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    Clinical Trial Results:
    Interventional clinical trial to assess efficacy and safety of the extemporaneous combination of Zofenopril calcium and amlodipine in grade 1-2 hypertensive patients versus each monotherapy

    Summary
    EudraCT number
    		 2021-000745-40
    Trial protocol
    		 IT  
    Global end of trial date
    28 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 May 2023
    First version publication date
    14 May 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MEIN/20/ZoAm-Hyp/001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05279807
    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
    Medical Affairs & Clinical Operation Director Paolo Fabrizzi, Menarini , +39 055568091, pfabrizzi@menarini.it
    Scientific contact
    Medical Affairs & Clinical Operation Director Paolo Fabrizzi, 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
    24 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective: To assess the anti-hypertensive efficacy of the extemporaneous combination of ZOF 30 mg with AML 5 mg or AML 10 mg in lowering the sitting diastolic BP between Visit 2 (Week 0) and Visit 4 (Week 8) in patients with uncontrolled BP previously treated with ZOF (30 mg) or AML (5 mg) 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
    15 Oct 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
    Hungary: 270
    Country: Number of subjects enrolled
    Russian Federation: 7
    Worldwide total number of subjects
    277
    EEA total number of subjects
    270
    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)
    277
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study started on 15 October 2021 and terminated on 28 April 2022 290 patients were screened for the study. 277 patients entered the run-in period and were assigned for monotherapy to Amlodipine (AML) 5 mg or Zofenopril (ZOF) 30 mg. All 271 completed patients in monotherapy were assigned to combination therapy and 269 completed the study.

    Pre-assignment
    Screening details
    		 290, Grade 1-2 hypertensive patients with blood pressure [BP] ranging from ≥ 140 / 90 mmHg to ≤ 179 / 109 mmHg) in treatment with any ACE-I or CCBs, including ZOF 30 mg or AML 5 mg (only dosage allowed) for at least one month prior to Visit 1 (Week -4), were screened for eligibility.

    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 30mg
    Arm description
    		 Eligible patients entered a 4 week run-in period on the same day of the screening visit. Patients previously receiving ZOF 30 mg continued the same treatment, patients receiving any other ACE-i were switched to ZOF 30 mg
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Zofenopril 30mg
    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 administered with a glass of water once daily

    Arm title
    		 Amlodipine 5mg
    Arm description
    		 Eligible patients entered a 4 week run-in period on the same day of the screening visit. Patients previously receiving AML 5 mg continued the same treatment, while patients receiving any other CCBs were switched to AML 5 mg
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Amlodipine 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 30mg Amlodipine 5mg
    Started
    144
    133
    Completed
    142
    132
    Not completed
    2
    1
         Consent withdrawn by subject
    1
    -
         Laboratory Abnormal Results
    1
    1
    Period 2
    Period 2 title
    Assessment
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Combination Therapy Zofenopril 30mg/Amlodipine 5mg or 10mg
    Arm description
    		 Patients having uncontrolled BP (SBP/DBP > 130 / 80 mmHg) at Visit 2 (Week 0), were assigned to the extemporaneous combination of ZOF 30 mg and AML 5 mg. After 4 Weeks ± 2 days the BP was assessed again (Visit 3, Week 4): controlled patients (SBP/DBP ≤ 130 / 80 mmHg) continued the same extemporaneous combination, while uncontrolled (SBP/DBP > 130 / 80 mmHg) patients were up-titrated to extemporaneous combination of ZOF/AML 30 mg / 10 mg for another 4 weeks ± 2 days (Visit 4, Week 8). At Visit 2 (Week 0) and Visit 3 (Week 4) patients with SBP/DBP value classified as Grade 3 (SBP ≥ 180 or DBP ≥ 110 mmHg) hypertension were withdrawn from the study. To correctly evaluate additional effect of the combination therapy, the number of patients with uncontrolled BP on AML or ZOF monotherapy needed to be balanced at Week 0. Weekly evaluations were performed to maintain a 1:1 ratio during the assessment period 2. Corrective measures were initiated in case of 5% differences between the two groups.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zofenopril 30mg
    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 administered with a glass of water once daily

    Investigational medicinal product name
    Amlodipine 5/10 mg
    Investigational medicinal product code
    Amlodipine besylate
    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.

    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/Amlodipine) 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/Amlodipine 5mg or 10mg
    Started
    271
    Completed
    269
    Not completed
    2
         Consent withdrawn by subject
    1
         Laboratory Abnormal Results
    1
    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: 277 patients are enrolled patients that are included in the study and start the Run-in period (Period 1). Period 1 is not the baseline period. The baseline period is Period 2 (Assessment) where patients start to take the combination therapy ZOF 30 mg/AML 5 mg /AML 10 mg
    [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 (3 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
    		 271 271
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 271 271
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.3 ( 9.83 ) -
    Gender categorical
    Units: Subjects
        Female
    		 151 151
        Male
    		 120 120

    End points

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    End points reporting groups
    Reporting group title
    Zofenopril 30mg
    Reporting group description
    		 Eligible patients entered a 4 week run-in period on the same day of the screening visit. Patients previously receiving ZOF 30 mg continued the same treatment, patients receiving any other ACE-i were switched to ZOF 30 mg

    Reporting group title
    Amlodipine 5mg
    Reporting group description
    		 Eligible patients entered a 4 week run-in period on the same day of the screening visit. Patients previously receiving AML 5 mg continued the same treatment, while patients receiving any other CCBs were switched to AML 5 mg
    Reporting group title
    Combination Therapy Zofenopril 30mg/Amlodipine 5mg or 10mg
    Reporting group description
    		 Patients having uncontrolled BP (SBP/DBP > 130 / 80 mmHg) at Visit 2 (Week 0), were assigned to the extemporaneous combination of ZOF 30 mg and AML 5 mg. After 4 Weeks ± 2 days the BP was assessed again (Visit 3, Week 4): controlled patients (SBP/DBP ≤ 130 / 80 mmHg) continued the same extemporaneous combination, while uncontrolled (SBP/DBP > 130 / 80 mmHg) patients were up-titrated to extemporaneous combination of ZOF/AML 30 mg / 10 mg for another 4 weeks ± 2 days (Visit 4, Week 8). At Visit 2 (Week 0) and Visit 3 (Week 4) patients with SBP/DBP value classified as Grade 3 (SBP ≥ 180 or DBP ≥ 110 mmHg) hypertension were withdrawn from the study. To correctly evaluate additional effect of the combination therapy, the number of patients with uncontrolled BP on AML or ZOF monotherapy needed to be balanced at Week 0. Weekly evaluations were performed to maintain a 1:1 ratio during the assessment period 2. Corrective measures were initiated in case of 5% differences between the two groups.

    Subject analysis set title
    Efficacy Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All study participants who signed informed consent , met all screening criteria, were enrolled and received at least one dose of the assigned treatment during run-in period, completed the 4-week run-in period and met criteria at Visit 2 (Week 0) [uncontrolled BP (sitting SBP/DBP > 130 / 80 mmHg)], tolerated treatment, had treatment adherence between 80 – 120 % and had at least one available post baseline primary efficacy assessment [(from Visit 3 (Week 4) or Visit 4 (Week 8)].

    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 (Week 0) to study Visit 4 (Week 8)
    End point values
    		 Combination Therapy Zofenopril 30mg/Amlodipine 5mg or 10mg Efficacy Population
    Number of subjects analysed
    269 [1]
    271 [2]
    Units: mmHG
        arithmetic mean (standard deviation)
    78.9 ( 6.46 )
    92.4 ( 5.78 )
    Notes
    [1] - Values collected here are DBP measurement at the end of the study
    [2] - Only 271 patients have valid DBP measurement at baseline. Values collected here are baseline ones
    Statistical analysis title
    		 DBP at Visit 2 (Week 0) vs Visit 4 (Week 8)
    Statistical analysis description
    Change from Baseline in the Diastolic Blood Pressure (DBP).
    Comparison groups
    Combination Therapy Zofenopril 30mg/Amlodipine 5mg or 10mg v Efficacy Population
    Number of subjects included in analysis
    540
    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
    Reporting groups
    Reporting group title
    Combination Therapy Zofenopril 30mg/Amlodipina 5mg or 10mg
    Reporting group description
    		 Patients having uncontrolled BP (SBP/DBP > 130 / 80 mmHg) at Visit 2 (Week 0), were assigned to the extemporaneous combination of ZOF 30 mg and AML 5 mg. After 4 Weeks ± 2 days the BP was assessed again (Visit 3, Week 4): controlled patients (SBP/DBP ≤ 130 / 80 mmHg) continued the same extemporaneous combination, while uncontrolled (SBP/DBP > 130 / 80 mmHg) patients were up-titrated to extemporaneous combination of ZOF/AML 30 mg / 10 mg for another 4 weeks ± 2 days (Visit 4, Week 8). At Visit 2 (Week 0) and Visit 3 (Week 4) patients with SBP/DBP value classified as Grade 3 (SBP ≥ 180 or DBP ≥ 110 mmHg) hypertension were withdrawn from the study. To correctly evaluate additional effect of the combination therapy, the number of patients with uncontrolled BP on AML or ZOF monotherapy needed to be balanced at Week 0. Weekly evaluations were performed to maintain a 1:1 ratio during the assessment period. Corrective measures were initiated in case of 5% differences between the two groups.

    Serious adverse events
    		 Combination Therapy Zofenopril 30mg/Amlodipina 5mg or 10mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 271 (0.37%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Oesophageal food impaction
         subjects affected / exposed
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Combination Therapy Zofenopril 30mg/Amlodipina 5mg or 10mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 271 (7.01%)
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 271 (1.85%)
         occurrences all number
    5
    Infections and infestations
    COVID-19
         subjects affected / exposed
    3 / 271 (1.11%)
         occurrences all number
    3
    Respiratory tract infection
         subjects affected / exposed
    8 / 271 (2.95%)
         occurrences all number
    8
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    3 / 271 (1.11%)
         occurrences all number
    3

    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 540 patients included in the analysis and not 271 as they effectively are. 540 are indeed the 271 data collected before and the 269 after combined therapy intake
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