Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Angiotensin Converting Enzyme Inhibitor (ACE) Induced Angioedema BERINERT Randomized, double-blind, two arms, multicenter, Phase III study of Berinert for treatment of ACE induced Angioedema

    Summary
    EudraCT number
    		 2012-001670-28
    Trial protocol
    		 DE  
    Global end of trial date
    30 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 May 2020
    First version publication date
    21 May 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BER-1272-0058-I
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Technische Universität München, Fakultät für Medizin
    Sponsor organisation address
    Ismaninger Str. 22, München, Germany, 81675
    Public contact
    PD Dr. med. Ulrich Strassen, Klinikum rechts der Isar der TU München Hals-Nasen-Ohrenklinik und Poliklinik, 49 89 4140 2390,
    Scientific contact
    PD Dr. med. Ulrich Strassen, Klinikum rechts der Isar der TU München Hals-Nasen-Ohrenklinik und Poliklinik, 49 89 4140 2390, murat.bas@tum.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
    24 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary Objective: To show that Berinert shortens the time to complete resolution of signs and symptoms of acute ACE-induced angioedema of the upper airway tract compared to placebo when given on top standard treatment
    Protection of trial subjects
    The conduct of this clinical study met the local legal and regulatory requirements. The study was conducted in accordance the ethical principles of Good Clinical Practice (GCP). Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. The study was regularly monitored by the Sponsor and all investigators connected to the study were GCP trained.
    Background therapy
    		 Standard of care.
    Evidence for comparator
    		 ACE inhibitors are the most common cause of drug-induced angioedema (0.2 to 0.7% of patients receiving ACEi). ACEi are used widely in the treatment of hypertension, heart failure, myocardial infarction, renal failure, and diabetic nephropathy. Over the last several years, the use of ACEi has increased enormously, which could lead to a greater prevalence of angioedema. ACE inhibitors block ACE, the enzyme that among other actions, degrades bradykinin. In ACE induced angioedema a local imbalance between production and breakdown of bradykinin exists. C1 inhibitor is believed to suppress the local over-production of bradykinin under these circumstances. Berinert® is a plasma-derived C1 esterase inhibitor concentrate, which is approved for the indication of acute hereditary angioedema (HAE). It is able to act as a substitute for the missing protein or the functional deficit it causes in patients with type I or II HAE. Berinert® has been successfully used also in single cases of very severe ACE-induced angioedema for more than 10 years and additional cases of a successful treatment response to Berinert have been reported since then. However, a placebo-controlled trial to demonstrate the efficacy of Berinert® for ACE induced angioedema has not been performed.
    Actual start date of recruitment
    14 Oct 2013
    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: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    11
    From 65 to 84 years
    14
    85 years and over
    5

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Between 22.12.2013 and 05.09.2018 30 patients were randomised. All 30 patients were analysed in the "Intent-to Treat Population", 21 patients were analysed in the "Per-Protocol Population".

    Pre-assignment
    Screening details
    		 Patients arrive at the emergency department of the clinic with an acute angioedema of the head and neck area and are admitted. The admission of the patient, study suitability assessment and randomisation take place according to the clinical study protocol. Patients wer enrolled to the study, if eligibility was confirmed.

    Pre-assignment period milestones
    Number of subjects started
    		 30
    Number of subjects completed

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Due to many aspects, a classical double blinding procedure was not possible. It was not possible to create a placebo solution similar to the Berinert® solution since the specific solution properties of this substance cannot be unrecognizably copied with corresponding placebo powder. The lyophilised Berinert® must be dissolved and have to be prepared in the time limit prescribed. Therefore was necessary to have one unblinded physician. Appropriate working procedures have been established.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard + Berinert
    Arm description
    		 Standard + Berinert Standard (prednisolone-21-hydrogensuccinat / Clemastinfumarat i.v.) + Body weight adjusted 20IU/kg b.w. Berinert® rounded to the next 500 IU vial.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Berinert
    Investigational medicinal product code
    B02AB03
    Other name
    C1-Esterase-Inhibitor
    Pharmaceutical forms
    Powder and solvent for solution for injection/skin-prick test
    Routes of administration
    Intravenous use
    Dosage and administration details
    Body weight adjusted 20IU/kg b.w. Berinert® rounded to the next 500 IU vial. If no improvement of the symptoms has occurred within six hours after the first administration of the medicine, then in both the patient groups a second administration of Berinert 500 mg prednisolone-21-hydrogensuccinat and Clemastinfumarat i.v. is possible.

    Investigational medicinal product name
    Prednisolon-21-hydrogensuccinat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    One Dose of Prednisolone-21-hydrogensuccinat 500 mg i.v (reconstituted in 5ml of sterile water for injection) After 6 hours decision whether a second dose of Cortisone should be administered.

    Investigational medicinal product name
    Clemastinfumarat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    One dose 2,68 mg milligram(s) Clemastinfumarat i.v (Baseline Visite 0) After 6 hours decision whether a second dose of Clemastin should be administered.

    Arm title
    		 Standard + Placebo
    Arm description
    		 Standard + Placebo Standard (prednisolone-21-hydrogensuccinat / Clemastinfumarat i.v.) + Placebo (10ml 0,9% NaCl ) rounded to next 10 ml step.
    Arm type
    		 Placebo

    Investigational medicinal product name
    NaCl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    One dose Placebo (10ml 0, 9% NaCl)

    Investigational medicinal product name
    Prednisolon-21-hydrogensuccinat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    One Dose of Prednisolone-21-hydrogensuccinat 500 mg i.v (reconstituted in 5ml of sterile water for injection) After 6 hours decision whether a second dose of Cortisone should be administered.

    Investigational medicinal product name
    Clemastinfumarat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    One dose 2,68 mg milligram(s) Clemastinfumarat i.v (Baseline Visite 0) After 6 hours decision whether a second dose of Clemastin should be administered.

    Number of subjects in period 1
    		Standard + Berinert Standard + Placebo
    Started
    16
    14
    Completed
    14
    11
    Not completed
    2
    3
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    1
    3

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Standard + Berinert
    Reporting group description
    		 Standard + Berinert Standard (prednisolone-21-hydrogensuccinat / Clemastinfumarat i.v.) + Body weight adjusted 20IU/kg b.w. Berinert® rounded to the next 500 IU vial.

    Reporting group title
    Standard + Placebo
    Reporting group description
    		 Standard + Placebo Standard (prednisolone-21-hydrogensuccinat / Clemastinfumarat i.v.) + Placebo (10ml 0,9% NaCl ) rounded to next 10 ml step.

    Reporting group values
    		 Standard + Berinert Standard + Placebo Total
    Number of subjects
    		 16 14 30
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 75 ± 11.3 67 ± 11.1 -
    Gender categorical
    Units: Subjects
        Female
    		 6 4 10
        Male
    		 10 10 20
    Earlier episodes of ACE-induced angioedema
    Units: Subjects
        yes
    		 4 3 7
        no
    		 12 11 23
    Concomitant diseases
    Units: Subjects
        yes
    		 16 14 30
        no
    		 0 0 0

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Standard + Berinert
    Reporting group description
    		 Standard + Berinert Standard (prednisolone-21-hydrogensuccinat / Clemastinfumarat i.v.) + Body weight adjusted 20IU/kg b.w. Berinert® rounded to the next 500 IU vial.

    Reporting group title
    Standard + Placebo
    Reporting group description
    		 Standard + Placebo Standard (prednisolone-21-hydrogensuccinat / Clemastinfumarat i.v.) + Placebo (10ml 0,9% NaCl ) rounded to next 10 ml step.

    Primary: TCER

    		 Close Top of page
    End point title
    		 TCER
    End point description
    TCER is set to the first visit time, according to the visit schedule, at which complete resolution is marked to be present. As this potentially leads to equal TCER for some subjects (called `bindings’ in statistics), the exact p-value are computed for the Wilcoxon-Mann-Whitney-U test. Missing TCER in the treatment group are imputed by the longest TCER observed for all patients. In the control group, complete resolution is assumed to have taken place instantly after the last known observation of the respective patients.
    End point type
    Primary
    End point timeframe
    Time to complete edema restitution (TCER)
    End point values
    		 Standard + Berinert Standard + Placebo
    Number of subjects analysed
    16
    14
    Units: hours
        median (full range (min-max))
    24 (6 to 48)
    15 (4 to 30)
    Statistical analysis title
    		 Primary endpoint analysis on ITT
    Statistical analysis description
    Scheduled imputed TCER on ITT. The ITT population contains all randomized patients with results attributed to the treatment group they were randomized to and who received at least one dose of study medication. Exact Wilcoxon-Mann-Whitney U test
    Comparison groups
    Standard + Berinert v Standard + Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0457 [1]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - Exact test
    Statistical analysis title
    		 Sensitivity analysis actual imputed on ITT
    Statistical analysis description
    Actual imputed TCER on ITT. The ITT population contains all randomized patients with results attributed to the treatment group they were randomized to and who received at least one dose of study medication. Exact Wilcoxon-Mann-Whitney U test
    Comparison groups
    Standard + Berinert v Standard + Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0852 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - Analysis is performed using the actual TCER as an outcome instead of the visit schedule based TCER.
    [3] - exact
    Statistical analysis title
    		 Sensitivity analysis scheduled ignoring 1h on ITT
    Statistical analysis description
    Scheduled TCER ignoring the 1h rule on ITT. The ITT population contains all randomized patients with results attributed to the treatment group they were randomized to and who received at least one dose of study medication. Exact Wilcoxon-Mann-Whitney-U test
    Comparison groups
    Standard + Berinert v Standard + Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.1354 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - As there were seven patients without confirmation of TCER after one hour, additional analyses are conducted while ignoring the one hour rule in the actual and scheduled TCER.
    [5] - exact
    Statistical analysis title
    		 Sensitivity analysis actual ignoring 1h on ITT
    Statistical analysis description
    Actual TCER ignoring the 1h rule on ITT. The ITT population contains all randomized patients with results attributed to the treatment group they were randomized to and who received at least one dose of study medication. Exact Wilcoxon-Mann-Whitney-U test
    Comparison groups
    Standard + Berinert v Standard + Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.184 [7]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - Analysis is performed using the actual TCER as an outcome instead of the visit schedule based TCER. As there were seven patients without confirmation of TCER after one hour, additional analyses are conducted while ignoring the one hour rule in the actual and scheduled TCER.
    [7] - exact
    Statistical analysis title
    		 Sensitivity analysis scheduled imputed on PP
    Statistical analysis description
    Scheduled imputed TCER on PP. The PP population contains all patients in the ITT population except for those with major protocol violations and those who received per-protocol rescue medication. Exact Wilcoxon-Mann-Whitney U test
    Comparison groups
    Standard + Berinert v Standard + Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4718 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - exact
    Statistical analysis title
    		 Sensitivity analysis actual imputed on PP
    Statistical analysis description
    Actual imputed TCER on PP. The PP population contains all patients in the ITT population except for those with major protocol violations and those who received per-protocol rescue medication. Exact Wilcoxon-Mann-Whitney-U test
    Comparison groups
    Standard + Berinert v Standard + Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6511 [9]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [9] - exact
    Statistical analysis title
    		 Sensitivity analysis scheduled ignoring 1h on PP
    Statistical analysis description
    Scheduled TCER ignoring the 1h rule on PP. The PP population contains all patients in the ITT population except for those with major protocol violations and those who received per-protocol rescue medication. Exact Wilcoxon-Mann-Whitney-U test
    Comparison groups
    Standard + Berinert v Standard + Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2869 [10]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [10] - exact
    Statistical analysis title
    		 Sensitivity analysis actual ignoring 1h on PP
    Statistical analysis description
    Actual TCER ignoring the 1h rule on PP.The PP population contains all patients in the ITT population except for those with major protocol violations and those who received per-protocol rescue medication. Exact Wilcoxon-Mann-Whitney-U test
    Comparison groups
    Standard + Berinert v Standard + Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4561 [11]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [11] - exact

    Secondary: TOR

    		 Close Top of page
    End point title
    		 TOR
    End point description
    Time between start of study medication administration and time of onset of relief (TOR), defined as at least one point reduction of the sum-score of the edema severity scale.
    End point type
    Secondary
    End point timeframe
    Time to onset of relief
    End point values
    		 Standard + Berinert Standard + Placebo
    Number of subjects analysed
    16
    14
    Units: hours
        median (full range (min-max))
    2 (2 to 12)
    2 (2 to 6)
    Statistical analysis title
    		 Scheduled TOR on ITT
    Statistical analysis description
    Scheduled TOR on ITT. The ITT population contains all randomized patients with results attributed to the treatment group they were randomized to and who received at least one dose of study medication. Exact Wilcoxon-Mann-Whitney-U test
    Comparison groups
    Standard + Berinert v Standard + Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4443 [12]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [12] - exact

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs were documented in the timeframe from signed informed consent till the end of the follow-up period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Standard + Berinert
    Reporting group description
    		 Standard + Berinert Standard (prednisolone-21-hydrogensuccinat / Clemastinfumarat i.v.) + Body weight adjusted 20IU/kg b.w. Berinert® rounded to the next 500 IU vial.

    Reporting group title
    Standard + Placebo
    Reporting group description
    		 Standard + Placebo Standard (prednisolone-21-hydrogensuccinat / Clemastinfumarat i.v.) + Placebo (10ml 0,9% NaCl ) rounded to next 10 ml step.

    Serious adverse events
    		 Standard + Berinert Standard + Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 14 (14.29%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Troponin T increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard + Berinert Standard + Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 16 (31.25%)
    4 / 14 (28.57%)
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Device dislocation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jul 2014
    Clarification of 1 inclusion Criterion : Patients with ACE induced angioedema (grade II-III in at least one severity scale) with imminent airway obstruction admitted to an Emergency department

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27886906
    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.

    European Medicines Agency © 1995-Sun Apr 28 21:01:48 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA