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Clinical Trial Results:
A multicenter, randomized, double-blind, 8 week study to evaluate the dose response, efficacy and safety of aliskiren in paediatric hypertensive subjects 6-17 years of age.

Summary
EudraCT number	2009-017028-22
Trial protocol	HU BE FR DE SK PL Outside EU/EEA
Global end of trial date	14 Aug 2014

Results information
Results version number	v1(current)
This version publication date	13 Jul 2016
First version publication date	29 Jul 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CSPP100A2365

ISRCTN number

US NCT number

NCT01150357

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Novartis Pharma AG, Clinical Disclosure Office, +41 613241111,

Scientific contact

Novartis Pharma AG, Clinical Disclosure Office, +41 613241111,

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000362-PIP01-08

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

14 Aug 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 Aug 2014

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of this study were: • In Phase 1 (dose response phase), to evaluate the dose response of aliskiren in msSBP change at end of Phase 1 from the baseline, as measured by office BP reading, in children 6 to 17 years old with hypertension. • In Phase 2 (placebo-controlled withdrawal phase), to evaluate pooled treatment effect of aliskiren (mid and high doses) in msSBP change at end of Phase 2 from the end of Phase 1, compared to placebo pooled from corresponding arms, as measured by office BP reading, in children 6 to 17 years old with hypertension

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

10 Jun 2010

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

1 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Guatemala: 18

Country: Number of subjects enrolled

Poland: 19

Country: Number of subjects enrolled

Slovakia: 60

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

Hungary: 59

Country: Number of subjects enrolled

Turkey: 6

Country: Number of subjects enrolled

United States: 102

Worldwide total number of subjects

268

EEA total number of subjects

142

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

129

Adolescents (12-17 years)

139

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 51 centres in 8 countries.

Screening details

A total of 334 subjects were enrolled in a screening phase of single-blind placebo wash-out period for up to a maximum of three weeks. Out of 334, 268 subjects were randomised in Phase 1 including 1 mis-randomised subject who did not receive any medication.

Period 1 title

Dose Response Phase (Phase 1)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Assessor

Blinding implementation details

Randomisation data were kept strictly confidential and the identity of treatments were concealed by the use of identical study drugs. Unblinding was allowed from randomisation to database lock, except in case of subject emergencies and at the conclusion of the study.

Are arms mutually exclusive

Yes

Phase 1: Aliskiren Low (6.25/12.5/25 mg)

Arm description

Subjects received body-weight stratified dose of aliskiren capsules (6.25/12.5/25 mg) once daily. Subjects whose body weight ≥ 20 kilogram(kg) to less than < 50 kg received 6.25 mg; ≥50 kg and < 80 kg received 12.5 mg and ≥ 80 kg and ≤ 150 kg received 25 mg of aliskiren.

Arm type

Experimental

Investigational medicinal product name

Aliskiren

Investigational medicinal product code

SPP100

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Aliskiren dispensing capsules containing minitablets (3.125 mg per minitablet). For the low dose arm, patients used one or more of the 6.25 mg capsule (containing 2 minitablets) once daily to reach the body-weight stratified dose of aliskiren.

Phase 1: Aliskiren Mid (37.5/75/150 mg)

Arm description

Subjects received body-weight stratified dose of aliskiren capsules (37.5/75/150 mg) once daily. Subjects whose body weight ≥ 20 kg to < 50 kg received 37.5 mg; ≥50 kg and < 80 kg received 75 mg and ≥ 80 kg and ≤ 150 kg received 150 mg of aliskiren.

Arm type

Experimental

Investigational medicinal product name

Aliskiren

Investigational medicinal product code

SPP100

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Aliskiren dispensing capsules containing minitablets( 3.125 mg per minitablet). For the medium dose arm, patients used one or more of the 37.5 mg capsule (containing 12 minitablets) once daily to reach the body-weight stratified dose of aliskiren.

Phase 1: Aliskiren High (150/300/600 mg)

Arm description

Subjects received body-weight stratified dose of aliskiren capsules (150/300/600 mg) once daily. Subjects whose body weight ≥ 20 kg to < 50 kg received 150 mg; ≥50 kg and < 80 kg received 300 mg and ≥ 80 kg and ≤ 150 kg received 600 mg of aliskiren.

Arm type

Experimental

Investigational medicinal product name

Aliskiren

Investigational medicinal product code

SPP100

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Aliskiren dispensing capsules containing minitablets (3.125 mg per minitablet). For the high dose arm, patients used one or more of the 150 mg capsule (containing 48 minitablets) once daily to reach the body-weight stratified dose of aliskiren.

Number of subjects in period 1 ^[1]	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)
Started	108	54	105
Completed	107	51	102
Not completed	1	3	3
Consent withdrawn by subject	-	2	1
Adverse event, non-fatal	-	-	1
Unsatisfactory therapeutic effect	1	-	-
Protocol deviation	-	1	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Out of 268 subjects randomised in Phase 1, 1 subject was mis-randomised who did not receive any medication and thus was not included in the safety or full analysis sets for evaluation.

Period 2 title

Placebo-controlled withdrawal (Phase 2)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Assessor

Blinding implementation details

Randomisation data were kept strictly confidential and the identity of treatments were concealed by the use of identical study drugs. Unblinding was allowed only in case of subject emergencies and at the conclusion of the study.

Are arms mutually exclusive

Yes

Phase 2: Aliskiren Low (6.25/12.5/25 mg)

Arm description

Subjects received body-weight stratified dose of aliskiren capsules (6.25/12.5/25 mg) once daily. Subjects whose body weight ≥ 20 kg to < 50 kg received 6.25 mg; ≥50 kg and < 80 kg received 12.5 mg and ≥ 80 kg and ≤ 150 kg received 25 mg of aliskiren.

Arm type

Experimental

Investigational medicinal product name

Aliskiren

Investigational medicinal product code

SPP100

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Phase 2: Placebo Low

Arm description

Subjects received placebo capsules matching to aliskiren capsules (6.25/12.5/25 mg) once daily.

Arm type

Placebo

Investigational medicinal product name

Placebo low

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo capsules (containing minitablets) matching in size, shape, color and number of minitablets to aliskiren capsules

Phase 2: Aliskiren Mid (37.5/75/150 mg)

Arm description

Arm type

Experimental

Investigational medicinal product name

Aliskiren

Investigational medicinal product code

SPP100

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Phase 2: Placebo Mid

Arm description

Subjects received placebo capsules matching to aliskiren capsules (37.5/75/150 mg) once daily.

Arm type

Placebo

Investigational medicinal product name

Placebo mid

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo capsules (containing minitablets) matching in size, shape, color and number of minitablets to aliskiren capsules.

Phase 2: Aliskiren High (150/300/600 mg)

Arm description

Arm type

Experimental

Investigational medicinal product name

Aliskiren

Investigational medicinal product code

SPP100

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Phase 2: Placebo High

Arm description

Subjects received placebo capsules matching to aliskiren capsules (150/300/600 mg) once daily.

Arm type

Placebo

Investigational medicinal product name

Placebo high

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo capsules (containing minitablets) matching in size, shape, color and number of minitablets to aliskiren capsules

Number of subjects in period 2	Phase 2: Aliskiren Low (6.25/12.5/25 mg)	Phase 2: Placebo Low	Phase 2: Aliskiren Mid (37.5/75/150 mg)	Phase 2: Placebo Mid	Phase 2: Aliskiren High (150/300/600 mg)	Phase 2: Placebo High
Started	50	57	30	21	50	52
Completed	50	54	30	21	49	51
Not completed	0	3	0	0	1	1
Consent withdrawn by subject	-	2	-	-	-	-
Adverse event, non-fatal	-	-	-	-	1	1
Lost to follow-up	-	1	-	-	-	-

Baseline characteristics

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Reporting group title

Phase 1: Aliskiren Low (6.25/12.5/25 mg)

Reporting group description

Reporting group title

Phase 1: Aliskiren Mid (37.5/75/150 mg)

Reporting group description

Reporting group title

Phase 1: Aliskiren High (150/300/600 mg)

Reporting group description

Reporting group values	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)	Total
Number of subjects	108	54	105	267
Age categorical
Units: Subjects
Children 6 – 11 years	49	28	51	128
Adolescents 12 – 17 years	59	26	54	139
Age continuous
Units: years
arithmetic mean (standard deviation)	11.9 ( 3.27 )	11.6 ( 3.29 )	11.8 ( 3.5 )	-
Gender categorical
Units: Subjects
Female	35	17	39	91
Male	73	37	66	176

End points

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Reporting group title

Phase 1: Aliskiren Low (6.25/12.5/25 mg)

Reporting group description

Reporting group title

Phase 1: Aliskiren Mid (37.5/75/150 mg)

Reporting group description

Reporting group title

Phase 1: Aliskiren High (150/300/600 mg)

Reporting group description

Reporting group title

Phase 2: Aliskiren Low (6.25/12.5/25 mg)

Reporting group description

Reporting group title

Phase 2: Placebo Low

Reporting group description

Subjects received placebo capsules matching to aliskiren capsules (6.25/12.5/25 mg) once daily.

Reporting group title

Phase 2: Aliskiren Mid (37.5/75/150 mg)

Reporting group description

Reporting group title

Phase 2: Placebo Mid

Reporting group description

Subjects received placebo capsules matching to aliskiren capsules (37.5/75/150 mg) once daily.

Reporting group title

Phase 2: Aliskiren High (150/300/600 mg)

Reporting group description

Reporting group title

Phase 2: Placebo High

Reporting group description

Subjects received placebo capsules matching to aliskiren capsules (150/300/600 mg) once daily.

Primary: Change from baseline in mean sitting systolic blood pressure (msSBP) at endpoint (Phase 1)

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End point title

Change from baseline in mean sitting systolic blood pressure (msSBP) at endpoint (Phase 1)

End point description

Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the subject remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sSBP measurements were used as the average sitting office blood pressure for that visit. The primary analysis was performed on the Full Analysis Set (FAS), defined as all subjects who received at least one dose of study treatment and had at least one post-baseline assessment for primary efficacy. Here, "Number of subjects analysed" signifies subjects evaluable for msSBP at Week 4 (or LOCF) for each arm, respectively.

End point type

Primary

End point timeframe

Baseline to endpoint (Week 4 or Last observation carried forward (LOCF))

End point values	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)
Number of subjects analysed	108	53	104
Units: millimetre(s) of mercury (mmHg)
arithmetic mean (standard error)	-5.54 ( 0.78 )	-5.42 ( 1.331 )	-9.03 ( 1.008 )

Dose-response for change in msSBP

Statistical analysis description

The slope for change from baseline in mean sitting systolic blood pressure (msSBP) was analysed.

Comparison groups

Phase 1: Aliskiren Low (6.25/12.5/25 mg) v Phase 1: Aliskiren Mid (37.5/75/150 mg) v Phase 1: Aliskiren High (150/300/600 mg)

Number of subjects included in analysis

265

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

< 0.001 ^[2]

Method

ANCOVA

Parameter type

Slope

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.27

upper limit

-0.07

Notes
[1] - The null hypothesis for Phase 1 was that the slope of the dose-response curve for change from baseline in msSBP was not statistically different from zero at the end of Phase 1.
[2] - P-value was obtained from ANCOVA model fitted with weight, age, region and hypertension etiology as factors and baseline msSBP and dose ratio as covariates.

Primary: Change in mean sitting systolic blood pressure (msSBP) from Week 4 to endpoint (Phase 2)

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End point title

Change in mean sitting systolic blood pressure (msSBP) from Week 4 to endpoint (Phase 2)

End point description

End point type

Primary

End point timeframe

Week 4 to endpoint (Week 8 or LOCF)

End point values	Phase 2: Aliskiren Low (6.25/12.5/25 mg)	Phase 2: Placebo Low	Phase 2: Aliskiren Mid (37.5/75/150 mg)	Phase 2: Placebo Mid	Phase 2: Aliskiren High (150/300/600 mg)	Phase 2: Placebo High
Number of subjects analysed	50	57	30	21	49	52
Units: mmHg
arithmetic mean (standard error)	-0.53 ( 0.947 )	-0.64 ( 1.256 )	-2.59 ( 1.119 )	-2.9 ( 1.481 )	-1.97 ( 1.071 )	1.11 ( 1.185 )

Pooled aliskiren treatment vs pooled placebo

Statistical analysis description

Pooled treatment effect of aliskiren (mid and high doses) compared to pooled placebo (mid and high doses) in comparison with msSBP at Week 8 from Week 4.

Comparison groups

Phase 2: Aliskiren Mid (37.5/75/150 mg) v Phase 2: Placebo Mid v Phase 2: Aliskiren High (150/300/600 mg) v Phase 2: Placebo High

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

= 0.1152 ^[4]

Method

ANCOVA

Parameter type

Least square mean difference

Point estimate

-1.72

Confidence interval

level

95%

sides

2-sided

lower limit

-3.87

upper limit

0.43

Variability estimate

Standard error of the mean

Dispersion value

1.088

Notes
[3] - The null hypothesis for Phase 2 was that the change from end of Phase 1 in msSBP was not different between the pooled aliskiren high and mid doses, and placebo pooled from corresponding arms at the end of Phase 2.
[4] - P-value was obtained from the ANCOVA model fitted with treatment, weight, age, region, and hypertension etiology as factors and msSBP at end of Week 4 as a covariate, carried out at 2-sided significance level of 0.05.

Secondary: Number of subjects with adverse events and serious adverse events from baseline to week 4 (Phase 1)

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End point title

Number of subjects with adverse events and serious adverse events from baseline to week 4 (Phase 1)

End point description

Adverse events (AEs) were defined as any unfavourable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalisation, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards. The analysis was performed on the Safety Sets (SAF), SAF is all subjects who received at least one dose of study treatment during phase 1 (baseline to week 4)

End point type

Secondary

End point timeframe

From baseline to Week 4

End point values	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)
Number of subjects analysed	108	54	105
Units: Number of subjects
AEs	30	14	37
SAEs	0	0	1

No statistical analyses for this end point

Secondary: Number of subjects with adverse events and serious adverse events from Week 4 to Week 8 (Phase 2)

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End point title

Number of subjects with adverse events and serious adverse events from Week 4 to Week 8 (Phase 2)

End point description

AEs were defined as any unfavourable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalisation, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards. The analysis was performed on the SAF which included all subjects who received at least one dose of study treatment during phase 2 (week 4 to week 8).

End point type

Secondary

End point timeframe

From Week 4 to Week 8

End point values	Phase 2: Aliskiren Low (6.25/12.5/25 mg)	Phase 2: Placebo Low	Phase 2: Aliskiren Mid (37.5/75/150 mg)	Phase 2: Placebo Mid	Phase 2: Aliskiren High (150/300/600 mg)	Phase 2: Placebo High
Number of subjects analysed	50	57	30	21	50	52
Units: Number of subjects
AEs	18	22	10	5	21	17
SAEs	0	0	0	0	2	0

No statistical analyses for this end point

Secondary: Change from baseline in mean sitting diastolic blood pressure (msDBP) at endpoint (Phase 1)

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End point title

Change from baseline in mean sitting diastolic blood pressure (msDBP) at endpoint (Phase 1)

End point description

Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the subject remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sDBP measurements were used as the average sitting office blood pressure for that visit. The analysis was performed on the FAS population. Here, "Number of subjects analysed" signifies subjects evaluable for msDBP at Week 4 or LOCF for each arm, respectively.

End point type

Secondary

End point timeframe

Baseline to endpoint (Week 4 or LOCF)

End point values	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)
Number of subjects analysed	108	53	104
Units: mmHg
arithmetic mean (standard error)	-2.71 ( 0.67 )	-4.05 ( 1.116 )	-6.33 ( 0.793 )

No statistical analyses for this end point

Secondary: Change in mean sitting diastolic blood pressure (msDBP) from Week 4 to endpoint (Phase 2)

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End point title

Change in mean sitting diastolic blood pressure (msDBP) from Week 4 to endpoint (Phase 2)

End point description

Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the subject remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sDBP measurements were used as the average sitting office blood pressure for that visit. The analysis was performed on the FAS population. Here, "Number of subjects analysed" signifies subjects evaluable for msDBP at Week 8 or LOCF for each arm, respectively.

End point type

Secondary

End point timeframe

Week 4 to endpoint (Week 8 or LOCF)

End point values	Phase 2: Aliskiren Low (6.25/12.5/25 mg)	Phase 2: Placebo Low	Phase 2: Aliskiren Mid (37.5/75/150 mg)	Phase 2: Placebo Mid	Phase 2: Aliskiren High (150/300/600 mg)	Phase 2: Placebo High
Number of subjects analysed	50	57	30	21	49	52
Units: mmHg
arithmetic mean (standard error)	1.27 ( 1.025 )	-1.08 ( 1.012 )	0.89 ( 1.502 )	1.52 ( 1.248 )	0.37 ( 1.052 )	1.51 ( 1.009 )

No statistical analyses for this end point

Secondary: Change from baseline in mean arterial pressure (MAP) at endpoint (Phase 1)

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End point title

Change from baseline in mean arterial pressure (MAP) at endpoint (Phase 1)

End point description

MAP was defined as the average arterial pressure during a single cardiac cycle. The MAP was measured as sum of diastolic blood pressure (DBP) and one third of difference between systolic blood pressure (SBP) and DBP i.e. MAP = DBP+1/3*(SBP-DBP). The analysis was performed on the FAS population. Here, "Number of subjects analysed" signifies subjects evaluable for MAP at Week 4 or LOCF for each arm, respectively.

End point type

Secondary

End point timeframe

Baseline to endpoint (Week 4 or LOCF)

End point values	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)
Number of subjects analysed	108	53	104
Units: mmHg
arithmetic mean (standard error)	-3.65 ( 0.613 )	-4.51 ( 1.064 )	-7.23 ( 0.771 )

No statistical analyses for this end point

Secondary: Change in mean arterial pressure (MAP) from Week 4 to endpoint (Phase 2)

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End point title

Change in mean arterial pressure (MAP) from Week 4 to endpoint (Phase 2)

End point description

MAP was defined as the average arterial pressure during a single cardiac cycle. The MAP was measured as sum of DBP and one third of difference between SBP and DBP i.e. MAP = DBP+1/3*(SBP-DBP). The analysis was performed on the FAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.

End point type

Secondary

End point timeframe

Week 4 to endpoint (Week 8 or LOCF)

End point values	Phase 2: Aliskiren Low (6.25/12.5/25 mg)	Phase 2: Placebo Low	Phase 2: Aliskiren Mid (37.5/75/150 mg)	Phase 2: Placebo Mid	Phase 2: Aliskiren High (150/300/600 mg)	Phase 2: Placebo High
Number of subjects analysed	50	57	30	21	49	52
Units: mmHg
arithmetic mean (standard error)	0.67 ( 0.864 )	-0.93 ( 0.964 )	-0.27 ( 1.239 )	0.05 ( 1.14 )	-0.41 ( 0.885 )	1.37 ( 0.918 )

No statistical analyses for this end point

Secondary: Percentage of subjects achieving a positive treatment response at endpoint (Phase 1)

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End point title

Percentage of subjects achieving a positive treatment response at endpoint (Phase 1)

End point description

Treatment responders were defined as subjects with msSBP less than 95th percentile (for age, gender and height) or a 7 mmHg decrease in msSBP from the baseline. The analysis was performed on the FAS population. Here, "Number of subjects analysed" signifies subjects evaluable for this outcome measure at study endpoint which was week 4 or LOCF value in Phase 1.

End point type

Secondary

End point timeframe

Baseline to endpoint (Week 4 or LOCF)

End point values	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)
Number of subjects analysed	108	53	104
Units: Percentage of subjects
number (not applicable)	50.9	58.5	69.2

No statistical analyses for this end point

Secondary: Change from baseline in mean ambulatory systolic and diastolic blood pressure (MASBP and MADBP) at endpoint (Phase 1)

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End point title

Change from baseline in mean ambulatory systolic and diastolic blood pressure (MASBP and MADBP) at endpoint (Phase 1)

End point description

Ambulatory Blood Pressure Monitoring (ABPM) was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. The subjects who were selected for this evaluation wore the ABPM device for 24 hours, returned to the clinic upon completion of the 24-hour monitoring period for removal of device and BP assessments. The ABPM device was pre-set to collect readings every 20 minutes. Mean hourly systolic and diastolic blood pressure were calculated for each subject at post dosing 1 – 24 hours. Analysis was performed in subset of FAS subjects from selected centers who consented to undergo ABPM at baseline and at Week 4 or LOCF. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.

End point type

Secondary

End point timeframe

Baseline to endpoint (week 4 or LOCF)

End point values	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)
Number of subjects analysed	58	29	65
Units: mmHg
arithmetic mean (standard deviation)
MASBP (n=58, 29, 65)	-1.6 ( 6.48 )	-5.9 ( 5.8 )	-5.8 ( 7.15 )
MADBP (n=58, 29, 65)	-1.1 ( 5.33 )	-4.4 ( 4.41 )	-4.9 ( 6.05 )

No statistical analyses for this end point

Secondary: Change from baseline in mean ambulatory systolic blood pressure (MASBP) during day and night at week 4 (Phase 1)

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End point title

Change from baseline in mean ambulatory systolic blood pressure (MASBP) during day and night at week 4 (Phase 1)

End point description

ABPM was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. Day time was defined as the average of the hourly means between 6 am and 10 pm while the night time mean was the average of the hourly means between 10 pm and 6 am. Analysis was performed in subset of FAS subjects from selected centers who consented to undergo ABPM at baseline and at Week 4. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.

End point type

Secondary

End point timeframe

Baseline to week 4

End point values	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)
Number of subjects analysed	58	29	65
Units: mmHg
least squares mean (standard error)
Day time (n= 58, 29, 65)	-2.72 ( 1.031 )	-6.76 ( 1.381 )	-6.56 ( 0.95 )
Night time (n= 57, 29, 65)	-2.55 ( 1.035 )	-4.67 ( 1.381 )	-4.9 ( 0.95 )

No statistical analyses for this end point

Secondary: Change from baseline in mean ambulatory blood pressure (MABP) in dipper subjects at endpoint (Phase 1)

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End point title

Change from baseline in mean ambulatory blood pressure (MABP) in dipper subjects at endpoint (Phase 1)

End point description

ABPM was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. Dippers were defined as those subjects in whom there was a decrease in mean night time (6pm – 6am) ABPM more than or equal to (≥ ) 10% as compared to average daytime (6am –6pm) ABPM. Analysis was performed in subset of FAS subjects from selected centres who consented to undergo ABPM at baseline and at Week 4 or LOCF. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.

End point type

Secondary

End point timeframe

Baseline to endpoint (week 4 or LOCF)

End point values	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)
Number of subjects analysed	40	21	47
Units: mmHg
arithmetic mean (standard deviation)
MASBP	-1.2 ( 6.18 )	-4.6 ( 5.47 )	-6 ( 6.19 )
MADBP	-0.6 ( 5.78 )	-3.6 ( 4.19 )	-5.3 ( 5.55 )

No statistical analyses for this end point

Secondary: Change from baseline in mean ambulatory blood pressure (MABP) in non-dipper subjects at endpoint (Phase 1)

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End point title

Change from baseline in mean ambulatory blood pressure (MABP) in non-dipper subjects at endpoint (Phase 1)

End point description

ABPM was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. Non-dippers were defined as those subjects in whom there was a decrease in mean night time ABPM less than 10% as compared to average daytime ABPM. Analysis was performed in subset of FAS subjects from selected centers who consented to undergo ABPM at baseline and at Week 4. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.

End point type

Secondary

End point timeframe

Baseline to endpoint (Week 4 or LOCF)

End point values	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)
Number of subjects analysed	18	8	18
Units: mmHg
arithmetic mean (standard deviation)
MASBP	-2.6 ( 7.21 )	-9.3 ( 5.54 )	-5.2 ( 9.39 )
MADBP	-2.3 ( 4.05 )	-6.7 ( 4.45 )	-3.9 ( 7.3 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events are collected from First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV). All adverse events reported in this record are from date of First Subject First Treatment until LSLV.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Phase 1: Aliskiren Low (6.25/12.5/25 mg)

Reporting group description

Reporting group title

Phase 1: Aliskiren Mid (37.5/75/150 mg)

Reporting group description

Reporting group title

Phase 1: Aliskiren High (150/300/600 mg)

Reporting group description

Reporting group title

Phase 2: Aliskiren Low (6.25/12.5/25 mg)

Reporting group description

Reporting group title

Phase 2: Placebo Low

Reporting group description

Subjects received placebo capsules matching to aliskiren capsules (6.25/12.5/25 mg) once daily.

Reporting group title

Phase 2: Aliskiren Mid (37.5/75/150 mg)

Reporting group description

Reporting group title

Phase 2: Placebo Mid

Reporting group description

Subjects received placebo capsules matching to aliskiren capsules (37.5/75/150 mg) once daily.

Reporting group title

Phase 2: Aliskiren High (150/300/600 mg)

Reporting group description

Reporting group title

Phase 2: Placebo High

Reporting group description

Subjects received placebo capsules matching to aliskiren capsules (150/300/600 mg) once daily.

Serious adverse events	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)	Phase 2: Aliskiren Low (6.25/12.5/25 mg)	Phase 2: Placebo Low	Phase 2: Aliskiren Mid (37.5/75/150 mg)	Phase 2: Placebo Mid	Phase 2: Aliskiren High (150/300/600 mg)	Phase 2: Placebo High
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 108 (0.00%)	0 / 54 (0.00%)	1 / 105 (0.95%)	0 / 50 (0.00%)	0 / 57 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	2 / 50 (4.00%)	0 / 52 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Head injury
subjects affected / exposed	0 / 108 (0.00%)	0 / 54 (0.00%)	1 / 105 (0.95%)	0 / 50 (0.00%)	0 / 57 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 50 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	0 / 108 (0.00%)	0 / 54 (0.00%)	0 / 105 (0.00%)	0 / 50 (0.00%)	0 / 57 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 50 (2.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Suicide attempt
subjects affected / exposed	0 / 108 (0.00%)	0 / 54 (0.00%)	0 / 105 (0.00%)	0 / 50 (0.00%)	0 / 57 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 50 (2.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase 1: Aliskiren Low (6.25/12.5/25 mg)	Phase 1: Aliskiren Mid (37.5/75/150 mg)	Phase 1: Aliskiren High (150/300/600 mg)	Phase 2: Aliskiren Low (6.25/12.5/25 mg)	Phase 2: Placebo Low	Phase 2: Aliskiren Mid (37.5/75/150 mg)	Phase 2: Placebo Mid	Phase 2: Aliskiren High (150/300/600 mg)	Phase 2: Placebo High
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 108 (10.19%)	6 / 54 (11.11%)	14 / 105 (13.33%)	8 / 50 (16.00%)	7 / 57 (12.28%)	7 / 30 (23.33%)	3 / 21 (14.29%)	9 / 50 (18.00%)	5 / 52 (9.62%)
Nervous system disorders
Headache
subjects affected / exposed	5 / 108 (4.63%)	3 / 54 (5.56%)	7 / 105 (6.67%)	4 / 50 (8.00%)	3 / 57 (5.26%)	1 / 30 (3.33%)	2 / 21 (9.52%)	4 / 50 (8.00%)	3 / 52 (5.77%)
occurrences all number	6	3	9	4	3	1	2	5	3
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	3 / 108 (2.78%)	3 / 54 (5.56%)	2 / 105 (1.90%)	0 / 50 (0.00%)	0 / 57 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 50 (0.00%)	0 / 52 (0.00%)
occurrences all number	3	3	2	0	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	1 / 108 (0.93%)	0 / 54 (0.00%)	1 / 105 (0.95%)	1 / 50 (2.00%)	3 / 57 (5.26%)	2 / 30 (6.67%)	0 / 21 (0.00%)	2 / 50 (4.00%)	0 / 52 (0.00%)
occurrences all number	1	0	1	1	3	2	0	2	0
Infections and infestations
Acute tonsillitis
subjects affected / exposed	0 / 108 (0.00%)	0 / 54 (0.00%)	0 / 105 (0.00%)	0 / 50 (0.00%)	0 / 57 (0.00%)	2 / 30 (6.67%)	0 / 21 (0.00%)	0 / 50 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Upper respiratory tract infection
subjects affected / exposed	3 / 108 (2.78%)	3 / 54 (5.56%)	5 / 105 (4.76%)	3 / 50 (6.00%)	2 / 57 (3.51%)	3 / 30 (10.00%)	1 / 21 (4.76%)	4 / 50 (8.00%)	2 / 52 (3.85%)
occurrences all number	3	3	6	3	2	4	1	4	2

More information

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Were there any global substantial amendments to the protocol? Yes

19 Jan 2010

• Obviated requirement to collect pregnancy outcomes for partners of subjects who took study drug • Required echocardiography to be performed at baseline, prior to the administration of study drug • Addition of medical history to the assessment schedule

05 Apr 2010

• Clarified age at randomization • Clarified echocardiography requirements • Added 4 study visits for the purpose of collecting weekly trough BP • Addition of trough PK collection at Visit 4. • Addition of glucose to clinical chemistry parameters • Removal of alkaline phosphotase from the clinical chemistry parameters • Addition of sodium, potassium, chloride and BUN collection at Visit 2

29 Sep 2010

Prohibited treatment with itraconazole after start of the single-blind placebo run-in period

24 Jun 2013

Reduced the minimum requirement of randomized subjects with secondary hypertension to 10%

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A multicenter, randomized, double-blind, 8 week study to evaluate the dose response, efficacy and safety of aliskiren in paediatric hypertensive subjects 6-17 years of age.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in mean sitting systolic blood pressure (msSBP) at endpoint (Phase 1)

Primary: Change from baseline in mean sitting systolic blood pressure (msSBP) at endpoint (Phase 1)

Primary: Change in mean sitting systolic blood pressure (msSBP) from Week 4 to endpoint (Phase 2)

Primary: Change in mean sitting systolic blood pressure (msSBP) from Week 4 to endpoint (Phase 2)

Secondary: Number of subjects with adverse events and serious adverse events from baseline to week 4 (Phase 1)

Secondary: Number of subjects with adverse events and serious adverse events from baseline to week 4 (Phase 1)

Secondary: Number of subjects with adverse events and serious adverse events from Week 4 to Week 8 (Phase 2)

Secondary: Number of subjects with adverse events and serious adverse events from Week 4 to Week 8 (Phase 2)

Secondary: Change from baseline in mean sitting diastolic blood pressure (msDBP) at endpoint (Phase 1)

Secondary: Change from baseline in mean sitting diastolic blood pressure (msDBP) at endpoint (Phase 1)

Secondary: Change in mean sitting diastolic blood pressure (msDBP) from Week 4 to endpoint (Phase 2)

Secondary: Change in mean sitting diastolic blood pressure (msDBP) from Week 4 to endpoint (Phase 2)

Secondary: Change from baseline in mean arterial pressure (MAP) at endpoint (Phase 1)

Secondary: Change from baseline in mean arterial pressure (MAP) at endpoint (Phase 1)

Secondary: Change in mean arterial pressure (MAP) from Week 4 to endpoint (Phase 2)

Secondary: Change in mean arterial pressure (MAP) from Week 4 to endpoint (Phase 2)

Secondary: Percentage of subjects achieving a positive treatment response at endpoint (Phase 1)

Secondary: Percentage of subjects achieving a positive treatment response at endpoint (Phase 1)

Secondary: Change from baseline in mean ambulatory systolic and diastolic blood pressure (MASBP and MADBP) at endpoint (Phase 1)

Secondary: Change from baseline in mean ambulatory systolic and diastolic blood pressure (MASBP and MADBP) at endpoint (Phase 1)

Secondary: Change from baseline in mean ambulatory systolic blood pressure (MASBP) during day and night at week 4 (Phase 1)

Secondary: Change from baseline in mean ambulatory systolic blood pressure (MASBP) during day and night at week 4 (Phase 1)

Secondary: Change from baseline in mean ambulatory blood pressure (MABP) in dipper subjects at endpoint (Phase 1)

Secondary: Change from baseline in mean ambulatory blood pressure (MABP) in dipper subjects at endpoint (Phase 1)

Secondary: Change from baseline in mean ambulatory blood pressure (MABP) in non-dipper subjects at endpoint (Phase 1)

Secondary: Change from baseline in mean ambulatory blood pressure (MABP) in non-dipper subjects at endpoint (Phase 1)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A multicenter, randomized, double-blind, 8 week study to evaluate the dose response, efficacy and safety of aliskiren in paediatric hypertensive subjects 6-17 years of age.