Clinical Trial Results:
Evaluation of the clinical efficacy and safety of perindopril 10 mg/indapamide 2.5 mg/amlodipine 5 or 10 mg/bisoprolol 5 mg in single-pill combination after 8 weeks of treatment versus the free combination of perindopril 10 mg, indapamide 2.5 mg and amlodipine 5 or 10 mg in patients with uncontrolled essential hypertension. An international, multicentre, randomised, double-blind, 16-week study.
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Summary
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EudraCT number |
2020-004891-16 |
Trial protocol |
PL PT LT IT LV SK HU CZ BG HR |
Global end of trial date |
14 Dec 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Nov 2024
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First version publication date |
09 Nov 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CL3-05179-002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Institut de Recherches Internationales Servier (I.R.I.S.)
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Sponsor organisation address |
22, route 128, Gif-sur-Yvette, France, 91190
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Public contact |
Clinical Studies Department, Institut de Recherches Internationales Servier, +33 1 55724366, clinicaltrials@servier.com
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Scientific contact |
Clinical Studies Department, Institut de Recherches Internationales Servier, +33 1 55724366, clinicaltrials@servier.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Dec 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
14 Dec 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate the superiority of S05179 over Free [Per + Ind + Aml] (a tritherapy) on the lowering of office sitting SBP after 8 weeks of treatment (following a tritherapy run-in period).
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Protection of trial subjects |
The study was initiated only after the Ethics Committee’s approval, in accordance with the local regulations in each of the countries. Amendments to the protocol were applied only after the Ethics Committee's approval and in accordance with the local regulatory requirements.
The study was conducted in accordance with the protocol and with the following:
• Consensus ethical principles derived from international guidelines including the Declaration of Helsinki, 1964, as revised in Fortaleza, 2013.
• Applicable Good Clinical Practice (GCP) guidelines.
• Applicable laws and regulations.
In addition to the main study information and consent form (ICF) for study participation, this study also used a separate ICF for optional assessments (24-hour Ambulatory Blood Pressure Monitoring (ABPM) post-W008 visit and HBPM post-W000 visit) and for the consent of a pregnant partner of a study participant (for Italy).
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Background therapy |
99 patients (54.1%) were reported with concomitant therapy during the treatment period: mainly lipid lowering agents (36.6%) and diabetes drugs (26.2%). | ||
Evidence for comparator |
Tritherapy free combination of: Perindopril, Indapamine and Amlodipine | ||
Actual start date of recruitment |
12 Feb 2022
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Armenia: 56
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Country: Number of subjects enrolled |
Russian Federation: 30
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Country: Number of subjects enrolled |
Argentina: 27
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Country: Number of subjects enrolled |
Brazil: 8
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Country: Number of subjects enrolled |
Kazakhstan: 7
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Country: Number of subjects enrolled |
Poland: 14
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Country: Number of subjects enrolled |
Slovakia: 1
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Country: Number of subjects enrolled |
Bulgaria: 5
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Country: Number of subjects enrolled |
Czechia: 8
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Country: Number of subjects enrolled |
Hungary: 5
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Country: Number of subjects enrolled |
Italy: 8
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Country: Number of subjects enrolled |
Latvia: 10
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Country: Number of subjects enrolled |
Lithuania: 4
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Worldwide total number of subjects |
183
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EEA total number of subjects |
55
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
135
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From 65 to 84 years |
48
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85 years and over |
0
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Recruitment
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Recruitment details |
The study planned to enroll 968 patients. 183 patients in 13 countries were included. In July 2023, the sponsor decided to close patient selections before reaching the planned number of included patients due to recruitment difficulties. | |||||||||||||||
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Pre-assignment
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Screening details |
All patients were adults aged 18+ years. Patients were eligible for selection if they had uncontrolled BP despite treatment with 3 antihypertensive drugs at the optimal tolerated dose (including a diuretic) for at least 1 month prior to the selection visit. | |||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
469 [1] | |||||||||||||||
Number of subjects completed |
183 | |||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Screening failure: 267 | |||||||||||||||
Reason: Number of subjects |
Adverse event, non-fatal: 5 | |||||||||||||||
Reason: Number of subjects |
Consent withdrawn by subject: 14 | |||||||||||||||
| Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The pre-assignment period is a run-in period (8 weeks): from ASS1 selection visit (8 weeks before the inclusion visit) to inclusion visit (W000). The Run-in period was dedicated to confirming the essential uncontrolled HT on tritherapy free combination perindopril 10 mg, indapamide 2.5 mg and amlodipine 5 or 10 mg. The presented numbers are the numbers of all selected patients included in the Run-in period with uncontrolled essential hypertension. |
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Period 1
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Period 1 title |
Treatment period (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Arm S05179 | |||||||||||||||
Arm description |
Patients randomized to receive 1 capsule of quadritherapy drug S05179, 1 capsule of placebo and 1 tablet of placebo once daily for 8 weeks according to randomized treatment. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
S05179
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Investigational medicinal product code |
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Other name |
Per/Ind/Aml/Biso; Perindpril/Indapamine/Amlodipine/Bisoprolol
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
One capsule of S05179 single-pill combination (SPC) at one of the following strengths: Per/Ind/Aml/Biso 10/2.5/5/5 mg or 10/2.5/10/5 mg was taken once daily. The dose of amlodipine in the combination 5 mg or 10 mg was defined at ASS1 for each patient.
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Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
One capsule of placebo was taken once daily for purpose of maintain the blinding of the study.
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Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
One tablet of placebo was taken once daily for purpose of maintain the blinding of the study.
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Arm title
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Arm Tritherapy free combination | |||||||||||||||
Arm description |
Patients randomized to receive tritherapy free combination of perindopril, indapamide and amlodipine once daily for 8 weeks. | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Per 10 mg
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Investigational medicinal product code |
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Other name |
perindopril
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
One 10 mg capsule was taken once daily for 8 week.
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Investigational medicinal product name |
Ind 2.5 mg
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Investigational medicinal product code |
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Other name |
indapamide
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
One 2.5 mg tablet was taken once daily for 8 week.
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Investigational medicinal product name |
Aml 5 or 10 mg
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Investigational medicinal product code |
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Other name |
amlodipine
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
One 5 mg or 10 mg capsule was taken once daily for 8 week. The dose of amlodipine of 5 mg or 10 mg was defined at ASS1 (first selection visit) for each patient and remained unchanged for the whole study duration.
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Baseline characteristics reporting groups
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Reporting group title |
Arm S05179
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Reporting group description |
Patients randomized to receive 1 capsule of quadritherapy drug S05179, 1 capsule of placebo and 1 tablet of placebo once daily for 8 weeks according to randomized treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm Tritherapy free combination
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Reporting group description |
Patients randomized to receive tritherapy free combination of perindopril, indapamide and amlodipine once daily for 8 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Arm S05179
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Reporting group description |
Patients randomized to receive 1 capsule of quadritherapy drug S05179, 1 capsule of placebo and 1 tablet of placebo once daily for 8 weeks according to randomized treatment. | ||
Reporting group title |
Arm Tritherapy free combination
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Reporting group description |
Patients randomized to receive tritherapy free combination of perindopril, indapamide and amlodipine once daily for 8 weeks. | ||
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End point title |
Office sitting Systolic Blood Pressure (SBP) | |||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
From baseline (Week 000) to Week 008
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| Notes [1] - Only randomized patients considered non-controlled at baseline are included in the analysis [2] - Only randomized patients considered non-controlled at baseline are included in the analysis. |
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Statistical analysis title |
Statistical analysis | |||||||||||||||
Comparison groups |
Arm S05179 v Arm Tritherapy free combination
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Number of subjects included in analysis |
162
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
Method |
General Linear Model | |||||||||||||||
Parameter type |
Adjusted difference from baseline - W008 | |||||||||||||||
Point estimate |
-8.04
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Confidence interval |
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95% | |||||||||||||||
sides |
2-sided
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lower limit |
-11.99 | |||||||||||||||
upper limit |
-4.09 | |||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
2.02
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events were collected during the period Week 000 - Week 008
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Adverse event reporting additional description |
Safety Set (SS) consisted of 183 patients (100%) according to actual treatment.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
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Reporting groups
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Reporting group title |
S05179 arm
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Reporting group description |
Patients receiving actually 1 capsule of quadritherapy drug S05179, 1 capsule of placebo and 1 tablet of placebo once daily for 8 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tritherapy free combination arm
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Reporting group description |
Patients receiving actually tritherapy free combination of perindopril, indapamide and amlodipine once daily for 8 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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05 Oct 2021 |
Amendment No. 1
- Addition of a paragraph regarding benefit-risk assessment, dose and duration in the background information.
- Addition of a blood pregnancy test at the inclusion visit and at the last study visit or withdrawal visit.
- Update of several non-selection criteria.
- Update of the period used to measure the BP uncontrolled status on the planned 24h-ABPM assessment (from real daytime period to 24h-period).
- Update of the 24h ABPM validity criteria.
- Addition of the possibility to perform a blinded sample size reassessment. |
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21 Jun 2022 |
Amendment No. 3
- Addition of a urine home (or on site) pregnancy test the day before ASS2 visit and W004 phone contact in order to have a pregnancy test at every visit.
- Clarification on sites’ internal organisation regarding ABPM/HBPM results and/or blood results assessments by the investigator.
- Imaging methods used to evaluate the function and structure of the kidneys were extended.
- Change renal echography by renal imagery.
- Change real daytime by 24-hour period.
- Update of selection criteria: the upper age limit was deleted (criterion 1); the criterion 2a. regarding patient with very high cardiovascular risk was clarified.
- imaging modalities to document absence of renal secondary HT were extended.
- Update of non-selection criteria: addition of a urine home (or on site) pregnancy test the day before ASS2; clarification of the type of (i.e. symptomatic) bradycardia and other diseases and the severity of asthma histories; harmonisation of non-selection criteria N° 25 and N° 26 with selection criterion N° 2; clarification of criterion N° 30: patients having a moderate or severe renal failure.
- Update of inclusion criteria: clarification of criterion 55a. regarding 12-lead ECG and an exemption for AV block Grade consistent with Bisoprolol SmPC.
- Update of exclusion criteria: criterion 69a. (imaging modalities to document absence of renal secondary HT were extended.); criteria 71a. (clarification of the criterion about abnormal results of TSH.)
- Clarification of withdrawal criteria and procedure during the run-in period.
- Clarification of Office BP measurements.
- The documentation of the adverse event was aligned with ICH E6 R2.
- The procedure for ERIN was clarified.
- Renal arteries assessments were clarified.
- e-CRF signature was clarified.
- Blind-reviews and database managements were clarified.
- Update of the section “printing the data” of the Appendix 3 was updated. |
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17 Oct 2022 |
Amendment No. 4
- Update of the non-selection criteria 13a in order to exclude patients with the most severe obesity forms (BMI > 35 kg/m2). Consequently, Background information and References were updated.
- Procedure for an ERIN was updated: addition of the 24-hour phone line (outside working hours). |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
