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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy and Safety of Lefamulin (BC 3781) Versus Moxifloxacin (With or Without Adjunctive Linezolid) in Adults With Community-Acquired Bacterial Pneumonia

    Summary
    EudraCT number
    		 2014-005169-63
    Trial protocol
    		 NL   HU   LV   PL   BG  
    Global end of trial date
    12 May 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Dec 2018
    First version publication date
    18 Jul 2018
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Re-submission of the CSR has been made.

    Trial information

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    Trial identification
    Sponsor protocol code
    NAB-BC-3781-3101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02559310
    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, +43 16109182842, Jennifer.Schranz@nabriva.com
    Scientific contact
    Jennifer Schranz, MD, Nabriva Therapeutics plc, +43 16109182842, 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
    17 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2017
    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 (with or without adjunctive linezolid) was chosen as the active comparator for multiple reasons. Consensus guidelines on the management of CABP in adults recommend a respiratory fluoroquinolone as an appropriate option for hospitalized patients admitted to a general ward. Moxifloxacin has established efficacy against the primary CABP pathogens, and is globally available in both IV and oral formulations, which made it a suitable comparator in this study. Moreover, moxifloxacin does not require dose adjustment in patients with renal impairment. Consensus guidelines also recommend the use of adjunctive linezolid for suspected MRSA. Therefore, linezolid was to be added to the moxifloxacin group and linezolid placebo was to be added to the lefamulin group if the Investigator determined that MRSA was a probable pathogen at Screening. Similar to moxifloxacin, linezolid is available in IV and oral formulations, and does not require dose adjustment in patients with renal impairment.
    Actual start date of recruitment
    23 Feb 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
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Romania: 11
    Country: Number of subjects enrolled
    Bulgaria: 123
    Country: Number of subjects enrolled
    Hungary: 23
    Country: Number of subjects enrolled
    Latvia: 28
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 25
    Country: Number of subjects enrolled
    Georgia: 54
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    Serbia: 57
    Country: Number of subjects enrolled
    Ukraine: 116
    Country: Number of subjects enrolled
    Argentina: 9
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Peru: 4
    Country: Number of subjects enrolled
    United States: 3
    Country: Number of subjects enrolled
    Philippines: 40
    Country: Number of subjects enrolled
    South Africa: 27
    Country: Number of subjects enrolled
    Thailand: 1
    Worldwide total number of subjects
    551
    EEA total number of subjects
    193
    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)
    311
    From 65 to 84 years
    214
    85 years and over
    26

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was designed to enroll adults with CABP that was severe enough to require a minimum of at least 3 days of IV treatment. Subjects with a PORT score of III, IV and V were eligible. The first subject was randomized in February 2016 and the last subject was randomized in April 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 IV 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
    Blinding implementation details
    This was a double-blind, double-dummy study. Blinding of IV lefamulin, moxifloxacin, linezolid and matching placebo was achieved using a bag cover and IV tubing cover. Intravenous infusions were administered by unblinded site personnel at a controlled rate (over approximately 60 minutes). 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 150 mg IV q12h with option to switch to 600 mg PO q12h after at least 3 days (6 doses) of IV treatment. Linezolid placebo q12h was added at baseline for patients with suspected MRSA. The total duration of study treatment was 7 to 10 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lefamulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Lefamulin 150 mg IV q12h with option to switch to 600 mg PO q12h after at least 3 days (6 doses) of IV treatment. Linezolid placebo q12h was added at baseline for patients with suspected MRSA.

    Arm title
    		 Moxifloxacin ± Linezolid for suspected MRSA
    Arm description
    		 Moxifloxacin 400 mg IV q24h with option to switch to 400 mg PO q24h after at least 3 days (6 doses) of IV treatment. Linezolid 600 mg IV q12h was added at baseline for patients with suspected MRSA. The total duration of study treatment was 7 to 10 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Moxifloxacin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Moxifloxacin 400 mg IV q24h with option to switch to 400 mg PO q24h after at least 3 days (6 doses) of IV treatment. Linezolid 600 mg IV q12h was added at baseline for patients with suspected MRSA.

    Investigational medicinal product name
    Linezolid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Subjects in the moxifloxacin arm with suspected MRSA at baseline were to receive adjunctive Linezolid 600 mg IV q12h (or linezolid placebo in the lefamulin arm). Linezolid treatment was to be continued only in the presence of a microbiological culture confirming the presence of MRSA. If cultures did not grow MRSA, linezolid (or linezolid placebo) was to be discontinued and subjects were to be discontinued on moxifloxacin. Subjects could continue on lefamulin therapy. If linezolid was given for at least 3 days (6 doses) the Investigator had the option to switch to linezolid 600mg PO q12h.

    Number of subjects in period 1
    		Lefamulin Moxifloxacin ± Linezolid for suspected MRSA
    Started
    276
    275
    Completed
    249
    256
    Not completed
    27
    19
         Adverse event, serious fatal
    4
    3
         Consent withdrawn by subject
    13
    9
         Physician decision
    2
    1
         Randomized but not treated
    3
    2
         Lost to follow-up
    5
    3
         Sponsor decision
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lefamulin
    Reporting group description
    		 Lefamulin 150 mg IV q12h with option to switch to 600 mg PO q12h after at least 3 days (6 doses) of IV treatment. Linezolid placebo q12h was added at baseline for patients with suspected MRSA. The total duration of study treatment was 7 to 10 days.

    Reporting group title
    Moxifloxacin ± Linezolid for suspected MRSA
    Reporting group description
    		 Moxifloxacin 400 mg IV q24h with option to switch to 400 mg PO q24h after at least 3 days (6 doses) of IV treatment. Linezolid 600 mg IV q12h was added at baseline for patients with suspected MRSA. The total duration of study treatment was 7 to 10 days.

    Reporting group values
    		 Lefamulin Moxifloxacin ± Linezolid for suspected MRSA Total
    Number of subjects
    		 276 275 551
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 144 167 311
        From 65-84 years
    		 116 98 214
        85 years and over
    		 16 10 26
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61 ( 16.3 ) 59.6 ( 14.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 106 115 221
        Male
    		 170 160 330
    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
    551
    546
    481
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    311
    307
    269
        From 65-84 years
    214
    213
    189
        85 years and over
    26
    26
    23
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.3 ( 15.6 )
    60.3 ( 15.63 )
    60.5 ( 15.59 )
    Gender categorical
    Units: Subjects
        Female
    221
    219
    195
        Male
    330
    327
    286

    End points

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    End points reporting groups
    Reporting group title
    Lefamulin
    Reporting group description
    		 Lefamulin 150 mg IV q12h with option to switch to 600 mg PO q12h after at least 3 days (6 doses) of IV treatment. Linezolid placebo q12h was added at baseline for patients with suspected MRSA. The total duration of study treatment was 7 to 10 days.

    Reporting group title
    Moxifloxacin ± Linezolid for suspected MRSA
    Reporting group description
    		 Moxifloxacin 400 mg IV q24h with option to switch to 400 mg PO q24h after at least 3 days (6 doses) of IV treatment. Linezolid 600 mg IV q12h was added at baseline for patients with suspected MRSA. The total duration of study treatment was 7 to 10 days.

    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: 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
    		 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 ± Linezolid for suspected MRSA Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    276
    275
    551
    Units: Number of patients
        Clinical Success
    241
    248
    489
        Failure
    29
    21
    50
        Indeterminate
    6
    6
    12
    Statistical analysis title
    		 ITT Statistical Analysis Plan
    Statistical analysis description
    A 2 sided 95% CI for the observed difference in ECR responder rates (lefamulin group minus the moxifloxacin group) was calculated to test the null hypothesis in ITT Analysis Set. If the lower limit of the 95% CI for the difference in ECR responder rates in the ITT Analysis Set was greater than 12.5%, then the null hypothesis was rejected and the NI of lefamulin to moxifloxacin was concluded.
    Comparison groups
    Moxifloxacin ± Linezolid for suspected MRSA v Lefamulin
    Number of subjects included in analysis
    551
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.5
         upper limit
    		 2.8
    Variability estimate
    Standard deviation

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

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    End point title
    		 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 ± Linezolid for suspected MRSA mITT Analysis Set
    Number of subjects analysed
    273
    273
    546
    Units: Number of patients
        Clinical Success
    223
    230
    453
        Failure
    43
    40
    83
        Indeterminate
    7
    3
    10
    Statistical analysis title
    		 mITT Statistical Analysis Plan
    Statistical analysis description
    A 2 sided 95% CI adjusted for the randomization stratification factors of prior antibiotic use and PORT risk class for the observed difference in IACR success rates (lefamulin group minus the moxifloxacin group) was calculated to test the null hypothesis in the mITT and CE TOC Analysis Sets.
    Comparison groups
    Moxifloxacin ± Linezolid for suspected MRSA v Lefamulin
    Number of subjects included in analysis
    546
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.9
         upper limit
    		 3.9
    Variability estimate
    Standard deviation

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

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    End point title
    		 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 ± Linezolid for suspected MRSA Clinically Evaluable at TOC (CE-TOC) Analysis Set
    Number of subjects analysed
    236
    245
    481
    Units: Number of patients
        Clinical Success
    205
    219
    424
        Failure
    31
    26
    57
        Indeterminate
    0
    0
    0
    Statistical analysis title
    		 CE-TOC Statistical Analysis Plan
    Statistical analysis description
    A 2 sided 95% CI adjusted for the randomization stratification factors of prior antibiotic use and PORT risk class for the observed difference in IACR success rates (lefamulin group minus the moxifloxacin group) was calculated to test the null hypothesis in the mITT and CE TOC Analysis Sets.
    Comparison groups
    Moxifloxacin ± Linezolid for suspected MRSA v Lefamulin
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 3.4
    Variability estimate
    Standard deviation

    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
    		 -

    Reporting group title
    Moxifloxacin
    Reporting group description
    		 -

    Serious adverse events
    		 Lefamulin Moxifloxacin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 273 (6.96%)
    13 / 273 (4.76%)
         number of deaths (all causes)
    6
    5
         number of deaths resulting from adverse events
    6
    5
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Function Test Increased
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bronchial Carcinoma
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Neoplasm
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma of Lung
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular Seminoma (Pure)
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Shock Haemorrhagic
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         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
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiogenic Shock
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Arrhythmia
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (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
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injection Site Reaction
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial Disorder
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Necrosis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infectious Pleural Effusion
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Abscess
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 273 (1.47%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Pharyngitis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 273 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 273 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    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
    105 / 273 (38.46%)
    105 / 273 (38.46%)
    Investigations
    Investigations
         subjects affected / exposed
    17 / 273 (6.23%)
    14 / 273 (5.13%)
         occurrences all number
    32
    29
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    24 / 273 (8.79%)
    15 / 273 (5.49%)
         occurrences all number
    39
    17
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    18 / 273 (6.59%)
    37 / 273 (13.55%)
         occurrences all number
    27
    49
    Diarrhoea
         subjects affected / exposed
    2 / 273 (0.73%)
    21 / 273 (7.69%)
         occurrences all number
    2
    21
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic, and mediastinal disorders
         subjects affected / exposed
    16 / 273 (5.86%)
    13 / 273 (4.76%)
         occurrences all number
    16
    16
    Infections and infestations
    Infections and Infestations
         subjects affected / exposed
    20 / 273 (7.33%)
    22 / 273 (8.06%)
         occurrences all number
    25
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Oct 2015
    Addressed changes requested during the Voluntary Harmonization Procedure in Europe during assessment of the original protocol including clarification to eligibility criteria. Collection of a nasopharyngeal swab was also added.
    04 Mar 2016
    Addressed changes to the treatment duration for CABP not caused by MRSA, a decrease in the sample size, and other clarifications or corrections to align with other studies in the lefamulin clinical development program.
    15 Mar 2016
    Addressed an inconsistency within the protocol regarding the prohibited use of strong P-gp inhibitors during study participation.

    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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