Clinical trial NCT02451150: A Phase 3 Pharmacokinetic Study of TAK-536 (Azilsartan) in Pediatric Patients 6 to Less Than 16 Years With Hypertension
Official title: An Open-label, Phase 3, Multicenter Study to Evaluate the Pharmacokinetics Following a Single Oral Dose of TAK-536 in Pediatric Patients 6 to Less Than 16 Years of Age With Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pediatric Hypertension
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2015-05-21
Enrollment: 6
Sex: ALL
Minimum age (years): 6
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the pharmacokinetics and safety of a single dose of TAK-536 (azilsartan) in pediatric patients aged 6 to less than 16 years with hypertension.

Detailed description: The drug being tested in this study is called azilsartan. Azilsartan was being tested to evaluate how it is processed by the body (pharmacokinetics). This study looked at lab results in pediatric participants who took azilsartan.

The study enrolled 6 patients. Participants were assigned to study medication dose by body weight as follows:

* Body Weight \<50 kg: azilsartan 5 mg
* Body Weight ≥50 kg: azilsartan 10 mg

All participants took a single oral dose of azilsartan on Day 1 of the study.

This multi-center trial was conducted in Japan. The overall time to participate in this study was 17 days. Participants made multiple visits to the clinic, and were contacted by telephone on Day 6 and Day 15 after last dose of study drug for a follow-up assessment.

Eligibility criteria: Inclusion Criteria:

1. In the opinion of the investigator or subinvestigator, the participant's parent or legal guardian is capable of understanding and complying with the study requirements.
2. The participant's parent or legal guardian is capable of signing and dating a written informed consent form on behalf of the participant prior to the initiation of any study procedures. Written informed assent is also obtained from the participant as much as possible.
3. The participant is diagnosed as hypertensive (if the participant is not receiving antihypertensive therapy, the diagnosis will be based on the Age- and Gender-Based Blood Pressure Reference for Children. Sitting diastolic blood pressure \[DBP\] or systolic blood pressure \[SBP\] is to be in at least the 95th percentile if essential hypertension is present without concurrent hypertensive organ damage and at least the 90th percentile if secondary hypertension is present with concurrent chronic renal disease, diabetes mellitus, heart failure, or hypertensive organ damage).
4. The participant is male or female and aged 6 to less than 16 years at the time of consent.
5. The participant weighs at least 20 kg during the observation period.
6. The participant is capable of taking the tablets provided as study drug.
7. Participants after renal transplants should meet the following conditions:

   At least 6 months has elapsed from the transplant to the start of the observation period with stable graft function for more than 6 months (and estimated glomerular filtration rate \[eGFR\] ≥ 30 mL/min/1.73 m\^2) and historical documentation (Doppler echo or computed tomography \[CT\], magnetic resonance imaging \[MRI\], etc.) which verify that arterial stenosis is not present in the transplanted kidney. For participants receiving immunosuppressive therapy, the dose should have been stable at least 30 days before study drug administration.
8. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent to within 1 month after the completion of the study and have a negative pregnancy test result during the observation period.

Exclusion Criteria:

1. The participant received an investigational drug within 30 days prior to the start of the observation period or is currently participating in another clinical study or post-marketing study.

   Note: This does not apply to participants participating in observational studies without interventional or invasive therapy.
2. The participant is determined to have poorly controlled hypertension (as a general guideline, when clinical sitting blood pressure is measured, SBP is to be at least 15 mmHg higher and/or DBP is to be at least 10 mmHg higher than the 99th percentile in the Age- and Gender-Based Blood Pressure Reference for Children).
3. The participant is diagnosed with malignant hypertension or rapidly progressive hypertension.
4. The participant has severe renal dysfunction (eGFR \<30 mL/min/1.73 m\^2), dialysis treatment, renovascular disease affecting both kidneys or a solitary kidney, severe nephrotic syndrome not in remission, or serum albumin \<2.5 g/dL.
5. The participant has a history or clinical manifestations of serious cardiovascular, hepatobiliary, gastrointestinal, endocrine (e.g., hyperthyroidism and Cushing's syndrome), hematologic, immunologic, genitourinary, or psychiatric disease; cancer; and/or any conditions that would interfere with the health status of the participant through study participation or would jeopardize study integrity in the opinion of the investigator or subinvestigator.
6. The participant has left ventricular outflow tract obstruction affecting hemodynamics due to aortic stenosis, aortic valve disease, or the like or is scheduled to have surgery affecting blood pressure (e.g., repair of arterial anomalies) during the study.
7. The participant underwent a surgical procedure with major bleeding within 6 months before the start of the observation period.
8. The participant has past or present clinically significant abnormalities on the 12-lead electrocardiogram and is ineligible for the study in the opinion of the investigator or subinvestigator.
9. The participant has poorly controlled diabetes mellitus (hemoglobin A1c \[HbA1c\] \>9.0% during the observation period)
10. The participant has any of either alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] at least 2.5 times the upper limit of standard value or total bilirubin at least 1.5 times the upper limit of standard value, severe hepatic dysfunction, active liver disease (regardless of etiology), and jaundice during the observation period.
11. The participant has hyperkalemia exceeding the upper limit of standard value during the observation period.
12. The participant has a history of hepatitis B, hepatitis C, or human immunodeficiency virus infection at the start of the observation period.
13. The participant has a history of hypersensitivity or allergy to angiotensin II receptor blockers (ARBs).
14. The participant requires treatment with prohibited concomitant drug(s).
15. Peripheral venous blood collection from the participant is difficult.
16. The participant had a clinically significant acute disease within 30 days from the day before study drug administration.
17. If female, the participant is pregnant or lactating, or intending to become pregnant before giving consent, during the study period, or within 1 month after study completion.

Primary outcomes:
measure: AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of TAK-536 (Azilsartan)
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: Cmax: Maximum Observed Plasma Concentration of TAK-536 (Azilsartan)
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of TAK-536 (Azilsartan)
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of TAK-536 (Azilsartan)
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: T1/2: Terminal Elimination Half-Life of TAK-536 (Azilsartan)
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of TAK-536 (Azilsartan) Metabolite M-I
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: Cmax: Maximum Observed Plasma Concentration of TAK-536 (Azilsartan) Metabolite M-I
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: AUC(0-inf) Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of TAK-536 (Azilsartan) Metabolite M-I
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of TAK-536 (Azilsartan) Metabolite M-I
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: T1/2: Terminal Elimination Half-Life of TAK-536 (Azilsartan) Metabolite M-I
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of TAK-536 (Azilsartan) Metabolite M-II
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: Cmax: Maximum Observed Plasma Concentration of TAK-536 (Azilsartan) Metabolite M-II
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: AUC(0-inf) Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of TAK-536 (Azilsartan) Metabolite M-II
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of TAK-536 (Azilsartan) Metabolite M-II
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: T1/2: Terminal Elimination Half-Life of TAK-536 (Azilsartan) Metabolite M-II
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose
measure: Cumulative Urinary Excretion Ratio of TAK-536 (Azilsartan)
timeFrame: Day 1 from 0 to 24 hours post-dose
measure: Cumulative Urinary Excretion Ratio of TAK-536 (Azilsartan) Metabolite M-I
timeFrame: Day 1 from 0 to 24 hours post-dose
measure: Cumulative Urinary Excretion Ratio of TAK-536 (Azilsartan) Metabolite M-II
timeFrame: Day 1 from 0 to 24 hours post-dose
measure: Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Up to 15 Days
measure: Percentage of Participants With Remarkable Findings of Clinical Concern From Baseline in Vital Signs
timeFrame: Baseline and Day 2
measure: Percentage of Participants With Remarkable Findings of Clinical Concern From Baseline in Body Weight
timeFrame: Baseline and Day 2
measure: Percentage of Participants With Remarkable Findings of Clinical Concern From Baseline in Resting 12-Lead Electrocardiogram (ECG)
timeFrame: Baseline and Day 2
measure: Percentage of Participants With Remarkable Findings of Clinical Concern From Baseline in Laboratory Test Results
timeFrame: Baseline and Day 2
Secondary outcomes:
Other outcomes:
Locations:
city: Fuchu
country: Japan
city: Oofu
country: Japan
city: Setagaya-ku
country: Japan
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_CHAIR
References:
citation: Enya K, Saji BT, Kato T, Okamoto H, Koumura E. Pharmacokinetics of a Single Dose of Azilsartan in Pediatric Patients: A Phase 3, Open-Label, Multicenter Study. Adv Ther. 2018 Aug;35(8):1181-1190. doi: 10.1007/s12325-018-0754-5. Epub 2018 Jul 19.