Clinical trial NCT01617681
Conditions: Pediatric Hypertension With or Without CKD
Keywords: Hypertension; CKD; Pediatric
Sponsor: Novartis Pharmaceuticals
Start date: 2012-11-08; Completion date: 2017-01-24
Enrollment: 127 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: Valsartan oral solution 0.25mg/kg once daily + matching placebo of valsartan oral solution 4 mg/kg once daily for 6 weeks (period 1) arm 2: 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) arm 3: 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.
Interventions: intervention 1: VAL489 intervention 2: VAL489 matching placebo
Intervention descriptions: intervention 1: Valsartan 3mg/kg oral solution intervention 2: Valsartan 3 mg/kg oral solution

Protocol documents:
Prot_000.pdf: 
 
 
 
Clinical Development 
VAL489/Valsartan 
 
Clinical Trial Protocol CVAL489K2306 
 
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 
Authors: 
  
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
2011-005991-40 
Version number: 
v00 (original protocol) 
Development phase: 
III  
Release date: 
31-May-2012 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
 
 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 9 
Protocol synopsis ............................................................................................................... 10 
1 
Introduction ....................................................................................................................... 16 
1.1 
Background ............................................................................................................ 16 
1.2 
Purpose .................................................................................................................. 17 
2 
Study objectives ................................................................................................................. 17 
2.1 
Primary objectives ................................................................................................. 17 
2.2 
Secondary objectives ............................................................................................. 17 
2.3 
Exploratory objectives ........................................................................................... 18 
3 
Investigational plan ........................................................................................................... 18 
3.1 
Study design .......................................................................................................... 18 
3.2 
Rationale of study design ...................................................................................... 21 
3.3 
Rationale of dose/regimen, duration of treatment ................................................. 22 
3.4 
Rationale for choice of comparator ....................................................................... 22 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 22 
3.6 
Risks and benefits .................................................................................................. 22 
4 
Population .......................................................................................................................... 23 
4.1 
Inclusion criteria .................................................................................................... 24 
4.2 
Exclusion criteria ................................................................................................... 24 
5 
Treatment ........................................................................................................................... 26 
5.1 
Protocol requested treatment ................................................................................. 26 
5.1.1 
Investigational treatment ....................................................................... 26 
5.1.2 
Additional study treatment .................................................................... 27 
5.2 
Treatment arms ...................................................................................................... 27 
5.3 
Treatment assignment, randomization ................................................................... 27 
5.4 
Treatment blinding ................................................................................................ 28 
5.5 
Treating the patient ................................................................................................ 28 
5.5.1 
Patient numbering ................................................................................. 28 
5.5.2 
Dispensing the investigational treatment .............................................. 28 
5.5.3 
Handling of study treatment .................................................................. 29 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 29 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 30 
 


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5.5.6 
Rescue medication ................................................................................ 30 
5.5.7 
Concomitant treatment .......................................................................... 30 
5.5.8 
Prohibited treatment .............................................................................. 31 
5.5.9 
Discontinuation of study treatment and premature patient 
withdrawal ............................................................................................. 31 
5.5.10 
Emergency breaking of treatment assignment ...................................... 33 
5.5.11 
Study completion and post-study treatment .......................................... 34 
5.5.12 
Early study termination ......................................................................... 34 
6 
Visit schedule and assessments ......................................................................................... 34 
6.1 
Information to be collected on screening failures.................................................. 37 
6.2 
Patient demographics/other baseline characteristics ............................................. 37 
6.3 
Treatment exposure and compliance ..................................................................... 38 
6.4 
Efficacy .................................................................................................................. 38 
6.4.1 
Office blood pressure ............................................................................ 38 
6.4.2 
Appropriateness of efficacy assessments .............................................. 39 
6.5 
Safety ..................................................................................................................... 39 
6.5.1 
Physical examination ............................................................................ 39 
6.5.2 
Vital signs.............................................................................................. 39 
6.5.3 
Height, weight, and head circumference ............................................... 39 
6.5.4 
Laboratory evaluations .......................................................................... 40 
6.5.5 
Electrocardiogram (ECG) ..................................................................... 41 
6.5.6 
Pregnancy and assessments of fertility ................................................. 42 
6.5.7 
Appropriateness of safety measurements .............................................. 42 
6.6 
Other assessments .................................................................................................. 42 
6.6.1 
Resource utilization ............................................................................... 42 
6.6.2 
Health-related Quality of Life ............................................................... 42 
6.6.3 
Pharmacokinetics .................................................................................. 42 
6.6.4 
Pharmacogenetics/pharmacogenomics ................................................. 42 
6.6.5 
Other biomarkers ................................................................................... 42 
7 
Safety monitoring .............................................................................................................. 42 
7.1 
Adverse events ....................................................................................................... 42 
7.2 
Serious adverse event reporting ............................................................................. 44 
7.3 
Liver safety monitoring ......................................................................................... 45 
7.4 
Pregnancy reporting ............................................................................................... 45 
7.5 
Prospective suicidality assessment ........................................................................ 46 
8 
Data review and database management ............................................................................. 46 
8.1 
Site monitoring ...................................................................................................... 46 
 


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8.2 
Data collection ....................................................................................................... 46 
8.3 
Database management and quality control ............................................................ 46 
8.4 
Data Monitoring Committee .................................................................................. 47 
8.5 
Adjudication Committee ........................................................................................ 47 
9 
Data analysis ...................................................................................................................... 47 
9.1 
Analysis sets .......................................................................................................... 47 
9.2 
Patient demographics and other baseline characteristics ....................................... 48 
9.3 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) ........................................................................................................... 48 
9.4 
Analysis of the primary variable(s) ....................................................................... 48 
9.4.1 
Variable ................................................................................................. 48 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 49 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 49 
9.4.4 
Supportive analyses ............................................................................... 49 
9.5 
Analysis of secondary variables ............................................................................ 49 
9.5.1 
Key secondary variables ....................................................................... 49 
9.5.2 
Efficacy variables .................................................................................. 49 
9.5.3 
Safety variables ..................................................................................... 50 
9.5.4 
Resource utilization ............................................................................... 50 
9.5.5 
Health-related Quality of Life ............................................................... 50 
9.5.6 
Pharmacokinetics .................................................................................. 50 
9.5.7 
Pharmacogenetics/pharmacogenomics ................................................. 50 
9.5.8 
Biomarkers ............................................................................................ 50 
9.5.9 
PK/PD ................................................................................................... 50 
9.6 
Interim analyses ..................................................................................................... 50 
9.7 
Sample size calculation ......................................................................................... 50 
9.8 
Power for analysis of key secondary variables ...................................................... 51 
9.9 
Interim analyses ..................................................................................................... 51 
10 Ethical considerations ........................................................................................................ 51 
10.1 
Regulatory and ethical compliance ........................................................................ 51 
10.2 
Informed consent procedures ................................................................................. 51 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 51 
10.4 
Publication of study protocol and results............................................................... 52 
11 Protocol adherence ............................................................................................................ 52 
11.1 
Protocol Amendments ........................................................................................... 52 
12 References ......................................................................................................................... 53 
13 Appendix 1: Clinically notable laboratory values ............................................................. 55 
 


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Appendix 2: Pediatric blood pressure tables and growth charts ........................................ 56 
Special methods and scales ............................................................................................... 57 
BP Levels for girls by Age and Height Percentile (1-6 years old) .................................... 61 
BP Levels for boys by Age and Height Percentile (1-6 years old) ................................... 63 
 
List of tables 
Table 5-1 
Prohibited treatment .............................................................................. 31 
Table 6-1 
Assessment schedule ............................................................................. 36 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 19 
Figure 3-2  
Blood pressure cuff size ........................................................................ 21 
 
 


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List of abbreviations 
ACE 
Angiotensin Converting Enzyme 
ACEi 
Angiotensin Converting Enzyme Inhibitor 
ADD 
Attention Deficit Disorder 
ADHD 
Attention Deficit Hyperactivity Disorder 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase / Serum Glutamic Pyruvic Transaminase / SGPT 
ANOVA 
Analysis of Covariance 
ARB 
Angiotensin Receptor Blocker 
AST 
Aspartate Aminotransferase / Serum Glutamic Oxaloacetic Transaminase / 
 
SGOT 
B-hCG 
Beta human Chorionic Gonadotrophin 
BP 
Blood Pressure 
CHMP 
EMA Committee for Medicinal Products 
CKD 
Chronic Kidney Disease 
CO2 
Carbon Dioxide 
COX-2 
Cyclooxygenase-2 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
CPO 
Country Pharma Organization 
CSR 
Clinical Study Report 
CTH 
Clinical Trial Head 
DBP 
Diastolic Blood Pressure 
dL 
Deciliter 
DRI 
Direct Renin Inhibitor 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
GFR 
Glomerular Filtration Rate 
EMA 
European Medicines Agency 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
 


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HCTZ 
Hydrochlorothiazide 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IIS 
Integrated Information Sciences 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology  
kg 
Kilograms 
L 
Liter 
LFT 
Liver Function Test 
LOCF 
Last Observation Carried Forward 
MAO 
Mono Amine Oxidase 
MAX 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligrams 
min 
Minute  
mL 
Milliliter(s) 
mmHg 
Millimeters of Mercury 
mmol 
Millimole(s) 
MSBP 
Mean Systolic Blood Pressure 
MDBP 
Mean Diastolic Blood Pressure 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
NYHA 
New York Heart Association 
OFAS 
Open-label Full Analysis Set 
OSAF 
Open-label Safety  
PDCO 
Paediatric Committee 
PPS 
Per Protocol Set 
RAAS 
Renin Angiotensin Aldosterone System 
RAN 
Randomized set 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
 


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SBP 
Systolic Blood Pressure 
SGOT 
Serum Glutamic Oxaloacetic Transaminases / Alanine Aminotransferase / 
 
AST 
SGPT 
Serum Glutamic Pyruvic Transaminases / Aspartate Aminotransferase / ALT 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
UACR 
Urine Albumin Creatinine Ratio 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study drug used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.” 
Medication number 
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IVR system 
Patient number 
A number assigned to each patient who enrolls in the study. When 
combined with the center number, a unique identifier is created for each 
patient in the study. 
Period 
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time 
all study drug administration is discontinued and no further assessments 
are planned 
Randomization number 
A unique identifier assigned to each randomized patient, corresponding to 
a specific treatment arm assignment 
Stage 
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study drug was discontinued whichever is later 
Study drug/ treatment 
Any drug administered to the patient as part of the required study 
procedures; includes investigational drug and any control drugs 
Study drug discontinuation 
Point/time when patient permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature patient 
withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints 
 


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Protocol synopsis 
Protocol number 
CVAL489K2306 
Title 
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 
 
Brief title 
 
Dose response study of valsartan in children (1-5 years) with 
hypertension, with or without chronic kidney disease 
 
Sponsor and Clinical 
Phase 
Novartis  
 
Investigation type 
• 
VAL489 (Valsartan) 0.25 mg/kg or 4 mg/kg and matching placebo 
• 
VAL489 (Valsartan) 4 mg/kg 
Study type 
Interventional 
 
Purpose and rationale 
This study is part of the European Diovan® pediatric program and is 
conducted at the request of the EMA/Pediatric Committee (PDCO).  Two 
previous trials, using valsartan, have been conducted in hypertensive 
children between 6 months and 5 years with mixed results.  The EMA 
Committee for Medicinal Products for Human Use (CHMP) emphasized 
that a clinical need in this age group exists and that it would be relevant to 
conduct a new study (Section 3.2).  The purpose of this study is to 
establish a dose response for valsartan solution in children 1-5 years old 
with hypertension (mean systolic blood pressure ≥ 95th percentile), with or 
without chronic kidney disease (CKD). A sub-analysis will be performed to 
study the safety and tolerability of valsartan in children with CKD.  An 
open-label phase has been added to study the safety of valsartan.  The 
effects of valsartan on renal function and proteinuria will also be evaluated 
in CKD patients. 
 
Primary Objective(s) 
and Key Secondary 
Objective 
Primary: 
• 
To evaluate if a dose dependent reduction in mean systolic blood 
pressure (MSBP) exists when comparing two doses of valsartan 
solution (0.25 mg/kg and 4 mg/kg) over a 6 week period in children 1-
5 years old with hypertension (MSBP ≥ 95th percentile for age, gender 
and height), with or without CKD. 
Secondary:  
• 
To assess the efficacy of valsartan in reducing the mean diastolic 
blood pressure (MDBP) in children with hypertension. 
• 
To assess the efficacy of valsartan in controlling the MSBP and MDBP 
in children with hypertension.  The target mean BP is <90th percentile 
for age, gender and height.  
• 
To assess the safety and tolerability profile of valsartan in children with 
 


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hypertension, with or without CKD. 
• 
To assess the effect of valsartan on proteinuria and eGFR in a subset 
of children with hypertension and CKD 
 
Secondary Objectives 
 
Refer to above 
Study design 
This is a 6 week, randomized, multicenter, double-blind, double-dummy 
study to evaluate the dose response of valsartan solution 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 phase 
with an optional titration period. 
Period 1 is a 6 week double-blind dose- ranging period to ensure that the 
maximum antihypertensive effect of valsartan will be reached.  Period 2 is 
an open-label optional titration phase, where the safety of valsartan can be 
assessed including potential effects on proteinuria. 
Patients entering the study receiving background antihypertensive 
treatments may continue on these medications as long as they meet the 
eligibility criteria for MSBP (≥ 95th percentile).  The background therapy 
and dose should remain unchanged for the duration of the study. No 
patients will be permitted in the study with background RAAS blocker 
therapy (ARBs, ACEi, DRIs). 
This study consists of three periods: 
A Screening period of up to 28 days 
Period 1: A six-week randomized, double-blind, double-dummy dose-
ranging period consisting of 2 valsartan dose groups (0.25 mg/kg and 4 
mg/kg), and randomization will be 1:1. 
Period 2: A 20 week open-label titration phase where all patients will start 
with 1 mg/kg valsartan for four weeks then be optionally titrated every four 
weeks.  Patients may receive up to 4 mg/kg of valsartan. 
 
Population 
The study population will consist of a representative group of 130, male 
and female children age 1-5 years by visit 2. All patients must have a 
history of hypertension defined as a MSBP ≥ٛ 95th percentile to be eligible 
for randomization into this study. Approximately 50 sites are planned for 
this study. A total of 200 patients will be screened to randomize 130 
patients with an anticipated screen failure rate of 35%. A drop out rate of 
10% during the double-blind period is expected.  A total of 116 patients are 
expected to complete the double-blind period and enter the open-label 
period. Patients will be stratified based on CKD status (yes /no). 
At least 50% of patients enrolled will be CKD patients.  CKD patients must 
have a documented history of CKD. 
 
Inclusion criteria 
1. Written informed consent must be obtained before any 
assessment is performed.  Parent(s)/guardian(s) have to provide 
consent in writing (written informed consent) after the purpose and 
nature of the study has been clearly explained to them.  
 


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2. Male or female, 1 to 5 years at baseline (visit 2), with a 
documented diagnosis of hypertension (National High Blood 
Pressure Education Program 2004) 
3. CKD patients must be defined as any of the following criteria 
(Hogg et al 2003) (At least 50% of enrolled patients will be CKD-
patients): 
a. 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 
b. Estimated GFR <60 mL/min/1.73m2 (calculated by Modified 
Schwartz Formula) for ≥3 months, with or without the other 
signs of kidney damage described above. 
4. MSBP (mean of 3 measurements) must be ≥95th percentile, and 
≤25% above the 95th percentile, for age, gender and height, at 
baseline (visit 2) (Appendix 2), by office automatic blood pressure 
monitor and cuff, provided by the Sponsor. Confirmation of MSBP 
≥95th percentile must be made using the auscultatory blood 
pressure method. 
5. Able to swallow the valsartan solution 
6. Body weight must be ≥8 kg and ≤40 kg at baseline 
7. Must be able to safely washout prior ARB, ACEi and DRI therapy 
(if applicable) and other antihypertensive therapy (if applicable). 
Exclusion criteria 
1. Any clinically significant physical abnormality or clinically relevant 
abnormal laboratory values (other than those relating to renal 
function) obtained at the screening visit (Visit 1), including the 
following: 
a. AST/SGOT or ALT/SGPT >3 times the upper limit of the 
reference range. Patients known to have active or chronic 
hepatitis will be excluded. 
b. Total bilirubin >2 times the upper limit of the reference range 
c. Estimated Glomerular Filtration Rate [eGFR] <30 
mL/min/1.73m² (calculated using Modified Schwartz Formula)
d. WBC count <3000/mm³ 
e. Platelet count <100,000/mm³ 
f. 
Serum potassium >5.3 mmol/L 
g. Hemoglobin <9 g/dL 
2. Uncontrolled diabetes mellitus, as defined by the investigator 
3. Unilateral, bilateral and graft renal artery stenosis 
4. Current diagnosis of heart failure (NYHA Class II-IV) 
5. Patients taking any of the following concomitant medications 
following screening: 
a. RAAS blockers other than study drug 
b. Lithium 
 


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c. Potassium-sparing diuretics, potassium supplements, salt 
substitutes containing potassium and other substances that 
may increase potassium levels 
d. Non-steroidal anti-inflammatory drugs (NSAIDS), including 
selective COX-2 inhibitors, acetylsalicylic acid >3g/day, and 
non-selective NSAIDs (paracetamol/acetaminophen is 
permitted) 
e. Antidepressant drugs in the class of MAO inhibitors (e.g. 
phenelzine) 
f. 
Chronic use of stimulant therapy for ADD/ADHD 
6. Patients with ECG abnormalities associated with left ventricular 
hypertrophy are permitted to enroll. Patients who demonstrate 
clinically significant ECG abnormalities such as concurrent 
potentially life threatening arrhythmias or symptomatic 
arrhythmias are excluded, as are patients with second or third 
degree heart block without a pacemaker.  
7. Patients who have coarctation of the aorta with a gradient of ≥30 
mmHg 
8. 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. Stable doses of immunosuppressive therapy are 
defined as no change in frequency or total daily doses of 
immunosuppressive therapy for at least two months prior to 
screening.  
9. Patients known to be positive for the human immunodeficiency 
virus (HIV) 
10. Any clinically significant medical condition that would put the 
patient at risk of experiencing an adverse event associated with 
the expected pharmacodynamic effects of the study drug 
11. Any surgical or medical condition which might significantly alter 
the absorption, distribution, metabolism, or excretion of the study 
drug including, but not limited to, any of the following: 
a. History of major gastrointestinal tract surgery such as 
gastrectomy, gastroenterostomy, or bowel resection. 
b. Currently active or previously active inflammatory bowel 
disease during the 12 months prior to Visit 1. 
c. Patients known to have currently active gastritis, duodenal or 
gastric ulcers, or gastrointestinal/rectal bleeding during the 3 
months prior to Visit 1. 
d. Patients known to have active pancreatic injury, pancreatitis 
or evidence of impaired pancreatic function/injury as indicated 
by abnormal lipase or amylase. 
e. History of hepatic encephalopathy, a history of esophageal 
varices, or a history of porto-caval shunt. 
f. 
Current obstruction of the urinary tract or difficulty in voiding 
due to mechanical or inflammatory conditions which is likely 
to require intervention during the course of the study or is 
regarded as clinically meaningful by the investigator. 
12. Known or suspected contraindications to the study drug, including 
 


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severe hepatic impairment, biliary cirrhosis, cholestasis and 
history of allergy to other ARBs or to ACEIs and/or DRIs 
13. 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 
14. 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. 
15. History of hypersensitivity to the study drug or to drugs of similar 
chemical classes. 
16. Patients with rare hereditary problems of fructose intolerance, 
glucose-galactose malabsorption or sucrose-isomaltase 
insufficiency since the study drug solution contains sucrose.   
If there is any question that the patient will not reliably comply, they should 
not be entered in the study. 
 
Investigational and 
reference therapy 
Period 1: 
VAL489 (Valsartan) 0.25 mg/kg or 4 mg/kg 
VAL489 (Valsartan) 0.25 mg/kg or 4 mg/kg matching placebo 
Period 2: 
VAL489 (Valsartan) 1 mg/kg, optional titration 2 mg/kg, 3 mg/kg and 4 
mg/kg (max dose). 
Efficacy assessments 
Mean office blood pressure (mean of 3 measurements) 
 
 
Safety assessments 
Safety and tolerability assessments: 
Adverse event assessment 
Hematology laboratory assessments are performed at Visits 1, 2, 5, 8, 9, 
10 and 11.   
Hematology: Red blood cell count, hemoglobin, hematocrit, white blood 
cell count with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) and platelet count.  
Complete blood chemistry laboratory assessments are performed at Visits 
1, 2, 5, 8 and 11.  Abbreviated blood chemistry laboratory assessments 
are performed at Visits 9 and 10. 
Complete blood chemistry: urea, creatinine, non-fasting glucose, total 
bilirubin, AST/SGOT, ALT/SGPT, ALP, sodium, potassium, bicarbonate 
(total CO2), chloride, calcium, phosphorous, total protein, albumin, uric 
acid, cholesterol, triglycerides and eGFR 
Abbreviated blood chemistry: urea, creatinine, sodium, potassium, 
bicarbonate (total CO2) and eGFR 
Cystatin C is obtained only for CKD patients at Visits 2, 5, 10 and 11. 
Urine Albumin Creatinine Ratio (UACR) (in CKD patients only) at Visits 2, 
 


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5, 10, and 11. 
eGFR 
For all patients eGFR will be calculated using the Modified Schwartz 
formula 
For CKD patients the eGFR will also be calculated using the cystatin C 
value. 
Urine dipstick at Visits 1, 2, 5 and 11. 
Urinalysis done locally by dipstick: glucose, protein, bilirubin, ketones, 
leukocytes, blood 
Electrocardiogram (ECG) at Visits 1, 5 and 11. 
 
Other assessments 
Not applicable 
 
Data analysis 
The primary objective is to evaluate if a dose dependent reduction in 
MSBP exists when comparing two doses of valsartan solution (0.25 mg/kg 
and 4 mg/kg) over a 6 week period in children 1-5 years old with 
hypertension (MSBP ≥ 95th percentile for age, gender and height), with or 
without CKD. The null hypothesis is that there is no treatment difference in 
the reduction of MSBP between dose groups 0.25 mg/kg and 4 mg/kg.  
The alternative hypothesis is that there is a difference between dose 
groups 0.25 mg/kg and 4 mg/kg.  
The comparison will be tested at a two-sided significance level of 0.05.  
The change from baseline in MSBP at Week 6 endpoint during double-
blind period will be analyzed using an analysis of covariance model 
(ANCOVA) with treatment and CKD strata as factors and baseline MSBP 
as a covariate for the FAS population. 
The secondary variables are change from baseline in mean diastolic blood 
pressure (MDBP) at Week 6 endpoint and end of study; percentage of 
patients achieving MSBP < 90th percentile for age, gender and height at 
Week 6 endpoint and end of study; UACR response (defined as % change 
from baseline in UACR ≤ 25%) at Week 6 endpoint and end of study. 
The sample size of 116 completed patients is calculated based on the 
primary efficacy variable, change from baseline in mean systolic blood 
pressure, and a standard deviation of 11 mmHg (based on previous data) 
is used. The sample size is calculated to ensure at least 80% power to 
detect statistical significance for the comparison valsartan 0.25 mg/kg 
versus valsartan 4 mg/kg under the alternative hypothesis that the 
treatment difference is 6 mmHg at a two-sided significance level of 0.05. 
Assuming 10% drop-out rate, the total targeted sample size to be 
randomized is 130 patients. 
 
Key words 
Randomized, multicenter, double-blind, double-dummy study,  evaluate, 
dose response of valsartan on blood pressure reduction in children 1-5 
years old (males/females) with hypertension, with or without chronic 
kidney disease  
 
 


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1 
Introduction 
1.1 
Background  
Hypertension in children is defined as a persistent systolic blood pressure (SBP) or diastolic 
blood pressure (DBP) ≥ 95th percentile for age, gender, and height (National High Blood 
Pressure Education Program 2004, Lurbe 2009). Obesity, insulin resistance, inactivity, ethnic 
predisposition to essential hypertension, and family history of hypertension are the common 
causes of hypertension in older children and adolescents. However, in children younger than 
10 years of age, secondary causes of hypertension, including renal and reno-vascular disease, 
are more commonly observed (National High Blood Pressure Education Program 2004). 
Current epidemiologic data indicate that the prevalence of persistent hypertension in school-
age children or above is approximately 1-2 percent, and in younger age children (< 6 years 
old) is extremely low (0.017%) (Morgenstern 1994, Reid and Chantler 2002). Most children 
found to be hypertensive in the < 6 year old age group present with severe, symptomatic 
hypertension due to underlying diseases (secondary hypertension). These patients often 
require pharmacological therapy to control blood pressure (Arar et al, 1994, Sadowski and 
Falkner 1996, Reid and Chantler 2002). There is a paucity of data regarding the efficacy and 
pharmacokinetics of antihypertensive medications in children. Antihypertensive medications 
have been extensively studied in adults, and most of them have been used commonly in 
hypertensive children, though few of them had been studied systematically in children until 
recently (Swindford and Portman 2004, Sinaiko 1994). As in adults, and based on a survey 
from North American pediatric nephrologists, ACE inhibitors and ARBs are commonly 
prescribed antihypertensive agents for children with hypertension and children with chronic 
kidney disease (Woroniecki and Flynn 2005). 
Valsartan (Diovan®) is an angiotensin II receptor blocker (ARB), approved in adults for the 
treatment of hypertension. Valsartan 80-160 mg has been approved in the United States for 
use in adults since 1996.  In the United States and other countries, valsartan 320 mg has been 
available for use in adults since 2001. Valsartan has been marketed in Europe in adults in 
doses of 80-160 mg since 1996 and in the highest dose of 320 mg since 2006. Valsartan has 
been approved for the treatment of hypertension in children 6-17 years of age in the United 
States since 2007 and in children 6-18 years of age in Europe since 2010.  
Valsartan exerts its antihypertensive effect mainly by blocking the vasoconstriction, 
aldosterone secretion and sodium retention mediated by angiotensin II via selectively 
blocking the binding of angiotensin II to the AT1 receptor in tissues such as vascular smooth 
muscle and the adrenal gland. Valsartan has been shown to be effective in reducing both 
systolic and diastolic blood pressure in adults when used as monotherapy or in combination 
with other antihypertensive agents and is relatively well-tolerated. 
The efficacy and safety of valsartan in children has been evaluated in four well controlled, 
prospective, multicenter studies where more than 700 hypertensive children aged 1-17 years 
old have been enrolled worldwide (Flynn 2008; Schaefer 2011; Schaefer 2011; Wells 2011; 
and Novartis, unpublished data). A wide dose range of valsartan (0.10 mg/kg to 4.94 mg/kg) 
has been evaluated in these studies. In studies in older children, valsartan was found to be 
efficacious, provided dose dependent reductions in blood pressure, and demonstrated 
 


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comparable efficacy to enalapril. Valsartan was well tolerated with a safety profile in older 
children not different from that observed in adults.  
The efficacy of valsartan in younger children could not be consistently established. 
Inconsistent results were observed in two placebo-controlled trials: Study CVAL489A2307 in 
patients aged 1-5 years old and Study CVAL489K2303 in patients aged 6 months -5 years old. 
In Study CVAL489A2307, valsartan was efficacious compared to placebo during the placebo 
withdrawal period; however, a dose response was not demonstrated. In the other study, Study 
CVAL489K2303, although a trend in dose response was observed; no   significant treatment 
difference compared to placebo was demonstrated. 
Additional detailed summaries of these valsartan pediatric studies can be found in the 
investigator’s brochure. The current study is designed to provide additional clinical data to 
determine the benefit/risk profile in children 1-5 years old.   
1.2 
Purpose  
This study is part of the European Diovan® pediatric program and is conducted at the request 
of the EMA/Pediatric Committee (PDCO).  Two previous trials, using valsartan, have been 
conducted in hypertensive children between 6 months and 5 years with mixed results.  The 
EMA Committee for Medicinal Products for Human Use (CHMP) emphasized that a clinical 
need in this age group exists and that it would be relevant to conduct a new study (Section 
3.2).  The purpose of this study is to establish a dose response for valsartan solution in 
children 1-5 years old with hypertension (mean systolic blood pressure ≥ 95th percentile), with 
or without chronic kidney disease (CKD). A sub-analysis will be performed to study the 
safety and tolerability of valsartan in children with CKD.  An open-label phase has been 
added to study the safety of valsartan.  The effects of valsartan on renal function and 
proteinuria will also be evaluated in CKD patients. 
2 
Study objectives 
2.1 
Primary objectives 
To evaluate if a dose dependent reduction in mean systolic blood pressure (MSBP) exists 
when comparing two doses of valsartan solution (0.25 mg/kg and 4 mg/kg) over a 6 week 
period in children 1-5 years old with hypertension (MSBP ≥ 95th percentile for age, gender 
and height), with or without CKD. 
2.2 
Secondary objectives 
• To assess the efficacy of valsartan in reducing the mean diastolic blood pressure (MDBP) 
in children with hypertension. 
• To assess the efficacy of valsartan in controlling the MSBP and MDBP in children with 
hypertension.  The target mean BP is <90th percentile for age, gender and height.  
• To assess the safety and tolerability profile of valsartan in children with hypertension, 
with or without CKD. 
• To assess the effect of valsartan on proteinuria and eGFR in a subset of children with 
hypertension and CKD. 
 


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2.3 
Exploratory objectives  
None 
3 
Investigational plan 
3.1 
Study design 
This is a 6 week, randomized, multicenter, double-blind, double-dummy study to evaluate the 
dose response of valsartan solution 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 phase 
with an optional titration period.  Figure 3-1 shows the overall study design. 
Period 1 is a 6 week double-blind dose ranging period to ensure that the maximum 
antihypertensive effect of valsartan will be reached.  Period 2 is an open-label optional 
titration phase, where the safety of valsartan can be assessed including potential effects on 
proteinuria. 
Patients entering the study receiving background antihypertensive treatments may continue on 
these medications as long as they meet the eligibility criteria for MSBP (≥ 95th percentile). 
The background therapy and dose should remain unchanged for the duration of the study. No 
patients will be permitted in the study with background RAAS blocker therapy (ARBs, ACEi, 
DRIs). 
This study consists of three periods: 
• A Screening period of up to 28 days 
• Period 1: A six-week randomized, double-blind, double-dummy dose-ranging period 
consisting of 2 valsartan dose groups (0.25 mg/kg and 4 mg/kg), and randomization will 
be 1:1. 
• Period 2: A 20 week open-label titration phase where all patients will start with 1 mg/kg 
valsartan for four weeks then be optionally titrated every four weeks.  Patients may 
receive up to 4 mg/kg of valsartan. 
 


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Figure 3-1 
Study design 
 
Screening 
A screening visit (Visit 1) will be performed 1 to 28 days before enrollment to test eligibility 
for study participation. A parent/guardian of the patient will sign the Informed Consent Form 
after the purpose and nature of the study has been clearly explained to them.  
Washout period 
Under the supervision of the study investigator, a wash-out period of 28 days will be included 
for eligible patients on prior treatments that inhibit the renin angiotensin aldosterone system 
(RAAS blockers), which include angiotensin receptor blockers (ARB), angiotensin converting 
enzyme inhibitors (ACEi) and direct renin inhibitors (DRI). During the wash-out period 
patients should come to the clinic approximately once a week for safety blood pressure 
measurements. If MSBP rises more than 20% above the 95th percentile for age, gender and 
height during wash-out, or if the investigator deems hypertensive treatment necessary, then 
the patient may commence with the study drug treatment earlier, once all eligibility criteria 
have been met.  
Patients currently taking antihypertensive medications other than RAAS blockers, who have a 
MSBP <95th percentile for age, gender and height at screening, can be tapered off these 
medications according to investigator instruction and manufacturer’s labeling, in order to 
meet entry criteria. Patients who are not on RAAS inhibitor therapy can enter the treatment 
phase of the trial (Visit 2) once the patient has achieved a MSBP ≥ 95th percentile for age, 
gender and height, screening laboratory results have been received and reviewed, and all other 
inclusion criteria have been met. Patients currently taking non-RAAS blockers, who have a 
MSBP ≥ 95th percentile for age, gender and height, can continue taking these antihypertensive 
medications throughout the trial provided their dose remains unchanged. 
Dose ranging period (Period 1): 
 


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Patients should be seen in the clinic on a weekly basis during screening, to determine if they 
meet the blood pressure criteria (MSBP ≥ 95th percentile) for randomization. Qualified 
patients will be randomized and all Visit 2 procedures completed.  If the patient’s blood 
pressure does not meet criteria, the patient can return to the research center once a week for a 
qualifying blood pressure evaluation for up to 28 days, beyond which they will be considered 
a screen failure. 
Decisions regarding patient study enrollment MUST be made based on office blood pressure 
readings (mean SBP/mean DBP) using the office automatic blood pressure monitor and 
appropriately sized cuff (Figure 3-2 Blood pressure cuff size), provided by the Sponsor.  
Following the automatic blood pressure check, the patient’s blood pressure must then be taken 
using the auscultatory method.  The auscultatory blood pressure check must confirm that the 
patient does have MSBP ≥ 95th percentile.   
At Visit 2 (week 0), eligible patients will be randomized into the study using the Interactive 
Response Technology (IRT) system. Patients will be randomized to one of two valsartan 
treatment arms: valsartan 0.25 mg/kg or valsartan 4 mg/kg in a 1:1 ratio.  Patients will remain 
on their dose for 6 weeks. 
Open-label period (Period 2) 
Following the double-blind treatment phase, all patients will move into a 20 week open-label 
phase (Visit 5).  All patients will start on 1 mg/kg of valsartan and remain on this dose for 4 
weeks.  If, after 4 weeks (Visit 7) the patient’s MSBP is ≥ 90th percentile for age, gender and 
height, the investigator may increase the dose to 2 mg/kg. If, after 4 weeks (Visit 8) the 
patient’s MSBP is ≥ 90th percentile for age, gender and height, the investigator may increase 
the dose to 3 mg/kg.  The dose can be further increased to 4 mg/kg at Visit 9, in order to 
control MSBP (<90th percentile). Patients can remain on the 4mg/kg dose from Visit 9 
through the end of the study.  The study medication may be down titrated at the investigator’s 
discretion.  After down titration the investigator may up titrate again to the maximum dose as 
necessary.  The maximum dose the patient can take is 4 mg/kg for a maximum of 8 weeks. 
Unscheduled visits can be performed as needed to monitor patient safety. 
If, at any time after Visit 2, the patient’s office-measured MSBP is ≥ 25% above the 95th 
percentile for age, gender, and height, the patient should be discontinued (Appendix 2). 
 


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Figure 3-2  
Blood pressure cuff size  
 
3.2 
Rationale of study design 
Two previous valsartan trials in hypertensive children between 6 months and 5 years showed 
mixed results with one study demonstrating a trend toward a positive dose response and the 
other not. Following consultation between the PDCO and the EMA committee CHMP, the 
CHMP indicated that the reasons behind the inconsistent results in the younger age group 
were not entirely understood and that no clear approach exists in the design of clinical trials 
for antihypertensive agents in the pediatric population. The CHMP recognized the clinical 
need in this age group and that it would be relevant to conduct a new study. The CHMP’s 
Scientific Advice Procedure with the involvement of the PDCO was initiated for protocol 
assistance (
). Ultimately, an overall study design 
agreement was reached to perform an additional study in 1 to 5 year old children with 
hypertension 
using 
a 
similar 
design 
as 
in 
a 
previous 
study 
(
). 
The study would consist of three periods. The first would be the Screening period, followed 
by a six-week randomized (1:1 ratio), double-blind, double-dummy dose-ranging period 
consisting of 2 valsartan dose groups (0.25 mg/kg and 4 mg/kg).  The study would conclude 
with a 20 week open-label titration phase. All patients will be placed on a stabilized dose after 
the double-blind period (valsartan 1 mg/kg), with 3 optional titration steps during the open-
label phase. The intent is to investigate the interrelation between the required starting dose 
 


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and potential risk factors.  Duration of 26 weeks was selected as it is considered to provide the 
most appropriate time course to study proteinuria. 
3.3 
Rationale of dose/regimen, duration of treatment 
There is currently no approved valsartan dose in this age group.  The dose ranges to be used in 
this study have been tested in previous trials in hypertensive children between 6 months and 5 
years.  
An oral solution (3 mg/ml) will be used in the study. The mean valsartan concentration-time 
profiles following the oral administration of valsartan oral solution formulation and valsartan 
tablet formulation from previous pharmacokinetic studies showed the relative bioavailability 
of valsartan oral solution is 1.75 fold higher as compared to valsartan tablet formulation. In 
addition, the Cmax is 2.2 fold higher. Therefore, relatively higher exposure will be achieved 
in this study using the solution compared to the administration of tablets in adults.  
It was also decided to extend the duration of this study to assess the safety of valsartan in 
children with hypertension, who also have chronic kidney disease. 
3.4 
Rationale for choice of comparator 
Not applicable 
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable 
3.6 
Risks and benefits 
As seen in previous pediatric trials using valsartan, the beneficial effects of valsartan in 
reducing blood pressure in children were confirmed both with short-term and long-term 
administration. Additionally, valsartan was well tolerated.  
The VAL489K2306 trial is being conducted at the request of the EMA/PDCO, in order to 
assess the safety, tolerability and efficacy in children 1-5 years of age with hypertension, with 
or without CKD.   
There are several direct and perceived benefits for children participating in this trial.  Some of 
the benefits can be summarized as the following: 
• Participation in this study will allow patients to receive medical attention by pediatric 
hypertension experts during the entire study duration. During screening, a thorough 
physical examination, detailed medical history, and complete laboratory tests will be 
performed for each potential patient. Some medical conditions may be detected early and 
get attention sooner due to the increased medical attention participation in this study.   
• Study participation will also provide an opportunity for parents of the patients to discuss 
their children’s medical conditions with these experts in great detail and formalize an 
individualized treatment plan for hypertension. During study participation, the patient and 
parent will have access to physicians and their medical teams to address any questions or 
concerns. The risk to patients will also be further minimized by complying with the study 
protocol and close clinical monitoring 
 


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Some of the risks associated with this trial include: 
• Hyperkalemia: Hyperkalemia is a known and identified risk with drugs that interfere with 
the renin-angiotensin system especially in patients with concomitant renal disease. Since 
at least 50% of patients enrolled in this trial will have CKD, it is likely that some will 
experience hyperkalemia. To ensure their safety, patients with a serum potassium level > 
5.3 mmol/L during the trial will need to repeat the laboratory test (advisable within one 
week after results were sent). All patients with serum potassium > 5.3 mmol/L should be 
followed and appropriate medical care given. If the repeat value confirms serum 
potassium > 5.5 mmol/L, the patient must be immediately discontinued from the study and 
the appropriate medical care given. 
 
• Study drug solution contains sucrose (0.3 g  per milliliter) which should be taken into 
account in diabetic patients because it may increase blood sugar levels; methyl 
parahydroxybenzoate which may cause an allergic reaction (possibly delayed), and 
poloxamer (188) which may cause softened stools. 
• Liver function monitoring: 
For patients with any clinically relevant degree of LFT elevation (AST/ALT/total 
bilirubin), frequent monitoring will be performed until the values approach either normal 
range or baseline values. For patients with LFT elevation of > 3 x ULN, a hepatitis panel 
test (A, B, C, D, E) will be requested and a retest will be done for the LFT and to rule out 
viral hepatitis. If the retest shows that the LFT elevation is still > 3 x ULN, then the 
patient must be discontinued from the study immediately. If the retest shows that the LFT 
elevation is less than or equal to 3 x ULN, the patient may remain in the study, if 
considered medically safe to do so by the investigator.  
• Hypotension: Hypotension is an identified risk in certain patients and is an extension of 
the pharmacologic effect. Dizziness, vertigo, and syncope may be related to low blood 
pressure, but may also be associated with other conditions. The protocol has specific 
detailed procedures for careful blood pressure monitoring at each visit.   The protocol has 
defined stopping rules for study medication or study discontinuation based on blood 
pressure measurements. 
• As in any clinical study, there are always unknown risks and new side effects that are not 
now known could also occur. 
The results from this trial will provide further information on the efficacy, safety, and 
tolerability of valsartan in hypertensive pediatric patients with or without CKD. 
4 
Population 
The study population will consist of a representative group of 130, male and female children 
age 1-5 years by visit 2. All patients must have a history of hypertension defined as a MSBP 
≥ٛ 95th percentile to be eligible for randomization into this study. Approximately 50 sites are 
planned for this study. A total of 200 patients will be screened to randomize 130 patients with 
an anticipated screen failure rate of 35%. A drop out rate of 10% during the double-blind 
period is expected.  A total of 116 patients are expected to complete the double-blind period 
and enter the open-label period. Patients will be stratified based on CKD status (yes /no). 
 


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At least 50% of patients enrolled will be CKD patients.  CKD patients must have a 
documented history of CKD. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed.  
Parent(s)/guardian(s) have to provide consent in writing (written informed consent) after 
the purpose and nature of the study has been clearly explained to them.  
2. Male or female, 1 to 5 years at baseline (visit 2), with a documented diagnosis of 
hypertension (National High Blood Pressure Education Program 2004) 
3. CKD patients must be defined as any of the following criteria (Hogg et al 2003) (At least 
50% of enrolled patients will be CKD-patients): 
a. 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 
b.   Estimated GFR <60 mL/min/1.73m2 (calculated by Modified Schwartz Formula) for 
≥3 months, with or without the other signs of kidney damage described above. 
4. MSBP (mean of 3 measurements) must be ≥95th percentile, and ≤25% above the 95th 
percentile, for age, gender and height, at baseline (visit 2) (Appendix 2), by office 
automatic blood pressure monitor and cuff, provided by the Sponsor. Confirmation of 
MSBP ≥95th percentile must be made using the auscultatory blood pressure method. 
5. Able to swallow the valsartan solution 
6. Body weight must be ≥8 kg and ≤40 kg at baseline 
7. Must be able to safely washout prior ARB, ACEi and DRI therapy (if applicable) and 
other antihypertensive therapy (if applicable) 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
1. Any clinically significant physical abnormality or clinically relevant abnormal laboratory 
values (other than those relating to renal function) obtained at the screening visit (Visit 1), 
including the following: 
a. AST/SGOT or ALT/SGPT >3 times the upper limit of the reference range. Patients 
known to have active or chronic hepatitis will be excluded. 
b. Total bilirubin >2 times the upper limit of the reference range 
c. Estimated Glomerular Filtration Rate [eGFR] <30 mL/min/1.73m² (calculated using 
Modified Schwartz Formula) 
 


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d. WBC count <3000/mm³ 
e. Platelet count <100,000/mm³ 
f. Serum potassium >5.3 mmol/L 
g. Hemoglobin <9 g/dL 
2. Uncontrolled diabetes mellitus, as defined by the investigator  
3. Unilateral, bilateral and graft renal artery stenosis 
4. Current diagnosis of heart failure (NYHA Class II-IV) 
5. Patients taking any of the following concomitant medications following screening: 
a. RAAS blockers other than study drug 
b. Lithium 
c. Potassium-sparing diuretics, potassium supplements, salt substitutes containing 
potassium and other substances that may increase potassium levels 
d. Non-steroidal anti-inflammatory drugs (NSAIDS), including selective COX-2 
inhibitors, acetylsalicylic acid >3g/day, and non-selective NSAIDs 
(paracetamol/acetaminophen is permitted) 
e. Antidepressant drugs in the class of MAO inhibitors (e.g. phenelzine) 
f. Chronic use of stimulant therapy for ADD/ADHD 
6. Patients who demonstrate clinically significant ECG abnormalities such as concurrent 
potentially life threatening arrhythmias or symptomatic arrhythmias are excluded, as are 
patients with second or third degree heart block without a pacemaker. Patients with ECG 
abnormalities associated with left ventricular hypertrophy are permitted to enroll. 
7. Patients who have coarctation of the aorta with a gradient of ≥30 mmHg 
8. 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. Stable doses 
of immunosuppressive therapy are defined as no change in frequency or total daily doses 
of immunosuppressive therapy for at least two months prior to screening.  
9. Patients known to be positive for the human immunodeficiency virus (HIV) 
10. Any clinically significant medical condition that would put the patient at risk of 
experiencing an adverse event associated with the expected pharmacodynamic effects of 
the study drug 
11. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of the study drug including, but not limited to, any 
of the following: 
a. History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, 
or bowel resection. 
b. Currently active or previously active inflammatory bowel disease during the 12 
months prior to Visit 1. 
c. Patients known to have currently active gastritis, duodenal or gastric ulcers, or 
gastrointestinal/rectal bleeding during the 3 months prior to Visit 1. 
 


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d. Patients known to have active pancreatic injury, pancreatitis or evidence of impaired 
pancreatic function/injury as indicated by abnormal lipase or amylase. 
e. History of hepatic encephalopathy, a history of esophageal varices, or a history of 
porto-caval shunt. 
f. Current obstruction of the urinary tract or difficulty in voiding due to mechanical or 
inflammatory conditions which is likely to require intervention during the course of 
the study or is regarded as clinically meaningful by the investigator. 
12. Known or suspected contraindications to the study drug, including severe hepatic 
impairment, biliary cirrhosis, cholestasis and history of allergy to other ARBs or to 
ACEi(s) and/or DRIs 
13. 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 
14. 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. 
15. History of hypersensitivity to the study drug or to drugs of similar chemical classes 
16. Patients with rare hereditary problems of fructose intolerance, glucose-galactose 
malabsorption or sucrose-isomaltase insufficiency since the study drug solution contains 
sucrose.   
If there is any question that the patient will not reliably comply, they should not be entered in 
the study. 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
The sponsor will provide the following double-blind study medication (Day 1 – Day 42): 
• VAL489 (Valsartan) 3 mg/ml oral solution 
• Placebo to match VAL489 (Valsartan) 3 mg/ml oral solution 
During the double-blind Period 1, a double-dummy design will be used since there will be 
volume differences between the doses.  
The sponsor will provide the following open label study medication (Day 43 – Day 182): 
• VAL489 (Valsartan) 3mg/ml oral solution 
No other drugs will be supplied.  Medication will be supplied in bottles.  Sufficient 
medication will be provided for treatment according to the protocol. 
Each study site will be supplied by Novartis with study drug.  The study drug packaging has a 
2-part label.  A unique number is printed on each part of this label which corresponds to one 
of the 2 treatment arms.  Investigator staff will identify the study drug bottle(s) to dispense to 
the patient by contacting the IRT system and obtaining the medication number(s).  
Immediately before dispensing the bottle(s) to the patient, investigator staff will detach the 
 


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outer part of the label from the packaging and affix it to the source document (drug label 
form) for that patient’s unique patient number. 
All bottles assigned by the IRT system will be recorded in the IRT database. 
The drug labels will comply with local legal requirements and be printed in the local language.  
Study drug must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated staff have access. Upon receipt, all study drugs should be stored according to the 
instructions specified on the drug labels. Clinical supplies are to be dispensed only in 
accordance with the protocol. 
Medication labels will comply with the legal requirements of each country. They will contain 
no information about the patient but will carry the medication number. 
Each patient will receive medication bottles at each visit. Patients will be instructed to take 
study medication once daily at approximately the same time each day, in the morning with or 
without food, except on the days of study visits. On the days of study visits the study drug 
should be taken after all study visit assessments have been completed.  
5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this trial. 
5.2 
Treatment arms 
• Period 1: 
VAL489 (Valsartan) 0.25 mg/kg or 4 mg/kg 
VAL489 (Valsartan) 0.25 mg/kg or 4 mg/kg matching placebo 
• Period 2: 
VAL489 (Valsartan) 1 mg/kg, optional titration 2 mg/kg, 3 mg/kg and 4 mg/kg (max dose).      
5.3 
Treatment assignment, randomization  
At Visit 2, all eligible patients will be randomized via Interactive Voice Response System to 
one of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the patient fulfills all the inclusion/exclusion criteria.  The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study drug to be 
dispensed to the patient.  The randomization number will not be communicated to the caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
 


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the random assignment of medication numbers to study drug packs containing each of the 
study drugs.  
The randomization scheme for patients will be reviewed and approved by a member of the IIS 
Randomization Group. 
5.4 
Treatment blinding  
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatments from the time of randomization up to Visit 5 (Week 6) 
using the following methods. 
1. Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study. 
2. The identity of the treatments will be concealed by the use of study drugs that are all 
identical in packaging, labeling, and schedule of administration and appearance. 
A double-dummy design is used because the identity of the study drugs cannot be disguised 
due to their different forms. 
Unblinding will only occur in the case of patient emergencies (see Section 5.5.10) and at the 
conclusion of the study.  
An assessment will be done by the appropriate site personnel and the CTH for any patient 
whose treatment code has been broken inadvertently or for any non-emergency reason to 
assess whether or not study drug should be discontinued and, if applicable, whether the patient 
can continue into the next trial phase (e.g., open-label extension). 
Starting from Visit 5 (Week 6) up to Visit 11 (Week 26) the identity of the treatments will be 
open-label. 
5.5 
Treating the patient 
5.5.1 
Patient numbering  
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused.  
Upon signing the informed consent form, the patient (parent) is assigned the next sequential 
number by the investigator. The investigator or his/her staff will contact the IRT and provide 
the requested identifying information for the patient to register them into the IRT.  
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening Log 
CRF. 
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with study drug in packaging of identical 
appearance. 
 


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The investigational treatment packaging has a 2-part label. A unique randomization number is 
printed on each part of this label which corresponds to one of the “n” treatment arms and a 
specific visit. Investigator staff will identify the investigational treatment package(s) to 
dispense to the patient by contacting the IRT and obtaining the medication number(s). 
Immediately before dispensing the package to the patient, investigator staff will detach the 
outer part of the label from the packaging and affix it to the source document (Drug Label 
Form) for that patient’s unique subject number.  
5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment  
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment should be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed only 
in accordance with the protocol. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the patient except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits and at the completion of the trial. Patients 
will be asked to return all unused investigational treatment and packaging at the end of the 
study or at the time of discontinuation of investigational treatment.  
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused investigational treatment, packaging, drug labels, and a 
copy of the completed drug accountability log to the CRO monitor or to the Novartis address 
provided in the investigator folder at each site. 
5.5.4 
Instructions for prescribing and taking study treatment  
The investigator should insure that the patient’s parent or guardian clearly understands the 
following dosing instructions: 
Study drug will be dispensed at Visits 2, 3, 4, 5, 7, 8, 9 and 10.  All study medication will be 
supplied in the form of an oral solution.   
This study consists of two periods: 
• Period 1:  valsartan 0.25 mg/kg or 4 mg/kg and valsartan matching placebo 0.25 mg/kg or 
4 mg/kg  
• Period 2:  valsartan 1 mg/kg open label, optional 2 mg/kg, 3 mg/kg and 4 mg/kg (max. 
dose). 
Starting at Visit 7 (Week 10) 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 
(visits 8, 9 and 10) until maximum dose of 4 mg/kg is achieved.  Titration criteria can be 
found in section 3.1. 
 


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Additionally, all dosages prescribed and dispensed to the patient and all dose changes during 
the study must be recorded on the Dosage Administration Record CRF.  
All kits of investigational treatment assigned by the IRT will be recorded/databased in the IRT. 
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient should be instructed to contact the investigator if he/she 
is unable for any reason to take the study drug as prescribed. 
First dose of study medication should be administered at Visit 2, after all study visit 
assessments have been completed.  All study treatment will be taken orally and will be 
administered once daily, at approximately the same time each day, in the morning, with or 
without food, except on the days of study visits. On the days of study visits the study drug 
should be taken after all study visit assessments have been completed (see Section 6). 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
The open-label study medication doses (Figure 3-1) may be down titrated, at the investigator’s 
discretion.  After down titration the investigator may up titrate again but cannot exceed the 
maximum dose of 4 mg/kg of valsartan.  
Study drug treatment interruptions are only allowed for safety reasons. 
All changes in study drug must be recorded on the Dosage Administration Record CRF. 
5.5.6 
Rescue medication  
No rescue medication will be allowed.   
Background antihypertensive medication other than RAAS blockers are allowed from 
screening through the end of study.  
Use of background antihypertensive medication must be recorded on the Prior and 
concomitant anti-hypertensive medications CRF.   
5.5.7 
Concomitant treatment  
All medications and significant non-drug therapies (including lifestyle intervention, physical 
therapy and blood transfusions) administered prior to the patient start of treatment with study 
drug must be listed on the Concomitant medications/Significant non-drug therapies prior to 
start of study CRF. 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study drug. All medications and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the patient 
starts treatment with study drug must be listed on the Concomitant medications/Significant 
non-drug therapies after start of study drug CRF.  
All antihypertensive medication administered prior to the patient start of treatment with study 
drug, as well as antihypertensive medication continued or added must be listed on the Prior 
and concomitant anti-hypertensive medications CRF. 
 


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5.5.8 
Prohibited treatment  
Use of any of the treatments displayed in Table 5-1 is NOT allowed after screening until the 
end of the study.  The prohibited medications and the specified timeframes are based on the 
potential that these medications may confound either the evaluation of efficacy or safety 
during the trial.  Patients who are receiving such medication(s) should not be enrolled, or if 
ethically justified the medication(s) may be withdrawn prior to or at Visit 2. 
Table 5-1 
Prohibited treatment 
Medication 
Action to be taken 
RAAS blockers other than study drug (e.g. ARB, ACEi, 
DRI, aldosterone antagonists) 
Consult with Sponsor to determine if study 
discontinuation is required. 
Lithium 
Consult with Sponsor to determine if study 
discontinuation is required. 
Potassium-sparing diuretics, potassium supplements, 
salt substitutes containing potassium and other 
substances that may increase potassium levels 
Consult with Sponsor to determine if study 
discontinuation is required. 
Non-steroidal anti-inflammatory drugs (NSAIDs), 
including selective COX-2 inhibitors, acetylsalicylic 
acid>3 g/day, and non-selective NSAIDs. 
Paracetamol/acetaminophen is permitted.  
Discontinue study treatment if chronic use is needed. 
None, if acute use for less than 7 days.  Consult with 
Sponsor to determine if study discontinuation is 
required if acute use is for 7 days or longer. 
Steroid therapy:  Chronic use of steroids is permitted as 
long as their use is stable at least 1 month prior to 
screening and does not increase during the study.  
Changes in steroid dose should not occur during 
double-blind phase.  Decreases during the open-label 
phase are allowed. 
Consult with Sponsor to determine if study 
discontinuation is required if steroid dose changed 
during the double-blind phase. Discontinue study 
treatment if dose increase in steroids is required for 
more than 7 days during open-label phase.  
No action if acute use for less than 7 days during open-
label phase.  Consult with Sponsor to determine if 
study discontinuation is required if acute use is for 7 
days or longer.  
Immunosuppressive therapy: Immunosuppressive 
therapy is permitted as long as their use is stable at 
least 2 months prior to screening.  Dose increases due 
to weight change in order to keep patient within 
therapeutic range are permitted. Dose increases for 
other reasons (e.g., transplant rejection) are not 
permitted.  
Discontinue if dose increase in immunosuppressive 
therapy was due to reasons other than weight change 
(e.g. transplant rejection).   
Antidepressant drugs in the class of MAO inhibitors 
(e.g. phenelzine) 
Consult with Sponsor to determine if study 
discontinuation is required. 
Over The Counter decongestants are disallowed 24 
hours prior to a scheduled study visit, after Visit 1 
None 
Chronic use of stimulant therapy for ADD/ADHD 
Consult with Sponsor to determine if study 
discontinuation is required. 
5.5.9 
Discontinuation of study treatment and premature patient withdrawal  
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for a visit or 
become lost to follow up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the Study Completion CRF. 
 


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The investigator should discontinue study treatment for a given patient or withdraw the 
patient from the study if, on balance, he/she believes that continuation would be detrimental to 
the patient’s well-being. 
Study drug must be discontinued for a given patient if the investigator determines that 
continuing it would result in a significant safety risk for that patient. If one of the following 
applies, the patient should be thoroughly evaluated by the Investigator within 48 hours, and 
should be discontinued from study drug. 
• Withdrawal of informed consent 
• MSBP is >25% above the 95th percentile for age, gender and height at any time during the 
study after baseline 
• Symptomatic hypotension and MSBP ≤50th percentile for gender, age and height at any 
time during the study  
• Any of the following laboratory abnormalities: 
o If patient has an eGFR <30 mL/min/1.73m2, the patient will need a repeat lab test, 
advisable within one week after results were sent.  If the repeat value confirms eGFR 
<30 mL/min/1.73m2, the patient must be discontinued per valsartan label 
o >50 % decrease in eGFR from baseline 
o Severe anemia: defined as hemoglobin <9 g/dL 
o WBC <3000/mm3 
• Hyperkalemia: If a serum potassium level is >5.3 mmol/L (as per central lab), the patient 
will need a repeat lab test, advisable within one week after results were sent. All patients 
with serum potassium of 5.3 mmol/L or higher should be followed and appropriate 
medical care given. 
If the repeat value confirms serum potassium > 5.5 mmol/L (as per central lab), the patient 
must be immediately discontinued from the study and the appropriate medical care given. 
• Liver function monitoring: 
For patients with any clinically relevant degree of LFT elevation (AST/ALT/total 
bilirubin), frequent monitoring will be performed until the values approach either normal 
range or baseline values. For patients with LFT elevation of > 3 x ULN, a hepatitis panel 
test (A, B, C, D, E) will be requested and a retest will be done for the LFT and to rule out 
viral hepatitis.  If the retest shows that the LFT elevation is still > 3 x ULN, then the 
patient must be discontinued from the study immediately. If the retest shows that the LFT 
elevation is less than or equal to 3 x ULN, the patient may remain in the study, if 
considered medically safe to do so by the investigator.   
• Interruption of study drug treatment for longer than two consecutive weeks because of 
non-compliance. 
• Any other protocol deviation that results in a significant risk to the patient’s safety. 
If one of the following applies, the patient should be thoroughly evaluated by the Investigator 
within 48 hours, and the investigator should consider discontinuation from study drug and 
contact the Sponsor if applicable: 
 


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• Patients with MSBP >20% above the 95th percentile for age, gender and height after visit 5 
should be thoroughly evaluated by the Investigator to determine if the patient should 
continue on current therapy. 
• Acute dehydration:  
If a patient presents with acute dehydration the patient’s study drug is to be temporarily 
interrupted until the patient is fully hydrated for at least 3 days. 
The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any patient whose treatment code has been broken inadvertently 
for any reason.  
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information on the Study Completion CRF. Patients who discontinue study treatment 
before completing the study, and those who prematurely withdraw from the study for any 
reason, should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final visit will be performed. At a minimum, those patients will be 
contacted for safety evaluations during the 30 days following the last dose of study drug, 
including a final contact at the 30-day point.  
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study. A Study Drug Discontinuation form should be completed, giving the date and primary 
reason for stopping study treatment. See Section 6 for the required assessments of these 
patients after discontinuation of study treatment. 
The investigator must also contact the IRT system to register the patient’s discontinuation 
from study drug.  
For patients who are lost to follow-up (i.e. those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the 
patient, e.g. dates of telephone calls, registered letters, etc. 
Patients who are prematurely withdrawn from the study will not be replaced by an equal 
number of newly enrolled patients. 
5.5.10 
Emergency breaking of treatment assignment  
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, study discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. Emergency treatment code breaks are performed using the IRT. When 
the investigator contacts the system to break a treatment code for a patient, he/she must 
provide the requested patient identifying information and confirm the necessity to break the 
treatment code for the patient. The investigator will then receive details of the investigational 
drug treatment for the specified patient and a fax or email confirming this information. The 
system will automatically inform the Novartis monitor for the site and the Clinical Trial Head 
(CTH) that the code has been broken. 
 


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It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT code break cards in case of emergency. The investigator will inform the patient 
how to contact his/her backup in cases of emergency when he/she is unavailable. The 
investigator will provide protocol number, study drug name if available, patient number, and 
instructions for contacting the local Novartis CPO (or any entity to which it has delegated 
responsibility for emergency code breaks) to the patient in case emergency unblinding is 
required at a time when the investigator and backup are unavailable. 
5.5.11 
Study completion and post-study treatment  
Study completion for a patient in this study is defined as having performed the final study 
visit within the time window of Visit 11. 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
5.5.12 
Early study termination  
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated as described in Section 6 for a 
prematurely withdrawn patient. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator will be responsible for informing IRBs and/or ECs of the 
early termination of the trial. 
6 
Visit schedule and assessments 
Screening/washout: The vital signs and medical history collected during the screening visit 
will be documented in source documents. Once the patient qualifies for the study (Visit 2), 
information from Visit 1 should be entered into the Visit 1 CRF. 
Further details about the screening, washout and treatment period can be found in Section 3.1.  
Table 6-1 lists all of the assessments and indicates with an “x” the visits when these 
assessments are performed. During the treatment period patients should be seen for all visits 
on the designated day with a visit window of ±7 days between visits 2 through 11.  
All visits should be conducted at the same time of the day, in the morning, and approximately 
24 hours (± 4 hours) post study drug dosage. Patients will be instructed not to take their study 
drug on the day of the visit before they have completed all study assessments for the same 
visit. If study drug has been taken on the day of the scheduled visit prior to assessments, the 
visit should be postponed and rescheduled within 3 days. 
Unscheduled visits may be performed as needed at the discretion of the investigator to 
monitor patient’s safety.All inclusion criteria are based upon office BP reading using the 
automated device provided by the Sponsor. 
All data obtained from the assessments in Table 6-1 and all BP and AE data obtained from 
unscheduled visits must be supported in the patient’s source documentation and will be added 
to the database accordingly. 
 


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Patients, who discontinue study treatment before completing the study, and those who 
prematurely withdraw from the study for any reason, should be scheduled for a visit as soon 
as possible, at which time all of the assessments listed for the final visit will be performed. 
The site must register the patient discontinuation in the IRT system. 
 


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Table 6-1 
Assessment schedule 
Visit 
11 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11/ End of 
study6 
Day 
-28 - -1 
1 
7 
21 
42 
56 
70 
98 
126 
154 
182 
Week 
-4 - -1 
BL 
1 
3 
6 
8 
10 
14 
18 
22 
26 
Obtain informed 
consent 
S 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
S 
S 
 
 
 
 
 
 
 
 
 
Medical history2 
X 
X2 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination – 
complete 
S 
 
 
 
S 
 
 
 
 
 
S 
Physical examination – 
short 
 
S 
S 
S 
 
 
S 
S 
S 
S 
 
Blood pressure 7and 
pulse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Head Circumference 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Height 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
X 
 
 
 
 
 
X 
Hematology 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
Complete blood 
chemistry  
X 
X 
 
 
X 
 
 
X 
 
 
X 
Abbreviated blood 
chemistry 
 
 
 
 
 
 
 
 
X 
X 
 
Urine dipstick  
X 
X 
 
 
X 
 
 
 
 
 
X 
UACR/Cys. C GFR (in 
CKD only)3, 4 
 
X 
 
 
X 
 
 
 
 
X 
X 
eGFR 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
IRT5 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Washout prior RAAS 
treatments 
X 
 
 
 
 
 
 
 
 
 
 
Dispense study drug 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Drug accountability 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X = assessment to be recorded on clinical data base 
S = assessment to be recorded on source documentation 
 
1All patients have up to 28 days to meet MSBP enrollment criteria. Patients not taking RAAS 
blockers can qualify once the patient has achieved a MSBP ≥ 95th percentile for age, gender and 
height (Appendix 2), screening laboratory results have been received and reviewed, and all other 
inclusion criteria have been met (Section 3.1). 
2 Medical history is collected at Visits 1-2. If patient has any event after first dose of study 
medication, event is recorded as AE (Section 7). 
3 CKD is defined in Section 4. 
4Urine collection will begin 3 days prior to the study visit. UACR and Cystatin C GFR tests are done 
in CKD patients only.  
5IRT: Visit 1: Patient registration information entered at Visit 1, including body weight and CKD 
status; Visit 2: weight and CKD status entered into IRT and study drug assigned; Visit 5-weight 
 


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Visit 
11 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11/ End of 
study6 
Day 
-28 - -1 
1 
7 
21 
42 
56 
70 
98 
126 
154 
182 
Week 
-4 - -1 
BL 
1 
3 
6 
8 
10 
14 
18 
22 
26 
entered in IRT for open-label dose; Visit 8: weight entered in IRT for open-label dose 
6 End of study assessments must be done for patients who discontinue from the study any time 
after Visit 2. 
7 Blood pressure: 3 oscillometric readings are taken at every visit, followed by one auscultatory 
blood pressure measurement.  At Visit 2, the auscultatory measurement must confirm that the 
patient does have hypertension (MSBP ≥ 95th percentile for age, gender and height). 
6.1 
Information to be collected on screening failures  
If the patient fails to be enrolled into the treatment phase for any reason, the IRT system must 
be notified that the patient was a screen failure and the reason for not being enrolled will be 
entered on the screening log. Detailed instructions regarding use of the IRT will be provided 
in the IRT user manual.  
6.2 
Patient demographics/other baseline characteristics  
Patient demographic and baseline characteristic data to be collected on all patients include 
date of birth, sex, race and ethnicity, height, weight, and head circumference.  
Relevant medical history/current medical condition data includes data until the start of study 
drug. Where possible, diagnoses, and not symptoms will be recorded. Patients with CKD as 
defined in Section 4 should have a corresponding medical history of chronic kidney disease 
etiology recorded. 
Visit 1 
At Visit 1, the investigator or investigator’s staff will call into IRT and register the patient. 
During this call, the patient’s date of birth, gender, CKD status, and body weight will be 
entered into the IRT, along with the patient number. 
Visit 2 
The patient is enrolled into the trial at Visit 2 once all eligibility criteria are met (within 28 
days of Visit 1). At this visit, the investigator or investigator’s staff will call into IRT and 
enter the patient’s body weight and CKD status. 
CKD status, age and region 
At Visit 2, the investigator or staff will also enter the patient’s CKD status (CKD or non-CKD 
patient). The CKD definition is discussed in Section 4. At least 50% of the patients enrolled 
into the trial must have CKD. IRT will be used to track CKD status at Visit 2. IRT will be 
used to prevent over enrollment of non-CKD patients, in order to ensure that a sufficient 
number of CKD patients are enrolled (e.g. should enrollment of 65 non-CKD patients be 
achieved, IRT will not permit enrollment and assignment of study drug to further non-CKD 
patients in the study).  Patients will be stratified by CKD status. 
 


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Visit 2 to Visit 10 
The IRT system will be called at every visit.  Study medication number assignment will be at 
every dispensing visit (Visit 2-Visit 10). The dose of medication that the patient receives will 
be based on the patient’s weight at Visit 2 for double blind, and at Visit 5 and Visit 8 during 
the open-label phase.  
6.3 
Treatment exposure and compliance  
Study medication and concomitant therapies will be recorded on the Dosage Administration 
CRF, the Concomitant medication/significant therapies prior to study drug administration 
CRF, and the concomitant medications/significant non-drug therapies after study drug 
administration CRF. 
Patient compliance with the study drug treatment will be assessed by the investigator and/or 
study personnel using pill count, information from the patient/caregiver and drug 
accountability. This information should be captured in the source documents and in the CRF. 
Patient compliance should be at least 75% during the study. The investigator and/or study 
personnel will counsel the patient on proper method of taking the study drug as appropriate to 
ensure compliance during the trial. Patients who miss study drug for 2 weeks consecutively or 
more should be discontinued. 
6.4 
Efficacy 
The following efficacy assessments will be performed as scheduled in Table 6-1. 
6.4.1 
Office blood pressure 
Patient’s blood pressure should be measured in the same position at every visit (lying down, 
sitting, being held in parent’s arms or lap, etc).  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) for 
that visit, and will be recorded in the CRF. All blood pressure measurements will be recorded 
in the patient’s source documents. The pulse rate is a safety assessment and will be performed 
immediately after the 3 blood pressure measurements. Every effort should be made to 
minimize staff-patient interaction, such as talking, for maximum reproducibility. 
Automated arterial blood pressure determinations will be made with an automatic blood 
pressure monitor and appropriate size pediatric/small cuff in accordance with the Guidelines 
for management of hypertension: report of the fourth working party of the British 
Hypertension Society, 2004-BHS IV (Williams et al, 2004).  The automatic blood pressure 
monitor and cuff will be provided by the Sponsor. The automated blood pressure machine will 
be used at every visit. After all three blood pressures are taken for a patient, study staff should 
print out the three BP readings and place it in the patient’s source document, noting the 
patient’s initials, and corresponding visit date and time on the BP record.  A photocopy of the 
BP readings should also be made, as the printer ink may fade over time.  The oscillometric 
method is to be used at every visit. 
One auscultatory blood pressure reading using a calibrated standard sphygmomanometer and 
appropriate cuff size must be taken, following the three oscillometric readings, at every visit. 
 


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The reading will be documented in the patient’s source document and CRF. At Visit 2, patient 
hypertension must be confirmed (MSBP ≥95th percentile for age, gender and height) by the 
auscultatory blood pressure method. 
Arterial blood pressure determinations will be made in accordance with the National High 
Blood Pressure Education Program Working Group on High Blood Pressure in Children and 
Adolescents (NHBPEP Fourth Report 2004). Tables to determine the percentile for age, 
gender and height are provided in Appendix 2. 
With the arm supported at the level of the heart, systolic pressure will be recorded when the 
initial sound is heard (Phase I of the Korotkoff sound); diastolic pressure will be recorded at 
the disappearance of the sound (Phase V of the Korotkoff sound). The cuff should be deflated 
at a rate not greater than 2 mmHg/second. At the first study visit, the arm in which the highest 
systolic blood pressure is found will be the arm used for all subsequent readings throughout 
the study and should be documented in the source documents. Every effort will be made to 
have the same staff member obtain blood pressure measurements for the same patient, at the 
same time of day in the morning, using the same equipment, at each visit. 
6.4.2 
Appropriateness of efficacy assessments  
The efficacy parameters selected are standard for this indication and patient population.  
6.5 
Safety  
The safety assessments consist of (serious) adverse event monitoring and the following 
evaluations. The assessments will be performed as scheduled in Table 6-1. Clinically notable 
values are defined in Appendix 1. 
6.5.1 
Physical examination  
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular (including blood pressure, pulse rate and ECG) and neurological system.  
A short physical examination will include the examination of vital signs, heart, lungs, 
abdomen, extremities and any other evaluation the Investigator considers appropriate based on 
the patient’s clinical status at the time of the visit.  
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of study drug must be 
included in the patient’s Relevant Medical History/Current Medical Conditions CRF. 
Significant findings made after the start of study drug must be reported as an Adverse Event. 
6.5.2 
Vital signs  
Blood pressure measurements are efficacy assessments.  The pulse rate will be measured for 
30 seconds just after the last blood pressure measurement. 
6.5.3 
Height, weight, and head circumference  
Height in centimeters (cm), body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes), and head circumference will be measured.   
 


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6.5.4 
Laboratory evaluations  
A central laboratory will be used for analysis of all specimens collected, except for urine 
dipstick. Details on the collections, shipment of samples and reporting of results by the central 
laboratory are provided to investigators in the laboratory manual. Unscheduled local lab CRFs 
will be available, should a local lab be used in an emergency. For UACR see Section 6.5.4.4. 
Clinically notable laboratory findings are defined in Appendix 1. 
6.5.4.1 
Hematology 
Hematology laboratory assessments are performed at Visits 1, 2, 5, 8, 9, 10 and 11.  
• Hematology: red blood cell count, hemoglobin, hematocrit, white blood cell count with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count 
6.5.4.2 
Clinical chemistry 
Complete blood chemistry laboratory assessments are performed at Visits 1, 2, 5, 8 and 11.  
• Complete blood chemistry: urea, creatinine, non-fasting glucose, total bilirubin, 
AST/SGOT, ALT/SGPT, ALP, sodium, potassium, bicarbonate (total CO2), chloride, 
calcium, phosphorous, total protein, albumin, uric acid, cholesterol, triglycerides and 
eGFR 
Abbreviated blood chemistry laboratory assessments are performed at Visits 9, and 10. 
• Abbreviated blood chemistry: urea, creatinine, sodium, potassium, bicarbonate (total CO2) 
and eGFR 
Cystatin C is obtained only for CKD patients at Visits 2, 5, 10 and 11. 
6.5.4.3 
Urinalysis 
Urine dipstick analyses will be done locally on site at Visits 1, 2, 5, and 11. Materials will be 
provided by the central laboratory. 
• Urinalysis: pH, specific gravity, glucose, protein, bilirubin, ketones, leukocytes, blood  
 


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6.5.4.4 
Urinary albumin creatinine ratio (UACR) 
For CKD patients, UACR will be measured from 3 consecutive early morning urine 
collections, beginning 3 days prior to the scheduled visit (see Table 6-1).  UACR will be 
measured at Visits 2, 5, 10, and 11. 
Urine collection materials and instructions will be provided to the patients prior to their visit. 
The patients will collect these three samples on the three days prior to their study visit and 
they will bring them when they return to the site. A central laboratory will be used for analysis 
of UACR samples. Details on the collections, shipment of samples and reporting of results by 
the central laboratory are provided to investigators in the laboratory manual. UACR will be 
calculated as follows: 
UACR [mg/mmol] = urine albumin [mg/L] / urine creatinine [mmol/L] 
6.5.4.5 
Estimated Glomerular filtration rate (eGFR) 
Schwartz GFR 
For all patients, eGFR will be calculated using the Modified Schwartz Formula (Schwartz et. 
al 1976). This formula to estimate eGFR uses serum creatinine, height and a constant 
depending on age and gender: 
eGFR [ml/min/1.73m2] = k * Height [cm] / Serum Creatinine [mg/dL] 
Age 
K 
< 1 year 
0.45 
1 to 12 years 
0.55 
13 to 20 years (adolescent 
females) 
0.55 
13 to 20 years (adolescent males) 
0.70 
(Schwartz et al 1976) 
Cystatin C eGFR 
For CKD patients, the eGFR will also be calculated using the cystatin C value.  
A serum cystatin C sample will be collected and the GFR will be estimated with the following 
formula (Filler et al 2003): 
Log GFR [ml/min/1.73m2] = 1.962 + [1.123 * log (1 / serum cystatin C)] 
6.5.5 
Electrocardiogram (ECG)  
A standard 12-lead ECG will be performed at Visits 1, 5, and 11. The tracings will be dated 
and signed by the physician who provides the clinical interpretation of the ECG. The patient’s 
identification number, the date and actual time of the tracing, and the study code “Study 
CVAL489K2306” must appear on each ECG tracing. In the CRF any ECG abnormalities will 
be recorded. 
 


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6.5.6 
Pregnancy and assessments of fertility  
Not applicable 
6.5.7 
Appropriateness of safety measurements  
The safety assessments selected are standard for this indication/patient population. 
6.6 
Other assessments  
Parents of the patients will be given a taste assessment at the final study visit.  Investigator 
staff will ask the parent to evaluate how their child interpreted the taste of the study 
medication throughout the trial.  The study staff will document this information in the 
patient’s source document and complete this on the End of Study Case Report Form. 
6.6.1 
Resource utilization  
Not applicable 
6.6.2 
Health-related Quality of Life  
Not applicable 
6.6.3 
Pharmacokinetics 
 Not applicable 
6.6.4 
Pharmacogenetics/pharmacogenomics  
Not applicable. 
6.6.5 
Other biomarkers  
Not applicable 
7 
Safety monitoring  
7.1 
Adverse events  
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. Medical conditions/diseases present before starting study 
drug are only considered adverse events if they worsen after starting study drug.  
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments.  
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
 


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• they induce clinical signs or symptoms,  
• they are considered clinically significant,  
• they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1 
. 
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information. 
• the severity grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
All adverse events must be recorded on the Adverse Events CRF with the following 
information: 
1. the severity grade (mild, moderate, severe) 
2. its relationship to the study drug (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. to action taken regarding study treatment 
5. whether it constitutes a serious adverse event (SAE) 
6. whether other medication or therapies have been taken (concomitant medication/non-
drug therapy) 
7. its outcome (continuing/not continuing) 
An SAE is defined as an event which: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
 


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• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given; patient hospitalized/patient’s 
hospitalization prolonged. The action taken to treat the adverse event should be recorded on 
the Adverse Event CRF.  
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
7.2 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 30 days after the patient has stopped study 
participation (defined as time of last dose of study drug taken or last visit whichever is 
later).must be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs 
experienced after the 30 days period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment.  
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
 


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Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess the relationship of any SAE to study treatment, complete 
the SAE Report Form in English, and send the completed, signed form by fax within 24 hours 
to the local Novartis Drug Safety and Epidemiology Department. The telephone and fax 
number of the contact persons in the local department of Drug Safety and Epidemiology, 
specific to the site, are listed in the investigator folder provided to each site. The original copy 
of the SAE Report Form and the fax confirmation sheet must be kept with the case report 
form documentation at the study site. Follow-up information should be provided using a new 
paper SAE Report Form stating that this is a follow-up to a previously reported SAE. 
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC or as per national 
regulatory requirements in participating countries. 
7.3 
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.  
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate; see to section 5.5.9  
• Hospitalization of the patient if appropriate 
• A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
• An investigation of the liver event which needs to be followed until resolution.  
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages. 
7.4 
Pregnancy reporting  
Not applicable 
 


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7.5 
Prospective suicidality assessment  
Not applicable 
8 
Data review and database management  
8.1 
Site monitoring  
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that study drug is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. Data not requiring a separate written record will be defined before study start 
and will be recorded directly on the CRFs. The investigator must also keep the original 
informed consent form signed by the patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
8.2 
Data collection  
Designated investigator staff must enter the information required by the protocol onto the 
Novartis CRFs that are printed on 2-part, non-carbon-required paper. Field monitors will 
review the CRFs for completeness and accuracy and instruct site personnel to make any 
required corrections or additions. The CRFs are forwarded to a designated Contract Research 
Organization (CRO) working on behalf of Novartis by field monitors or by the investigational 
site, with one copy being retained at the investigational site. Once the CRFs are received by 
the CRO, their receipt is recorded, the original copy scanned into the database for processing, 
and then placed in Central Files.  
8.3 
Database management and quality control  
Data from the CRFs are entered into the study database by Contract Research Organization 
(CRO) staff following their own internal standard operating procedures that have been 
reviewed and approved by Novartis. 
 


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Subsequently, the entered data are systematically checked by Data Management staff, using 
error messages printed from validation programs and database listings. Errors or omissions 
are entered on Data Query Forms, which are returned to the investigational site for resolution. 
The signed original and resolved Data Query Forms are returned back to the CRO so the 
resolutions can be entered into the database and a copy is kept with the CRFs at the 
investigator site. Quality control audits of all key safety and efficacy data in the database are 
made prior to locking the database. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
Randomization codes and data about all study drug(s) dispensed to the patient and all IRT 
recorded dosage changes will be tracked using an Interactive Voice Response System (IRT). 
The system will be supplied by a vendor, who will also manage the database. The database 
will be sent electronically to a designated CRO. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
8.4 
Data Monitoring Committee 
Not required 
8.5 
Adjudication Committee 
Not required 
9 
Data analysis  
9.1 
Analysis sets  
The following analysis populations will be defined for statistical analyses: 
Randomized Set (RAN) - All patients who receive a randomization number, regardless of 
receiving double blind study medication.  
Full-analysis Set (FAS) - All patients randomized with at least 1 follow-up efficacy 
assessment. Following the intent-to-treat principle, patients will be analyzed according to the 
treatment assigned at randomization. The primary analysis will be performed on the FAS 
population. However, patients who were not qualified for randomization and were 
inadvertently randomized into the study are excluded from the FAS, provided these patients 
did not receive study drug. 
Per-protocol Set (PPS) - All patients in FAS without any major protocol deviations. This 
supplement efficacy population is used to assess robustness of the primary analysis results. 
 


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The major protocol deviations will be pre-specified prior to unblinding the treatment codes for 
analyses.    
Safety Set (SAF) - All patients who received at least one dose of study medication. Patients 
will be analyzed according to treatment they received. 
Open-label Full Analysis Set (OFAS) - All patients entering the open label period with at least one follow-up 
efficacy assessment during open label period.  
Open-label Safety Set (OSAF) - All patients who received at least one dose of trial medication in open-label 
period.  
9.2 
Patient demographics and other baseline characteristics  
Patient demographics and baseline characteristics will be summarized by treatment group for 
randomized patients. Continuous variables (e.g. age, weight, MSBP, MDBP) will be 
summarized with descriptive statistics (n, mean, standard deviation, median, minimum, 
maximum). Qualitative variables (e.g. age group, gender and race) will be summarized with 
counts and percentages. The summaries will be performed on Randomized Set (RAN). 
Comparisons of treatment groups with respect to the demographics and baseline 
characteristics will be performed using chi-square tests or F tests as appropriate. The results of 
these tests are provided for descriptive purposes, and will not be used as a formal basis to 
determine the factors to be included in statistical models. 
Relevant medical history and continued medical conditions will be summarized by treatment 
group for randomized patients. 
9.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)  
Duration of exposure to study drug will be summarized by treatment group with descriptive 
statistics for safety set (SAF) during double-blind period. Duration of exposure to study drug 
in open-label period will be summarized by dose with descriptive statistics for patients in the 
Open-label Safety Set.  
Concomitant medications and significant non-drug therapies will be summarized with 
frequency tables for patients in safety set and open-label safety patients. 
9.4 
Analysis of the primary variable(s) 
The primary objective is to evaluate if a dose dependent reduction in MSBP exists when 
comparing two doses of valsartan solution (0.25 mg/kg and 4 mg/kg) over a 6 week period in 
children 1-5 years old with hypertension (MSBP ≥ 95th percentile for age, gender and height), 
with or without CKD. The primary statistical model to be used is an analysis of covariance 
(ANCOVA) model with treatment and CKD strata as factors, and baseline MSBP as a 
covariate.  
9.4.1 
Variable 
The primary efficacy variable is change from baseline (Week 0) in mean systolic blood 
pressure (MSBP) at Week 6 endpoint. For each patient, the last post-baseline measurement 
 


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during the double-blind period will be carried forward to Week 6 endpoint measurement for 
the variable to be analyzed. The primary analysis timepoint will be the Week 6 endpoint. The 
primary analysis will be performed on the Full-analysis Set (FAS). 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The null hypothesis is that there is no treatment difference in the reduction of MSBP between 
dose groups 0.25mg/kg and 4 mg/kg.  The alternative hypothesis is that there is a difference 
between dose groups 0.25 mg/kg and 4 mg/kg.  
The comparison will be tested at a two-sided significance level of 0.05.  The change from 
baseline in MSBP at Week 6 endpoint during double-blind period will be analyzed using an 
analysis of covariance model (ANCOVA) with treatment and CKD strata as factors and 
baseline MSBP as a covariate for the FAS population.  
9.4.3 
Handling of missing values/censoring/discontinuations 
For patients with missing values at Week 6, the last post-baseline observation during double-
blind will be carried forward (LOCF) as the Week 6 endpoint. 
9.4.4 
Supportive analyses  
In addition to the primary analysis based on the FAS population, a similar analysis will also 
be performed on the PPS population as a supplementary assessment. 
To further assess the dose response, an analysis of covariate (ANCOVA) will be performed 
on the change from baseline at Week 6 endpoint in MSBP with CKD strata as a factor, dose 
per body weight as the main regressor, and baseline MSBP as a covariate. The analysis will be 
performed for the FAS population. The least-squares mean estimate for the slope will be 
provided.  
The change from baseline in MSBP during double-blind period will be summarized by 
treatment and study week for the FAS and PPS populations respectively. 
9.5 
Analysis of secondary variables 
9.5.1 
Key secondary variables 
• Change from baseline in mean diastolic blood pressure (MDBP) at Week 6 and end of 
study. 
• Percentage of patients achieving MSBP < 90th percentile for age, gender and height at 
Week 6 endpoint and end of study. 
• UACR response (defined as % change from baseline in UACR≤ 25%) at Week 6 endpoint 
and end of study. 
9.5.2 
Efficacy variables  
To evaluate the overall blood pressure changes for patients treated with valsartan throughout 
the study, the change from baseline (Week 0) in MSBP at the end of study will be 
summarized by open-label visits for OFAS population.  A similar summary will be provided 
for MDBP. 
 


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9.5.3 
Safety variables  
The assessment of safety will be based mainly on the frequency of adverse events and on the 
summary of laboratory values for the safety populations. Other safety data (e.g. weight, height, 
resting pulse and head circumference) will be summarized as appropriate. The safety (SAF) 
and open-label safety (OSAF) populations will be used as appropriate for summaries of the 
double-blind and open-label periods. 
Adverse events newly occurring or worsening during the double-blind treatment period and 
open-label period will be summarized by primary system organ class, preferred term, and 
treatment (only for double-blind period). Suspected study-drug related adverse events will be 
summarized similarly. 
Serious adverse events and adverse events leading to study drug discontinuation (based on 
CRF AE data) will be summarized by primary system organ class, preferred term, and 
treatment, and will be listed by patient. 
Laboratory data will be summarized by treatment for change from baseline and for occurrence 
of abnormality as appropriate. 
9.5.4 
Resource utilization  
Not applicable 
9.5.5 
Health-related Quality of Life  
Not applicable 
9.5.6 
Pharmacokinetics  
Not applicable 
9.5.7 
Pharmacogenetics/pharmacogenomics  
Not applicable 
9.5.8 
Biomarkers 
Not applicable 
9.5.9 
PK/PD  
Not applicable 
9.6 
Interim analyses 
Not applicable 
9.7 
Sample size calculation 
The sample size of 116 completed patients is calculated based on the primary efficacy 
variable, change from baseline in mean systolic blood pressure, and a standard deviation of 11 
mmHg (based on previous data) is used. The sample size is calculated to ensure at least 80% 
power to detect statistical significance for the comparison valsartan 0.25 mg/kg versus 
 


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valsartan 4 mg/kg under the alternative hypothesis that the treatment difference is 6 mmHg at 
a two-sided significance level of 0.05. Assuming 10% drop-out rate, the total targeted sample 
size to be randomized is 130 patients. 
9.8 
Power for analysis of key secondary variables 
Not applicable 
9.9 
Interim analyses  
There will be no interim analysis for this study. 
10 
Ethical considerations  
10.1 
Regulatory and ethical compliance  
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
10.2 
Informed consent procedures  
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents.  
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval. 
10.3 
Responsibilities of the investigator and IRB/IEC  
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
 


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of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs/REBs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made. 
10.4 
Publication of study protocol and results  
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
11 
Protocol adherence  
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted. 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants.  Under no circumstances should an investigator collect additional data 
or conduct any additional procedures for any research related purpose involving any 
investigational drugs.  
If the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR 
11.1 
Protocol Amendments  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days. 
 


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12 
References  
Arar MY, Hogg RJ, Arant BS, Seikaly MG (1994) Etiology of sustained hypertension in 
children in the southwestern United States. Pediatric Nephrology; vol. 8: 186-189. 
CDC Growth charts: www.cdc.gov/growthcharts (2000) 
Filler G, Lepage N (2003) Should the Schwartz formula for estimation of GFR be replaced by 
Cystatin C formula. Pediatric Nephrology; vol. 18: 981-985. 
Flynn J, Meyers K, Pacheco Neto J, et al (2008) Efficacy and Safety of the Angiotensisn 
Receptor Blocker Valsartan in Children with Hypertension Aged 1 to 5 years; vol. 52: 222-
228. 
Hogg R, Furth S, Lemley K, et al (2003) National Kidney Foundation’s Kidney Disease 
Outcomes Quality Initiative Clinical Practice Guidelines for Chronic Kidney Disease in 
Children and Adolescents: Evaluation, Classification, and Stratification. Pediatrics; vol. 111 
(6): 1416-1421. 
Lurbe E, Cifkova R, Cruickshank J, Dillon M, et al (2009) Management of high blood 
pressure in children and adolescents: recommendations of the European Society of 
Hypertension.  Journal of Hypertension; 27: 1719-1742. 
Morgenstern BZ (1994) Hypertension in pediatric patients: Current issues. Mayo Clin Proc; 
69: 1089-1097. 
National High Blood Pressure Education Program Working Group on High Blood Pressure in 
Children and Adolescents (2004) The fourth report on the diagnosis, evaluation, and treatment 
of high blood pressure in children and adolescents. Pediatrics; 114:555-576. 
Reid C, Chantler C (2002) Systemic hypertension. Paediatric Cardiology 2nd ed, Churchill 
Livingstone. 
Sadowski R, Falkner B (1996) Hypertension in pediatric patients. American Journal of 
Kidney Diseases; 27: 305-315.  Journal of Hypertension; 28: 1083-1090. 
Schaefer F, Mieczyslaw L, Zachwieja J, et al (2011) Efficacy and safety of valsartan 
compared to enalapril in hypertensive children: a 12-week, randomized, double-blind, 
parallel-group study. Journal of Hypertension; 29:000-000  1-7. 
Schaefer F, Coppo R, Kadwa M.Y, et al (2011) Efficacy and safety of valsartan in 
hypertensive children 6 months to 5 years of age: A randomized, double-blind, dose-response 
study.   Journal of Hypertension28 (Suppl. A):E473. 
Schwartz GJ, Haycock CW, Edelmann CM Jr, (1976) A simple estimate of glomerular 
filtration rate in children derived from body length and plasma creatinine. Pediatrics; vol. 58: 
259-263. 
Sinaiko A (1994) Treatment of hypertension in children. Pediatric Nephrol; 8:603-609. 
 


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Swinford RD, Portman RJ, (2004) Measurement and treatment of elevated blood pressure in 
the pediatric patient with chronic kidney disease. Advances in Chronic Kidney Disease; 11:2 
143-161.  
Wells T, Blumer J, Meyers KE, et al (2011) Effectiveness and Safety of Valsartan in Children 
Aged 6 to 16Years With Hypertension. Journal of Clinical Hypertension; 13 (5):357-365. 
Williams B, Poulter NR, Brown MJ, et al. (2004) Guidelines for management of 
hypertension: report of the fourth working party of the British Hypertension Society, 2004-
BHS IV. J Human Hypertens; 18(3):139-185. 
Woroniecki R, Flynn J, (2005) How are hypertensive children evaluated and managed?  A 
survey of North American pediatric nephrologists.  Pediatr Nephrol: 20:791-797. 
 


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13 
Appendix 1: Clinically notable laboratory values 
Hematology 
Erythrocyte count 
>50% increase, >30% decrease 
Hemoglobin  
>50% increase, >30% decrease 
Hematocrit  
>50% increase, >30% decrease 
Leukocyte count  
>50% increase, >50% decrease 
Platelet count  
>75% increase, >50% decrease 
Blood Chemistry 
Albumin  
>50% increase, >25% decrease 
Urea  
>50% increase 
Creatinine  
>50% increase 
Glucose  
>50% increase, >50% decrease 
Total bilirubin  
>100% increase 
SGOT / AST 
>150% increase 
SGPT / ALT 
>150% increase 
Sodium  
>5% decrease 
Potassium  
>20% increase, >20% decrease, or any value >5.3 mmol/L 
Chloride  
>10% increase, >10% decrease 
Calcium  
>10% increase, >10% decrease 
Uric Acid  
>50% increase 
GFR (Schwartz) 
>25% decrease 
Clinically notable laboratory values will be forwarded to Novartis at the same time when the 
sites are notified by the Central Lab. 
 


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Appendix 2: Pediatric blood pressure tables and growth charts 
Blood pressure percentiles will be determined with the below BP tables which were published 
by the National High Blood Pressure Education Program Working Group on High Blood 
Pressure in Children and Adolescents (NHBPEP Fourth Report 2004, Lurbe 2009). 
Height percentiles will be determined with below growth charts published by Centers for 
Chronic Disease Control and Prevention (http://www.cdc.gov/growthcharts). 
Using the tables 
 
Use the correct gender growth chart to determine the height percentile. 
Measure and record the child’s MSBP and MDBP. 
Use the correct gender table for SBP and DBP. 
Find the child’s age on the left side of the table. Follow the age row horizontally across the 
table to the intersection of the line for the height percentile (vertical column). 
There, find the 50th and 95th percentiles or values for 20% and 25% above 95th percentile for 
SBP in the left columns and for DBP in the right columns. 
 


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Special methods and scales 
 
 


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BP Levels for girls by Age and Height Percentile (1-6 years old) 
Age (years) 
BP Percentile 
SBP percentile of height (mmHg) 
DBP percentile of height (mmHg) 
  
  
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
50th 
83 
84 
85 
86 
88 
89 
90 
38 
39 
39 
40 
41 
41 
42 
  
95th 
100 
101 
102 
104 
105 
106 
107 
56 
57 
57 
58 
59 
59 
60 
  
20% 
120 
121 
122 
125 
126 
127 
128 
67 
68 
68 
70 
71 
71 
72 
  
25% 
125 
126 
128 
130 
131 
133 
134 
70 
71 
71 
73 
74 
74 
75 
2 
50th 
85 
85 
87 
88 
89 
91 
91 
43 
44 
44 
45 
46 
46 
47 
  
95th 
102 
103 
104 
105 
107 
108 
109 
61 
62 
62 
63 
64 
65 
65 
  
20% 
122 
124 
125 
126 
128 
130 
131 
73 
74 
74 
76 
77 
78 
78 
  
25% 
128 
129 
130 
131 
134 
135 
136 
76 
78 
78 
79 
80 
81 
81 
3 
50th 
86 
87 
88 
89 
91 
92 
93 
47 
48 
48 
49 
50 
50 
51 
  
95th 
104 
104 
105 
107 
108 
109 
110 
65 
66 
66 
67 
68 
68 
69 
  
20% 
125 
125 
126 
128 
130 
131 
132 
78 
79 
79 
80 
82 
82 
83 
  
25% 
130 
130 
131 
134 
135 
136 
138 
81 
83 
83 
84 
85 
85 
86 
4 
50th 
88 
88 
90 
91 
92 
94 
94 
50 
50 
51 
52 
52 
53 
54 
  
95th 
105 
106 
107 
108 
110 
111 
112 
68 
68 
69 
70 
71 
71 
72 
  
20% 
126 
127 
128 
130 
132 
133 
134 
82 
82 
83 
84 
85 
85 
86 
  
25% 
131 
133 
134 
135 
138 
139 
140 
85 
85 
86 
88 
89 
89 
90 
5 
50th 
89 
90 
91 
93 
94 
95 
96 
52 
53 
53 
54 
55 
55 
56 
  
95th 
107 
107 
108 
110 
111 
112 
113 
70 
71 
71 
72 
73 
73 
74 
  
20% 
128 
128 
130 
132 
133 
134 
136 
84 
85 
85 
86 
88 
88 
89 
  
25% 
134 
134 
135 
138 
139 
140 
141 
88 
89 
89 
90 
91 
91 
93 
6 
50th 
91 
92 
93 
94 
96 
97 
98 
54 
54 
55 
56 
56 
57 
58 
  
95th 
108 
109 
110 
111 
113 
114 
115 
72 
72 
73 
74 
74 
75 
76 
  
20% 
130 
131 
132 
133 
136 
137 
138 
86 
86 
88 
89 
89 
90 
91 
 


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Age (years) 
BP Percentile 
SBP percentile of height (mmHg) 
DBP percentile of height (mmHg) 
  
25% 
135 
136 
138 
139 
141 
143 
144 
90 
90 
91 
93 
93 
94 
95 
Source: The Fourth Report on the Diagnosis. Evaluation, and Treatment of High Blood Pressure in Children and Adolescents, Pediatrics. Vol. 114, pp. 555. 
Table modified to delete 99th percentile values and to include calculated percentages (20% and 25 %) above 95th percentile values for ease of reference. 
 


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BP Levels for boys by Age and Height Percentile (1-6 years old)  
Age (years) 
BP Percentile 
SBP percentile of height (mmHg) 
DBP percentile of height (mmHg) 
  
  
5th 
10th 
25th
50th
75th
90th  
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
50th 
80 
81 
83 
85 
87 
88 
89 
34 
35 
36 
37 
38 
39 
39 
  
95th 
98 
99 
101 
103 
104 
106 
106 
54 
54 
55 
56 
57 
58 
58 
  
20% 
118 
119 
121 
124 
125 
127 
127 
65 
65 
66 
67 
68 
70 
70 
  
25% 
123 
124 
126 
129 
130 
133 
133 
68 
68 
69 
70 
71 
73 
73 
2 
50th 
84 
85 
87 
88 
90 
92 
92 
39 
40 
41 
42 
43 
44 
44 
  
95th 
101 
102 
104 
106 
108 
109 
110 
59 
59 
60 
61 
62 
63 
63 
  
20% 
121 
122 
125 
127 
130 
131 
132 
71 
71 
72 
73 
74 
76 
76 
  
25% 
126 
128 
130 
133 
135 
136 
138 
74 
74 
75 
76 
78 
79 
79 
3 
50th 
86 
87 
89 
91 
93 
94 
95 
44 
44 
45 
46 
47 
48 
48 
  
95th 
104 
105 
107 
109 
110 
112 
113 
63 
63 
64 
65 
66 
67 
67 
  
20% 
125 
126 
128 
131 
132 
134 
136 
76 
76 
77 
78 
79 
80 
80 
  
25% 
130 
131 
134 
136 
138 
140 
141 
79 
79 
80 
81 
83 
84 
84 
4 
50th 
88 
89 
91 
93 
95 
96 
97 
47 
48 
49 
50 
51 
51 
52 
  
95th 
106 
107 
109 
111 
112 
114 
115 
66 
67 
68 
69 
70 
71 
71 
  
20% 
127 
128 
131 
133 
134 
137 
138 
79 
80 
82 
83 
84 
85 
85 
  
25% 
133 
134 
136 
139 
140 
143 
144 
83 
84 
85 
86 
88 
89 
89 
5 
50th 
90 
91 
93 
95 
96 
98 
98 
50 
51 
52 
53 
54 
55 
55 
  
95th 
108 
109 
110 
112 
114 
115 
116 
69 
70 
71 
72 
73 
74 
74 
  
20% 
130 
131 
132 
134 
137 
138 
139 
83 
84 
85 
86 
88 
89 
89 
  
25% 
135 
136 
138 
140 
143 
144 
145 
86 
88 
89 
90 
91 
93 
93 
6 
50th 
91 
92 
94 
96 
98 
99 
100 
53 
53 
54 
55 
56 
57 
57 
  
95th 
109 
110 
112 
114 
115 
117 
117 
72 
72 
73 
74 
75 
76 
76 
  
20% 
131 
132 
134 
137 
138 
140 
140 
86 
86 
88 
89 
90 
91 
91 
 


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Age (years) 
BP Percentile 
SBP percentile of height (mmHg) 
DBP percentile of height (mmHg) 
  
25% 
136 
138 
140 
143 
144 
146 
146 
90 
90 
91 
93 
94 
95 
95 
Source: The Fourth Report on the Diagnosis. Evaluation, and Treatment of High Blood Pressure in Children and Adolescents, Pediatrics. Vol. 114, pp. 555. 
Table modified to delete 99th percentile values and to include calculated percentages (20% and 25 %) above 95th percentile values for ease of reference. 
 
 

SAP_001.pdf: 
Clinical Development
VAL489/Valsartan
Clinical Trial Protocol CVAL489K2306
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
RAP Module 3 – Detailed Statistical Methodology
Author:
 
Document type:
RAP Documentation
Document status:
Final Draft 2.0
Release date:
Nov 11, 2016
Number of pages:
14
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
9.7
Statistical methods planned in the protocol and determination of
sample size
Data will be analyzed by according to the data analysis section 9 of the study protocol that is 
available in Appendix 16.1.1 of the CSR.  Important information is given in the following 
sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR.
An overview of the study design is presented in the following figure:
9.7.1
Statistical and analytical plans
9.7.1.1
Subjects and treatments 
The following analysis populations will be defined for statistical analyses:
Randomized Set (RAN) - All patients who receive a randomization number, regardless of 
receiving double blind study medication. 
Full-analysis Set (FAS) - All patients randomized with at least one follow-up efficacy 
assessment in the double blind phase. Following the intent-to-treat principle, patients will be 
analyzed according to the treatment assigned at randomization. However, patients who were 
not qualified for randomization and were inadvertently randomized into the study are 
excluded from the FAS, provided these patients did not receive study drug.


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Per-protocol Set (PPS) - All patients in FAS without any major protocol deviations in the 
double-blind phase. The major protocol deviations will be pre-specified prior to unblinding 
the treatment codes for analyses.   
Safety Set (SAF) - All patients who received at least one dose of study medication in the 
double blind phase. Patients will be analyzed according to treatment they received.
Open-label Full Analysis Set (OFAS) - All patients entering the open label phase with at 
least one follow-up efficacy assessment during open label phase. 
Open-label Safety Set (OSAF) - All patients who received at least one dose of study
medication in open-label phase. 
Subject disposition will be summarized for the following three periods: screening period (for 
all screened patients), double-blind period (period 1) and open-label period (period 2).  The 
number of patients for the analysis sets will be provided.
   
Table 1 Subject Classification
Analysis Set
PD severity codes that
   
cause subjects to be excluded
Non-PD criteria that cause a
subject to be excluded
RAN
NA
Not randomized
FAS
8
Not in RAN;
Mistakenly randomized and not receive study
drug;
No post-randomization assessment of any 
efficacy variables during the double-blind 
treatment period
PPS
1*, 8
Not in FAS;
SAF
5, 8
NA
OFAS
8
No post-randomization assessment of any 
efficacy variables during the open label treatment 
period
OSAF
5,8
Not received any study medication in open-label 
phase
* PDs with which occurred in the open-label phase do not lead to exclusion from FAS, PPS or 
SAF.  
The severity codes of PDs causing subjects to be excluded from analysis set are recorded in
the latest version of VAP M3 document.  Protocol deviations (with and without leading to 
exclusion from analysis sets) will be summarized during the double-blind period for RAN and 
also during the open-label period 2 for the randomized patients who entered the open-label 
period 2.
For RAN, summary statistics will be provided by treatment group for demographics and other 
baseline characteristics including age, height, weight, BMI, head circumference, MSBP (mean 
systolic blood pressure), MDBP (mean diastolic blood pressure), pulse, as continuous 
variables and  gender, race, ethnicity, continuing use of prior antihypertensive treatment


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(Yes/No), CKD (chronic kidney disease) /non-CKD as qualitative variables. Comparisons of 
treatment groups with respect to the demographics and baseline characteristics will be 
performed using chi-square tests or a t test as appropriate. The results of these tests are 
provided for descriptive purposes, and will not be used as a formal basis to determine the 
factors to be included in statistical models.
Relevant medical history and current medical conditions will be summarized by treatment 
group for RAN.
Study drug exposure in Period 1 (double-blind phase):
Duration (in days) of exposure to study drug in Period 1 will be computed and summarized by 
treatment group(for all patients as well) for SAF as follows.
last study drug date in Period 1 – study drug start date in Period 1+ 1, 
or 
last visit date in Period 1 – study drug start date in Period 1 if the last study drug date in 
Period 1 is missing or incomplete.
Study drug start date in Period 1 is Visit 2 date. Last study drug date in Period 1 is the last 
known study drug date from the study phase completion panel.
Study drug exposure in Period 2 (open-label phase):
Duration (in days) of exposure to study drug in period 2 will be summarized by each dose, i.e. 
1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg (and non-protocol defined dose, if any) as well as total 
exposure on any dose for OSAF as follows. 
The total study drug exposure to any dose in Period 2 is calculated as below:
Last study drug date in Period 2 – study drug start date in Period 2 +1
or 
last visit date in Period 2 – study drug start date in Period 2 if the last study drug date in 
Period 2 is missing or incomplete.
Study drug start date in Period 2 is Visit 5 date. Last study drug date in Period 2 is the last 
known study drug date from the study completion panel.
Start and end dates for individual doses will be used to calculate duration of exposure by dose.  
For each dose, duration of total exposure to each specific dose will be derived accordingly.   
In addition, duration (in days) of exposure to study drug during the entire study (with Period 1 
and Period 2 together) will be summarized similarly by dose and overall (including all doses)  
for SAF.
Prior and concomitant antihypertensive medications taken during the study will be 
summarized by treatment for the following 3 periods separately: prior to taking study 
medication by double-blind treatment in SAF, double-blind treatment period 1 by treatment 
in SAF and open-level period 2 in OSAF.  Concomitant non-antihypertensive medications and 
significant non-drug therapies during the study will be summarized for (i) prior to study drug 
and (ii) after study drug.


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The same summaries as above will be performed for the subgroups of CKD and non-CKD
patients.
9.7.1.2
Efficacy evaluation
9.7.1.2.1 Analysis of the primary variable(s)
The primary objective is to evaluate if a dose dependent reduction in MSBP exists when 
comparing two doses of valsartan solution (0.25 mg/kg and 4 mg/kg) over a 6 week period in 
children 1-5 years old with hypertension (MSBP ≥ 95th percentile for age, gender and height), 
with or without CKD. 
The primary efficacy variable is change from baseline (Visit 2) in mean systolic blood 
pressure (MSBP) at Week 6 endpoint during the double-blind period 1. The primary analysis 
will be performed on the FAS.
Statistical hypothesis, model, and method of analysis
The null hypothesis is that there is no treatment difference in the reduction of MSBP (mmHg) 
between dose groups 0.25mg/kg (low) and 4 mg/kg (high).  The alternative hypothesis is that 
there is a difference between dose groups 0.25 mg/kg and 4 mg/kg. The hypotheses were 
expressed as follows:
H0: δlow = δhigh    versus H1: δlow ≠ δhigh    
where δs are the mean changes from baseline at Week 6 endpoint in MSBP in the treatment 
group indicated.
The treatment comparison will be tested at a two-sided significance level of 0.05.  The change 
from baseline in MSBP at Week 6 endpoint during double-blind phase will be analyzed in the 
FAS using an analysis of covariance model (ANCOVA) as the primary analysis model with 
treatment and CKD strata as factors and baseline MSBP as the covariate. The baseline MSBP 
values will be centered by subtracting the overall mean of all patients included in the analysis 
for FAS. For patients with missing values at Week 6, the last post-baseline observation during 
the double-blind period will be carried forward (LOCF) as the Week 6 endpoint. CKD strata
(yes/no) are the stratification factor used for IRT randomization. When the investigator 
entered a wrong stratification stratum in IRT, a protocol deviation (PD code = S01) is
registered and the correct stratification factor is used for all analyses. The estimated treatment 
difference for the treatment comparison will be tabulated along with the associated 95% 
confidence interval and two-sided p-value. Treatment by baseline MSBP interaction will be 
examined by adding the treatment-by-baseline-MSBP term to the primary analysis model.  
The results of this assessment will be presented in the CSR section 16.1.9. 
Supportive analyses 
In addition to the primary analysis based on the FAS population, a similar analysis for the 
primary endpoint will also be performed on the PPS population as a supplementary 
assessment.


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To further assess the dose response, the change from baseline at Week 6 endpoint in MSBP 
will be analyzed in FAS by an analysis of covariance model with CKD strata as the factor and 
baseline MSBP as a covariate, and dose per body weight (mg/kg) as the main regressor.  The 
estimated slope with 95% confidence interval and p-value for the dose per body weight will 
be provided.  
Subgroup analysis for CKD/non CKD patients
Similar analysis of the primary efficacy variable for the treatment comparison will be 
performed for the subgroup of CKD patients and for the subgroup of non-CKD patients (per 
CKD yes/no strata).  The estimated treatment difference, 95% confidence interval and two-
sided p-value for the treatment comparison within each subgroup analysis will be provided.  
Furthermore, treatment-by-CKD strata interaction in the entire FAS will be assessed by 
inclusion of the additional interaction term to the primary analysis model for the overall 
analysis in FAS and the p-value for the respective interaction term will be provided.
Descriptive statistics
The change from baseline in MSBP (together with the corresponding baseline and post-
baseline MSBP) during double-blind phase will be summarized by treatment and visit 
(including Week 6 LOCF endpoint) for the FAS (for overall as well as for each of the
CKD/non-CKD subgroup)  . The MSBP will be plotted versus visit (not including Week 6 
LOCF endpoint) by treatment group for the FAS (for overall as well as for each of CKD/non-
CKD subgroup). In addition, change from baseline in MSBP will also be plotted versus visit 
by treatment group for the FAS (for overall as well as for each of CKD/non-CKD subgroup).
9.7.1.2.2 Analysis of secondary variable(s)
The two-sided 0.05 significance level and 95% confidence interval will be provided for the 
following analyses as applicable.  The analyses described below will be carried out in FAS for 
the double-blind period 1 and in OFAS for the open-label period 2.    
Period 1
Change from baseline in mean diastolic blood pressure (MDBP) 
Similar analysis as for MSBP will be performed for MDBP to evaluate the reduction of 
MDBP from baseline. Change from baseline at Week 6 endpoint in the double-blind period
(using LOCF) in MDBP will be analyzed for FAS patients using an analysis of covariance 
(ANCOVA) model with treatment and CKD strata as factors and baseline MDBP as the
covariate. Treatment comparison will be performed at the two-sided significance level of 0.05. 
The estimated treatment effects, treatment difference, 95% confidence interval, and p-value
for the treatment comparison will be provided.  In addition, similar supportive analysis for 
PPS will be also provided.
Similar summary statistics and plots as for MSBP will be provided for change from baseline 
in MDBP.
Percentage of patients achieving MSBP < 90th percentile for age, gender and height
Percentage of patients achieving MSBP < 90th percentile for age, gender and height at Week 6 
endpoint will be analyzed using a logistic regression model with treatment and CKD strata as 


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factors and baseline MSBP as the covariate. The odds ratio of Valsartan 4.0 mg/kg / Valsartan 
0.25 mg/kg will be computed, along with the associated 95% confidence interval and p-value.   
In addition, the number and % of patients achieving MSBP < 90th percentile for age, gender 
and height will be summarized by treatment and visit (including the Week 6 endpoint).   
Similar analyses will be carried out for the CKD and non-CKD subgroups of patients.
Percentage of patients achieving MSBP < 95th percentile for age, gender and 
height
Percentage of patients achieving MSBP < 95th percentile for age, gender and height at Week 6 
endpoint will be also analyzed using a logistic regression model with treatment and CKD 
strata as factors and baseline MSBP as the covariate. The odds ratio of Valsartan 4.0 mg/kg / 
Valsartan 0.25 mg/kg will be computed, along with the associated 95% confidence interval
and p-value.  In addition, the number (and %) of patients achieving MSBP < 95th percentile 
for age, gender and height will be summarized by treatment and visit (including the Week 6 
endpoint). Similar analyses will be carried out for the CKD and non-CKD subgroups of 
patients.
Percentage of patients achieving both MSBP and MDBP < 90th percentile for age, 
gender and height; percentage of patients achieving both MSBP and MDBP < 95th 
percentile for age, gender and heights.
Percentage of patients achieving both MSBP and MDBP < 90th percentile for age, gender and 
height at Week 6 endpoint will be analyzed using a logistic regression model with treatment
and CKD strata as factors and baseline MSBP as the covariate. The odds ratio of Valsartan 4.0 
mg/kg / Valsartan 0.25 mg/kg will be computed, along with the associated 95% confidence 
interval and p-value.  In addition, the number (and %) of patients achieving both MSBP and 
MDBP < 90th percentile for age, gender and height will be summarized by treatment and visit 
(including the Week 6 endpoint).   Similar analyses will be carried out for the CKD and non-
CKD subgroups of patients.
Similar analyses will be also performed for the percentage of patients achieving both MSBP
and MDBP < 95th percentile for age, gender and height at Week 6 endpoint.
UACR (Urine Albumin Creatinine Ratio) in CKD patients
UACR was collected for CKD patients only.  The UACR value at a given visit for a patient is 
to be derived by the median of the three lab values collected for that visit.  The UACR value
will be assessed in the CKD patients.
Change from baseline in log(base 10)-transformed UACR will be analyzed using an 
ANCOVA model with treatment as a factor and log (base 10)-transformed baseline UACR as 
a covariate.  The estimated treatment effects, treatment difference, 95% confidence interval, 
and p-value for the treatment comparison will be provided.  The estimates to be presented will 
be in back-transformed scale.   


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Instead of the specified % change from baseline in UACR <= 25% in the protocol, the UACR 
response is to be defined as a percentage reduction from baseline in UACR ≥25%.  The 
proportion of patients with UACR response at Week 6 endpoint (LOCF) will be analyzed 
using a logistic regression with treatment as a factor and baseline UACR as a covariate. The 
odds ratio of Valsartan 4.0 mg/kg / Valsartan 0.25 mg/kg will be computed, along with the 
associated 95% confidence interval and p-value.  
Summary statistics (n, mean, standard deviation, median, min, max, geometric mean) of the 
UACR values for baseline, Week 6 endpoint and the respective change (from baseline at 
Week 6 endpoint) will be provided by treatment group. The number and percent of patients
will be summarized by treatment group for each of the following categories in change from 
baseline at Week 6 endpoint: >= 25% reduction, change is less than 25% in positive/negative 
direction, and >=25% increase.  Similar summary will be also provided by treatment group 
for the following categories: :  >= 50% reduction, change is less than 50% in positive/negative 
direction and >=50% increase.
Cystain C GFR (Glomerular filtration rate) in CKD patients
cGFR (Cystain C GFR) was collected and assessed for CKD patients only.
Change from baseline in log(base 10)-transformed cGFR will be analyzed using an ANCOVA 
model with treatment as a factor and log(base 10)-transformed baseline cGFR as a covariate.  
The estimated treatment effects, treatment difference, 95% confidence interval and p-value for 
the treatment comparison will be provided.  The estimates to be presented will be in back -
transformed scale.   
Summary statistics (n, mean, standard deviation, median, min, max, geometric mean) of the 
cGFR values for baseline, Week 6 endpoint and the respective change (from baseline at Week 
6 endpoint) will be provided by treatment group.
Period 2
The efficacy data during the open-label period 2 will be assessed based on the summary 
statistics and plots below in OFAS.  The summaries and plots will be presented with one 
single arm including all patients evaluated in the open-label period 2.
1. Change from baseline (Visit 2) in MSBP (together with the corresponding baseline 
and post-baseline MSBP) will be summarized (with n, mean, standard deviation, 
median, min, and max) by visit (including LOCF endpoint at end of the open-label 
period 2) during the open-label period 2.  Similar summary will be provided for 
MDBP.  Similar summaries for MSBP and MDBP will also be provided for the CKD 
and non-CKD subgroups.  In addition, similar plots as for MSBP/MDBP in the 
double-blind period will be provided with one single arm for the OFAS in the open-
label period 2.    
2. Percentage of patients achieving MSBP < 90th percentile (as well as MSBP < 95th
percentile, both MSBP/MDBP < 90th percentile, and both MSBP/MDBP < 95th
percentile) for age, gender and height will be summarized by visit during the open-


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label period 2.  In addition, similar summaries will be provided for the CKD and non-
CKD patients
3. In the CKD patients, change from baseline in UACR (together with the corresponding 
baseline and post-baseline UACR) will be summarized (with n, mean, standard 
deviation, median, min, max and geometric mean) by visit during the open-label 
period 2.  In addition, the n and percentage of CKD patients in the categories of 
UACR changes (as defined in the assessment during the period 1) will be provided by 
visit during the open-label period 2. 
4. In the CKD patients, change from baseline in cGFR (together with the corresponding 
baseline and post-baseline cGFR) will be summarized (with n, mean, standard 
deviation, median, min, max and geometric mean) by visit during the open-label 
period 2.  
9.7.1.3
Safety evaluation
The safety (SAF) and open-label safety (OSAF) populations will be used as appropriate for 
summaries of the double-blind and open-label phases, respectively. Unless specified 
otherwise, comparison will be made to Baseline, which will be the measurement taken at Day 
1 (Visit 2), or the sample obtained at an earlier visit (scheduled or unscheduled) which is
closest to Day 1 if Day 1 measurement is missing.
9.7.1.3.1 Adverse Events
The number and percentage of patients reporting any adverse event during the double-blind 
treatment period and open-label phase will be summarized by primary system organ class, 
preferred term, and treatment (only for double-blind phase). Adverse events that are suspected 
to be related to study drug will be summarized.  The maximum severity of all adverse events 
will be summarized.  Serious adverse events and adverse events leading to study drug 
discontinuation (based on CRF AE data) will be summarized by primary system organ class, 
preferred term, and treatment (only for double-blind phase), and will be listed by patient.
In addition, all summaries will also be performed for the subgroups of CKD and non-CKD 
patients for double-blind phase and open-label phase, respectively.
9.7.1.3.2 Laboratory values
The details of lab parameters collected, SI units (note, only SI units will be reported), and 
normal ranges will be listed in CSR Section 16.
Table 2 Laboratory schedules by study protocol
Safety measurement
Visit 
Standard hematology:
Red blood cell count, hemoglobin, 
hematocrit, white blood cell count with 
differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils), 
platelet count
Visits 1, 2, 5, 8, 9, 10 and 11


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Safety measurement
Visit 
Complete blood chemistry :
Creatinine, non-fasting glucose, total 
bilirubin, AST/SGOT, ALT/SGPT, ALP, 
sodium, potassium, bicarbonate (total 
CO2), chloride, calcium, phosphorous, 
total protein, albumin, uric acid, 
cholesterol, triglycerides and eGFR
Visits 1, 2, 5, 8 and 11
Abbreviated blood chemistry:
Urea, creatinine, sodium, potassium, 
bicarbonate (total CO2) and eGFR
Visits 9, and 10
Cystatin C GFR for CKD patients
Visits 2, 5, 10 and 11
Standard urinalysis: pH, specific 
gravity, glucose, protein, bilirubin, 
ketones, leukocytes, blood
Visits 1, 2, 5, and 11
Urinary albumin creatinine ratio 
(UACR) for CKD patients
Visits 2, 5, 10, and 11
Laboratory data will be summarized at baseline, endpoint of Period 1 (using LOCF) and
endpoint of Period 2 (using LOCF) for absolute values and changes from baseline for each
treatment. Baseline is defined as the last non-missing value prior to or at Week 0 (Visit 2). 
Laboratory shift tables are presented using normal ranges. In addition, the number and 
percentage of patients meeting pre-specified notable percentage change (see below) from 
baseline to any post-baseline result will be summarized. Separate listings are provided for 
hematology, blood chemistry, and urinalysis. 
Pre-specified notable percentage changes for laboratory tests
Hematology
Erythrocyte count
>50% increase, >30% decrease
Hemoglobin 
>50% increase, >30% decrease
Hematocrit 
>50% increase, >30% decrease
Leukocyte count 
>50% increase, >50% decrease
Platelet count 
>75% increase, >50% decrease
Blood Chemistry
Albumin 
>50% increase, >25% decrease
BUN
>50% increase
Creatinine 
>50% increase
Glucose 
>50% increase, >50% decrease


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Total bilirubin 
>100% increase
SGOT / AST
>150% increase
SGPT / ALT
>150% increase
Sodium 
>5% decrease
Potassium 
>20% increase, >20% decrease
Chloride 
>10% increase, >10% decrease
Calcium 
>10% increase, >10% decrease
Uric Acid 
>50% increase
GFR (Schwartz)
>25% decrease
*Protocol stated that the laboratory variable is “urea”. BUN (blood urea nitrogen) was reported in the 
study. Both urea and BUN were analyzed using the same analytical test and were identical when 
expressed in mmol/L. 
Programming notes: the attached spreadsheet provides details regarding the parameters 
included in each laboratory relevant output.
CVAL489K2306  
RAP M7 lrs report
In addition, the number and percentage of patients meeting pre-specified selected notable 
absolute biochemistry values (see below) will be summarized.(Table 3) will be summarized.
   
Table 3
Pre-specified selected notable absolute values for laboratory tests  
Laboratory Variables
Notable criteria
Total bilirubin
> 2 x upper limit of the reference range
SGOT
> 3 x upper limit of the reference range
> 5 x upper limit of the reference range
> 8 x upper limit of the reference range
> 10 x upper limit of the reference range
SGPT
> 3 x upper limit of the reference range
> 5 x upper limit of the reference range
> 8 x upper limit of the reference range
> 10 x upper limit of the reference range
Potassium
> 5.3 mEq/L
> 5.5 mEq/L


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> 6.0 mEq/L
9.7.1.3.3 Vital signs and other safety assessments
The change from baseline in pulse, height, body weight, and head circumference will be 
summarized by treatment (only for double-blind phase) and visit for both periods.
The number of subjects with or without clinically significant ECG abnormalities at each ECG 
assessment will be tabulated.
The taste assessment will also be summarized on SAF.
9.7.1.4
Interim analyses
NA
9.7.1.5
Other topics
NA
9.7.2
Determination of sample size
The sample size of 116 completed patients is calculated based on the primary efficacy 
variable, change from baseline in mean systolic blood pressure, and a standard deviation of 11 
mmHg (based on previous data) is used. The sample size is calculated to ensure at least 80% 
power to detect statistical significance for the comparison valsartan 0.25 mg/kg versus 
valsartan 4 mg/kg under the alternative hypothesis that the treatment difference is 6 mmHg at 
a two-sided significance level of 0.05. Assuming 10% drop-out rate, the total targeted sample 
size to be randomized is 130 patients.
10
Clinical Study Report -
Appendix 16.1.9  Documentation of statistical methods
10.1
Introduction
This appendix gives details about statistical methods in addition to the report text. All 
analyses will be performed using SAS Version 9.4 in a UNIX environment. 
10.2
Definition of pooled centers for efficacy analysis
Due to small sample size at most individual study centers, data from centers within a 
geographic region will be pooled for the efficacy analysis. Center pooling will be pre-defined 
prior to the database lock and used in the efficacy analyses. If one or two particular centers 


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have substantially larger enrollment than other centers in one geographic area, the “super 
center” may be left as one group by itself.  
10.3
Sample SAS program for efficacy analyses
The SAS code provided is intended to reflect the type of analyses planned; however, the 
actual code used may not be a verbatim of this example.  The variable names used in this code 
were selected for understanding of the methodology and do not necessarily reflect the actual 
variable names in the data.
ANCOVA model for primary analysis
For the ANCOVA model in the analysis of change from baseline in MSBP at Week 6, the 
following SAS code are used:
PROC MIXED DATA=eff;
CLASS treatment CKD;
WHERE population = population (FAS);
MODEL response= treatment  CKD  baseline_MSBP;
             ESTIMATE ‘Valsartan High dose vs. Valsartan Low dose’ treatment 1 -1/CL;
run;
   - “eff” denotes the efficacy data set containing individual observations for the change from 
baseline in MSBP
   - “treatment” denotes the variable containing the treatment groups (Low, High)   
  - “CKD” denotes the variable containing the CKD strata (CKD and non-CKD )
   - “baseline_MSBP” denotes the centered baseline variable containing individual patient 
baseline MSBP deviation from the mean of all FAS patients.
Logistic regression model 
The SAS procedure MIXED is used with the following SAS code:
proc logistic data=eff;
  class treatment CKD/(param=ref ref=’Low’);
  model response = trt base;
  contrast 'High dose vs. Low dose' treatment 1
-1 / estimate=exp;
run;
where y, region, trt, and base denote control or response variable, region, treatment, and 
baseline value (msSBP, or msDBP for y involving only msDBP) respectively.
The odds ratio of High dose /Low dose will be computed, along with associated 95% 
confidence intervals.


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Comparability of baseline characteristics
Baseline comparability between the three treatment groups, for continuous parameters, was 
tested using two-sample t-test:
proc ttest;
  
class treatment;
  
  variable <Quantitative baseline variable>;
run;
Baseline comparability between treatment groups, for categorical parameters, was tested using 
a CMH chi square-test:
      proc freq ;
        tables treatment* < Qualitative baseline variable > / cmh noprint;
        output out=<output dataset> cmhga;
      run;