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    Clinical Trial Results:
    A Randomized Open Label, Parallel Group Study to Evaluate the Hemodynamic Effects of Cafedrine/Theodrenaline vs Norepinephrine in the Treatment of Intraoperative Arterial Hypotension in Adults after Induction of General Anesthesia

    Summary
    EudraCT number
    		 2021-001954-76
    Trial protocol
    		 DE  
    Global end of trial date
    29 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Dec 2024
    First version publication date
    28 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV48531-CV-40190
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ratiopharm GmbH Teva EU Medical Affairs
    Sponsor organisation address
    Graf-Arco-Str. 3, Ulm, Germany, 89079
    Public contact
    Medical Affairs Germany, ratiopharm GmbH, medical.affairs@teva.de
    Scientific contact
    Medical Affairs Germany, ratiopharm GmbH, medical.affairs@teva.de
    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
    01 Oct 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Dec 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the hemodynamic effects of the test (Cafedrine/Theodrenaline) and reference (Noradrenaline) IMPs administered as bolus injection and subsequently as continuous infusion in a surgical cohort of at-risk adult patients who develop intraoperative hypotension
    Protection of trial subjects
    This study was conducted in full accordance with the ICH Harmonised Tripartite Guideline, Guideline for Good Clinical Practice. The leading ethic committee of the Medical Faculty of the Philipps-University Marburg approved this trial on 23rd February 2022 (Az.202/21 A-ff). All participating hospitals obtained approval by their responsible ethics committees. Written informed consent was obtained from each patient before any study specific procedures or assessments were done.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 May 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
    Germany: 212
    Worldwide total number of subjects
    212
    EEA total number of subjects
    212
    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)
    49
    From 65 to 84 years
    149
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study duration: one and a half years

    Pre-assignment
    Screening details
    		 221 participants with planned elective vascular surgery and 212 participants were randomly assigned; 192 of the randomized participants received treatment and were evaluable for safety and efficacy-analysis; 190 participants completed the trial.

    Period 1
    Period 1 title
    Overall Study Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cafedrine/Theodrenaline
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Akrinor®, Cafedrine/Theodrenaline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study Phase 1: Bolus injection at MAP <70 mmHg: 1.0 mg Cafedrine/kg body weight (idealized). Additional bolus at MAP <70 mmHg: 1.0 mg Cafedrine/kg body weight (idealized). Study Phase 2: Continuous Infusion: Initial Infusion Rate: MAP <70 mmHg: 160 mg Cafedrine/h PLUS Rescue Bolus (0.5 mg Cafedrine/kg IBW); MAP: 70-90 mmHg: 80 mg Cafedrine/h; MAP >90 mmHg: 40 mg Cafedrine/h.

    Arm title
    		 Noradrenaline
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sinora 1 mg/ml concentrate for solution for infusion
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study Phase 1: Bolus injection at MAP <70 mmHg: 0.1 mcg Noradrenaline/kg body weight (idealized). Additional bolus at MAP <70 mmHg: 0.1 mcg Noradrenaline/kg body weight (idealized). Study Phase 2: Continuous Infusion: Initial Infusion Rate: MAP <70 mmHg: 180 mcg Noradrenaline/h PLUS Rescue Bolus (0.05 mcg Noradrenaline/kg IBW); MAP = 70-90 mmHg: 60 mcg Noradrenaline/h MAP >90 mmHg: 30 mcg Noradrenaline/h

    Number of subjects in period 1
    		Cafedrine/Theodrenaline Noradrenaline
    Started
    108
    104
    Treated
    99
    93
    Modified Intent-to-treat
    98
    92
    Completed
    98
    92
    Not completed
    10
    12
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    3
    2
         Did not develop IOH
    2
    1
         Physician decision
    2
    2
         Surgery postponed/canceled or nobody available
    2
    5
         Not specified
    -
    1
         Surgery (cut) started prior or during study
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cafedrine/Theodrenaline
    Reporting group description
    		 -

    Reporting group title
    Noradrenaline
    Reporting group description
    		 -

    Reporting group values
    		 Cafedrine/Theodrenaline Noradrenaline Total
    Number of subjects
    		 108 104 212
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 32 17 49
        From 65-84 years
    		 67 82 149
        85 years and over
    		 9 5 14
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70 ( 9 ) 71 ( 8 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 36 34 70
        Male
    		 72 70 142

    End points

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    End points reporting groups
    Reporting group title
    Cafedrine/Theodrenaline
    Reporting group description
    		 -

    Reporting group title
    Noradrenaline
    Reporting group description
    		 -

    Primary: The treatment related difference in average CI [DaCI] during study phase 1

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    End point title
    		 The treatment related difference in average CI [DaCI] during study phase 1
    End point description
    The treatment related difference is calculated as the difference in means of individual area above the CI ref* (CI ref is individually defined as the CI-measurement at the start of the treatment)
    End point type
    Primary
    End point timeframe
    0-20 minutes after initial treatment
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    99
    93
    Units: units
        arithmetic mean (confidence interval 95%)
    0.189 (0.123 to 0.254)
    0.075 (0.035 to 0.116)
    Statistical analysis title
    		 Difference in average CI during study phase 1
    Comparison groups
    Cafedrine/Theodrenaline v Noradrenaline
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0022
    Method
    		 ANOVA
    Parameter type
    		 Difference in average CI above reference
    Point estimate
    0.113
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0.036
         upper limit
    		 -

    Primary: Treatment-related difference in average MAP [DaMAP] during study phase 2

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    End point title
    		 Treatment-related difference in average MAP [DaMAP] during study phase 2
    End point description
    Difference calculated as the mean difference between areas below the target MAP value (90 mmHg). Non-inferiority is concluded, if DaMAP can be shown to be lower than the non-inferiority margin (5 mmHg) at one-sided alpha-level 0.025
    End point type
    Primary
    End point timeframe
    >20-40 minutes after initial treatment with IMP-bolus injection
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    98
    92
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    3.16 (2.27 to 4.05)
    5.35 (4.41 to 6.29)
    Statistical analysis title
    		 Difference in average MAP in study phase 2
    Statistical analysis description
    Non-inferiority
    Comparison groups
    Cafedrine/Theodrenaline v Noradrenaline
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Difference in average MAP below 90 mmHg
    Point estimate
    -2.19
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -0.91
    Notes
    [1] - CT arm - NR arm

    Secondary: Treatment related difference in average MAP [DaMAP] below the target MAP value (90 mmHg) during study phase 1

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    End point title
    		 Treatment related difference in average MAP [DaMAP] below the target MAP value (90 mmHg) during study phase 1
    End point description
    End point type
    Secondary
    End point timeframe
    0-20 minutes after initial treatment with IMP-bolus injection
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    99
    93
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    8.80 (7.62 to 9.97)
    13.64 (12.65 to 14.63)
    No statistical analyses for this end point

    Secondary: Treatment related differences in change in SVRI (systemic vascular resistance index) (study phase 1)

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    End point title
    		 Treatment related differences in change in SVRI (systemic vascular resistance index) (study phase 1)
    End point description
    End point type
    Secondary
    End point timeframe
    0-20 minutes after initial treatment with IMP-bolus injection
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    99
    93
    Units: dyne-s/cm5/m2
        arithmetic mean (confidence interval 95%)
    2666.75 (2646.21 to 2687.29)
    2614.60 (2593.04 to 2636.15)
    No statistical analyses for this end point

    Secondary: Treatment related differences in change in SVI (Stroke volume index) (study phase 1)

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    End point title
    		 Treatment related differences in change in SVI (Stroke volume index) (study phase 1)
    End point description
    End point type
    Secondary
    End point timeframe
    0-20 minutes after initial treatment with IMP-bolus injection
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    99
    93
    Units: ml/beat/m2
        arithmetic mean (confidence interval 95%)
    38.22 (38.01 to 38.42)
    38.47 (38.26 to 38.68)
    No statistical analyses for this end point

    Secondary: Treatment related differences in heart rate (study phase 1)

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    End point title
    		 Treatment related differences in heart rate (study phase 1)
    End point description
    End point type
    Secondary
    End point timeframe
    0-20 minutes after initial treatment with IMP-bolus injection
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    99
    93
    Units: bpm
        arithmetic mean (confidence interval 95%)
    70.69 (70.43 to 70.95)
    62.72 (62.45 to 62.99)
    No statistical analyses for this end point

    Secondary: Treatment related differences in change of dP/dtmax (study phase 1)

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    End point title
    		 Treatment related differences in change of dP/dtmax (study phase 1)
    End point description
    End point type
    Secondary
    End point timeframe
    0-20 minutes after initial treatment with IMP-bolus injection
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    99
    93
    Units: mmHg/sec
        arithmetic mean (confidence interval 95%)
    975.24 (968.23 to 982.25)
    765.40 (758.16 to 772.63)
    No statistical analyses for this end point

    Secondary: Treatment related differences in change of CI (Cardiac Index) (study phase 1)

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    End point title
    		 Treatment related differences in change of CI (Cardiac Index) (study phase 1)
    End point description
    End point type
    Secondary
    End point timeframe
    0-20 minutes after initial treatment with IMP-bolus injection
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    99
    93
    Units: L/min/m2
        arithmetic mean (confidence interval 95%)
    2.63 (2.62 to 2.64)
    2.36 (2.35 to 2.38)
    No statistical analyses for this end point

    Secondary: Difference in change of MAP (mean arterial blood pressure) (study phase 1)

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    End point title
    		 Difference in change of MAP (mean arterial blood pressure) (study phase 1)
    End point description
    End point type
    Secondary
    End point timeframe
    0-20 minutes after initial treatment with IMP-bolus injection
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    99
    93
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    86.62 (86.24 to 87.01)
    78.47 (78.08 to 78.87)
    No statistical analyses for this end point

    Secondary: Ratio of treatment specific incidence rates of overshooting blood pressure (MAP ˃110 mmHg) events during study phase 1

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    End point title
    		 Ratio of treatment specific incidence rates of overshooting blood pressure (MAP ˃110 mmHg) events during study phase 1
    End point description
    End point type
    Secondary
    End point timeframe
    0-20 minutes after initial treatment with IMP-bolus injection
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    99
    93
    Units: Overshooting events/100 measurements
        arithmetic mean (confidence interval 95%)
    9.33 (8.57 to 10.14)
    3.45 (2.98 to 3.97)
    No statistical analyses for this end point

    Secondary: Ratio of treatment specific incidence rates of low blood pressure (MAP <80 mmHg) events during study phase 1

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    End point title
    		 Ratio of treatment specific incidence rates of low blood pressure (MAP <80 mmHg) events during study phase 1
    End point description
    blood pressure (bp)
    End point type
    Secondary
    End point timeframe
    0-20 minutes after initial treatment with IMP-bolus injection
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    99
    93
    Units: low bp events/100 measurements
        arithmetic mean (confidence interval 95%)
    41.0 (39.4 to 42.7)
    62.6 (60.5 to 64.7)
    No statistical analyses for this end point

    Secondary: Treatment related differences in number of additional bolus-injections during study phase 1

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    End point title
    		 Treatment related differences in number of additional bolus-injections during study phase 1
    End point description
    End point type
    Secondary
    End point timeframe
    First IMP-application until start of infusion
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    99
    93
    Units: bolus injections per 100 minutes
        arithmetic mean (confidence interval 95%)
    9.9 (8.585 to 11.392)
    39.9 (37.060 to 42.837)
    No statistical analyses for this end point

    Secondary: Treatment related differences in extra measures to stabilize blood pressure during study phase 1

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    End point title
    		 Treatment related differences in extra measures to stabilize blood pressure during study phase 1
    End point description
    Measures include: `Volume/Fluid´, `Medication´, `Position´, `Anesthesia depth´ and `Other´
    End point type
    Secondary
    End point timeframe
    First IMP-application until start of infusion
    End point values
    		 Cafedrine/Theodrenaline Noradrenaline
    Number of subjects analysed
    99
    93
    Units: measures per 100 minutes
        arithmetic mean (confidence interval 95%)
    0.448 (0.205 to 0.851)
    0.481 (0.220 to 0.913)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The study period was defined for each patient as the time period from the first administration of the IMP to the end of study for the patient.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Cafedrine/Theodrenaline
    Reporting group description
    		 -

    Reporting group title
    Noradrenaline
    Reporting group description
    		 -

    Serious adverse events
    		 Cafedrine/Theodrenaline Noradrenaline
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 99 (2.02%)
    3 / 93 (3.23%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    septic shock
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cafedrine/Theodrenaline Noradrenaline
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 99 (6.06%)
    9 / 93 (9.68%)
    Investigations
    Troponin T increased
         subjects affected / exposed
    2 / 99 (2.02%)
    1 / 93 (1.08%)
         occurrences all number
    2
    1
    Troponin I increased
         subjects affected / exposed
    0 / 99 (0.00%)
    2 / 93 (2.15%)
         occurrences all number
    0
    2
    Vascular disorders
    Procedural hypertension
         subjects affected / exposed
    1 / 99 (1.01%)
    3 / 93 (3.23%)
         occurrences all number
    1
    3
    Arterial hemorrhage
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Compartment syndrome
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 93 (1.08%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 93 (1.08%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 93 (1.08%)
         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
    30 Mar 2023
    The following major procedural changes (not all-inclusive) were made to the protocol: 1) Definition of Reference Cardiac Index (CIref) was changed (Primary Endpoint 1): Old: CImin is individually defined as the mean of three measurements obtained directly prior to induction of anesthesia. New: CI ref is individually defined as the CI-measurement obtained at the start of the treatment
    25 Sep 2023
    1) Time specification (Study Phase 2): old: 21-40 min. new: ˃20-40 min. 2) Secondary endpoint 2e and 2f was added 3) Exploratory endpoint 1f and 1g was added 4) Collection of basal parameters (prior anesthesia induction): HR was added 5) Clinical laboratory test, parameter evaluated: Troponin T was added 6) Recording and Reporting of Adverse Events: time period for recording of (serious) adverse event was changed: old: from signature of informed consent to the end of the study; new: from first administration of IMP to the end of the study for the patient. All events occurring between signing the informed consent form to the first administration of the IMP will be recorded in CRF as Medical events and are not considered as adverse events.

    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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    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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