A Comparative Single-Dose Pharmacokinetic (PK) and Safety Study of Azilsartan Medoxomil in Children With Hypertension and in Healthy Adults

Phase 1

Terminated

• Conditions: Hypertension
• Interventions: Drug: Azilsartan medoxomil (TAK-491)

• Registration Number: NCT01078376
• Lead Sponsor: Takeda

Brief Summary

The purpose of this study was to assess the pharmacokinetics (PK) and safety of a single dose of azilsartan medoxomil in children with hypertension, and comparative PK in healthy adults.

Detailed Description

Within the past 10 years, the incidence of high blood pressure (hypertension) in children and adolescents has increased all over the world. This increase is connected in part to a growing number of people who are overweight and do not eat right or exercise enough. In younger children though, high blood pressure is a common consequence of underlying diseases, such as renal diseases.

This study looked at a blood pressure medicine called TAK-491 (azilsartan medoxomil) to see how it works in children who have hypertension. Azilsartan medoxomil is a prodrug that converts into TAK-536 (azilsartan), a blood pressure lowering medicine that had not been tested in children.

To be eligible to take part in this study, children with a diagnosis of hypertension (primary or secondary) must have been between the ages of 1 year and 16 years old (up to their 17th birthday). Each child was given one dose of azilsartan medoxomil, followed by a number of blood tests and assessments within 24 hours after taking azilsartan medoxomil to see how the medication is working. Adults who do not have hypertension also took part in this study to provide comparison.

This study took place in 9 sites in the UK and USA. A total of 20 children with hypertension and 9 adults without hypertension participated in this study.

This study lasted about 43 days. This included a 28 day screening period, a 2 day treatment phase and a follow up period. Each participant taking part in this study may have been requested to remain in a hospital for one overnight stay during the course of the study. Each participant was contacted by telephone 6 days and 15 days after taking azilsartan medoxomil.

Takeda has decided to close Cohort 3 (participants between 1 and 6 years of age with hypertension) enrollment early and end this study with the agreement of both the US Food and Drug Administration (FDA) and the Pediatric Committee (PDCO) at the European Medicines Agency. Requests to the FDA and PDCO were submitted to close the study without completion of enrollment in Cohort 3 due to difficulty enrolling this particular patient population. Takeda proposed an alternative option to collect PK data in this age subset by utilizing PK modeling to determine the appropriate doses in children 1-5 years of age in lieu of completing Cohort 3. The FDA and PDCO agreed with this approach.

Study Timeline

• Study First Submitted: 2010-02-26
• Study First Submitted QC: 2010-03-01
• Study First Posted: 2010-03-02
• Study Start: 2010-05
• Primary Completion: 2013-07
• Study Completion: 2013-09
• Status Verified: 2014-06
• Results First Submitted: 2014-06-26
• Results First Submitted QC: 2014-06-26
• Last Update Submitted: 2014-06-26
• Results First Posted: 2014-07-25
• Last Update Posted: 2014-07-25

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 29

Inclusion Criteria

For Pediatric Participants:

Must have a diagnosis of hypertension (SBP and/or DBP ≥95th percentile for age/gender/height).

• For Cohorts 1 and 2 only, is within the weight range of 20 kg (44 pounds) to 100 kg (220 pounds), inclusive, at Screening.
• For Cohort 3 only, weighs at least 8.0 kg (17.6 pounds) at Screening.
• Participants greater than or equal to 6 years of age must have the ability to swallow a tablet of the size 6.0 millimeter diameter and 3.5 millimeter thickness.
• Has no known history of hepatitis B, hepatitis C, and human immunodeficiency virus.
• For Cohort 3 only, may be renal transplant patient if all other inclusion and none of the exclusion criteria are met, along with additional criteria.
• Must have been at a constant weight, or expected weight gain for that particular age, for 30 days with no change to the dose of their diuretic drugs.

For Healthy Adult Participants:

• Weighs at least 50 kilograms (110 pounds) and has a screening body mass index between 18 and 32 kilograms/m2, inclusive.
• Is in good health as determined by the physician
• Has a negative test result for hepatitis B surface antigen and antibody to hepatitis C virus, and has no known history of human immunodeficiency virus.
• Must have a negative urine test result for selected substances of abuse .
• Has a diastolic blood pressure between 60 and 90 mm Hg, inclusive, and a systolic blood pressure between 100 and 140 mm Hg, inclusive.

For All Participants:

• Females of child bearing potential who are sexually active, as well as sexually active male participants, agree to routinely use adequate contraception from Screening until 30 days after receiving the last dose of study medication.
• Has clinical laboratory results within the reference range for the testing laboratory unless the results are deemed not clinically significant by the investigator.

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Exclusion Criteria

For Pediatric Participants:

• Is currently treated with more than 2 antihypertensive agents.
• Has sitting trough clinic systolic blood pressure greater than 15 mm Hg or diastolic blood pressure greater than 10 mm Hg above the 99th percentile for age, gender, and height at Check-in .
• Has renovascular disease affecting both kidneys or a solitary kidney, dialysis treatment, severe nephrotic syndrome and not in remission.
• For Cohort 1 and 2 only, a previous renal transplant.
• Has a creatinine clearance less than 30 mL/min/1.73 m2.

For all participants:

• Has previously received azilsartan or azilsartan medoxomil.

• Has a known hypersensitivity or allergy to any angiotensin type II receptor blockers or to any of the excipients in the azilsartan medoxomil formulation to be taken.

• Has a history or clinical manifestations of severe cardiovascular disease, psychiatric disease, and any conditions that would interfere with gastrointestinal absorption.

• Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease, cardiomyopathy, or uncorrected coarctation of the aorta.

• Has been diagnosed with malignant or accelerated hypertension.

• Has severe hepatic impairment.

• Has a serum albumin less than 2.5 g/dL.

• Has a glycosylated hemoglobin value greater than 8.5%.

• Has alanine aminotransferase, aspartate aminotransferase greater than 2 times the upper limit of normal, or total bilirubin greater than 1.5 times the upper limit of normal, active liver disease, or jaundice.

• Has hyperkalemia as defined by the laboratory normal reference range or any pertinent electrolyte disorders.

• Is participating in another investigational study or has taken an investigational drug within 30 days prior to Check-in .

• Has a history of drug abuse or a history of alcohol abuse within 1 year prior to study Check-in.

• Has a history of abdominal surgery or thoracic or nonperipheral vascular surgery within 6 months prior to study Check-in.

• Has a history of cancer, other than basal cell carcinoma or stage I squamous cell carcinoma of the skin that has not been in remission for at least 5 years prior to study Check-in.

• Has taken any cytotoxic drugs within 12 months prior to study Check-in .

• Has a history or presence of a clinically significant abnormal 12-lead electrocardiogram as determined by the investigator or sponsor/designee.

• Has poor peripheral venous access.

• Has any other condition or prior therapy that, in the opinion of the investigator, would make the participant unsuitable for the study.

• Has taken or requires the use of any medications, supplements, or food products within the stated time periods, including:

  • Pediatric participants taking angiotensin-converting enzyme inhibitors and other angiotensin II receptor blockers will be required to withhold these medications from the morning of Day -1 until the 24 hour pharmacokinetic sample is completed on Day 2.
  • Only pediatric participants will be allowed to take medications for primary renal or urologic conditions or hypertension as long as they have been on a stable dose of their medication for at least 30 days prior to Check-in (Day -1) and those medications are not potent cytochrome P-450 inhibitors or inducers.
  • Nutraceuticals including herbal or dietary preparations such as ginseng, kava kava, and ginkgo biloba.
  • Over-the-counter medications.
  • Vitamin supplements except for pediatric participants only.
  • Alcohol-containing products.
  • Products that contain caffeine or xanthine-related compounds.
  • Foods or beverages containing grapefruit juice or Seville-type oranges.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1: Healthy Adults (18 years to 45 years old)	Azilsartan medoxomil (TAK-491)	Azilsartan medoxomil 80 mg, tablets, orally, one day only
Cohort 2: Children (≥6 to <12 years old)	Azilsartan medoxomil (TAK-491)	Azilsartan medoxomil 20 mg to 60 mg (based on participant weight), tablets, orally, one day only
Cohort 1: Adolescents (≥12 to <17 years old)	Azilsartan medoxomil (TAK-491)	Azilsartan medoxomil 20 mg to 60 mg (based on participant weight), tablets, orally, one day only
Cohort 3: Children (≥1 to <6 years old)	Azilsartan medoxomil (TAK-491)	Azilsartan medoxomil 0.66 mg/kg participant body weight, granules, reconstituted orally, one day only

Primary Outcome Measures

Name	Time	Method
Terminal Elimination Half-life (T1/2) for TAK-536	Day 1	Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Apparent Oral Clearance (CL/F) for TAK-536	Day 1	CL/F is apparent clearance of the drug from the plasma, expressed in L/hr.
Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-tlqc]) for TAK-536 Metabolite M-II.	Day 1	AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC\[0-tlqc\]).
Total Amount of Drug Excreted in Urine From Time 0 to 24 Hours Postdose (Ae[0-t]) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536)	Day 1
Fraction of Unchanged Drug Excreted in Urine From 0 to 24 Hours Postdose (Fe%) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536)	Day 1	Fe=\[Ae(0-24)/dose\]×100 (molecular weight adjusted for metabolites.
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) for TAK-536	Day 1	Area under the plasma concentration-time curve from time 0 to infinity, calculated as AUC(0-inf)=AUC(0-tlqc) + Clast/λz.
Time to Reach Cmax (Tmax) for TAK-536	Day 1	Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax, as observed on Day 1.
Time to Reach Cmax (Tmax) for TAK-536 Metabolite M-II	Day 1	Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax, as observed on Day 1.
Total Amount of Drug Excreted in Urine From Time 0 to 24 Hours Postdose (Ae[0-t]) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II)	Day 1
Renal Clearance (CLr) From 0 to 24 Hours Postdose (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II)	Day 1	Renal clearance, calculated as CLr=Ae(0-24)/AUC(0-24).
Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-tlqc]) for TAK-536	Day 1	AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC\[0-tlqc\]).
Fraction of Unchanged Drug Excreted in Urine From 0 to 24 Hours Postdose (Fe%) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II)	Day 1	Fe=\[Ae(0-24)/dose\]×100 (molecular weight adjusted for metabolites.
Renal Clearance (CLr) From 0 to 24 Hours Postdose (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536)	Day 1	Renal clearance, calculated as CLr=Ae(0-24)/AUC(0-24).
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) for TAK-536 Metabolite M-II	Day 1	Area under the plasma concentration-time curve from time 0 to infinity, calculated as AUC(0-inf)=AUC(0-tlqc) + Clast/λz.
Maximum Observed Plasma Concentration (Cmax) for TAK-536	Day 1	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Maximum Observed Plasma Concentration (Cmax) for TAK-536 Metabolite M-II	Day 1	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Terminal Elimination Half-life (T1/2) for TAK-536 Metabolite M-II	Day 1	Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.