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    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.

    Summary
    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

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Nov 2024
    First version publication date
    09 Nov 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL3-05179-002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier (I.R.I.S.)
    Sponsor organisation address
    22, route 128, Gif-sur-Yvette, France, 91190
    Public contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 1 55724366, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 1 55724366, clinicaltrials@servier.com
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Dec 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    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).
    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).
    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
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Armenia: 56
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Argentina: 27
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Kazakhstan: 7
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Latvia: 10
    Country: Number of subjects enrolled
    Lithuania: 4
    Worldwide total number of subjects
    183
    EEA total number of subjects
    55
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    135
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

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    Recruitment
    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.

    Pre-assignment
    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.

    Pre-assignment period milestones
    Number of subjects started
    469 [1]
    Number of subjects completed
    183

    Pre-assignment subject non-completion reasons
    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.
    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    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
    Investigational medicinal product code
    Other name
    Per/Ind/Aml/Biso; Perindpril/Indapamine/Amlodipine/Bisoprolol
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    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.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule of placebo was taken once daily for purpose of maintain the blinding of the study.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet of placebo was taken once daily for purpose of maintain the blinding of the study.

    Arm title
    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
    Investigational medicinal product code
    Other name
    perindopril
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One 10 mg capsule was taken once daily for 8 week.

    Investigational medicinal product name
    Ind 2.5 mg
    Investigational medicinal product code
    Other name
    indapamide
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 2.5 mg tablet was taken once daily for 8 week.

    Investigational medicinal product name
    Aml 5 or 10 mg
    Investigational medicinal product code
    Other name
    amlodipine
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    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.

    Number of subjects in period 1
    Arm S05179 Arm Tritherapy free combination
    Started
    89
    94
    Completed
    89
    93
    Not completed
    0
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm S05179
    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
    Reporting group description
    Patients randomized to receive tritherapy free combination of perindopril, indapamide and amlodipine once daily for 8 weeks.

    Reporting group values
    Arm S05179 Arm Tritherapy free combination Total
    Number of subjects
    89 94 183
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    64 71 135
        From 65-84 years
    25 23 48
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.9 ( 11.4 ) 57.8 ( 9.8 ) -
    Gender categorical
    Units: Subjects
        Female
    37 49 86
        Male
    52 45 97

    End points

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    End points reporting groups
    Reporting group title
    Arm S05179
    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
    Reporting group description
    Patients randomized to receive tritherapy free combination of perindopril, indapamide and amlodipine once daily for 8 weeks.

    Primary: Office sitting Systolic Blood Pressure (SBP)

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    End point title
    Office sitting Systolic Blood Pressure (SBP)
    End point description
    End point type
    Primary
    End point timeframe
    From baseline (Week 000) to Week 008
    End point values
    Arm S05179 Arm Tritherapy free combination
    Number of subjects analysed
    80 [1]
    82 [2]
    Units: number
    arithmetic mean (standard deviation)
        Change in SBP from Baseline to week 008
    -20.67 ( 15.37 )
    -11.32 ( 14.77 )
    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.
    Statistical analysis title
    Statistical analysis
    Comparison groups
    Arm S05179 v Arm Tritherapy free combination
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    General Linear Model
    Parameter type
    Adjusted difference from baseline - W008
    Point estimate
    -8.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.99
         upper limit
    -4.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.02

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected during the period Week 000 - Week 008
    Adverse event reporting additional description
    Safety Set (SS) consisted of 183 patients (100%) according to actual treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    S05179 arm
    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
    Reporting group description
    Patients receiving actually tritherapy free combination of perindopril, indapamide and amlodipine once daily for 8 weeks.

    Serious adverse events
    S05179 arm Tritherapy free combination arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 95 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    S05179 arm Tritherapy free combination arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 88 (11.36%)
    8 / 95 (8.42%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 95 (0.00%)
         occurrences all number
    1
    0
    Heart rate increased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 95 (1.05%)
         occurrences all number
    0
    1
    Human chorionic gonadotropin increased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 95 (1.05%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 95 (1.05%)
         occurrences all number
    0
    1
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    3 / 88 (3.41%)
    1 / 95 (1.05%)
         occurrences all number
    3
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 95 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 95 (1.05%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 95 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 95 (0.00%)
         occurrences all number
    1
    0
    Stress
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 95 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 95 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 95 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 88 (0.00%)
    2 / 95 (2.11%)
         occurrences all number
    0
    2
    Acute sinusitis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 95 (1.05%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 88 (2.27%)
    0 / 95 (0.00%)
         occurrences all number
    2
    0
    Dyslipidaemia
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 95 (1.05%)
         occurrences all number
    0
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 95 (1.05%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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.
    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.
    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).

    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.
    None reported
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