A Multicenter, Double-blind 52 to 104 Week Off-therapy Extension Study to Evaluate the Long Term Growth and Development of Pediatric Hypertensive Patients 6 - 17 Years of Age Previously Treated With Aliskiren in Studies CSPP100A2365 and/or CSPP100A2365E1
Conditions: Hypertension
Sponsor: Noden Pharma

 
Document Type: 
 
Protocol and Protocol Amendments 
Official Title:  
 
A multicenter, 52 to 104 week extension study to 
 
 
 
 
evaluate the long term growth and development of 
 
 
 
 
pediatric hypertensive patients 6–17 years of age treated 
 
 
 
 
previously with aliskiren 
NCT Number: 
 
NCT01420068 
Document Release Date: 
Final Protocol: 10 June 2011 

 
 
 
Clinical Development 
SPP100A/Aliskiren 
Clinical Trial Protocol CSPP100A2365E2 
A multicenter, 52 to 104 week extension study to evaluate 
the long term growth and development of pediatric 
hypertensive patients 6 – 17 years of age treated previously 
with aliskiren 
Authors: 
Satlin Li
InYoung 
Document type: 
Clinical Trial Protocol 
Version number: 
Original protocol 
Development phase: 
III  
Release date: 
10-Jun-2011 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
Template version 24 May 2011 
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Clinical Trial Protocol 
 
Protocol No. CSPP100A2365E2 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 4 
List of figures ...................................................................................................................... 4 
Protocol synopsis ................................................................................................................. 7 
1 
Introduction ......................................................................................................................... 9 
1.1 
Background .............................................................................................................. 9 
1.2 
Purpose .................................................................................................................. 11 
2 
Study objectives ................................................................................................................. 11 
2.1 
Primary objectives ................................................................................................. 11 
2.2 
Secondary objectives ............................................................................................. 12 
2.3 
Exploratory objectives ........................................................................................... 12 
3 
Investigational plan ........................................................................................................... 12 
3.1 
Study design........................................................................................................... 12 
3.2 
Rationale of study design ....................................................................................... 12 
3.3 
Rationale of dose/regimen, duration of treatment ................................................. 13 
3.4 
Rationale for choice of comparator ....................................................................... 13 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 13 
4 
Population .......................................................................................................................... 13 
4.1 
Inclusion criteria .................................................................................................... 13 
4.2 
Exclusion criteria ................................................................................................... 13 
5 
Treatment ........................................................................................................................... 14 
5.1 
Investigational and control treatment .................................................................... 14 
5.2 
Treatment arms ...................................................................................................... 14 
5.3 
Treatment assignment ............................................................................................ 14 
5.4 
Treatment blinding ................................................................................................. 14 
5.5 
Treating the patient ................................................................................................ 14 
5.5.1 
Patient numbering ................................................................................. 14 
5.5.2 
Dispensing the study treatment ............................................................. 14 
5.5.3 
Supply, storage and tracking of study treatment ................................... 14 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 14 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 14 
5.5.6 
Rescue medication ................................................................................ 14 
5.5.7 
Concomitant treatment .......................................................................... 14 
5.5.8 
Prohibited treatment .............................................................................. 15 
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Clinical Trial Protocol 
 
Protocol No. CSPP100A2365E2 
 
5.5.9 
Discontinuation of study treatment and premature patient 
withdrawal ............................................................................................. 15 
5.5.10 
Emergency unblinding of treatment assignment ................................... 15 
5.5.11 
Study completion and post-study treatment .......................................... 15 
5.5.12 
Early study termination ......................................................................... 15 
6 
Visit schedule and assessments ......................................................................................... 16 
6.1 
Information to be collected on screening failures.................................................. 16 
6.2 
Patient demographics/other baseline characteristics ............................................. 16 
6.3 
Treatment exposure and compliance ..................................................................... 16 
6.4 
Efficacy .................................................................................................................. 16 
6.5 
Safety ..................................................................................................................... 16 
6.5.1 
Height and weight ................................................................................. 16 
6.5.2 
Laboratory evaluations .......................................................................... 16 
6.5.3 
Clinical chemistry ................................................................................. 17 
6.5.4 
Pregnancy and assessments of fertility ................................................. 17 
6.5.5 
Appropriateness of safety measurements .............................................. 17 
6.6 
Other assessments .................................................................................................. 17 
6.6.1 
Neurocognitive evaluation .................................................................... 17 
6.6.2 
Resource utilization ............................................................................... 17 
6.6.3 
Health-related Quality of Life ............................................................... 17 
6.6.4 
Pharmacokinetics .................................................................................. 18 
6.6.5 
Pharmacogenetics/pharmacogenomics ................................................. 18 
6.6.6 
Other biomarkers ................................................................................... 18 
7 
Safety monitoring .............................................................................................................. 18 
7.1 
Adverse events ....................................................................................................... 18 
7.2 
Serious adverse event reporting ............................................................................. 18 
7.3 
Pregnancies ............................................................................................................ 19 
8 
Data review and database management ............................................................................. 19 
8.1 
Site monitoring ...................................................................................................... 19 
8.2 
Data collection ....................................................................................................... 20 
8.3 
Database management and quality control ............................................................ 20 
9 
Data analysis ...................................................................................................................... 20 
9.1 
Analysis sets .......................................................................................................... 21 
9.2 
Patient demographics and other baseline characteristics ....................................... 21 
9.3 
Treatments ............................................................................................................. 21 
9.4 
Analysis of the primary variable(s) ....................................................................... 21 
9.4.1 
Variable ................................................................................................. 21 
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Clinical Trial Protocol 
 
Protocol No. CSPP100A2365E2 
 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 21 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 21 
9.4.4 
Supportive analyses ............................................................................... 21 
9.5 
Analysis of secondary variables ............................................................................ 22 
9.5.1 
Key secondary variables ....................................................................... 22 
9.5.2 
Efficacy variables .................................................................................. 22 
9.5.3 
Safety variables ..................................................................................... 22 
9.5.4 
Pharmacokinetics .................................................................................. 22 
9.5.5 
Pharmacogenetics/pharmacogenomics ................................................. 22 
9.5.6 
Biomarkers ............................................................................................ 22 
9.5.7 
PK/PD ................................................................................................... 22 
9.6 
Sample size calculation .......................................................................................... 22 
9.7 
Power for analysis of key secondary variables ...................................................... 22 
9.8 
Interim analyses ..................................................................................................... 23 
10  Ethical considerations ........................................................................................................ 23 
10.1 
Regulatory and ethical compliance ........................................................................ 23 
10.2 
Informed consent procedures ................................................................................. 23 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 23 
10.4 
Publication of study protocol and results............................................................... 24 
11  Protocol adherence ............................................................................................................ 24 
11.1 
Protocol Amendments ........................................................................................... 24 
12  References ......................................................................................................................... 25 
13  Appendix 1: Clinically notable laboratory values ............................................................. 26 
14  Appendix 2:  Neurocognitive assessment .......................................................................... 27 
 
List of tables 
Table 3-1 
Study design .......................................................................................... 12 
Table 6-1 
Assessment schedule ............................................................................. 16 
Table 13-1 
Clinically notable laboratory values...................................................... 26 
Table 14-1 
Neurocognitive tests .............................................................................. 27 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 12 
 
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Clinical Trial Protocol 
 
Protocol No. CSPP100A2365E2 
 
List of abbreviations 
AE 
 
adverse event 
ALT 
 
alanine aminotransferase 
AST 
 
aspartate aminotransferase 
eCRF  
Electronic Case Report Form 
CPO 
 
Country Pharma Organization 
CRO  
Contract Research Organization 
DS&E  
Drug Safety & Epidemiology 
ECG  
Electrocardiogram 
EDC  
Electronic Data Capture 
EFS 
 
Enrolled to follow-up set 
ICH 
International Conference on Harmonization of Technical Requirements for    
Registration of Pharmaceuticals for Human Use 
IEC 
  
Independent Ethics Committee 
IRB 
 
Institutional Review Board 
IVRS  
Interactive Voice Response System  
PIP  
 
Pediatric Investigational Plan 
SAE 
 
serious adverse event 
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Clinical Trial Protocol 
 
Protocol No. CSPP100A2365E2 
 
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 
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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Clinical Trial Protocol 
 
Protocol No. CSPP100A2365E2 
 
Protocol synopsis 
Title of study:  A multicenter, 52 to 104 week off-therapy extension study to evaluate the long term 
growth and development of pediatric hypertensive patients 6 – 17 years of age previously treated with 
aliskiren in studies CSPP100A2365 and/or CSPP100A2365E1  
Purpose and rationale:  The purpose of this 52 to 104 week off-therapy follow-up to studies 
CSPP100A2365 and CSPP100A2365E1 is to evaluate the long term growth and development of 
children 6 – 17 years old (6 to less than 18 years old at baseline in study CSPP100A2365) with 
hypertension (msSBP ≥ 95th percentile for age, gender and height) at baseline in study 
CSPP100A2365, previously treated with aliskiren.  Patients identified in study CSPP100A2365 to have 
primary hypertension will be followed for 52 weeks (1 year) after the completion of study 
CSPP100A2365E1.  Patients identified in study CSPP100A2365 to have secondary hypertension will 
be followed for 104 weeks (2 years) after the completion of study CSPP100A2365E1.  The 
assessment of growth and development through height and weight measurement will be performed on 
all patients for 52 weeks, after which patients with primary hypertension will complete.  The 
assessment of patients with secondary hypertension will continue for an additional 52 weeks during 
which growth and development will continue to be assessed with added neurocognitive and renal 
function evaluations. 
This study is in compliance with the EMA PIP Positive Opinion in support of the monotherapy 
registration of aliskiren for the treatment of hypertension in pediatric patients 6 – 17 years of age. 
Objectives:  
• 
To evaluate the long term growth and development of pediatric hypertensive patients 6 – 17 years 
of age when previously treated with aliskiren 
Population: The study population will consist of male and female hypertensive pediatric patients who 
have completed the CSPP100A2365E1 protocol.  These patients were 6 – 17 years old and had an 
msSBP ≥ 95th percentile for age, gender and height at baseline (randomization) in study 
CSPP100A2365.  Patients will continue to be stratified by CSPP100A2365 baseline weight, age, 
hypertension etiology and region.  Centers from the US and EU participating in CSPP100A2365 and 
CSPP100A2365E1 will participate in this off-therapy follow-up.  
Inclusion/Exclusion criteria:  
All patients are to have met entry inclusion and exclusion criteria for CSPP100A2365 and 
CSPP100A2365E1. 
• 
Successful completion of the CSPP100A2365E1 protocol 
• 
Written informed consent; patients who are eligible to participate in this long-term off-therapy 
extension and whose parent(s)/guardian (s) consent in writing to their doing so after the purpose 
and nature of this investigation has been clearly explained to them.  An assent will be obtained for 
some patients depending upon their age, maturity, capacity for understanding, and the local 
requirements regarding assents.  Written informed consent must be obtained before any 
assessment is performed.  
Investigational and reference therapy:  
• 
Investigational therapy:  none 
• 
Reference therapy:  none 
Study medication is not used in this trial. 
Study design: This is a multicenter, 52 to 104 week off-therapy extension to evaluate long-term 
growth and development in pediatric hypertensive patients 6 – 17 years of age at initiation of treatment 
with aliskiren in study CSPP100A2365.  Eligible patients will continue to be stratified by age (6 to 11 
years and 12 to 17 years) at study CSPP100A2365 baseline (Visit 2) and by etiology of hypertension 
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Clinical Trial Protocol 
 
Protocol No. CSPP100A2365E2 
 
(primary and secondary).  Likewise, stratifications by weight group and region assigned at study 
CSPP100A2365 will remain. 
Efficacy assessments:  Not applicable.  
Safety assessments:  
• 
At LT weeks 104 and 156 height and weight measurements 
• 
At LT weeks 104 and 156 renal function evaluation only in patients with secondary hypertension  
Other assessments:  
• 
At LT weeks 104 and 156 neurocognitive evaluation only in patients with secondary hypertension  
Data analysis:  Demographics and baseline characteristics, safety data (height, weight, derived BMI, 
laboratory evaluations, SAE) and other data as appropriate, will be summarized descriptively by 
treatment regimen from CSPP100A2365E1. 
For the superiority assessment of change in weight, the null hypothesis to be tested is that the mean 
change of weight in the aliskiren regimen is equal to that in the enalapril regimen, versus the 
alternative hypothesis that they are not equal: 
H0: µ1 = µ2 versus H1: µ1 ≠ µ2 
The statistical test for change from baseline in weight will be performed using an analysis of 
covariance (ANCOVA) model with treatment regimen from CSPP10AE1, region (US, EU), age strata 
(6 to 11 years, 12 to 17 years), and hypertension etiology (primary, secondary) as factors, and with 
baseline weight as covariate.  The statistical test will be made at two-sided significance level of 0.05. 
The 95% confidence interval will be provided.  
Changes from baseline in height and derived BMI will be analyzed using the similar model. 
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Clinical Trial Protocol 
 
Protocol No. CSPP100A2365E2 
 
1 
Introduction 
1.1 
Background 
The renin-angiotensin system (RAS) plays a major role in the regulation of arterial blood 
pressure and the pathogenesis of hypertension.  Renin is secreted by the kidney in response to 
a decrease in circulating volume and blood pressure.  It cleaves the substrate angiotensinogen 
to form the inactive decapeptide angiotensin I (Ang I).  Angiotensin I is converted to the 
active octapeptide angiotensin II by angiotensin converting enzyme (ACE).  Angiotensin II 
interacts with cellular receptors (angiotensin II receptors) and through different mechanisms 
increases total peripheral resistance, resulting in the elevation of blood pressure. 
Blocking RAS with an ACE inhibitor or angiotensin II receptor blocker (ARB) has been 
commonly used in clinical practice for the treatment of patients with hypertension.  An 
alternative approach to blockade of the RAS is inhibition of renin, the rate limiting enzyme 
for the formation of angiotensin II.  Until recently, the introduction of renin inhibitors into 
clinical practice was limited by low oral bio-availability, short duration of action and high 
cost of chemical synthesis.  Aliskiren (SPP 100) is the first new, orally active, non-peptide, 
specific direct renin inhibitor and has been approved for use in adults in the treatment of 
hypertension. 
Aliskiren is a non-peptide with a low molecular weight (609.8).  In vitro, it is a potent direct 
inhibitor of human renin (IC50 = 0.6 nM).  In vivo, aliskiren administered both orally (p.o.) or 
intravenously (i.v.) in several studies with sodium-depleted marmosets caused complete 
inhibition of plasma renin activity (PRA), sustained reductions in mean arterial pressure 
(MAP), and significant increases in plasma concentrations of active and total renin.  In 
humans, plasma concentrations of aliskiren increase rapidly after administration reaching 
peak levels usually within 1-3 hours.  The half-life of aliskiren is approximately 40 hours and 
its bioavailability is approximately 2.6%.  Renal and hepatic clearance of aliskiren is minimal.  
Changes in renal and hepatic function related to age are not anticipated to alter aliskiren 
elimination within the proposed range of 6 to 17 years.  Aliskiren is excreted mostly 
unchanged by the fecal route (~90%).  About 0.6% of an oral dose is renally excreted. 
In the adult population, aliskiren has been studied in clinical trials involving over 12,000 
patients with hypertension.  It has been demonstrated to be efficacious and safe when used 
alone or in combination with other antihypertensives for the treatment of hypertension.  In a 
clinical study in patients with mild to moderate hypertension, 652 patients were randomized to 
receive placebo, aliskiren 150, 300 or 600 mg or 150 mg of irbesartan once daily for 8 weeks.  
Patients receiving aliskiren 150 mg and 300 mg demonstrated dose related decreases in both 
systolic and diastolic blood pressure.  No additional blood pressure lowering effects were seen 
with aliskiren 600 mg as compared with aliskiren 300 mg.  Aliskiren 150 mg was comparable 
to irbesartan 150 mg in reducing diastolic blood pressure (DBP) while aliskiren 300 mg and 
600 mg showed a significantly greater DBP reduction than irbesartan 150 mg.  The overall 
incidences of adverse events seen in patients receiving aliskiren (150 mg and 300 mg) were 
similar to placebo.  There was a slight increase in GI adverse events (especially diarrhea) at 
the 600mg aliskiren dose. 
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Protocol No. CSPP100A2365E2 
 
In a 26-week, randomized, double-blind study with 1124 randomized patients, the 
combination of aliskiren with amlodipine was demonstrated to be effective and well tolerated.  
In addition, the efficacy and safety of the combination of aliskiren with HCTZ were shown in 
a 26-week, double-blind, randomized active-controlled study with a total number of 842 
patients with hypertension. 
The effect of aliskiren on the development of the juvenile rat was explored in three toxicology 
studies.  The effects of aliskiren have been tested in rats treated by gavage at 50, 150 or 300 
mg/kg/day from days 14 to 34 post-partum.  Effects on mortality, clinical signs, and body 
weight were measured, and following euthanasia at day 34, gross and microscopic pathology 
were examined.  No deaths were noted.  Diarrhea was present in most animals at the higher 
doses.  Dose-related 15-50% reductions in body weight gain as compared to controls were 
found early in the course of treatment, but tended to be slightly higher than controls thereafter.  
In other studies in which rats were treated by gavage with aliskiren at 30, 100, or 300 
mg/kg/day from post-partum day 8 to 35 and 14 to 70, respectively, morbidity (12-57% 
weight loss, diarrhea, and 20-30% reduction in the absolute lymphocyte count) and mortality 
(1 death at 100 mg/kg/day and 4 deaths at 300 mg/kg/day) were observed as in the 34 day 
study.  Pharmacokinetic measurements in these studies showed that aliskiren exposure (AUC 
in ng-h/ml) was 19-36% greater in 8 day old than in 14 day old rats at the 30 mg/kg/day dose, 
but more than 350% (3.5 fold) greater at the 100 mg/kg/day dose.  Remarkably, the AUC was 
more than 350-fold greater in 14 day old than the 64 day old rats at the 30 mg/kg/day dose, 
150-fold greater at the 100 mg/kg/day dose, and 85-fold greater in 14 day old than the 64 day 
old rats at the 300 mg/kg/day dose.  Moreover, the variability in exposure was more than 
twice as great when the animals were younger than when they were older. 
These findings demonstrate that aliskiren exposure is age related with declining exposure 
possibly related to the maturation of transporters and/or metabolizing systems.    
In humans, drugs that act directly on the renin-angiotensin system can cause injury and even 
death to the developing fetus when administered to pregnant women.  When pregnancy is 
detected, aliskiren should be discontinued as soon as possible.  For complete details of the 
toxicology program for aliskiren please refer to the SPP100 Aliskiren Investigator’s Brochure. 
As the first direct renin inhibitor for the treatment of hypertension in adults, aliskiren is 
proposed for use in hypertensive children 6-17 years of age, as an alternative to currently 
available therapies.  Aliskiren may offer a therapeutic profile distinct from that of ACE 
inhibitors and ARBs (Frampton and Curran 2007).  The course of hypertension and the effects 
of antihypertensive medications in adolescents are not likely to differ from the course of the 
disease and the effects of antihypertensive medications in adults.  The pediatric study for 
which this is an off-therapy follow-up will include a reasonable proportion of school-age, pre-
pubertal children with at least 50% of the children being 6-11 years of age. 
As the prevalence of hypertension in children increases (Soroff, et al 2004) treatment 
alternatives to those currently available will be of increasing significance.  It is known that 
hypertension prevalence increases progressively with increased BMI and in the pediatric 
population hypertension is detectable in approximately 30% of overweight children (NHLBI 
12th Report, 2004).  Obesity is thought to be a major contributor to essential hypertension in 
school age children and adolescents (Weinberger, et al 2008).  Primary essential hypertension 
in children is generally mild and associated with a positive family history of hypertension or 
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Protocol No. CSPP100A2365E2 
 
CVD and mild/moderate/severe obesity.  Aliskiren may therefore be particularly important in 
children 6-17 years of age with essential hypertension since it has been shown to be of 
comparable efficacy in obese adult patients compared to those of normal body mass index 
(BMI) (Jensen, et al 2008). 
In summary, the efficacy and tolerability of aliskiren alone or in combination with other 
agents are comparable to other commonly used antihypertensive medications in adults.  Given 
the results reported with aliskiren in adults with hypertension, a similar efficacy and 
tolerability of aliskiren in children 6-17 years of age would be anticipated, providing an 
additional treatment option for children with hypertension. 
This study is intended to evaluate the off-therapy long term growth and development of 
children 6 – 17 years old after exposure to aliskiren for at least one year in studies 
CSPP100A2365 and CSPP100A2365E1, and was developed to comply with the EMA 
Pediatric Committee Pediatric Investigational Plan (PIP). 
In study CSPP100A2365 the dose-response, efficacy and safety of aliskiren was evaluated in 
double-blind fashion over 8 weeks.  Study CSPP100A2365E1 provided double blind 
evaluation of the long-term safety, tolerability and efficacy of aliskiren compared to enalapril 
in the same patient population. 
1.2 
Purpose  
The purpose of this 52 to 104 week off-therapy extension to studies CSPP100A2365 and 
CSPP100A2365E1 is to evaluate the long term growth and development of children 6 – 17 
years old (6 to less than 18 years old at baseline in study CSPP100A2365) with hypertension 
(msSBP ≥ 95th percentile for age, gender and height) at baseline in study CSPP100A2365, 
previously treated with aliskiren.  Patients identified in study CSPP100A2365 to have primary 
hypertension will be followed for 52 weeks (1 year) after the completion of study 
CSPP100A2365E1.  Patients identified in study CSPP100A2365 to have secondary 
hypertension will be followed for 104 weeks (2 years) after the completion of study 
CSPP100A2365E1.  The assessment of growth and development through height and weight 
measurement will be performed on all patients for 52 weeks after which patients with primary 
hypertension will complete.  The assessment of patients with secondary hypertension will 
continue for an additional 52 weeks during which growth and development will continue to be 
assessed with added neurocognitive and renal function evaluations as follow-up measures. 
This study is in compliance with the EMA PIP Positive Opinion in support of the 
monotherapy registration of aliskiren for the treatment of hypertension in pediatric patients 6 
– 17 years of age. 
2 
Study objectives 
2.1 
Primary objectives 
• To evaluate the long term growth and development of pediatric hypertensive patients aged 
6 – 17 years when treated previously with aliskiren 
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Protocol No. CSPP100A2365E2 
 
2.2 
Secondary objectives 
Not applicable. 
2.3 
Exploratory objectives 
Not applicable. 
3 
Investigational plan 
3.1 
Study design 
This is a multicenter 52 to 104 week off-therapy extension to evaluate long-term growth and 
development in pediatric hypertensive patients 6 – 17 years of age at initiation of treatment 
with aliskiren in study CSPP100A2365.  Eligible patients will continue to be stratified by age 
(6 – 11 years and 12 – 17 years) at study CSPP100A2365 baseline (Visit 2) and by etiology of 
hypertension (primary and secondary).  Likewise, stratifications by weight group and region 
assigned in study CSPP100A2365 will remain. 
Table 3-1 
Study design 
CSPP100A2365E2 LT Safety Follow-up  
Week 52 LT (end of study visit 
CSPP100A2365E1) 
Week 104 LT 
Week 156 LT 
Day 365 (LT) 
Day 730 (LT) 
Day1095 (LT) 
Visit 17* 
Visit 18** 
Visit 19*** 
* Long-term (LT) safety extension visit numbers continue from CSPP100A2365E1 
** End of study for patients with primary hypertension 
*** End of study for patients with secondary hypertension 
Figure 3-1 
Study design 
 
  
  
  
Primary 
hypertension
  
  
  
  
  
  
  
Secondary 
hypertension
  
  
  
  
  
  
                           Visit 17, LT Wk 52              Visit 18, LT Wk 104            Visit 19, LT Wk 156 
 
3.2 
Rationale of study design 
This study is being conducted to comply with the EMA PIP Positive Opinion for the provision 
of long-term growth and development data including renal function and neurocognitive 
function data in children with secondary hypertension. 
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3.3 
Rationale of dose/regimen, duration of treatment 
Not applicable. 
3.4 
Rationale for choice of comparator 
Not applicable. 
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
4 
Population 
The study population will consist of male and female hypertensive pediatric patients who 
have completed the CSPP100A2365E1 protocol.  These patients were 6 – 17 years old and 
had an msSBP ≥ 95th percentile for age, gender and height at baseline (randomization) in 
study CSPP100A2365.  Patients will continue to be stratified by CSPP100A2365 baseline 
weight, age, hypertension etiology and region.  Centers from the US and EU participating in 
CSPP100A2365 and CSPP100A2365E1 will participate in this off-therapy follow-up. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Informed consent form (approved by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), signed by the parent(s)/legal guardian(s), after the purpose and 
nature of the investigation has been clearly explained to the parents and the patient.  An 
assent will be obtained for some patients depending upon their age, maturity, capacity for 
understanding, and the local requirements regarding assents.  Written informed consent 
must be obtained before any assessment is performed. 
2. Male or female patients ages 6 – 17 years at Visit 2 (randomization) in study 
CSPP100A2365, with a documented diagnosis of hypertension as defined in the NHLBI 
12th Report 2004 
3. msSBP (mean of 3 systolic blood pressure measurements) ≥ 95th percentile for age, gender 
and height at Visit 2 (randomization) in study CSPP100A2365 
4. ≥ 20 kg and ≤ 150 kg at Visit 2 (randomization) in study CSPP100A2365 
5. Successful completion of study  CSPP100A2365E1 
4.2 
Exclusion criteria 
1. Patients who did not successfully complete study CSPP100A2365 and CSPP100A2365E1 
are excluded from participation in CSPP100A2365E2. 
2. No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible patients. 
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5 
Treatment 
5.1 
Investigational and control treatment 
Not applicable. 
5.2 
Treatment arms 
Not applicable. 
5.3 
Treatment assignment 
Not applicable. 
5.4 
Treatment blinding 
Not applicable. 
5.5 
Treating the patient 
5.5.1 
Patient numbering 
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number.  The center number was assigned by Novartis to the investigative site in trial 
CSPP100A2365.  Upon signing the informed consent form and assent form, if applicable, the 
patient will continue to use the patient number assigned by the investigator in trial 
CSPP100A2365.  Only the assigned patient number should be entered in the field labeled 
“Patient ID” on the EDC data entry screen (e.g. enter ‘1’, ‘2’, etc.). 
5.5.2 
Dispensing the study treatment 
Not applicable. 
5.5.3 
Supply, storage and tracking of study treatment 
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment 
Not applicable. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Not applicable. 
5.5.6 
Rescue medication 
Not applicable. 
5.5.7 
Concomitant treatment 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study.  All medications and significant non-drug therapies 
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(including physical therapy and blood transfusions) administered must be listed on the 
Concomitant medications/Significant non-drug therapies eCRF. 
5.5.8 
Prohibited treatment 
Not applicable. 
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 visits, 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 eCRF. 
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 unblinding of treatment assignment 
Not applicable. 
5.5.11 
Study completion and post-study treatment 
Patients identified in study CSPP100A2365 as having primary hypertension should complete 
Visit 18 with assessments.  Patients identified in study CSPP100A2365 as having secondary 
hypertension should complete Visit 19 with assessments.  The study will end when all 
enrolled patients have completed last visit, last assessment. 
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. 
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6 
Visit schedule and assessments 
Table 6-1 
Assessment schedule 
Visit 
C4 
LT171 
LT18 
LT193 
Week 
 
52 
104 
156 
Informed consent/child assent 
S 
X 
 
 
Height 
D 
X 
X 
X 
Weight 
D 
X 
X 
X 
Concomitant Medication 
D 
X 
X 
X 
Neurocognitive Evaluation 
D 
 
X3 
X 
Chemistry 
D 
 
X3 
X 
Study Completion Form 
D 
 
X2 
X 
1 Extension 2 – Visit LT (long term) 17 should occur on the same day as CSPP100A2365E1 “end of 
study” V16.    Data for other identified evaluations will be obtained from Study CSPP100A2365E1. 
2 Visit LT18 is the end of study visit for patients identified in the core study (CSPP100A2365) as having 
primary hypertension. 
3 For patients with secondary hypertension only.  
4 C is the category; D = eCRF data, S = source document data 
6.1 
Information to be collected on screening failures 
Not applicable. 
6.2 
Patient demographics/other baseline characteristics 
Patient demographic data and baseline characteristic data will have been collected in study 
CSPP100A2365.  The stratifications applied in the core study will remain in place.  
6.3 
Treatment exposure and compliance 
Not applicable. 
6.4 
Efficacy 
Not applicable. 
6.5 
Safety 
6.5.1 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured at all visits.  BMI will be derived. 
6.5.2 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual. 
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Clinically notable laboratory findings are defined in Appendix 1. 
6.5.3 
Clinical chemistry 
Serum creatinine, blood urea, sodium, potassium, chloride and calcium will be measured at 
LT Visits 18 and 19 (patients with secondary hypertension only). 
6.5.4 
Pregnancy and assessments of fertility 
Not applicable. 
6.5.5 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population.  
6.6 
Other assessments 
6.6.1 
Neurocognitive evaluation 
All patients who were determined to have secondary hypertension in study CSPP100A2365 
and have a baseline (Visit 2) neurocognitive assessment will receive a neurocognitive 
assessment at LT V18 and LT V19. 
The neurocognitive assessment of development will include assessment of the following 
abilities: 
• Attention 
• Processing speed 
• Working memory 
• Motor speed 
These assessments were chosen based on their validity and reliability, ease and efficiency of 
administration and scoring by non-psychologists, availability, appropriateness for the age span 
included in this study and ability to be repeated without significant practice effect (defined as 
improvement in performance based solely on previous exposure to or practice with the test).  
A manual for standardized administration of the neurocognitive evaluation and scoring 
procedures for all assessments will be provided separately to each site.  The same battery of 
tests administered in the same order, where possible, will be used for each patient. 
Appendix 2 further outlines the neurocognitive assessment of development as it applies to this 
protocol and study population. 
6.6.2 
Resource utilization 
Not applicable. 
6.6.3 
Health-related Quality of Life 
Not applicable. 
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6.6.4 
Pharmacokinetics 
Not applicable. 
6.6.5 
Pharmacogenetics/pharmacogenomics 
Not applicable. 
6.6.6 
Other biomarkers 
Not applicable. 
7 
Safety monitoring 
7.1 
Adverse events 
This trial will only collect the occurrence of serious adverse events as defined below and in 
Section 7.2.   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  
• 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 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.  
7.2 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring until 30 days 
after the patient has completed study CSPP100A2365E1 (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 this 30 day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug.  
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Within this 30 day period, recurrent episodes, complications, or progression of the initial SAE 
must be reported as follow-up to the original episode, regardless of when the event occurred. 
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. 
SAE information is collected and recorded on the Serious Adverse Event Report Form.  The 
investigator must assess the relationship of any SAE to study drug, 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 telecopy number of 
the contact persons in the local department of Clinical 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 is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report.  The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.  
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 Novartis study drug, 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 drug 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 
Pregnancies 
Not applicable. 
8 
Data review and database management 
8.1 
Site monitoring 
A Novartis representative will review this protocol and eCRFs 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 eCRFs, the adherence to the 
protocol and to Good Clinical Practice.  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 eCRFs must be traceable to these source documents in the 
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patient's file.  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 eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, 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 eCRFs 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 will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained.  Automatic validation programs check for data discrepancies 
and, by generating appropriate error messages, allow the data to be confirmed or corrected 
before transfer of the data to the CRO working on behalf of Novartis.  The Investigator must 
certify that the data entered into the Electronic Case Report Forms are complete and accurate. 
After database lock, the investigator will receive a CD-ROM or paper copies of the patient 
data for archiving at the investigational site. 
8.3 
Database management and quality control 
CRO staff working on behalf of Novartis review the data entered into the eCRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions.  Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data.  If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site.  Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff to make the correction to the database.  The signed copy of the Data 
Query Form is kept at the investigator site. 
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 
the Novartis designated CRO. 
9 
Data analysis 
Unless otherwise stated, baseline refers to the core study (CSPP100A2365) baseline and 
treatment regimen to what was taken in CSPP100A2365E1 study. 
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9.1 
Analysis sets 
The enrolled to follow-up set (EFS) will consist of all patients who sign the informed consent 
form for CSPP100A2365E2 study. 
9.2 
Patient demographics and other baseline characteristics 
Patient demographics and relevant baseline characteristics will be obtained from the core 
study 
(CSPP100A2365) 
and 
summarized 
for 
EFS 
by 
treatment 
regimen 
in 
CSPP100A2365E1.  Continuous variables will be summarized with descriptive statistics (n, 
mean, standard deviation, median minimum and maximum) and categorical variables will be 
summarized with frequency by treatment regimen in CSPP100A2365E1. 
9.3 
Treatments  
Concomitant medication and significant non-drug therapies will be summarized with 
frequency for EFS by treatment regimen in CSPP100A2365E1. 
9.4 
Analysis of the primary variable(s) 
9.4.1 
Variable 
The primary assessment is the reporting of changes in weight, height and neurocognitive 
assessments for enrolled to follow-up set (EFS). 
9.4.2 
Statistical model, hypothesis, and method of analysis 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) of 
baseline, post-baseline values and changes from baseline will be summarized by treatment 
regimen in CSPP100A2365E1 and visit for EFS. 
For the superiority assessment of change in weight, the null hypothesis to be tested is that the 
mean change of weight in the aliskiren regimen is equal to that in the enalapril regimen, 
versus the alternative hypothesis that they are not equal: 
H0: µ1 = µ2 versus H1: µ1 ≠ µ2 
The statistical test for change from baseline in weight will be performed using an analysis of 
covariance (ANCOVA) model with treatment regimen, region (US, Euro), age strata (6 to 11 
years, 12 to 17 years), and hypertension etiology (primary, secondary) as factors, and with 
baseline weight as covariate.  The statistical test will be made at two-sided significance level 
of 0.05. The 95% confidence interval for the pairwise comparison will be provided.    
Changes from baseline in height and derived BMI will be analyzed using the similar model. 
9.4.3 
Handling of missing values/censoring/discontinuations 
Not planned. 
9.4.4 
Supportive analyses 
Not planned. 
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9.5 
Analysis of secondary variables 
9.5.1 
Key secondary variables 
Not applicable. 
9.5.2 
Efficacy variables 
Not applicable. 
9.5.3 
Safety variables 
The assessment of safety will be based primarily on the frequency of SAEs occurring within 
the first 30 days after the patient has completed study CSPP100A2365E1 (defined as time of 
last dose of study drug taken or last visit whichever is later).  SAEs experienced after this 30 
day period are to be reported to Novartis if the investigator suspects a causal relationship to 
the study drug. 
Occurrence and frequency of SAEs collected within this timeframe will be summarized by 
treatment regimen in CSPP100A2365E1, primary organ class and preferred term, and will be 
narrated if any. 
Summary statistics by treatment regimen in CSPP100A2365E1 and visit for laboratory values 
(in patients with secondary hypertension only) will be provided.  Occurrence of significant 
abnormalities in laboratory values from baseline will be summarized by treatment regimen in 
CSPP100A2365E1. 
9.5.4 
Pharmacokinetics 
Not applicable. 
9.5.5 
Pharmacogenetics/pharmacogenomics 
Not applicable. 
9.5.6 
Biomarkers 
Not applicable. 
9.5.7 
PK/PD 
Not applicable. 
9.6 
Sample size calculation 
All patients who successfully complete CSPP100A2365 and 2365E1 studies will be offered 
enrollment into the study CSPP100A2365E2 for 52 or 104 weeks follow-up. 
9.7 
Power for analysis of key secondary variables 
Not applicable. 
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9.8 
Interim analyses 
Not applicable. 
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 
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. 
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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 no authorized deviations are permitted. 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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References 
Available upon request. 
Bornkamp B, Pinheiro J, Bretz F. (2009) MCPMod - An R Package for the design and 
analysis of dose-finding studies.  Journal of Statistical Software; 29 (7): 1-23. 
Frampton JE, Curran MP. (2007) Aliskiren:  A review of its use in the management of 
hypertension.  Drugs; 67 (12): 1767-1792. 
Jensen C, Herold P, Brunner HR. (2008) Aliskiren:  The first renin inhibitor for clinical 
treatment.  Nature Reviews; 7: 399-410. 
McMurray JV, Pitt B, Latini R, et al. (2008) Effects of the oral renin inhibitor aliskiren in 
patients with symptomatic heart failure.  Circ Heart Fail; 1: 17 – 24. 
Muldoon MF, Waldstein SR, Ryan CM, et al. (2002) Effects of six anti-hypertensive 
medications on cognitive performance.  J Hypertens; 20(8):1643-52. 
Murray MD, Lane KA, Gao S, et al. (2002) Preservation of cognitive function with 
antihypertensive medications: a longitudinal analysis of a community-based sample of 
African Americans.  Arc Inter Med; 162(18): 2090-6. 
NHLBI (2004) The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood 
Pressure in Children and Adolescents:  National High Blood Pressure Program Working 
Group on High Blood Pressure in Children and Adolescents.  Pediatrics; 114: 555 – 576. 
Parving H, Persson F, Lewis JB, et al. (2008) Aliskiren combined with losartan in Type 2 
diabetes and nephropathy.  N Engl J Med; 358: 2433 – 46. 
Sorof JM, Lai D, Turner J, et al. (2004) Overweight, ethnicity, and the prevalence of 
hypertension in school-aged children.  Pediatrics; 113: 475-482. 
Starr JM, Whalley LJ, Deary IJ. (1996) The effects of antihypertensive treatment on cognitive 
function:  results from the HOPE study.  J Am Ger Soc; 44(4): 411-5. 
Tapaninen T, Backman JT, Kurkinen KJ, et al. (2010) Itraconazole, a P-Glycoprotein and 
CYP3A4 inhibitor, markedly raises the plasma concentrations and enhances the renin 
inhibiting effect of aliskiren. J Clin Pharmacol; published online 16 April 2010, DOI: 
10.1177/0091270010365885. 
Weinberger M. (2008) Are children doomed by what they eat and drink?  Hypertension; 51: 
615-616. 
Williams B, Poulter NR, Brown MJ, et al. (2004) Guidelines for management of 
hypertension:  report of the forth working party of the British Hypertension Society, 2004 
BHS IV.  J Hum Hypertens; 18(3): 139 – 185. 
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Appendix 1: Clinically notable laboratory values 
Table 13-1 
Clinically notable laboratory values 
Parameter 
CU 
Alert Value 
CU 
Units 
SI Alert 
Value 
SI 
Units 
Chemistry 
 
 
 
 
BUN 
>50% increase 
mg/dL 
>50% increase 
mmol/L 
Creatinine 
>50% increase 
mg/dL 
>50% increase 
umol/L 
Sodium 
>5% increase 
mEq/L 
>5% increase 
mmol/L 
Potassium 
>20% increase, >20% 
decrease, or any value 
>5.3 
mEq/L 
>20% increase, >20% 
decrease, or any value 
>5.3  
mmol/L 
Chloride 
>10% increase, >10% 
decrease 
mEq/L 
>10% increase, >10% 
decrease 
mmol/L 
Calcium 
>10% increase, >10% 
decrease 
mg/dL 
>10% increase, >10% 
decrease 
mmol/L 
Note:  Clinically notable laboratory values drawn after LT Visit 17 will be flagged on the laboratory 
reports sent to sites by the Central Laboratory at the same time that Novartis is notified (see Central 
Laboratory Manual for the Notable Laboratory Value Notification Process). 
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14 
Appendix 2:  Neurocognitive assessment 
The neurocognitive assessment of development is a sensitive marker of a cognitive change 
resulting from an insult to the brain such as head injury, toxin exposure and medication effect.   
Although it was previously thought that treatment with antihypertensive medication was a risk 
for cognitive decline in adults, there is more recent evidence that the treatment of 
hypertension with antihypertensive medication can improve functioning and has no effect on 
cognition or may be associated with mild decrements in performance on specific tasks of 
motor speed (Muldoon, et al 2002); (Murray, et al 2002); (Star, et al 1996).  Neurocognitive 
growth and development will be monitored during the investigation of aliskiren in the 
treatment of pediatric hypertension. 
The following neurocognitive evaluations will be documented at LT V18 and at LT V19 in 
patients with secondary hypertension only. 
Table 14-1 
Neurocognitive tests 
Function 
Test 
Applicable age for test 
Administration time 
Attention 
CMS Digits Forward 
5 – 16 
2 minutes 
Processing speed 
WJIII Visual Matching 
3 + 
5 minutes 
Working memory 
CMS Digits Backwards 
CMS Sequences 
5 – 16 
5 – 16 
2 minutes 
7 minutes 
Motor speed 
Timed gait and tapping 
6 + 
2 minutes 
CMS = Children’s Memory Scale 
WJIII = Woodcock Johnson Tests of cognitive ability 
Summary statistics of the raw scores and a frequency table for the number of patients with 
changes from LT V16 of raw test scores (positive, negative or no change) will be presented.  
No formal inferential analysis is planned. 
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