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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy and Safety of Oral Lefamulin (BC-3781) Versus Oral Moxifloxacin in Adults With Community-Acquired Bacterial Pneumonia

    Summary
    EudraCT number
    		 2015-004782-92
    Trial protocol
    		 LV   HU   ES   BG  
    Global end of trial date
    02 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jan 2019
    First version publication date
    18 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NAB-BC-3781-3102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02813694
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Nabriva Therapeutics GmbH (formerly Nabriva Therapeutics AG)
    Sponsor organisation address
    Leberstraße 20, Vienna, Austria, 1110
    Public contact
    Jennifer Schranz, MD, Nabriva Therapeutics plc, +1 6109182842, Jennifer.Schranz@nabriva.com
    Scientific contact
    Jennifer Schranz, MD, Nabriva Therapeutics plc, +1 6109182842, Jennifer.Schranz@nabriva.com
    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
    28 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The co-primary endpoints for the study were: • Demonstrate the non-inferiority (NI) of lefamulin versus comparator with respect to the Early Clinical Response (96 ± 24 hours after the first dose of study drug) in the Intent-to-Treat (ITT) Analysis Set (FDA endpoint). • Demonstrate the NI of lefamulin versus comparator with respect to the Investigator’s Assessment of Clinical Response at Test of Cure (TOC) (i.e., 5-10 days after the last dose of study drug) in the modified-ITT (mITT) and Clinically Evaluable at TOC (CE-TOC) Analysis Sets (EMA endpoint).
    Protection of trial subjects
    This clinical study was conducted in compliance with the protocol, ethical principles that have their origin in the Declaration of Helsinki in its revised edition, the guidelines of International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) (CPMP/ICH/135/95), European Union (EU) Clinical Trials Directive 2001/20/EC, EU Commission Directive 2005/28/EC, and Code of Federal Regulation Title 21, Parts 50, 56 and 312, designated Standard Operating Procedures, and with local laws and regulations in the country of conduct. The study protocol and amendments were reviewed and approved by an IEC/IRB before conduct of the study at each participating site.
    Background therapy
    		 -
    Evidence for comparator
    		 Moxifloxacin was chosen as the active comparator for multiple reasons. Consensus guidelines on the management of CAP in adults recommend a respiratory fluoroquinolone as an appropriate option for hospitalized patients admitted to a general ward, for outpatients with certain comorbid conditions, outpatients who have used antimicrobials in the previous few months, and outpatients in regions with high rates of macrolide-resistant S. pneumoniae regardless of co-morbidities or prior antibiotic use. The European Society of Clinical Microbiology and Infectious Diseases also supports the use of fluoroquinolones for outpatient treatment of CAP in areas with increased bacterial resistance rates to tetracyclines and macrolides, as well as for empiric therapy on hospitalized patients with CAP. Moxifloxacin has established efficacy against the primary CAP pathogens, and is globally available in an oral formulation, which made it a suitable comparator in this study. Moreover, moxifloxacin does not require dose adjustment in patients with renal impairment.
    Actual start date of recruitment
    31 Aug 2016
    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
    Romania: 18
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Bulgaria: 80
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Ukraine: 128
    Country: Number of subjects enrolled
    Argentina: 13
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Peru: 51
    Country: Number of subjects enrolled
    United States: 23
    Country: Number of subjects enrolled
    Philippines: 71
    Country: Number of subjects enrolled
    South Africa: 55
    Country: Number of subjects enrolled
    Korea, Republic of: 26
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Latvia: 3
    Country: Number of subjects enrolled
    Georgia: 41
    Country: Number of subjects enrolled
    Russian Federation: 55
    Country: Number of subjects enrolled
    Serbia: 129
    Worldwide total number of subjects
    738
    EEA total number of subjects
    137
    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)
    461
    From 65 to 84 years
    260
    85 years and over
    17

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was designed to enroll adults with CABP who were eligible for oral therapy. Subjects with a PORT score of II, III and IV were eligible. The first subject was randomized in August 2016 and the last subject was randomized in December 2017.

    Pre-assignment
    Screening details
    		 Subjects who met inclusion criteria and did not meet exclusion criteria were randomly assigned to a treatment group. Administration of study drug was expected to occur as soon as possible after the diagnosis of CABP with all Screening/Baseline assessments expected to be completed within 24 hours before the first dose of oral study drug.

    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
    Blinding implementation details
    This was a double-blind, double-dummy study. Oral formulations were provided in blister packs and all oral study medication administration utilized a “double-dummy” technique.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lefamulin
    Arm description
    		 Lefamulin 600 mg PO q12h for 5 days (10 doses) plus moxifloxacin placebo PO q24h for 7 days (7 doses).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lefamulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lefamulin 600 mg PO q12h for 5 days (10 doses). Moxifloxacin placebo PO q24h for 7 days (7 doses).

    Arm title
    		 Moxifloxacin
    Arm description
    		 Moxifloxacin 400 mg PO q24h for 7 days (7 doses) plus lefamulin placebo PO q12h for 5 days (10 doses).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Moxifloxacin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Moxifloxacin 400 mg PO q24h for 7 days (7 doses) Lefamulin placebo PO q12h for 5 days (10 doses)

    Number of subjects in period 1
    		Lefamulin Moxifloxacin
    Started
    370
    368
    Completed
    353
    354
    Not completed
    17
    14
         Adverse event, serious fatal
    3
    3
         Consent withdrawn by subject
    10
    9
         Physician decision
    -
    1
         Randomized but not treated
    2
    -
         Other
    1
    -
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lefamulin
    Reporting group description
    		 Lefamulin 600 mg PO q12h for 5 days (10 doses) plus moxifloxacin placebo PO q24h for 7 days (7 doses).

    Reporting group title
    Moxifloxacin
    Reporting group description
    		 Moxifloxacin 400 mg PO q24h for 7 days (7 doses) plus lefamulin placebo PO q12h for 5 days (10 doses).

    Reporting group values
    		 Lefamulin Moxifloxacin Total
    Number of subjects
    		 370 368 738
    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)
    		 234 227 461
        From 65-84 years
    		 126 134 260
        85 years and over
    		 10 7 17
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.4 ( 16.4 ) 57.7 ( 16.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 207 180 387
        Male
    		 163 188 351
    Subject analysis sets

    Subject analysis set title
    Intent-to-Treat (ITT) Analysis Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Analysis Set comprised all randomized subjects regardless of whether or not the subject received study drug. A subject was considered randomized when an IRT-generated randomization number was assigned.

    Subject analysis set title
    mITT Analysis Set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT Analysis Set comprised all randomized subjects who received any amount of study drug. Subjects were analyzed based on the randomized (ie, assigned) treatment group.

    Subject analysis set title
    Clinically Evaluable at TOC (CE-TOC) Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The CE-TOC Analysis Set comprised all subjects who completed the TOC Visit 5 to 10 days after the last dose of study drug, unless the subject was considered a failure at the EOT Visit based on the IACR, and had no confounding factors that affected the assessment of efficacy.

    Subject analysis sets values
    		 Intent-to-Treat (ITT) Analysis Set mITT Analysis Set Clinically Evaluable at TOC (CE-TOC) Analysis Set
    Number of subjects
    738
    736
    656
    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)
    461
    460
    409
        From 65-84 years
    260
    259
    233
        85 years and over
    17
    17
    14
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.5 ( 16.3 )
    57.5 ( 16.3 )
    57.7 ( 16.0 )
    Gender categorical
    Units: Subjects
        Female
    387
    386
    349
        Male
    351
    350
    307

    End points

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    End points reporting groups
    Reporting group title
    Lefamulin
    Reporting group description
    		 Lefamulin 600 mg PO q12h for 5 days (10 doses) plus moxifloxacin placebo PO q24h for 7 days (7 doses).

    Reporting group title
    Moxifloxacin
    Reporting group description
    		 Moxifloxacin 400 mg PO q24h for 7 days (7 doses) plus lefamulin placebo PO q12h for 5 days (10 doses).

    Subject analysis set title
    Intent-to-Treat (ITT) Analysis Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Analysis Set comprised all randomized subjects regardless of whether or not the subject received study drug. A subject was considered randomized when an IRT-generated randomization number was assigned.

    Subject analysis set title
    mITT Analysis Set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT Analysis Set comprised all randomized subjects who received any amount of study drug. Subjects were analyzed based on the randomized (ie, assigned) treatment group.

    Subject analysis set title
    Clinically Evaluable at TOC (CE-TOC) Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The CE-TOC Analysis Set comprised all subjects who completed the TOC Visit 5 to 10 days after the last dose of study drug, unless the subject was considered a failure at the EOT Visit based on the IACR, and had no confounding factors that affected the assessment of efficacy.

    Primary: EMA Co-Primary: Investigator Assessment of Clinical Response (IACR) at TOC in the mITT Analysis Set

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    End point title
    		 EMA Co-Primary: Investigator Assessment of Clinical Response (IACR) at TOC in the mITT Analysis Set
    End point description
    The EMA co-primary endpoints were the percentages of subjects with an IACR of success at TOC in the mITT and CE-TOC Analysis Sets. Investigators assessed clinical response at the TOC visit. Subjects were classified as a success, failure, or indeterminate at TOC based on predefined definitions. Success was defined as resolution or improvement of clinical signs and symptoms such that no additional antibacterial therapy was administered for the treatment of the current episode of CABP. Subjects who had an IACR of failure at a prior visit did not have an IACR performed at TOC and were considered an IACR of failure at TOC.
    End point type
    Primary
    End point timeframe
    The TOC visit occurred 5 to 10 days after the last dose of study drug.
    End point values
    		 Lefamulin Moxifloxacin mITT Analysis Set
    Number of subjects analysed
    368
    368
    736
    Units: Number of patients
        Clinical Success
    322
    328
    650
        Failure
    44
    32
    76
        Indeterminate
    2
    8
    10
    Statistical analysis title
    		 mITT Statistical Analysis Plan
    Statistical analysis description
    An adjusted (for the randomization stratification factors of prior antibiotic use and PORT risk class) 2 sided 95% CI for the observed difference in IACR success rates (lefamulin group minus the moxifloxacin group) was calculated using the method of Miettinen and Nurminen with Cochran-Mantel-Haenszel weights to test the null hypothesis.
    Comparison groups
    Moxifloxacin v Lefamulin
    Number of subjects included in analysis
    736
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.3
         upper limit
    		 3.1
    Variability estimate
    Standard error of the mean
    Notes
    [1] - If the lower limit of the 95% CI for the difference in IACR success rates in the mITT and the CE-TOC Analysis Sets was greater than 10%, then the null hypothesis was rejected and the NI of lefamulin to moxifloxacin was concluded.

    Primary: EMA Co-Primary: Investigator Assessment of Clinical Response at TOC in the CE-TOC Analysis Set

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    End point title
    		 EMA Co-Primary: Investigator Assessment of Clinical Response at TOC in the CE-TOC Analysis Set
    End point description
    The EMA co-primary endpoints were the percentages of subjects with an IACR of success at TOC in the mITT and CE-TOC Analysis Sets. Investigators assessed clinical response at the TOC visit. Subjects were classified as a success, failure, or indeterminate at TOC based on predefined definitions. Subjects who had an IACR of failure at a prior visit did not have an IACR performed at TOC and were considered an IACR of failure at TOC.
    End point type
    Primary
    End point timeframe
    The TOC visit occurred 5 to 10 days after the last dose of study drug
    End point values
    		 Lefamulin Moxifloxacin Clinically Evaluable at TOC (CE-TOC) Analysis Set
    Number of subjects analysed
    330
    326
    656
    Units: Number of patients
        Clinical Success
    296
    305
    601
        Failure
    34
    21
    55
        Indeterminate
    0
    0
    0
    Statistical analysis title
    		 CE-TOC Statistical Analysis Plan
    Statistical analysis description
    An adjusted (for the randomization stratification factors of prior antibiotic use and PORT risk class) 2 sided 95% CI for the observed difference in IACR success rates (lefamulin group minus the moxifloxacin group) was calculated using the method of Miettinen and Nurminen with Cochran-Mantel-Haenszel weights to test the null hypothesis.
    Comparison groups
    Moxifloxacin v Lefamulin
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.2
         upper limit
    		 0.5
    Variability estimate
    Standard error of the mean
    Notes
    [2] - If the lower limit of the 95% CI for the difference in IACR success rates in the mITT and the CE-TOC Analysis Sets was greater than 10%, then the null hypothesis was rejected and the NI of lefamulin to moxifloxacin was concluded.

    Primary: FDA Primary: Early Clinical Response (ECR) at 96 ± 24 hours After the First Dose of Study Drug in the ITT Analysis Set

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    End point title
    		 FDA Primary: Early Clinical Response (ECR) at 96 ± 24 hours After the First Dose of Study Drug in the ITT Analysis Set
    End point description
    The FDA primary endpoint was the percentage of subjects with an ECR of responder at 96 ±24 hours after the first dose of study drug in the ITT Analysis Set. Subjects were programmatically defined as a responder, non responder, or indeterminate based on CABP signs and symptoms, concomitant antibiotic use, and vital status.
    End point type
    Primary
    End point timeframe
    ECR was assessed 96 ±24 hours after the first dose of study drug.
    End point values
    		 Lefamulin Moxifloxacin Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    370
    368
    738
    Units: Number of patients
        Clinical Success
    336
    334
    670
        Failure
    29
    31
    60
        Indeterminate
    5
    3
    8
    Statistical analysis title
    		 ITT Statistical Analysis Plan
    Statistical analysis description
    The non-inferiority (NI) test was a 1 sided hypothesis test performed at the 2.5% level of significance. This was based on the lower limit of the 2 sided 95% confidence interval (CI) for the observed difference in ECR responder rates (lefamulin group minus moxifloxacin group). The CI was calculated using an unadjusted continuity corrected Z test.
    Comparison groups
    Moxifloxacin v Lefamulin
    Number of subjects included in analysis
    738
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 4.5
    Variability estimate
    Standard error of the mean
    Notes
    [3] - If the lower limit of the 95% CI for the difference in ECR responder rates in the ITT Analysis Set was greater than 10%, then the null hypothesis would be rejected and the NI of lefamulin to moxifloxacin would be concluded.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from the time of informed consent to the TOC Visit. Serious adverse events were recorded from the time of informed consent to the LFU Visit.
    Adverse event reporting additional description
    Subjects were evaluated for adverse events at each study visit. Questions were posed in a non leading manner so as not to bias the response. In addition to specific questioning, subjects were encouraged to spontaneously report adverse events. Adverse events were recorded whether or not they were considered to be study drug related.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Lefamulin
    Reporting group description
    		 The Safety Analysis Set comprised all randomized subjects who received any amount of study drug. Subjects were analyzed based on the study drug actually received. All safety analyses were conducted in this population.

    Reporting group title
    Moxifloxacin
    Reporting group description
    		 The Safety Analysis Set comprised all randomized subjects who received any amount of study drug. Subjects were analyzed based on the study drug actually received. All safety analyses were conducted in this population.

    Serious adverse events
    		 Lefamulin Moxifloxacin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 368 (4.62%)
    19 / 368 (5.16%)
         number of deaths (all causes)
    5
    3
         number of deaths resulting from adverse events
    5
    3
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nuclear magnetic resonance imaging brain abnormal
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukemia
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 368 (0.27%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrilation
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Inguinal hernia strangulated
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 368 (0.54%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Empyema
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 368 (0.27%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 368 (1.09%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculous pleurisy
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinrary tract infection
         subjects affected / exposed
    1 / 368 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lefamulin Moxifloxacin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 368 (17.39%)
    11 / 368 (2.99%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    45 / 368 (12.23%)
    4 / 368 (1.09%)
         occurrences all number
    48
    4
    Nausea
         subjects affected / exposed
    19 / 368 (5.16%)
    7 / 368 (1.90%)
         occurrences all number
    19
    12

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2016
    Amendment 1 addresses revisions to the protocol requested by the US Food and Drug Administration (FDA) with respect to the non-inferiority margin. The change in the non-inferiority margin resulted in the change of other statistical parameters including the randomization ratio and sample size. FDA also requested an increase in the number of subjects with a PORT Risk Class of III or IV; methicillin-resistant Staphylococcus aureus (MRSA) to be added to the list of pathogens that would exclude study eligibility; and increase in the number of pharmacokinetic sampling time points.
    17 Mar 2016
    Amendment 2 adresses an inconsistency within the protocol regarding the use of strong P-glycoprotein inhibitors

    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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