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    Clinical Trial Results:
    Open-label, multicenter, multinational, interventional clinical trial to assess effectiveness and safety of the extemporaneous combination of nebivolol and zofenopril calcium in grade 1 to 2 hypertensive patients versus each monotherapy

    Summary
    EudraCT number
    		 2020-002340-23
    Trial protocol
    		 IT  
    Global end of trial date
    22 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jan 2023
    First version publication date
    07 Jan 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MEIN/19/ZoNe-HYP/001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05257148
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Menarini International Operation Luxembourg SA
    Sponsor organisation address
    1, Avenue de la Gare, Luxembourg, Luxembourg, L-1611
    Public contact
    Clinical Operation Director, Menarini, +39 055568091, pfabrizzi@menarini.it
    Scientific contact
    Clinical Operation Director, Menarini, +39 055568091, pfabrizzi@menarini.it
    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
    23 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the antihypertensive effect of the extemporaneous combination of nebivolol 5 mg and zofenopril calcium 30 mg in lowering sitting diastolic blood pressure (DBP) after 8 weeks of treatment, in patients with uncontrolled blood pressure (BP) who were previously treated with nebivolol or zofenopril calcium monotherapies for at least 4 weeks
    Protection of trial subjects
    The study was conducted in compliance with International Council for Harmonisation (ICH) Good Clinical Practices (GCP), including the archiving of essential documents as well as the ethical principles of the Declaration of Helsinki.
    Background therapy
    		 No Background Therapy
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Mar 2021
    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
    Poland: 267
    Country: Number of subjects enrolled
    Italy: 16
    Worldwide total number of subjects
    283
    EEA total number of subjects
    283
    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)
    283
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study started on 26 May 2021 and terminated on 22 December 2021 296 patients were screened for the study. 283 patients entered the run-in period and were assigned for monotherapy to Nebivolol (NEB) 5 mg or Zofenopril (ZOF) 30 mg. Of the 269 completed patients in monotherapy, 246 were assigned to combination therapy and 238 competed the study

    Pre-assignment
    Screening details
    		 296 patients male and female Caucasian uncontrolled hypertensive patients ≥ 18 and < 65 years of age on monotherapy either with ACE-i or BBs since at least 1 month and with mean sitting SBP ≥ 140 mmHg and ≤ 179 mmHg and / or mean sitting DBP ≥ 90 mmHg and ≤ 109 mmHg, were screened.

    Period 1
    Period 1 title
    Run-in Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-label study, not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zofenopril 30 mg
    Arm description
    		 Patients in therapy with ACE-i, were assigned to monotherapy with ZOFENOPRIL 30 mg for 4 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Zofenopril 30 mg
    Investigational medicinal product code
    Zofenopril calcium
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of study drug was administered with a glass of water once daily

    Arm title
    		 Nebivolol 5 mg
    Arm description
    		 Patients in therapy with Beta Blockers, were assigned to monotherapy with Nebivolol 5 mg for 4 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nebivolol 5mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of study drug was administered with a glass of water once daily

    Number of subjects in period 1
    		Zofenopril 30 mg Nebivolol 5 mg
    Started
    137
    146
    Completed
    130
    139
    Not completed
    7
    7
         Lost to follow-up
    2
    5
         Protocol deviation
    5
    2
    Period 2
    Period 2 title
    Assessment
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-label study, not blinded

    Arms
    Arm title
    		 Combination Therapy Zofenopril 30mg/Nebivolol 5mg
    Arm description
    		 During the assessment period of 8 weeks, the eligible patients (uncontrolled hypertension with sitting BP of SBP/DBP > 130/80 mmHg, who tolerated the treatment and whose adherence to the therapies ranged from 80% to 120%) received a combination of NEB 5 mg and ZOF 30 mg to be taken orally once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nebivolol 5mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of study drug was administered with a glass of water once daily

    Investigational medicinal product name
    Zofenopril 30 mg
    Investigational medicinal product code
    Zofenopril calcium
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of study drug was administered with a glass of water once daily

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 is the Run-in period. The objective of the study is to evaluate the effectiveness and safety of the combination therapy (Zofenopril/Nebivolol) versus the monotherapy. Hence the baseline period starts on Period 2, with the assessment of blood pressure after the run-in period and the intake of the combination therapy.
    Number of subjects in period 2 [2] [3]
    		Combination Therapy Zofenopril 30mg/Nebivolol 5mg
    Started
    246
    Completed
    238
    Not completed
    8
         Consent withdrawn by subject
    4
         Adverse event, non-fatal
    2
         Protocol deviation
    2
    Notes
    [2] - 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: 283 patients are enrolled patients that are included in the Run-in period (Period 1). Period 1 is not the baseline period. Patients
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: After the Run-in Period, Patients with controlled BP (sitting SBP / DBP ≤ 130/80 mmHg) at Week 0 (Visit 2), patients with uncontrolled BP (sitting SBP / DBP > 130/80 mmHg) whose adherence to the treatment was not included from 80% to 120%, or patients who could not tolerate one of the mono therapies were discontinued from the study and excluded from the Assessment Period (23 patients in total)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Assessment
    Reporting group description
    		 -

    Reporting group values
    		 Assessment Total
    Number of subjects
    		 246 246
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 246 246
    Gender categorical
    Units: Subjects
        Female
    		 106 106
        Male
    		 140 140

    End points

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    End points reporting groups
    Reporting group title
    Zofenopril 30 mg
    Reporting group description
    		 Patients in therapy with ACE-i, were assigned to monotherapy with ZOFENOPRIL 30 mg for 4 weeks

    Reporting group title
    Nebivolol 5 mg
    Reporting group description
    		 Patients in therapy with Beta Blockers, were assigned to monotherapy with Nebivolol 5 mg for 4 weeks
    Reporting group title
    Combination Therapy Zofenopril 30mg/Nebivolol 5mg
    Reporting group description
    		 During the assessment period of 8 weeks, the eligible patients (uncontrolled hypertension with sitting BP of SBP/DBP > 130/80 mmHg, who tolerated the treatment and whose adherence to the therapies ranged from 80% to 120%) received a combination of NEB 5 mg and ZOF 30 mg to be taken orally once daily.

    Subject analysis set title
    Intention to treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    all patients who were enrolled and received at least 1 dose of study drug (combination therapy) and have at least 1 post baseline safety assessment.

    Primary: Change in mean sitting DBP

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    End point title
    		 Change in mean sitting DBP
    End point description
    End point type
    Primary
    End point timeframe
    8 weeks of combination therapy treatment. From study visit 2 to study visit 3.
    End point values
    		 Combination Therapy Zofenopril 30mg/Nebivolol 5mg Intention to treat population
    Number of subjects analysed
    241 [1]
    241 [2]
    Units: mmHG
        arithmetic mean (standard deviation)
    91.8 ± 5.5
    82.5 ± 7.91
    Notes
    [1] - Only 241 patient have valid SBP measurement at baseline. Values collected here are baseline ones
    [2] - Values collected here are SBP measurement at the end of the study
    Statistical analysis title
    		 Monotherapy vs Combination in DBP after 8 weeks
    Statistical analysis description
    Change from Baseline in the Diastolic Blood Pressure (DBP).
    Comparison groups
    Combination Therapy Zofenopril 30mg/Nebivolol 5mg v Intention to treat population
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Informed Consent signed to final visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Combination Therapy Zofenopril 30mg/Nebivolo l 5mg
    Reporting group description
    		 -

    Serious adverse events
    		 Combination Therapy Zofenopril 30mg/Nebivolo l 5mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 246 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Combination Therapy Zofenopril 30mg/Nebivolo l 5mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 246 (0.81%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 246 (0.41%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    1 / 246 (0.41%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Note that due to technical limits in the portal the statistical analysis reports 482 patients included in the analysis and not 241 as they effectively are. 482 are indeed the 241 data collected before and the 241 after combined therapy intake
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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