Clinical Trial Results:
Acceptability, safety, pharmacokinetics and effects on blood pressure of paediatric formulation of perindopril, S 90052 (0.020 to 0.110 mg/kg/d)/S 90652 (0.025 to 0.135 mg/kg/d), in hypertensive children. An open, noncomparative, 3-month then 24-month (minimal duration) multicentre study.

Summary
EudraCT number
2005-000077-22
Trial protocol
BE   IT  
Global end of trial date
27 Apr 2010

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

Trial information

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Trial identification
Sponsor protocol code
CL2-90652-001
Additional study identifiers
ISRCTN number
-
US NCT number
-
WHO universal trial number (UTN)
-
Sponsors
Sponsor organisation name
Institut de Recherches Internationales Servier
Sponsor organisation address
50 rue Carnot, Suresnes Cedex, France, 92284
Public contact
Clinical studies department, Institut de Recherches Internationales Servier 50 rue Carnot 92284 Suresnes Cedex, +33 155724366, [email protected]
Scientific contact
Clinical studies department, Institut de Recherches Internationales Servier 50 rue Carnot 92284 Suresnes Cedex, +33 155724366, [email protected]
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)
No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
Yes
Results analysis stage
Analysis stage
Final
Date of interim/final analysis
27 Apr 2010
Is this the analysis of the primary completion data?
Yes
Primary completion date
27 Apr 2010
Global end of trial reached?
Yes
Global end of trial date
27 Apr 2010
Was the trial ended prematurely?
No
General information about the trial
Main objective of the trial
The main objective of the study was to assess the acceptability of S 90052/S 90652, the orodispersible formulation of perindopril and to assess the safety of S 90052/S 90652.
Protection of trial subjects
Temporary discontinuations of the study treatment were allowed during the study if a dose decreasing procedure was decided. Definitive discontinuations of the study drug were to be decided in case of serious adverse drug reaction(s), or adverse event(s) not compatible with the continuation of the study treatment, or insufficient BP control. In the extension part of the study, the apparition of signs of pubescence in girls was also a reason for definitive discontinuations of the study drug: A serious adverse reaction was defined as a serious adverse event that the investigator considered might be due to the research. Adverse events considered as not compatible with the continuation of the study drug were the following angioedema postural hypotension or occurrences of malaises, serum potassium level > 5.5 mEq/L and estimated GFR ≤ 25 mL/min/1.73m². Insufficient BP control was defined as the occurrence of a threatening hypertension; SBP or DBP equal to or above the 97.5th percentile + 30 mmHg the occurrence of a SBP or a DBP equal to or above the 95th percentile in spite of the administration of the maximal authorised dose of S 90652 in combination with additional antihypertensive agent(s).
Background therapy
-
Evidence for comparator
-
Actual start date of recruitment
16 Jul 2003
Long term follow-up planned
Yes
Long term follow-up rationale
Safety, Efficacy
Long term follow-up duration
48 Months
Independent data monitoring committee (IDMC) involvement?
No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled
France: 43
Country: Number of subjects enrolled
Belgium: 11
Country: Number of subjects enrolled
Italy: 8
Worldwide total number of subjects
62
EEA total number of subjects
62
Number of subjects enrolled per age group
In utero
0
Preterm newborn - gestational age
0
Newborns (0-27 days)
0
Infants and toddlers (28 days-23 months)
0
Children (2-11 years)
54
Adolescents (12-17 years)
8
Adults (18-64 years)
0
From 65 to 84 years
0
85 years and over
0

Subject disposition

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Recruitment
Recruitment details
In all, 20 centres located in Belgium, France and Italy were opened: four centres in Belgium, 15 centres in France and one centre in Italy. Eighteen centres selected at least one patient, and 17 centres included at least one patient.

Pre-assignment
Screening details
-

Pre-assignment period milestones
Number of subjects started
62
Number of subjects completed
62

Period 1
Period 1 title
overall trial (overall period)
Is this the baseline period?
Yes
Allocation method
Not applicable
Blinding used
Not blinded

Arms
Are arms mutually exclusive
Yes

Arm title
Subgroup A
Arm description
Confirmed and untreated arterial hypertension (defined as a systolic blood pressure (SBP) or a diastolic blood pressure (DBP) equal to or above the 97.5th percentile + 10 mmHg)
Arm type
Experimental

Investigational medicinal product name
S 90052 (perindopril tert-butylamine salt)
Investigational medicinal product code
Other name
Pharmaceutical forms
Orodispersible tablet
Routes of administration
Oral use
Dosage and administration details
0.020 mg/kg/day, oral

Investigational medicinal product name
S 90652 (perindopril arginine salt)
Investigational medicinal product code
Other name
Pharmaceutical forms
Orodispersible tablet
Routes of administration
Oral use
Dosage and administration details
0.025 mg/kg/day, oral

Arm title
Subgroup B
Arm description
Arterial hypertension controlled with an ongoing treatment including an angiotensin-converting enzyme inhibitor (ACE-I) or other BP lowering medication(s), when the switch of the ACE-I (if an ACE-I was administered) or the switch of another BP lowering medication (if no ACE-I was administered) by S 90052/ S 90652 could be considered.
Arm type
Experimental

Investigational medicinal product name
S 90052 (perindopril tert-butylamine salt)
Investigational medicinal product code
Other name
Pharmaceutical forms
Orodispersible tablet
Routes of administration
Oral use
Dosage and administration details
0.020 mg/kg/day, 0.040 mg/kg/day or 0.080 mg/kg/day, oral

Investigational medicinal product name
S 90652 (perindopril arginine salt)
Investigational medicinal product code
Other name
Pharmaceutical forms
Orodispersible tablet
Routes of administration
Oral use
Dosage and administration details
0.025 mg/kg/day, 0.050 mg/kg/day or 0.100 mg/kg/day, oral, depending upon the previous antihypertensive treatment.

Arm title
Subgroup C
Arm description
Poorly controlled arterial hypertension treated with medication(s) that did not include any ACE-I, when the addition of S 90052/ S 90652 was expected to improve BP control.
Arm type
Experimental

Investigational medicinal product name
S 90052 (perindopril tert-butylamine salt)
Investigational medicinal product code
Other name
Pharmaceutical forms
Orodispersible tablet
Routes of administration
Oral use
Dosage and administration details
0.020 mg/kg/day, oral

Investigational medicinal product name
S 90652 (perindopril arginine salt)
Investigational medicinal product code
Other name
Pharmaceutical forms
Orodispersible tablet
Routes of administration
Oral use
Dosage and administration details
0.025 mg/kg/day, oral

Number of subjects in period 1
Subgroup A Subgroup B Subgroup C
Started
6
51
5
Completed
5
27
4
Not completed
1
24
1
     Protocol deviation
1
5
-
     Lack of efficacy
-
2
-
     non medical reason
-
10
1
     Adverse event, non-fatal
-
6
-
     Lost to follow-up
-
1
-

Baseline characteristics

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Baseline characteristics reporting groups
Reporting group title
Subgroup A
Reporting group description
Confirmed and untreated arterial hypertension (defined as a systolic blood pressure (SBP) or a diastolic blood pressure (DBP) equal to or above the 97.5th percentile + 10 mmHg)

Reporting group title
Subgroup B
Reporting group description
Arterial hypertension controlled with an ongoing treatment including an angiotensin-converting enzyme inhibitor (ACE-I) or other BP lowering medication(s), when the switch of the ACE-I (if an ACE-I was administered) or the switch of another BP lowering medication (if no ACE-I was administered) by S 90052/ S 90652 could be considered.

Reporting group title
Subgroup C
Reporting group description
Poorly controlled arterial hypertension treated with medication(s) that did not include any ACE-I, when the addition of S 90052/ S 90652 was expected to improve BP control.

Reporting group values
Subgroup A Subgroup B Subgroup C Total
Number of subjects
6 51 5 62
Age categorical
Units: Subjects
    In utero
0 0 0 0
    Preterm newborn infants (gestational age < 37 wks)
0 0 0 0
    Newborns (0-27 days)
0 0 0 0
    Infants and toddlers (28 days-23 months)
0 0 0 0
    Children (2-11 years)
3 23 1 27
    Adolescents (12-17 years)
3 28 4 35
    Adults (18-64 years)
0 0 0 0
    From 65-84 years
0 0 0 0
    85 years and over
0 0 0 0
Age continuous
Units: years
    arithmetic mean (standard deviation)
4.8 ± 1.6 6.8 ± 3.9 9.4 ± 3.8 -
Gender categorical
Units: Subjects
    Female
3 19 1 23
    Male
3 32 4 39

End points

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End points reporting groups
Reporting group title
Subgroup A
Reporting group description
Confirmed and untreated arterial hypertension (defined as a systolic blood pressure (SBP) or a diastolic blood pressure (DBP) equal to or above the 97.5th percentile + 10 mmHg)

Reporting group title
Subgroup B
Reporting group description
Arterial hypertension controlled with an ongoing treatment including an angiotensin-converting enzyme inhibitor (ACE-I) or other BP lowering medication(s), when the switch of the ACE-I (if an ACE-I was administered) or the switch of another BP lowering medication (if no ACE-I was administered) by S 90052/ S 90652 could be considered.

Reporting group title
Subgroup C
Reporting group description
Poorly controlled arterial hypertension treated with medication(s) that did not include any ACE-I, when the addition of S 90052/ S 90652 was expected to improve BP control.

Primary: No primary criterion

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End point title
No primary criterion [1]
End point description
End point type
Primary
End point timeframe
No primary efficacy criterion was defined as the main objective was to study the safety of S 90052/S 90652.
Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No primary efficacy criterion was defined as the main objective was to study the safety of S 90052/S 90652.
End point values
Number of subjects analysed
Units: Not applicable
No statistical analyses for this end point

Secondary: Evolution of systolic blood pressure over time until M24

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End point title
Evolution of systolic blood pressure over time until M24
End point description
End point type
Secondary
End point timeframe
From selection to last visit
End point values
Subgroup A Subgroup B Subgroup C
Number of subjects analysed
5
51
5
Units: mmHg
    arithmetic mean (standard deviation)
-7.8 ± 10.7
0.8 ± 16.4
-9.6 ± 13
Attachments
Statistical analysis_SBP
No statistical analyses for this end point

Secondary: Evolution of diastolic blood pressure over time until M24

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End point title
Evolution of diastolic blood pressure over time until M24
End point description
End point type
Secondary
End point timeframe
From selection to last visit
End point values
Subgroup A Subgroup B Subgroup C
Number of subjects analysed
5
51
5
Units: mmHg
    arithmetic mean (standard deviation)
-13.2 ± 12.1
-1 ± 12.1
-11 ± 4.8
Attachments
Statistical analysis_DBP
No statistical analyses for this end point

Adverse events

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Adverse events information
Timeframe for reporting adverse events
Over the course of the study
Assessment type
Systematic
Dictionary used for adverse event reporting
Dictionary name
MedDRA
Dictionary version
5.0
Reporting groups
Reporting group title
Subgroup A
Reporting group description
-

Reporting group title
Subgroup C
Reporting group description
-

Reporting group title
Subgroup B
Reporting group description
-

Serious adverse events
Subgroup A Subgroup C Subgroup B
Total subjects affected by serious adverse events
     subjects affected / exposed
4 / 6 (66.67%)
5 / 5 (100.00%)
28 / 51 (54.90%)
     number of deaths (all causes)
0
0
0
     number of deaths resulting from adverse events
0
0
0
Vascular disorders
Hypertensive crisis
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
2 / 51 (3.92%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hypertension NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Orthostatic hypotension
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Immune system disorders
Transplant rejection
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Liver transplant rejection
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
General disorders and administration site conditions
Fall
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Influenza like illness
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Injury, poisoning and procedural complications
Accidental overdose
     subjects affected / exposed
1 / 6 (16.67%)
0 / 5 (0.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Therapeutic agent toxicity
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Joint sprain
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Upper limb fracture NOS
     subjects affected / exposed
1 / 6 (16.67%)
0 / 5 (0.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Investigations
Biopsy kidney
     subjects affected / exposed
0 / 6 (0.00%)
2 / 5 (40.00%)
6 / 51 (11.76%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
0 / 7
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Transplant evaluation
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Weight decreased
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Investigations NOS
     subjects affected / exposed
0 / 6 (0.00%)
2 / 5 (40.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Congenital, familial and genetic disorders
Multiple epiphyseal dysplasia
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Blood and lymphatic system disorders
Haemolytic anaemia NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Respiratory, thoracic and mediastinal disorders
Tonsillar hypertrophy
     subjects affected / exposed
0 / 6 (0.00%)
2 / 5 (40.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Adenoidal hypertrophy
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Pharyngitis
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Nervous system disorders
Dyskinesia
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Headache
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Obstructive sleep apnoea syndrome
     subjects affected / exposed
1 / 6 (16.67%)
0 / 5 (0.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Gastrointestinal disorders
Diarrhoea NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
4 / 51 (7.84%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 5
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Gastroenteritis NOS
     subjects affected / exposed
0 / 6 (0.00%)
2 / 5 (40.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Gingival hypertrophy
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
2 / 51 (3.92%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Anal polyp
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Appendicitis
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Colonic polyp
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Inguinal hernia NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Vomiting NOS
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Renal and urinary disorders
Renal failure acute
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
2 / 51 (3.92%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 3
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Nephropathy NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
2 / 51 (3.92%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Vesico-ureteric reflux
     subjects affected / exposed
1 / 6 (16.67%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Nephrotic syndrome
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Neurogenic bladder
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Proteinuria aggravated
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Urinary tract operation
     subjects affected / exposed
1 / 6 (16.67%)
0 / 5 (0.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 2
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Adenotonsillectomy
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Angioplasty
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Bladder catheter removal
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Tonsillectomy
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Enema administration
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Otorhinolaryngological surgery
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hepatobiliary disorders
Cholangitis NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hepatic failure
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Skin and subcutaneous tissue disorders
Rash NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Henoch-Schonlein purpura
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Epiphysiolysis
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Jaw cyst
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Metabolism and nutrition disorders
Dehydration
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Diabetes mellitus NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Malnutrition NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Infections and infestations
Gastroenteritis viral NOS
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
2 / 51 (3.92%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Pyelonephritis acute NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
2 / 51 (3.92%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 4
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Viral infection NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
2 / 51 (3.92%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Peritonitis pneumococcal
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Cytomegalovirus infection
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Epstein-Barr virus infection
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Herpetic stomatitis
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Meningitis enteroviral
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Otitis media serous chronic NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Pharyngitis streptococcal
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Pneumonia mycoplasmal
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Pneumonia NOS
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Streptococcal sepsis
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
1 / 51 (1.96%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Varicella
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
0 / 51 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events
Subgroup A Subgroup C Subgroup B
Total subjects affected by non serious adverse events
     subjects affected / exposed
6 / 6 (100.00%)
5 / 5 (100.00%)
45 / 51 (88.24%)
Investigations
Biopsy kidney
     subjects affected / exposed
0 / 6 (0.00%)
2 / 5 (40.00%)
6 / 51 (11.76%)
     occurrences all number
0
2
7
Blood and lymphatic system disorders
Anaemia NOS
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
4 / 51 (7.84%)
     occurrences all number
0
1
4
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis
     subjects affected / exposed
1 / 6 (16.67%)
3 / 5 (60.00%)
11 / 51 (21.57%)
     occurrences all number
2
4
13
Pharyngitis
     subjects affected / exposed
2 / 6 (33.33%)
1 / 5 (20.00%)
9 / 51 (17.65%)
     occurrences all number
2
1
9
Cough
     subjects affected / exposed
0 / 6 (0.00%)
2 / 5 (40.00%)
7 / 51 (13.73%)
     occurrences all number
0
2
7
Rhinitis allergic NOS
     subjects affected / exposed
1 / 6 (16.67%)
0 / 5 (0.00%)
3 / 51 (5.88%)
     occurrences all number
1
0
7
Nervous system disorders
Headache
     subjects affected / exposed
2 / 6 (33.33%)
1 / 5 (20.00%)
8 / 51 (15.69%)
     occurrences all number
2
1
12
Ear and labyrinth disorders
Ear pain
     subjects affected / exposed
1 / 6 (16.67%)
0 / 5 (0.00%)
3 / 51 (5.88%)
     occurrences all number
1
0
4
General disorders and administration site conditions
Pyrexia
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
4 / 51 (7.84%)
     occurrences all number
0
5
4
Influenza like illness
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
4 / 51 (7.84%)
     occurrences all number
0
1
4
Gastrointestinal disorders
Gastroenteritis NOS
     subjects affected / exposed
3 / 6 (50.00%)
2 / 5 (40.00%)
13 / 51 (25.49%)
     occurrences all number
6
3
19
Diarrhoea NOS
     subjects affected / exposed
1 / 6 (16.67%)
1 / 5 (20.00%)
7 / 51 (13.73%)
     occurrences all number
2
1
11
Abdominal pain upper
     subjects affected / exposed
2 / 6 (33.33%)
2 / 5 (40.00%)
4 / 51 (7.84%)
     occurrences all number
2
3
6
Gingival hypertrophy
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
4 / 51 (7.84%)
     occurrences all number
0
1
4
Renal and urinary disorders
Nephropathy NOS
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
3 / 51 (5.88%)
     occurrences all number
0
1
3
Skin and subcutaneous tissue disorders
Ingrowing nail
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
3 / 51 (5.88%)
     occurrences all number
0
1
4
Rash NOS
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
3 / 51 (5.88%)
     occurrences all number
0
2
3
Infections and infestations
Urinary tract infection NOS
     subjects affected / exposed
0 / 6 (0.00%)
2 / 5 (40.00%)
9 / 51 (17.65%)
     occurrences all number
0
7
15
Bronchitis acute NOS
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
9 / 51 (17.65%)
     occurrences all number
0
1
12
Rhinitis NOS
     subjects affected / exposed
2 / 6 (33.33%)
1 / 5 (20.00%)
7 / 51 (13.73%)
     occurrences all number
2
1
10
Respiratory tract infection NOS
     subjects affected / exposed
0 / 6 (0.00%)
2 / 5 (40.00%)
7 / 51 (13.73%)
     occurrences all number
0
8
13
Ear infection NOS
     subjects affected / exposed
1 / 6 (16.67%)
1 / 5 (20.00%)
5 / 51 (9.80%)
     occurrences all number
2
2
10
Bronchitis NOS
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
6 / 51 (11.76%)
     occurrences all number
0
1
7
Upper respiratory tract infection NOS
     subjects affected / exposed
0 / 6 (0.00%)
2 / 5 (40.00%)
4 / 51 (7.84%)
     occurrences all number
0
6
5
Viral infection NOS
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
4 / 51 (7.84%)
     occurrences all number
0
1
5
Herpes simplex
     subjects affected / exposed
0 / 6 (0.00%)
0 / 5 (0.00%)
5 / 51 (9.80%)
     occurrences all number
0
0
5
Gastroenteritis viral NOS
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
3 / 51 (5.88%)
     occurrences all number
0
3
4
Influenza
     subjects affected / exposed
1 / 6 (16.67%)
1 / 5 (20.00%)
2 / 51 (3.92%)
     occurrences all number
1
1
2
Varicella
     subjects affected / exposed
0 / 6 (0.00%)
1 / 5 (20.00%)
3 / 51 (5.88%)
     occurrences all number
0
1
3

More information

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Substantial protocol amendments (globally)

Were there any global substantial amendments to the protocol? Yes
Date
Amendment
17 Nov 2003
The number of centres, the duration of the study, the study drug new formulation, the dosages and the assay centre for perindopril and perindoprilat assays. The protocol code changed from CL2-90052-002 to CL2-90652-001: - Due to the rate of inclusion lower than expected, the total number of centres was increased from 8 to 20. - For the same reason, the duration of the recruitment (12 months) was extended to 18 months and the duration of the study from 16 months to 22 months. - Perindopril tert-butylamine salt was replaced by arginine salt. The doses were modified to take into account the different molecular weights of the two salts; the packaging and the information/informed consent forms were modified. Upon approval of the amendment, the patients to be enrolled in the study received S 90652. Ongoing patients at the time of the implementation of the amendment completed D120 visit with S 90052. - Due to the small volume of blood collected from children, the assay centre AAI (Applied Analytical Industries), located in Germany, experienced difficulties to extract sufficient amounts of perindopril and perindoprilat from the small volume samples (0.2 mL). Therefore, the decision was made to have perindopril and perindoprilat assays performed by Technologie SERVIER (TES) in France, where the method had been validated.
24 Sep 2004
Included the following changes: - The study initially planned in French paediatric centres was extended to European paediatric centres. The total number of centres was increased to 20. - The duration of the recruitment (18 months) was extended to 36 months and the duration of the study from 22 months to 40 months. - The upper age limit was raised to 16 years old in boys. The information/informed consent form was modified accordingly.
11 Sep 2008
This amendment allowed to obtain echocardiographic data from exams performed within the usual medical follow-up of the patients but outside the study. Exams performed before study treatment initiation and after at least two years of study treatment were concerned, and allowed to assess cardiac function and structure parameters in hypertensive children. Concerning ongoing patients, if there was no echocardiographic data available (under study treatment) after at least two years of study treatment, an echocardiography was to be performed at one of the follow up visits. Each participant (if capable) and his/her parents were asked to sign an additional consent form.

Interruptions (globally)

Were there any global interruptions to the trial? No

Limitations and caveats

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
The section NSAE presented EAEs on treatment and included SEAEs. The causality and seriousness of reported SAE can be ultimately upgraded by the sponsor. The sponsor took these decisions to be compliant with the existing ICH E3 Clinical Study Report.