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A Phase 3 Long-term Study of TAK-536 in Pediatric Patients 6 to Less Than 16 Years With Hypertension

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ClinicalTrials.gov Identifier: NCT02791438
Recruitment Status : Completed
First Posted : June 6, 2016
Results First Posted : December 23, 2019
Last Update Posted : February 7, 2020
Sponsor:
Information provided by (Responsible Party):
Takeda

Brief Summary:
The purpose of this study is to evaluate the safety of administration of azilsartan in pediatric patients aged 6 to less than 16 years with hypertension.

Condition or disease Intervention/treatment Phase
Pediatric Hypertension Drug: Azilsartan Drug: Placebo Phase 3

Detailed Description:

The drug being tested in this study is called azilsartan. Azilsartan is being tested to treat pediatric participants with hypertension.

The study enrolled 27 participants. Following a 2-week Placebo Run-in Period, participants were assigned to one of the two treatment groups based on weight:

  • Azilsartan 2.5 - 20 mg (Participants < 50 kg)
  • Azilsartan 5 - 40 mg (Participants ≥ 50 kg)

Participants weighing < 50 kg were asked to take an initial dose azilsartan 2.5 mg (titrated as needed to the highest dose of 20 mg) and participants weighing ≥ 50 kg were asked to take an initial dose of 5 mg azilsartan (titrated as needed to the highest dose of 40 mg).

This multi-centre trial was conducted in Japan. The overall time to participate in this study is 56 weeks. The study consisted of a Run-in Period (Week -2 to Week 0), a 52-week Treatment Period, and a 2-week Follow-up Period (up to Week 54). Participants made multiple visits to the clinic and a final visit 2 weeks after the last dose of study drug for follow-up assessment.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3, Open-label, Multicenter, Long-term Study to Evaluate the Safety, Efficacy and Pharmacokinetics of TAK-536 in Pediatric Patients 6 to Less Than 16 Years of Age With Hypertension
Actual Study Start Date : August 18, 2016
Actual Primary Completion Date : June 4, 2019
Actual Study Completion Date : June 4, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Azilsartan 2.5 - 20 mg (Weight < 50 kg)
Following a 2-week placebo run-in period, azilsartan 2.5 mg (titrated as needed to the highest dose of 20 mg) was administered orally once daily before or after breakfast, for the participants weighing < 50 kg.
Drug: Azilsartan
Azilsartan granules and tablets
Other Names:
  • TAK-536
  • AZILVA ®

Drug: Placebo
Placebo-matching azilsartan granules and tablets

Experimental: Azilsartan 5 - 40 mg (Weight ≥ 50 kg)
Following a 2-week placebo run-in period, azilsartan 5 mg (titrated as needed to the highest dose of 40 mg) was administered orally once daily before or after breakfast, for the participants weighing ≥ 50 kg.
Drug: Azilsartan
Azilsartan granules and tablets
Other Names:
  • TAK-536
  • AZILVA ®

Drug: Placebo
Placebo-matching azilsartan granules and tablets




Primary Outcome Measures :
  1. Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to Week 54 ]
    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 (TEAE) is defined as an adverse event with an onset that occurs or worsens after receiving study drug.

  2. Number of Participants With TEAEs Related to Anthropometric Measurement (Weight, Height and Body Mass Index (BMI)) [ Time Frame: Up to Week 54 ]
    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 (TEAE) is defined as an adverse event with an onset that occurs or worsens after receiving study drug.

  3. Number Of Participants With Markedly Abnormal Values of Laboratory Parameters [ Time Frame: Up to Week 54 ]
    The laboratory values outside the range (Blood Urea Nitrogen (BUN) (mg/dL) >30, Creatinine (mg/dL) >2.0, eGFR (mL/min/1.73m^2) <30, Creatine Kinase (U/L) >5×ULN) are considered markedly abnormal.

  4. Number Of Participants With TEAEs Related To Resting 12-Lead Electrocardiogram (ECG) [ Time Frame: Up to Week 54 ]
    A standard 12-lead ECG was performed while the participant was at rest. Any abnormal ECG findings determined by the investigator to be clinically significant were reported as adverse events.

  5. Number Of Participants With TEAEs Related To Vital Signs (Hypotension) [ Time Frame: Up to Week 54 ]
    A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. Vital signs included office standing blood pressure, office sitting pulse rate, office standing pulse rate, and home sitting blood pressure. Any abnormal vital signs findings determined by the investigator to be clinically significant were reported as adverse events.


Secondary Outcome Measures :
  1. Change From Baseline in Office Trough Sitting Systolic Blood Pressure [ Time Frame: Baseline (Day 0), Weeks 2, 4, 8, 12,16, 20, 24, 32, 40, 52, Week 54 (Follow-up), End-of-treatment (EOT) 1 (Up to Week 12), EOT 2 (Up to Week 52) ]
    Office trough sitting blood pressure is defined as the blood pressure collected in the office while the participant was sitting at a time point immediately before the next dosing, when the blood drug concentration is assumed to be the lowest. A negative change from Baseline indicates improvement. The data of change from baseline to the End of Treatment Period I (EOT 1) and the End of the Treatment Period 2 (EOT 2) were calculated with the evaluable data within the acceptable time points (EOT1 was for up to Week 12 and EOT2 was for up to Week 52) with the largest Study Day was used. Meanwhile, change from baseline to Week 12 and 52 were calculated with the data of Week 12 and 52 respectively.

  2. Change From Baseline in Office Trough Sitting Diastolic Blood Pressure [ Time Frame: Baseline (Day 0), Weeks 2, 4, 8, 12,16, 20, 24, 32, 40, 52, Week 54 (Follow-up), EOT 1 (Up to Week 12), EOT 2 (Up to Week 52) ]
    Office trough sitting blood pressure is defined as the blood pressure collected in the office while the participant was sitting at a time point immediately before the next dosing, when the blood drug concentration is assumed to be the lowest. A negative change from Baseline indicates improvement. The data of change from baseline to the End of Treatment Period I (EOT 1) and the End of the Treatment Period 2 (EOT 2) were calculated with the evaluable data within the acceptable time points (EOT1 was for up to Week 12 and EOT2 was for up to Week 52) with the largest Study Day was used. Meanwhile, change from baseline to Week 12 and 52 were calculated with the data of Week 12 and 52 respectively.

  3. Percentage Of Participants Who Achieve The Target Blood Pressure [ Time Frame: Weeks 2, 4, 8, 12,16, 20, 24, 32, 40, 52, Week 54 (Follow-up), EOT 1 (Up to Week 12), EOT 2 (Up to Week 52) ]
    Target blood pressure is defined as the normal reference range for blood pressure by age according to Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular Diseases by the Japanese Circulation Society JCS 2012 (JCS 2012). The data of change from baseline to EOT 1 and EOT 2 were calculated with the evaluable data within the acceptable time points (EOT1 was for up to Week 12 and EOT2 was for up to Week 52) with the largest Study Day was used. Meanwhile, change from baseline to Week 12 and 52 were calculated with the data of Week 12 and 52 respectively. Target blood pressure were described on Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular Diseases by the Japanese Circulation Society JCS 2012 (JCS 2012) (see Links on Registration Section).

  4. Observed Plasma Concentration for Azilsartan [ Time Frame: Predose and 2 hours postdose Weeks 2, 4, 8, 12 and 2 hours postdose Week 16 ]
    Reported data were observed plasma concentration for Azilsartan for each arm. Dosage of the study drug after Week 2 (postdose) is different among participants.

  5. Observed Plasma Concentration for Azilsartan Metabolites (M-I) [ Time Frame: Predose and 2 hours postdose Weeks 2, 4, 8, 12 and 2 hours postdose Week 16 ]
    Reported data were observed plasma concentration for Azilsartan Metabolites (M-I) for each arm. Dosage of the study drug after Week 2 (postdose) is different among participants.

  6. Observed Plasma Concentration for Azilsartan Metabolites (M-II) [ Time Frame: Predose and 2 hours postdose Weeks 2, 4, 8, 12 and 2 hours postdose Week 16 ]
    Reported data were observed plasma concentration for Azilsartan Metabolites (M-II) for each arm. Dosage of the study drug after Week 2 (postdose) is different among participants.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Years to 15 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. In the opinion of the investigator or subinvestigator, the participant's parent or the participant's legal guardian is capable of understanding and complying with protocol requirements.
  2. The participant's parent or the participant's 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 Japanese participant who has a diagnosis of hypertension. A participant is eligible if he/she is deemed hypertensive according to the Reference Blood Pressure Values of Children by Gender and Age; office sitting diastolic or systolic blood pressure ≥ 95 percentile for essential hypertension without concomitant hypertensive organ damage, and ≥ 90 percentile for secondary hypertension with concomitant chronic kidney disease (CKD), diabetes mellitus, heart failure or any hypertensive organ damage.

    In addition, participants need to meet the following criteria:

    - If currently treated with any antihypertensive drugs at the start of the Run-in Period: Participant has a documented historical diagnosis of hypertension and an office sitting diastolic or systolic blood pressure meeting the above criteria at the end of the Run-in Period (Week 0).

    - If currently untreated with any antihypertensive drugs at the start of the Run-in Period: Participant who meets the above criteria on 3 separate time points including screening and the end of the Run-in Period (Week 0). In addition, participant with essential hypertension without concomitant hypertensive organ damage still maintains hypertension with non-pharmacotherapy including foods or exercises for at least 3 months within 1 year prior to the start of screening.

  4. The participant is male or female and aged 6 to less than 16 years at the time of informed consent.
  5. The participant weighs at least 20 kg at screening.
  6. The participant is capable of taking the tablets or granules supplied as the study drug.
  7. A participant who has undergone kidney transplantation is eligible if he/she underwent the transplantation at least 6 months earlier at screening, and the graft has been functionally stable (estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m^2) for at least 6 months with evidence (eg, Doppler echography, computed tomography (CT) scan or magnetic resonance imaging (MRI) excluding grafted kidney arterial stenosis. A participant on immunosuppressive therapy with a stable dose at least 30 days prior to screening is eligible.
  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 through 1 month after the completion of the study, and proves negative in the pregnancy test at screening.
  9. The participants judged by the investigator or subinvestigator that he/she can discontinue the therapy with renin-angiotensin-system (RAS) inhibitors for 2 weeks (acceptable range, 1 to 4 weeks) in safe prior to the Treatment Period.

Exclusion Criteria:

  1. The participant has received any investigational compound within 30 days prior to screening or is participating in another clinical study or a post-marketing clinical study.

    Note: This does not apply to participants participating in observational studies without interventional or invasive therapy.

  2. The participant previously received therapy with azilsartan. Note: This does not apply to participants participating in single dose pharmacokinetic studies of TAK-536.
  3. The participant has poorly controlled hypertension indicated by an office sitting systolic blood pressure higher by at least 15 mmHg and/or an office sitting diastolic blood pressure higher by at least 10 mmHg than the 99 percentiles of the Reference Blood Pressure Values of Children by Gender and Age.
  4. The participant has a diagnosis of malignant or accelerated hypertension.
  5. The participant was noncompliant (< 70% or > 130%) with the study drug during the Run-in Period.
  6. The participant has severe renal dysfunction (eGFR < 30 mL/min/1.73 m^2), is receiving dialysis, has a renovascular disease affecting one or both kidneys, severe nephrotic syndrome not in remission, or a serum albumin level < 2.5 g/dL.
  7. The participant has a history of, or the signs/symptoms of serious cardiovascular, hepatobiliary, gastrointestinal, endocrine (eg, hyperthyroidism, Cushing's syndrome), hematological, immunological, urinogenital, psychiatric disease, cancer, or any other disease that adversely affects participant's health, or, in the opinion of the investigator or subinvestigator, potentially confounds the study results.
  8. The participant has hemodynamically significant left ventricular outflow obstruction due to aortic stenosis or aortic valvular disease, or is scheduled to undergo a medical procedure affecting blood pressure during the study (eg, correction of arterial anomaly).
  9. The participant has a history of or concurrent clinically significant abnormality of 12-lead electrocardiogram (ECG) that, in the opinion of the investigator or subinvestigator, disqualifies the participant for participation in the study.
  10. The participant has poorly controlled diabetes mellitus indicated by hemoglobin A1c (HbA1c) > 9.0% at screening.
  11. The participant has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥ 2.5 × the upper limit of normal (ULN), or a total bilirubin level ≥ 1.5 × ULN at screening, severely impaired hepatic function, any active liver disease (regardless of the cause), or jaundice.
  12. The participant has hyperkalemia exceeding ULN at screening.
  13. The participant has a history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection at screening.
  14. The participant has a known hypersensitivity or allergy to any angiotensin II receptor blocker (ARBs).
  15. The participant needs treatment with any of the excluded medication.
  16. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after the completion of this study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02791438


Locations
Layout table for location information
Japan
Nagakute, Aichi, Japan
Nagoya, Aichi, Japan
Obu, Aichi, Japan
Sapporo, Hokkaido, Japan
Kobe, Hyogo, Japan
Kanazawa, Ishikawa, Japan
Yokohama, Kanagawa, Japan
Nankoku, Kochi, Japan
Sendai, Miyagi, Japan
Shimajiri-gun, Okinawa, Japan
Izumi, Osaka, Japan
Osaka Sayama, Osaka, Japan
Otsu, Shiga, Japan
Shimotsuke, Tochigi, Japan
Fuchu, Tokyo, Japan
Nerima-ku, Tokyo, Japan
Ota-ku, Tokyo, Japan
Setagaya-ku, Tokyo, Japan
Shinjuku-ku, Tokyo, Japan
Akita, Japan
Chiba, Japan
Fukuoka, Japan
Fukushima, Japan
Hiroshima, Japan
Niigata, Japan
Okayama, Japan
Osaka, Japan
Saitama, Japan
Shizuoka, Japan
Wakayama, Japan
Sponsors and Collaborators
Takeda
  Study Documents (Full-Text)

Documents provided by Takeda:
Study Protocol  [PDF] April 12, 2017
Statistical Analysis Plan  [PDF] October 5, 2018

Additional Information:
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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02791438    
Other Study ID Numbers: TAK-536/OCT-101
U1111-1182-4241 ( Other Identifier: UTN )
JapicCTI-163260 ( Registry Identifier: JapicCTI )
First Posted: June 6, 2016    Key Record Dates
Results First Posted: December 23, 2019
Last Update Posted: February 7, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hypertension
Vascular Diseases
Cardiovascular Diseases
Azilsartan medoxomil
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action