Pediatric Hypertension With or Without CKD
Conditions
Keywords
Hypertension; CKD; Pediatric
Brief summary
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.
Interventions
DRUGVAL489
Valsartan 3mg/kg oral solution
DRUGVAL489 matching placebo
Valsartan 3 mg/kg oral solution
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
1 Years to 5 Years
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Systolic Blood Pressure (MSBP) at Week 6 Endpoint | Baseline, 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) at Baseline and Week 6 endpoint in Period 1 Double Blind Phase |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Diastolic Blood Pressure (MDBP) at Week 6 | Baseline, 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 |
| Patients Achieving <90th Percentile for Age, Gender and Height at Week 6 Endpoint in Both MSBP and MDBP | 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) Week 6 |
| CKD Patients Achieving Urine Albumin Creatinine Ratio Percentage Reduction (UACR) >=25% at Week 6 | Week 6 weeks | 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. |
Countries
Belgium, Brazil, France, Germany, Guatemala, Hungary, Italy, Lithuania, Poland
Participant flow
Recruitment details
Overall, 156 patients were screened, of which 127 patients were enrolled in the double blind period 1 of the study. A total of 120 patients (94.5%) completed Period 1 and entered Open Label Period 2.
Pre-assignment details
Parallel= Period 1 (Double Blind phase) Single= Period 2 (Open Label phase)
Participants by arm
| Arm | Count |
|---|---|
| CKD Patients Valsartan 0.25 mg/kg CKD patients: Valsartan oral solution 0.25mg/kg once daily + matching placebo of valsartan oral solution 4 mg/kg once daily for 6 weeks (period 1) | 32 |
| CKD Patients Valsartan 4 mg/kg CKD patients: 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) | 31 |
| Non-CKD Patients Valsartan 0.25 mg/kg Non-CKD patients: Valsartan oral solution 0.25mg/kg once daily + matching placebo of valsartan oral solution 4 mg/kg once daily for 6 weeks (period 1) | 33 |
| Non-CKD Patients Valsartan 4 mg/kg Non-CKD patients: 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) | 31 |
| Total | 127 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Period 1 Double Blind | Adverse Event | 2 | 0 | 0 | 2 | 0 |
| Period 1 Double Blind | Withdrawal by Subject | 1 | 1 | 1 | 0 | 0 |
| Period 2 Open Label | Adverse Event | 0 | 0 | 0 | 0 | 3 |
| Period 2 Open Label | Withdrawal by Subject | 0 | 0 | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | CKD Patients Valsartan 0.25 mg/kg | CKD Patients Valsartan 4 mg/kg | Non-CKD Patients Valsartan 0.25 mg/kg | Non-CKD Patients Valsartan 4 mg/kg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 2.99 years STANDARD_DEVIATION 1.47 | 2.72 years STANDARD_DEVIATION 1.33 | 3.7 years STANDARD_DEVIATION 1.51 | 3.62 years STANDARD_DEVIATION 1.36 | 3.26 years STANDARD_DEVIATION 1.466 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 16 Participants | 14 Participants | 15 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 15 Participants | 19 Participants | 16 Participants | 70 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 12 Participants | 8 Participants | 14 Participants | 13 Participants | 47 Participants |
| Sex: Female, Male Male | 20 Participants | 23 Participants | 19 Participants | 18 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 64 | 0 / 62 | 0 / 120 |
| other Total, other adverse events | 19 / 64 | 13 / 62 | 62 / 120 |
| serious Total, serious adverse events | 2 / 64 | 2 / 62 | 6 / 120 |
Outcome results
Primary
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
Time frame: Baseline, week 6
Population: Full analysis set (FAS) included all randomized patient except for 1 patient that guardian did not sign informed consent
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CKD Patients Valsartan 0.25 mg/kg | Change From Baseline in Mean Systolic Blood Pressure (MSBP) at Week 6 Endpoint | -1.2 mmHg | Standard Error 2.05 |
| CKD Patients Valsartan 4 mg/kg | Change From Baseline in Mean Systolic Blood Pressure (MSBP) at Week 6 Endpoint | -9.2 mmHg | Standard Error 2.05 |
| Non-CKD Patients Valsartan 0.25 mg/kg | Change From Baseline in Mean Systolic Blood Pressure (MSBP) at Week 6 Endpoint | -6.9 mmHg | Standard Error 1.44 |
| Non-CKD Patients Valsartan 4 mg/kg | Change From Baseline in Mean Systolic Blood Pressure (MSBP) at Week 6 Endpoint | -7.8 mmHg | Standard Error 1.48 |
p-value: 0.009695% CI: [-13.86, -2.01]ANCOVA
p-value: 0.653195% CI: [-5.07, 3.2]ANCOVA
Secondary
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
Time frame: Baseline, Week 6
Population: Full analysis set (FAS) included all randomized patient except for 1 patient that guardian did not sign informed consent
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CKD Patients Valsartan 0.25 mg/kg | Change From Baseline in Mean Diastolic Blood Pressure (MDBP) at Week 6 | 1.3 mmHg | Standard Error 1.79 |
| CKD Patients Valsartan 4 mg/kg | Change From Baseline in Mean Diastolic Blood Pressure (MDBP) at Week 6 | -6.5 mmHg | Standard Error 1.79 |
| Non-CKD Patients Valsartan 0.25 mg/kg | Change From Baseline in Mean Diastolic Blood Pressure (MDBP) at Week 6 | -1.9 mmHg | Standard Error 1.26 |
| Non-CKD Patients Valsartan 4 mg/kg | Change From Baseline in Mean Diastolic Blood Pressure (MDBP) at Week 6 | -7.2 mmHg | Standard Error 1.3 |
p-value: 0.00395% CI: [-12.94, -2.78]ANCOVA
p-value: 0.004295% CI: [-8.98, -1.77]ANCOVA
Secondary
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.
Time frame: Week 6 weeks
Population: Full analysis set (FAS) included all randomized patient except for 1 patient that guardian did not sign informed consent - CKD patients only The number of patients with an UACR at baseline and week 6 endpoint (included in the analysis).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CKD Patients Valsartan 0.25 mg/kg | CKD Patients Achieving Urine Albumin Creatinine Ratio Percentage Reduction (UACR) >=25% at Week 6 | 12 participants |
| CKD Patients Valsartan 4 mg/kg | CKD Patients Achieving Urine Albumin Creatinine Ratio Percentage Reduction (UACR) >=25% at Week 6 | 9 participants |
p-value: 0.262495% CI: [0.16, 1.64]ANCOVA
Secondary
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
Time frame: Week 6
Population: Full analysis set (FAS) included all randomized patient except for 1 patient that guardian did not sign informed consent
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CKD Patients Valsartan 0.25 mg/kg | Patients Achieving <90th Percentile for Age, Gender and Height at Week 6 Endpoint in Both MSBP and MDBP | 6 participants |
| CKD Patients Valsartan 4 mg/kg | Patients Achieving <90th Percentile for Age, Gender and Height at Week 6 Endpoint in Both MSBP and MDBP | 9 participants |
| Non-CKD Patients Valsartan 0.25 mg/kg | Patients Achieving <90th Percentile for Age, Gender and Height at Week 6 Endpoint in Both MSBP and MDBP | 7 participants |
| Non-CKD Patients Valsartan 4 mg/kg | Patients Achieving <90th Percentile for Age, Gender and Height at Week 6 Endpoint in Both MSBP and MDBP | 8 participants |
p-value: 0.41195% CI: [0.49, 5.8]ANCOVA
p-value: 0.544395% CI: [0.44, 4.79]ANCOVA