Chronic Kidney Disease, Hypertension
Conditions
Keywords
Hypertension, pediatric, Hypertension with or without chronic kidney disease
Brief summary
The purpose of this study is to assess the long-term safety and tolerability profile of valsartan and valsartan-based treatments in children with hypertension, with or without chronic kidney disease.
Interventions
DRUGValsartan
week 1: 40/80/160 week 2-78: 80/160/320mg, oral, by mouth, once daily
DRUGamlodipine
added to valsartan after week 8 if the MSSBP and/or MSDBP was higher than 95th percentile for age, gender and height under the maintenance valsartan dose
DRUGHydrochlorothiazide
added to valsartan after week 8 if the MSSBP and/or MSDBP was higher than 95th percentile for age, gender and height under the maintenance valsartan dose
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Documented diagnosis of hypertension * able to swallow a tablet * body weight ≥18 kg and ≤160 kg at baseline * MSSBP must be ≥ 95th percentile and ≤25% above the 95th percentile for age, gender and height.
Exclusion criteria
* Any clinically significant physical abnormalities or clinically relevant abnormal laboratory values (other than those relating to renal function) obtained at the screening visit. Including the following: 1. AST/SGOT or ALT/SGPT \>3 times the upper limit of the reference range. Patients known to have active or chronic hepatitis were excluded. 2. Total bilirubin \>2 times the upper limit of the reference range 3. Estimated GFR \<30 mL/min/1.73m² (calculated using Modified Schwartz Formula) 4. WBC count \<3000/mm³ 5. Platelet count \<100,000/mm³ 6. Serum potassium \>5.3 mmol/L 7. Hemoglobin \<8 g/dL * Uncontrolled diabetes mellitus * Unilateral, bilateral and graft renal artery stenosis * Current diagnosis of heart failure (New York Heart Association Class II-IV) * Patients taking any of the following concomitant medications following screening: Renin-angiotensin receptor(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, Antidepressant drugs in the class of Monoamine oxidase (MAO) inhibitors (e.g. phenelzine), Chronic use of stimulant therapy for Attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD) -Patients who demonstrate clinically significant ECG abnormalities such as concurrent potentially life threatening arrhythmia or symptomatic arrhythmia and patients with second or third degree heart block without a pacemaker. * Coarctation of the aorta with a gradient of \>=30 mmHg * Previous solid organ transplantation except renal transplantation. * Patients known to be positive for the human immunodeficiency virus (HIV) * Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of the study drug * Known or suspected contraindications to the study drug, including severe hepatic impairment, biliary cirrhosis, cholestasis and history of allergy to ARBs and/or angiotensin-converting enzymes (ACE) and/or Direct Renin Inhibitors (DRIs) * History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. * History or evidence of drug or alcohol abuse within the last 12 months. * Female patients of child-bearing potential, defined as all female patients physiologically capable of becoming pregnant, unless they are willing to use highly effective contraception during the study * Pregnant or nursing (lactating) female patients * Participation in any investigational drug study within 30 days prior to screening or within 5 elimination half-lives of the study drug prior to screening, or whichever is longer. * History of hypersensitivity to the study drug or to drugs of similar chemical classes. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at End Point (Week 78 or Last Observation Carried Forward (LOCF) | Baseline, End Point (Week 78 or Last observation carried forward (LOCF) | Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 2 to 3 minute intervals and the mean of three sSBP measurements were used as the average sitting office blood pressure for that visit. |
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (MsDBP) at End Point (Week 78 or Last Observation Carried Forward (LOCF) | Baseline, End Point (Week 78 or Last observation carried forward (LOCF) | Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 2 to 3 minute intervals and the mean of three sDBP measurements were used as the average sitting office blood pressure for that visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With MSSBP, MSDBP and (MSSBP and MSDBP Combined) < 95th Percentile for Gender, Age, and Height | End Point (Week 78 or Last observation carried forward (LOCF) | Number of Participants with Mean sitting systolic (MSSBP) and mean sitting diastolic(MSDBP) blood pressure and both combined less than the 95th percentile for age, gender and height |
| Percentage of Chronic Kidney Disease (CKD) Patients Who Had >=50% Reduction in Urine Albumin/Creatinine Ratio (UACR) From Baseline to End Point | Baseline, End Point (Week 78 or Last observation carried forward (LOCF) | Percentage of Patients with CKD who had Urine albumin creatinine reduction \>/= 50% from baseline |
| Percentage of Chronic Kidney Disease (CKD) Patients Who Had Estimated Glomerular Filtration Rate (eGFR) Decrease > 25 % From Baselinefrom Baseline to End Point | Baseline, End Point (Week 78 or Last observation carried forward (LOCF) | Percentage of Patients with CKD who had eGFR decrease \> 25 % from Baseline |
Countries
Colombia, Finland, Germany, Guatemala, Philippines, Poland, Romania, Russia, Singapore, South Korea
Participant flow
Recruitment details
A 1 arm study of valsartan but with 2 groups for analyses. The valsartan +antihypertensive group includes the patients who received background antihypertensive medication or received antihypertensive medication including amlodipine or HCTZ during the study.
Pre-assignment details
These 2 groups were not randomized and considered to be 2 different populations since the patients in the valsartan+antihypertensive group had concomitant antihypertensive usage per individual patient's conditions at any time during treatment period.
Participants by arm
| Arm | Count |
|---|---|
| CKD Patients: Valsartan + Antihypertensive Group CKD Patients - Valsartan starting dose: ≥18 kg to \<35 kg is 40 mg, ≥35 kg to \<80 kg is 80 mg, ≥80 kg to ≤160 kg is 160 mg for 1 week then Valsartan maintenance dose: ≥18 kg to \<35 kg is 80 mg, ≥35 kg to \<80 kg is 160 mg, ≥80 kg to ≤160 kg is 320 mg after Week 8 if the Mean Sitting Systolic Blood Pressure (MSSBP) and/or Mean Sitting Diastolic Blood Pressure (MSDBP) was higher than 95th percentile for age, gender and height under the maintenance valsartan dose then add amlodipine and/or Hydrochlorothiazide (HCTZ). The valsartan +antihypertensive group includes patients who received background antihypertensive medication or received antihypertensive medication including amlodipine or HCTZ during the study. | 23 |
| CKD Patients: Valsartan Alone CKD Patients - Valsartan starting dose: ≥18 kg to \<35 kg is 40 mg, ≥35 kg to \<80 kg is 80 mg, ≥80 kg to ≤160 kg is 160 mg for 1 week then Valsartan maintenance dose: ≥18 kg to \<35 kg is 80 mg, ≥35 kg to \<80 kg is 160 mg, ≥80 kg to ≤160 kg is 320 mg. | 52 |
| Non-CKD Patients: Valsartan + Antihypertensive Group Non-CKD patients-Valsartan starting dose: ≥18 kg to \<35 kg is 40 mg, ≥35 kg to \<80 kg is 80 mg, ≥80 kg to ≤160 kg is 160 mg for 1 week then Valsartan maintenance dose: ≥18 kg to \<35 kg is 80 mg, ≥35 kg to \<80 kg is 160 mg, ≥80 kg to ≤160 kg is 320 mg after Week 8 if the Mean Sitting Systolic Blood Pressure (MSSBP) and/or Mean Sitting Diastolic Blood Pressure (MSDBP) was higher than 95th percentile for age, gender and height under the maintenance valsartan dose then add amlodipine and/or Hydrochlorothiazide (HCTZ). The valsartan +antihypertensive group includes patients who received background antihypertensive medication or received antihypertensive medication including amlodipine or HCTZ during the study. | 18 |
| Non-CKD Patients: Valsartan Alone Non-CKD patients-Valsartan starting dose: ≥18 kg to \<35 kg is 40 mg, ≥35 kg to \<80 kg is 80 mg, ≥80 kg to ≤160 kg is 160 mg for 1 week then Valsartan maintenance dose: ≥18 kg to \<35 kg is 80 mg, ≥35 kg to \<80 kg is 160 mg, ≥80 kg to ≤160 kg is 320 mg. | 57 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 0 | 1 | 0 | 0 |
| Overall Study | Administrative problems | 0 | 1 | 0 | 0 |
| Overall Study | Adverse Event | 6 | 9 | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 | 2 | 3 |
| Overall Study | Protocol deviation | 0 | 1 | 0 | 1 |
| Overall Study | Unsatisfactory therapeutic effect | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | CKD Patients: Valsartan + Antihypertensive Group | CKD Patients: Valsartan Alone | Non-CKD Patients: Valsartan + Antihypertensive Group | Non-CKD Patients: Valsartan Alone | Total |
|---|---|---|---|---|---|
| Age, Continuous | 12.90 years STANDARD_DEVIATION 3.35 | 12.30 years STANDARD_DEVIATION 3.2 | 13.79 years STANDARD_DEVIATION 2.64 | 14.37 years STANDARD_DEVIATION 2.83 | 13.36 years STANDARD_DEVIATION 3.13 |
| Age, Customized 12 - 17 years | 13 participants | 30 participants | 15 participants | 47 participants | 105 participants |
| Age, Customized 6 - 11 years | 10 participants | 22 participants | 3 participants | 10 participants | 45 participants |
| Sex: Female, Male Female | 12 Participants | 16 Participants | 3 Participants | 20 Participants | 51 Participants |
| Sex: Female, Male Male | 11 Participants | 36 Participants | 15 Participants | 37 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 34 / 41 | 68 / 109 | 18 / 23 | 36 / 52 | 16 / 18 | 32 / 57 |
| serious Total, serious adverse events | 8 / 41 | 7 / 109 | 7 / 23 | 4 / 52 | 1 / 18 | 3 / 57 |
Outcome results
Primary
Change From Baseline in Mean Sitting Diastolic Blood Pressure (MsDBP) at End Point (Week 78 or Last Observation Carried Forward (LOCF)
Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 2 to 3 minute intervals and the mean of three sDBP measurements were used as the average sitting office blood pressure for that visit.
Time frame: Baseline, End Point (Week 78 or Last observation carried forward (LOCF)
Population: The Full Analysis set (FAS) included all patients who entered the treatment period. ) This OM looked at the Valsartan + Antihypertensive and Valsartan alone for ALL patients and did not break up the analysis between CKD and non-CKD patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Valsartan + Antihypertensive Group | Change From Baseline in Mean Sitting Diastolic Blood Pressure (MsDBP) at End Point (Week 78 or Last Observation Carried Forward (LOCF) | -10.3 millimeter(s) of mercury (mmHg) | Standard Deviation 11.94 |
| Valsartan Alone | Change From Baseline in Mean Sitting Diastolic Blood Pressure (MsDBP) at End Point (Week 78 or Last Observation Carried Forward (LOCF) | -10.8 millimeter(s) of mercury (mmHg) | Standard Deviation 11.45 |
Primary
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at End Point (Week 78 or Last Observation Carried Forward (LOCF)
Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 2 to 3 minute intervals and the mean of three sSBP measurements were used as the average sitting office blood pressure for that visit.
Time frame: Baseline, End Point (Week 78 or Last observation carried forward (LOCF)
Population: The Full Analysis set (FAS) included all patients who entered the treatment period. ) This OM looked at the Valsartan + Antihypertensive and Valsartan alone for ALL patients and did not break up the analysis between CKD and non-CKD patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Valsartan + Antihypertensive Group | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at End Point (Week 78 or Last Observation Carried Forward (LOCF) | -13.3 millimeter(s) of mercury (mmHg) | Standard Deviation 13.69 |
| Valsartan Alone | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at End Point (Week 78 or Last Observation Carried Forward (LOCF) | -15.5 millimeter(s) of mercury (mmHg) | Standard Deviation 13.35 |
Secondary
Number of Participants With MSSBP, MSDBP and (MSSBP and MSDBP Combined) < 95th Percentile for Gender, Age, and Height
Number of Participants with Mean sitting systolic (MSSBP) and mean sitting diastolic(MSDBP) blood pressure and both combined less than the 95th percentile for age, gender and height
Time frame: End Point (Week 78 or Last observation carried forward (LOCF)
Population: The Full Analysis set (FAS) included all patients who entered the treatment period. This analysis includes only participants with baseline MSSBP or MSDBP or (MSSBP or MSDBP combined) ≥95th percentile for gender, age and height. n analyzed is displayed in left column. This OM did not break up the analysis between CKD and non-CKD patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Valsartan + Antihypertensive Group | Number of Participants With MSSBP, MSDBP and (MSSBP and MSDBP Combined) < 95th Percentile for Gender, Age, and Height | MSSBP (n=39, 105) | 23 Number of Participants |
| Valsartan + Antihypertensive Group | Number of Participants With MSSBP, MSDBP and (MSSBP and MSDBP Combined) < 95th Percentile for Gender, Age, and Height | MSDBP (n=28, 51) | 20 Number of Participants |
| Valsartan + Antihypertensive Group | Number of Participants With MSSBP, MSDBP and (MSSBP and MSDBP Combined) < 95th Percentile for Gender, Age, and Height | MSSBP and MSDBP combined (n=40, 105) | 22 Number of Participants |
| Valsartan Alone | Number of Participants With MSSBP, MSDBP and (MSSBP and MSDBP Combined) < 95th Percentile for Gender, Age, and Height | MSSBP (n=39, 105) | 90 Number of Participants |
| Valsartan Alone | Number of Participants With MSSBP, MSDBP and (MSSBP and MSDBP Combined) < 95th Percentile for Gender, Age, and Height | MSDBP (n=28, 51) | 47 Number of Participants |
| Valsartan Alone | Number of Participants With MSSBP, MSDBP and (MSSBP and MSDBP Combined) < 95th Percentile for Gender, Age, and Height | MSSBP and MSDBP combined (n=40, 105) | 88 Number of Participants |
Secondary
Percentage of Chronic Kidney Disease (CKD) Patients Who Had >=50% Reduction in Urine Albumin/Creatinine Ratio (UACR) From Baseline to End Point
Percentage of Patients with CKD who had Urine albumin creatinine reduction \>/= 50% from baseline
Time frame: Baseline, End Point (Week 78 or Last observation carried forward (LOCF)
Population: The Safety set (SAF) included all patients who received at least one dose of study medication that has Chronic Kidney Disease (CKD) only
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Valsartan + Antihypertensive Group | Percentage of Chronic Kidney Disease (CKD) Patients Who Had >=50% Reduction in Urine Albumin/Creatinine Ratio (UACR) From Baseline to End Point | 50.0 Percentage of patients | 404.08 |
| Valsartan Alone | Percentage of Chronic Kidney Disease (CKD) Patients Who Had >=50% Reduction in Urine Albumin/Creatinine Ratio (UACR) From Baseline to End Point | 41.9 Percentage of patients | 138.66 |
Secondary
Percentage of Chronic Kidney Disease (CKD) Patients Who Had Estimated Glomerular Filtration Rate (eGFR) Decrease > 25 % From Baselinefrom Baseline to End Point
Percentage of Patients with CKD who had eGFR decrease \> 25 % from Baseline
Time frame: Baseline, End Point (Week 78 or Last observation carried forward (LOCF)
Population: The Safety set (SAF) included all patients who received at least one dose of study medication.that has Chronic Kidney Disease (CKD)
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Valsartan + Antihypertensive Group | Percentage of Chronic Kidney Disease (CKD) Patients Who Had Estimated Glomerular Filtration Rate (eGFR) Decrease > 25 % From Baselinefrom Baseline to End Point | 30.4 Percentage of patients | 404.08 |
| Valsartan Alone | Percentage of Chronic Kidney Disease (CKD) Patients Who Had Estimated Glomerular Filtration Rate (eGFR) Decrease > 25 % From Baselinefrom Baseline to End Point | 27.5 Percentage of patients | 138.66 |