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    Clinical Trial Results:
    Use of doxapram as a new antiarrhythmic drug for a specific therapy of atrial fibrillation Doctos Trial (Doxapram conversion to sinus rhythm study)

    Summary
    EudraCT number
    		 2018-002979-17
    Trial protocol
    		 DE  
    Global end of trial date
    25 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Nov 2025
    First version publication date
    30 Nov 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    K620
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Heidelberg
    Sponsor organisation address
    Im Neuenheimer Feld 410, Heidelberg, Germany, 69120
    Public contact
    Department of Clinical Pharmacology, University of Heidelberg, 0049 6221568740, Walter.Emil.Haefeli@med.uni-heidelberg.de
    Scientific contact
    Department of Clinical Pharmacology, University of Heidelberg, 0049 6221568740, Walter.Emil.Haefeli@med.uni-heidelberg.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
    13 Aug 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Oct 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Antiarrhythmic potential for cardioversion from AF to SR after i.v. administration of doxapram
    Protection of trial subjects
    All drug used in this trial are approved in Germany and have a well-known side effect and acceptable safety profile. For all PK parameters, blood samples were taken from a perpheral venous catheter. This procedure is generally well tolerated. During the study, Patient's health was cloesly monitored during the trial. Precautions were taken to discover and treat any adverse events early and appropriatley. (S)AEs including SUSARs where reported.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jan 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    8
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 in-house patients suffering from Paroxysmal or persistent, non-valvular, atrial fibrillation (AF) meeting eligibility criteria for non-emergent, electrical or pharmacological cardioversion were included

    Pre-assignment
    Screening details
    		 right before treatment: Inclusion, exclusion criteria were checked; relevant medical history, current medical condition were assessed. Complete physical examination, urine and blood analysis, ECG were conducted. Abnormal parameters may re-tested. Last value obtained defined eligibility.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    not neccessary

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1
    Arm description
    		 2 x bolus of 0.5 mg/kg body weight IMP for conversion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxapram hydrochloride
    Investigational medicinal product code
    6743066.00.00
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    up to 2 identical doses, given as bolus, at least 20 min apart

    Arm title
    		 Cohort 2
    Arm description
    		 2 x 1 mg/kg body weight
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxapram hydrochloride
    Investigational medicinal product code
    6743066.00.00
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    up to 2 identical doses, given as bolus, at least 20 min apart

    Arm title
    		 Cohort 3
    Arm description
    		 2 x 2 mg/kg body weight
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxapram hydrochloride
    Investigational medicinal product code
    6743066.00.00
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    up to 2 identical doses, given as bolus, at least 20 min apart

    Arm title
    		 Cohort 4
    Arm description
    		 8 mg/kg body weight, infusion over 8 h
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxapram hydrochloride
    Investigational medicinal product code
    6743066.00.00
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Continous i. v. infusion over 8 h. Infusion was allowed to be interrupted and/or infusion time prolonged if required to limit blood preassure increase

    Number of subjects in period 1
    		Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Started
    7
    6
    6
    4
    Completed
    7
    6
    6
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 2 x bolus of 0.5 mg/kg body weight IMP for conversion

    Reporting group title
    Cohort 2
    Reporting group description
    		 2 x 1 mg/kg body weight

    Reporting group title
    Cohort 3
    Reporting group description
    		 2 x 2 mg/kg body weight

    Reporting group title
    Cohort 4
    Reporting group description
    		 8 mg/kg body weight, infusion over 8 h

    Reporting group values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Total
    Number of subjects
    		 7 6 6 4 23
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 2 2 3 1 8
        From 65-84 years
    		 5 4 3 3 15
    Gender categorical
    Units: Subjects
        Female
    		 1 1 4 0 6
        Male
    		 6 5 2 4 17

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 2 x bolus of 0.5 mg/kg body weight IMP for conversion

    Reporting group title
    Cohort 2
    Reporting group description
    		 2 x 1 mg/kg body weight

    Reporting group title
    Cohort 3
    Reporting group description
    		 2 x 2 mg/kg body weight

    Reporting group title
    Cohort 4
    Reporting group description
    		 8 mg/kg body weight, infusion over 8 h

    Primary: Rate of cardioversion from AF to SR after i. v. administration of doxapram.

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    End point title
    		 Rate of cardioversion from AF to SR after i. v. administration of doxapram. [1]
    End point description
    measured by 12-lead ECG
    End point type
    Primary
    End point timeframe
    within 6 h after i. v. doxapram
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: not enough data available to meet criteria for statistical analysis
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    7
    6
    6
    4
    Units: cardioversion
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: time to cardioversion from AF to SR after i. v. administration of doxapram

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    End point title
    		 time to cardioversion from AF to SR after i. v. administration of doxapram
    End point description
    End point type
    Secondary
    End point timeframe
    from start of treatment to end of study
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    7
    6
    6
    4
    Units: time
        arithmetic mean (full range (min-max))
    10.15 (6.87 to 13.42)
    0 (0 to 0)
    0 (0 to 0)
    16.1 (06.25 to 23.05)
    No statistical analyses for this end point

    Secondary: SR after pharmacological or electrical cardioversion at day 7

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    End point title
    		 SR after pharmacological or electrical cardioversion at day 7
    End point description
    End point type
    Secondary
    End point timeframe
    7 +- 2 days after doxapram exposure
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Number of subjects analysed
    6
    6
    6
    4
    Units: sinus rhytm
    6
    6
    6
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The observation period begins with the first administration of the IMP (any adverse events prior to the first administration of the IMP are documented as medical history) and ends after 7 ± 2 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5
    Reporting groups
    Reporting group title
    Treatment to EOS
    Reporting group description
    		 -

    Serious adverse events
    		 Treatment to EOS
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 23 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treatment to EOS
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 23 (100.00%)
    Cardiac disorders
    palpitation
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    sinusbradycardia
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Nervous system disorders
    headache
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    3
    tremor
         subjects affected / exposed
    10 / 23 (43.48%)
         occurrences all number
    10
    paresthesia (hands)
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    nightly confusion
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    General disorders and administration site conditions
    feeling of warmth
         subjects affected / exposed
    23 / 23 (100.00%)
         occurrences all number
    26
    preassure feeling head
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Ear and labyrinth disorders
    dizziness
         subjects affected / exposed
    11 / 23 (47.83%)
         occurrences all number
    11
    tinnitus
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Gastrointestinal disorders
    nausea
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    dry mouth
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    altered breathing
         subjects affected / exposed
    12 / 23 (52.17%)
         occurrences all number
    12
    Chest pain
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    rash
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    sweating
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    tingeling both upper legs
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Endocrine disorders
    latent hyperhyreosis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    muscle fasciculations (wohle body)
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Aug 2019
    Adjustment of: inclusion criteria, exclusion criteria, Dose escalation and dose deescalation, pregnancy prevention requirements
    29 Apr 2020
    Additional cohort, updated timelines, tighten blood pressure control, add exploratory evaluation of catecholamines during elebated blood pressure
    09 Jun 2022
    changes in: - safety or integrity of trial subjects - conduct or management of the trial - or addition of principal investigator(s), co-ordinating investigator

    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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