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

    Summary
    EudraCT number
    		 2021-005077-10
    Trial protocol
    		 BG   PL  
    Global end of trial date
    15 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Nov 2023
    First version publication date
    29 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MEIN/21/AmNe-Hyp/001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05513937
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Menarini International Operation Luxembourg SA
    Sponsor organisation address
    1, Avenue de la Gare, Luxembourg, Luxembourg, Luxembourg, L-1611
    Public contact
    Medical Affair & Clinical Operation Director, Menarini, +39 055 5680459, pfabrizzi@menarini.it
    Scientific contact
    Medical Affair & Clinical Operation Director, Menarini, +39 055 5680459, 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
    04 Jul 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Nov 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the antihypertensive efficacy of the extemporaneous combination of nebivolol (NEB) 5 mg with amlodipine (AML) 5 mg or AML 10 mg in lowering the sitting diastolic blood pressure (DBP) between Visit 2 (Week 0) and Visit 4 (Week 8) in patients with uncontrolled BP, previously treated with NEB 5 mg or AML 5 mg monotherapies for at least 4 weeks.
    Protection of trial subjects
    This study was performed 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
    09 Jun 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
    Poland: 70
    Country: Number of subjects enrolled
    Bulgaria: 231
    Worldwide total number of subjects
    301
    EEA total number of subjects
    301
    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)
    301
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study started on 9 June 2022 and terminated on 15 November 2022 302 patients were screened for the study. 301 patients entered the run-in period and were assigned for monotherapy to Amlodipine (AML) 5 mg or Nebivolol (NEB) 5 mg. All 291 patients that completed monotherapy were assigned to combination therapy and 276 completed the study.

    Pre-assignment
    Screening details
    		 302, Grade 1-2 hypertensive patients with blood pressure [BP] ranging from ≥ 140 / 90 mmHg to ≤ 179 / 109 mmHg) in treatment with any beta-blockers (BBs) or calcium channel blockers (CCBs), including NEB 5 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
    		 Nebivolol 5 mg
    Arm description
    		 Eligible patients entered a 4 week run-in period on the same day of the screening visit. Patients previously receiving NEB 5 mg continued the same treatment, patients receiving any other BBs were switched to NEB 5 mg
    Arm type
    		 Active comparator

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

    Arm title
    		 Amlodipine 5 mg
    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 5 mg
    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
    		Nebivolol 5 mg Amlodipine 5 mg
    Started
    143
    158
    Completed
    139
    152
    Not completed
    4
    6
         Consent withdrawn by subject
    1
    -
         Physician decision
    1
    -
         Protocol deviation
    2
    6
    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
    Not blinded

    Arms
    Arm title
    		 Combination Therapy Nebivolol 5 mg/Amlodipine 5 mg or 10 mg
    Arm description
    		 Patients having uncontrolled BP (SBP/DBP > 130 / 80 mmHg) at Visit 2 (Week 0), were assigned to the extemporaneous combination of NEB 5 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-tritrated to extemporaneous combination of NEB/AML 5 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
    Nebivolol 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of study medication was 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 (Nebivolol/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 Nebivolol 5 mg/Amlodipine 5 mg or 10 mg
    Started
    279
    Completed
    276
    Not completed
    3
         Adverse event, non-fatal
    2
         Protocol deviation
    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: 301 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 NEB 5 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%, patients who could not tolerate one of the mono therapies, or classified as Grade 3 (SBP ≥ 180 or DBP ≥ 110 mmHg) hypertensin were discontinued from the study and excluded from the Assessment Period (12 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
    		 279 279
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 279 279
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.2 ± 8.13 -
    Gender categorical
    Units: Subjects
        Female
    		 144 144
        Male
    		 135 135

    End points

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    End points reporting groups
    Reporting group title
    Nebivolol 5 mg
    Reporting group description
    		 Eligible patients entered a 4 week run-in period on the same day of the screening visit. Patients previously receiving NEB 5 mg continued the same treatment, patients receiving any other BBs were switched to NEB 5 mg

    Reporting group title
    Amlodipine 5 mg
    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 Nebivolol 5 mg/Amlodipine 5 mg or 10 mg
    Reporting group description
    		 Patients having uncontrolled BP (SBP/DBP > 130 / 80 mmHg) at Visit 2 (Week 0), were assigned to the extemporaneous combination of NEB 5 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-tritrated to extemporaneous combination of NEB/AML 5 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
    		 Modified 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 %, had at least one dose of combination therapy and had at least baseline [Visit 2 (Week 0)] and Visit 4 (Week 8) assessments with primary efficacy data. .

    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 Nebivolol 5 mg/Amlodipine 5 mg or 10 mg Efficacy Population
    Number of subjects analysed
    279
    276
    Units: mmHG
        arithmetic mean (standard deviation)
    93.3 ± 4.35
    78.2 ± 6.24
    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 Nebivolol 5 mg/Amlodipine 5 mg or 10 mg v Efficacy Population
    Number of subjects included in analysis
    555
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Signed Rank Test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Informed Consent signed to final visit
    Adverse event reporting additional description
    Safety analyses were carried out using the SAF analysis population, which was defined as all patients in the Enrolled population who received at least one dose of study medication (i.e., monotherapy and/or combination therapy )
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Monotherapy
    Reporting group description
    		 Safety Population that received Monotherapy

    Reporting group title
    Combination Therapy
    Reporting group description
    		 -

    Serious adverse events
    		 Monotherapy Combination Therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 301 (0.00%)
    0 / 279 (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
    		 Monotherapy Combination Therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 301 (1.99%)
    44 / 279 (15.77%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Feeling hot
         subjects affected / exposed
    0 / 301 (0.00%)
    2 / 279 (0.72%)
         occurrences all number
    0
    2
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 279 (0.00%)
         occurrences all number
    1
    0
    Ovarian cyst
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 279 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Lung consolidation
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 279 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 301 (0.00%)
    2 / 279 (0.72%)
         occurrences all number
    0
    2
    Blood creatinine increased
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Blood uric acid increased
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Heart rate increased
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 301 (0.00%)
    3 / 279 (1.08%)
         occurrences all number
    0
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 301 (0.33%)
    7 / 279 (2.51%)
         occurrences all number
    1
    7
    Intracranial aneurysm
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 279 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 301 (0.66%)
    3 / 279 (1.08%)
         occurrences all number
    2
    3
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    0 / 301 (0.00%)
    3 / 279 (1.08%)
         occurrences all number
    0
    3
    Diarrhoea
         subjects affected / exposed
    0 / 301 (0.00%)
    3 / 279 (1.08%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 279 (0.00%)
         occurrences all number
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 301 (0.00%)
    2 / 279 (0.72%)
         occurrences all number
    0
    2
    Pruritus
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Endocrine disorders
    Thyroid disorder
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 279 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 279 (0.00%)
         occurrences all number
    1
    0
    Temporomandibular joint syndrome
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 279 (0.00%)
         occurrences all number
    1
    0
    Arthralgia
         subjects affected / exposed
    0 / 301 (0.00%)
    6 / 279 (2.15%)
         occurrences all number
    0
    6
    Back pain
         subjects affected / exposed
    0 / 301 (0.00%)
    3 / 279 (1.08%)
         occurrences all number
    0
    3
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 279 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 301 (0.00%)
    2 / 279 (0.72%)
         occurrences all number
    0
    2
    Dehydration
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Dyslipidaemia
         subjects affected / exposed
    0 / 301 (0.00%)
    2 / 279 (0.72%)
         occurrences all number
    0
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    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 555 patients included in the analysis and not 279 as they effectively are. 555 are indeed the 279 data collected before and the 276 after combined therapy intake.
    For support, Contact us.
    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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