A Phase 2 Dose-finding Study of TAK-272 in Participants With Type 2 Diabetes Mellitus and Microalbuminuria
Condition: Type 2 Diabetes Mellitus and Microalbuminuria
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: TAK-272; TAK-272 Placebo; Candesartan cilexetil; Candesartan cilexetil Placebo
Intervention description: TAK-272 tablets; TAK-272 placebo-matching tablets; Candesartan cilexetil tablets; Candesartan cilexetil placebo-matching tablets
Intervention MeSH terms: Candesartan; Candesartan cilexetil; Imarikiren hydrochloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 415.0
Sex: All
Minimum age: 20 Years
Maximum age: 74 Years
Healthy volunteers: No
Keywords: Pharmacological therapy

Summary:

      The purpose of this study is to test the efficacy and safety on daily oral doses of TAK-272 5
      mg, 20 mg, 40 mg and 80 mg in patients with type 2 diabetes mellitus and microalbuminuria by
      randomized, double-blind, placebo-controlled, parallel-group comparison in order to determine
      the clinical dose of TAK-272.
    

Eligibility criteria:

        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.