648 solution<br>|
| Experimental: Part 1 Cohort 2: TAK-648 0.80 mg<br>Participants with T2DM on a stable dose of metformin in study Part 1, Cohort 2 received TAK-648 0.80 mg, solution, orally, single dose on Day 1, no drug administration on Days 2 to 3, followed by once daily (QD) doses starting on Day 4 and continuing through Day 17 (14 days). | Drug: TAK-648<br>* TAK-648 solution<br>|
| Placebo Comparator: Part 1: Placebo Cohort 1-2<br>Participants with T2DM on a stable dose of metformin in study Part 1 received placebo-matching TAK-648, solution, orally, single dose on Day 1, no drug administration on Days 2 to 3, followed by once daily (QD) doses starting on Day 4 and continuing through Day 17 (14 days). | Drug: Placebo<br>* TAK-648 placebo-matching solution<br>|
| Experimental: Part 2 Cohort 1: TAK-648 0.05 mg<br>Healthy participants of Japanese descent in study Part 2, Cohort 1 received TAK-648 0.05 mg, solution , orally, single dose on Day 1, no drug administration on Days 2 to 3, followed by multiple QD doses starting on Day 4 and continuing through Day 10 (7 days). | Drug: TAK-648<br>* TAK-648 solution<br>|
| Experimental: Part 2 Cohort 2: TAK-648 0.15 mg<br>Healthy participants of Japanese descent in study Part 2, Cohort 2 received TAK-648 0.15 mg, solution, orally, single dose on Day 1, no drug administration on Days 2 to 3, followed by multiple QD doses starting on Day 4 and continuing through Day 10 (7 days). | Drug: TAK-648<br>* TAK-648 solution<br>|
| Experimental: Part 2 Cohort 3: TAK-648 0.35 mg<br>Healthy participants of Japanese descent in study Part 2, Cohort 3 received TAK-648 0.35 mg, solution, orally, single dose on Day 1, no drug administration on Days 2 to 3, followed by multiple QD doses starting on Day 4 and continuing through Day 10 (7 days). | Drug: TAK-648<br>* TAK-648 solution<br>|
| Experimental: Part 2 Cohort 4: TAK-648 0.80 mg<br>Healthy participants of Japanese descent in study Part 2, Cohort 4 received TAK-648 0.80 mg, solution, orally, single dose on Day 1, no drug administration on Days 2 to 3, followed by multiple QD doses starting on Day 4 and continuing through Day 10 (7 days). | Drug: TAK-648<br>* TAK-648 solution<br>|
| Placebo Comparator: Part 2: Placebo Cohort 1-4<br>Healthy participants of Japanese descent in study Part 2, received TAK-648 placebo-matching solution, orally, single dose on Day 1, no drug administration on Days 2 to 3, followed by multiple QD doses starting on Day 4 and continuing through Day 10 (7 days). | Drug: Placebo<br>* TAK-648 placebo-matching solution<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Have at Least 1 Treatment-Emergent Adverse Event (TEAE) for Part 1 | 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. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. | Up to Day 34 | 
| Percentage of Participants Who Have at Least 1 Treatment-Emergent Adverse Event (TEAE) for Part 2 | 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. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. | Up to Day 26 | 
| Percentage of Participants With Markedly Abnormal Laboratory Values at Least Once Post-dose During Dosing for Part 1 |  | Up to Day 20 | 
| Percentage of Participants With Markedly Abnormal Laboratory Values at Least Once Post-dose During Dosing for Part 2 |  | Up to Day 13 | 
| Percentage of Participants With Markedly Abnormal Vital Sign Values at Least Once Post-dose During Dosing for Part 1 | Vital signs included body temperature (oral), sitting blood pressure (after 5 minutes resting), respiration rate and pulse (bpm). | Up to Day 20 | 
| Percentage of Participants With Markedly Abnormal Vital Sign Values at Least Once Post-dose During Dosing for Part 2 | Vital signs included body temperature (oral), sitting blood pressure (after 5 minutes resting), respiration rate and pulse (bpm), | Up to Day 13 | 
| Percentage of Participants Who Have Severe Hypoglycemia at Least Once Post-dose During Dosing For Part 1 | Severe hypoglycemia was defined as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. | Up to Day 20 | 
| Percentage of Participants Who Have Severe Hypoglycemia at Least Once Post-dose During Dosing For Part 2 | Severe hypoglycemia was defined as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. | Up to Day 13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum Plasma Concentration for TAK-648 for Part 1 |  | Days 1 and 17 pre-dose and multiple time-points post-dose (Up to 72 hours) | 
| Cmax: Maximum Plasma Concentration for TAK-648 for Part 2 |  | Days 1 and 10 pre-dose and multiple time-points post-dose (Up to 72 hours) | 
| Tmax: Time to Reach Maximum Plasma Concentration (Tmax) for TAK-648 for Part 1 |  | Days 1 and 17 pre-dose and multiple time-points post-dose (Up to 72 hours) | 
| Tmax: Time to Reach Maximum Plasma Concentration (Tmax) for TAK-648 for Part 2 |  | Days 1 and 10 pre-dose and multiple time-points post-dose (Up to 72 hours) | 
| AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-648 for Part 1 |  | Days 1 and 17 pre-dose and multiple time-points post-dose (Up to 72 hours) | 
| AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-648 for Part 2 |  | Days 1 and 10 pre-dose and multiple time-points post-dose (Up to 72 hours) | 
| AUC∞: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for TAK-648 for Part 1 |  | Days 1 and 17 pre-dose and multiple time-points post-dose (Up to 72 hours) | 
| AUC∞: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for TAK-648 for Part 2 |  | Days 1 and 10 pre-dose and multiple time-points post-dose (Up to 72 hours) | 
| AUCtau: Area Under the Plasma Concentration-time Curve From Time 0 Over the Dosing Interval for TAK-648 for Part 1 |  | Days 1 and 17 pre-dose and multiple time-points post-dose (Up to 72 hours) | 
| AUCtau: Area Under the Plasma Concentration-time Curve From Time 0 Over the Dosing Interval for TAK-648 for Part 2 |  | Days 1 and 10 pre-dose and multiple time-points post-dose (Up to 72 hours) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Drug therapy