A Phase 2 Dose-finding Study of TAK-272 in Participants With Type 2 Diabetes Mellitus and Microalbuminuria

The drug being tested in this study is called TAK-272. This study evaluated the dose-response relationship of the efficacy and safety of TAK-272 in participants with type 2 diabetes mellitus and microalbuminuria.

The study enrolled 415 patients. Participants were randomly assigned to one of the 6 treatment groups:

• TAK-272 5 mg
• TAK-272 20 mg
• TAK-272 40 mg
• TAK-272 80 mg
• Candesartan cilexetil 8 mg
• Placebo (dummy inactive pill) for TAK-272 or Candesartan cilexetil - this was a tablet that looks like the study drug but had no active ingredient

All participants were administered tablets, orally at the same time each day for 12 weeks in double-blind manner. Participants were administered TAK-272 placebo 4 tablets and Candesartan cilexetil placebo one tablet for 4 weeks (Week -4 to 0) in placebo run-in period and follow-up period (Week 12-14).

This multi-center trial was conducted in Japan. The overall time to participate in this study is 22 weeks including 2 weeks of follow-up assessment period after last dose of study drug. Participants made multiple visits to the clinic during these periods.

Inclusion criteria

• In the opinion of the investigator or the sub-investigator, the participant is capable of understanding and complying with protocol requirements.
• The participant signs and dates a written, informed consent form prior to the initiation of any study procedures.
• The participant is either male or female and aged 20 to less than 75 years at signing of informed consent.
• The participant is an early-stage nephropathy (Stage 2) patient with type 2 diabetes mellitus.
• Inpatient/outpatient: outpatient
• The participant is a patient with type 2 diabetes mellitus on a certain diet therapy and/or exercise therapy (if any).
• The participant has stability controlled blood glucose, blood pressure and lipid, and does not need any change in the drug and the dose of any antihypertensive, antidiabetic and antidyslipidemia or antihyperlipidemic drugs throughout the study period as judged by the investigator or the sub-investigator.
• The participant has urine albumin/creatinine ratio (UACR) of the first morning urine (the first urine immediately after rising prior to activities in standing position in the morning) is ≥30 to <300 mg/gCr on at least two of three measurements at the start of the pre-treatment period (Week -8), at Week -4 or Week -2.
• The participant has estimated glomerular filtration rate according to creatinine (eGFRcreat) ≥45 mL/min/1.73 m^2 at Week -4.
• 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 study period and for 12 weeks after the completion of the study.
• A female participant of childbearing potential who is sexually active with a nonsterilized male partner who agrees to routinely use adequate contraception from signing of informed consent until 1 month after the completion of the study.

Exclusion criteria

<Exclusion Criteria in whole pre-treatment period>

• The participant received TAK-272 in a previous clinical study.
• The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (e.g., spouse, parent, child, sibling) or may consent to participate under duress.
• The participant has a history of hypersensitivity or allergies to TAK-272, candesartan cilexetil and other renin-angiotensin system (RAS) inhibitors (angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor blocker [ARBs] or direct renin inhibitor [DRIs]).
• The participant needs to take the prohibited medications during the study period.
• The participant has hyperkalemia (e.g., serum potassium ≥ 5.0 mEq/L at the start of the pretreatment period (Week -8) and Week -4 or requiring regular use of a potassium adsorbent) or onset of hyperkalemia within 2 years prior to starting the pre-treatment period.
• The participant has at least class II hypertension (e.g., sitting systolic blood pressure [SBP] ≥160 mmHg or sitting diastolic blood pressure [DBP] ≥100 mmHg in the pre-treatment period) or malignant hypertension.
• The participant has a renal disease other than type 2 diabetic nephropathy (e.g., patients with renal sclerosis, acute or chronic glomerular nephritis, or polycystic kidney).
• The participant has bilateral or unilateral renal artery stenosis.
• The participant requires regular use of nonsteroidal anti-inflammatory drugs (excluding low-dose aspirin and locally-acting agents such as topical drugs) (e.g., rheumatoid arthritis patients, osteoarthritis patients, and low back pain patients).
• The participant has a history of any of the cardiovascular diseases listed below within 2 years prior to starting the pre-treatment period:

• Cardiac diseases: myocardial infarction, coronary arterial revascularization
• Cerebrovascular diseases: cerebral infarction (excluding lacunar infarction), cerebral hemorrhage, transient ischemic attack
• The participant has any of the cardiovascular diseases listed below:

• Cardiac diseases: angina pectoris, arrhythmia, and congested heart failure that requires medication
• Vascular diseases: arteriosclerosis obliterans with symptoms (e.g., intermittent claudication)
• The participant has a clinically significant hepatic disorder (e.g., either of alanine aminotransferase [ALT] or aspartate aminotransferase [AST] is ≥ 2.5 times the upper limit of normal at the start of the pre-treatment period (Week -8) or at Week -4).
• The participant has a complication of malignant tumor.
• If female, the participant is pregnant, lactating, or is intending to become pregnant before, during or within 1 month after participating in this study; or intending to donate ova during such time period.
• If male, the participant intends to donate sperm during the course of this study or for 12 weeks thereafter.
• The participant is judged by the investigator or the sub-investigator as being ineligible for any other reason.

<Exclusion Criteria at the start of the pre-treatment period (Week -8)>

• The participant has participated in another clinical study or post-marketing study within 30 days prior to starting the pre-treatment period.
• The participant has received the study medication within 12 weeks prior to starting the pre-treatment period.
• The participant has a history of drug abuse (defined as the use of an illicit drug) or history of alcohol abuse within 2 years prior to starting the pre-treatment period.
• The participant has changed the renin angiotensin system (RAS) inhibitor (angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor blocker [ARB] or direct renin inhibitors [DRI]) or its dose and regimen within 12 weeks prior to starting the pre-treatment period.
• The participant is treated with any RAS inhibitor (ACE inhibitor, ARB or DRI) at signing of informed consent, and whose UACR is <30 mg/gCr at the start of the pre-treatment period (Week -8).

<Exclusion Criteria at Week -4>

• The participant has hemoglobin A1c (HbA1c) (National Glycohemoglobin Standardization Program [NGSP]) ≥9.0% at Week -4.
• The participant has change in HbA1c (NGSP) from the start of the pre-treatment period (Week -8) to Week -4 by ≥10.0%* compared to the higher value of them.

*Second decimal place to be rounded off <Exclusion Criteria at the end of the Pre-treatment period (Week 0)>

• The participant's sitting SBP and sitting DBP changed by ≥20 mmHg or ≥10 mmHg, respectively, at the end of the pre-treatment period (Week 0) compared to Week -2.
• The participant's sitting SBP is <130 mmHg at the end of the pre-treatment period (Week 0).
• The participant's study drug compliance rate* during the pre-treatment period is <80.0%.

• Compliance rate (%)=(Prescribed amount-Retrieved amount)/ {(Completion date of study drug for the pre-treatment period-Starting date of study drug for the pre-treatment period+1)×5}×100, second decimal place to be rounded off.