Efficacy, Safety and Tolerability of Multiple Doses of Valsartan in Children With Hypertension With or Without CKD

Study Overview
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Brief Summary
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To assess efficacy, safety and tolerability of valsartan when comparing two doses of valsartan in reducing and controlling blood pressure in children with hypertension with or without CKD.

Official Title
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A 6 Week, Randomized, Multicenter, Double-blind, Double-dummy Study to Evaluate the Dose Response of Valsartan on Blood Pressure Reduction in Children 1-5 Years Old With Hypertension, With or Without Chronic Kidney Disease, Followed by a 20 Week Open-label Titration Phase

Conditions
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Pediatric Hypertension With or Without CKD

Intervention / Treatment
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* Drug: VAL489
* Drug: VAL489 matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients eligible for inclusion in this study have to fulfill all of the following criteria: Have the ability to provide written informed consent; Have at baseline , a documented diagnosis of hypertension (as defined in the National High Blood Pressure Education Program 2004); MSBP (mean of 3 measurements) must be ≥95th percentile, and ≤25% above the 95th percentile, for age, gender and height, at baseline; CKD patients must be defined as any of the following criteria: Kidney damage for ≥3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifested by one or more of the following features: Abnormalities in the composition of urine, Abnormalities in imaging tests, Abnormalities on kidney biopsy, Estimated eGFR <60 mL/min/1.73m2 for ≥3 months, with or without the other signs of kidney damage described above; Able to swallow the valsartan solution; Body weight must be ≥8 kg and ≤40 kg at baseline; Must be able to safely washout from other antihypertensive therapy (if applicable) Exclusion criteria AST/SGOT or ALT/SGPT >3 times the upper limit of the reference range; Estimated Glomerular Filtration Rate [eGFR] <30 mL/min/1.73m² (calculated using Modified Schwartz Formula); Serum potassium >5.3 mmol/L; Uncontrolled diabetes mellitus, as defined by the investigator; Unilateral, bilateral and graft renal artery stenosis; Current diagnosis of heart failure (NYHA Class II-IV); Patients taking any of the following concomitant medications following screening: RAAS blockers other than study drug, Lithium, Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels; Non-steroidal anti-inflammatory drugs (NSAIDS), including selective COX-2 inhibitors, acetylsalicylic acid >3g/day, and non-selective NSAIDs (paracetamol/acetaminophen is permitted); Antidepressant drugs in the class of MAO inhibitors (e.g. phenelzine); Chronic use of stimulant therapy for ADD/ADHD; patients who have coarctation of the aorta with a gradient of ≥30 mmHg; Previous solid organ transplantation except renal transplantation. Renal transplant must have occurred at least 1 year prior to enrollment; Patient must be on stable doses of immunosuppressive therapy and deemed clinically stable by the investigator; Patients known to be positive for the human immunodeficiency virus (HIV) Other protocol defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valsartan 0.25 mg/kg<br>Valsartan oral solution 0.25mg/kg once daily + matching placebo of valsartan oral solution 4 mg/kg once daily for 6 weeks (period 1) | Drug: VAL489<br>* Valsartan 3mg/kg oral solution<br>* Other names: Diovan;Drug: VAL489 matching placebo<br>* Valsartan 3 mg/kg oral solution<br>* Other names: Diovan;|
| Experimental: Valsartan 4 mg/kg<br>Valsartan oral solution 4 mg/kg once daily + matching placebo of valsartan oral solution 0.25 mg/kg once daily for 6 weeks (period 1) | Drug: VAL489<br>* Valsartan 3mg/kg oral solution<br>* Other names: Diovan;Drug: VAL489 matching placebo<br>* Valsartan 3 mg/kg oral solution<br>* Other names: Diovan;|
| Experimental: Valsartan 1 mg/kg<br>Open-label (Period 2) valsartan will be optionally titrated from 1 mg/kg to 2 mg/kg. Valsartan will continue to be optionally up titrated in 1 mg/kg increments every 4 weeks until maximum dose of 4 mg/kg is achieved. Duration 20 weeks. | Drug: VAL489<br>* Valsartan 3mg/kg oral solution<br>* Other names: Diovan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Systolic Blood Pressure (MSBP) at Week 6 Endpoint | Patient's blood pressure will be measured in the same position at every visit Systolic and diastolic blood pressures will be measured three times at 2-3 minute intervals. The arithmetic mean of these three blood pressure measurements will be used as the mean office blood pressure (MSBP and MDBP) at Baseline and Week 6 endpoint in Period 1 Double Blind Phase | Baseline, week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Diastolic Blood Pressure (MDBP) at Week 6 | Patient's blood pressure will be measured in the same position at every visit Systolic and diastolic blood pressures will be measured three times at 2-3 minute intervals. The arithmetic mean of these three blood pressure measurements will be used as the mean office blood pressure (MSBP and MDBP) Baseline and Week 6 endpoint in Period 1 Double Blind Phase | Baseline, Week 6 | 
| Patients Achieving <90th Percentile for Age, Gender and Height at Week 6 Endpoint in Both MSBP and MDBP | Patient's blood pressure will be measured in the same position at every visit Systolic and diastolic blood pressures will be measured three times at 2-3 minute intervals. The arithmetic mean of these three blood pressure measurements will be used as the mean office blood pressure (MSBP and MDBP) Week 6 | Week 6 | 
| CKD Patients Achieving Urine Albumin Creatinine Ratio Percentage Reduction (UACR) >=25% at Week 6 | UACR response is defined as percentage change from baseline in UACR≤ 25%. UACR [mg/mmol] = urine albumin [mg/L] / urine creatinine [mmol/L] UACR was collected for CKD patients only. The UACR value at a given visit for a patient was to be derived by the median of the three lab values collected for that visit Week 6. | Week 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension; CKD; Pediatric