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    Clinical Trial Results:
    Adjunctive Rifampicin to Reduce Early mortality from Staphylococcus aureus bacteraemia: a randomised controlled trial

    Summary
    EudraCT number
    2012-000344-10
    Trial protocol
    GB  
    Global end of trial date
    18 Jan 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Jan 2018
    First version publication date
    31 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ARREST
    Additional study identifiers
    ISRCTN number
    ISRCTN37666216
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Medical Research Council
    Sponsor organisation address
    90 High Holborn, 2nd Floor, London, United Kingdom, WC1V 6LJ
    Public contact
    Professor A Sarah Walker, MRC Clinical Trials Unit at UCL, 44 2076704726, rmjlasw@ucl.ac.uk
    Scientific contact
    Professor A Sarah Walker, MRC Clinical Trials Unit at UCL, 44 2076704726, rmjlasw@ucl.ac.uk
    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
    20 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does the addition of 14 days rifampicin to initial standard antibiotic therapy reduce bacteriological failure/death through 12 weeks from randomisation in adults with Staphylococcus aureus bacteraemia?
    Protection of trial subjects
    A Data Monitoring Committee (DMC) was established. The DMC could recommend premature closure or reporting of the trial, or that recruitment be discontinued or modified.
    Background therapy
    Despite scant data from controlled trials, current treatment guidelines recommend that S. aureus bacteraemia should be treated with at least 14 days of an intravenous (IV) beta-lactam antibiotic, or a glycopeptide if the bacteria are meticillin-resistant. Combination antimicrobial therapy is generally not recommended, except in severe meticillin-resistant S. aureus (MRSA) infections (e.g. endocarditis, prosthetic joint infections). Most of the recommendations are based on uncontrolled observational studies and clinical experience, and views of how to manage S. aureus bacteraemia differ widely. To estimate the degree of uncertainty around clinical practice within the NHS we conducted a multi-centre, prospective observational study of patients with S. aureus bacteraemia. The findings from the first year (November 2008-2009; 549 cases) revealed that management varied widely among NHS Trusts, with little adherence to the published guidelines. Centres varied significantly (p<0.01) in the proportions given oral treatment alone for >50% of treatment (range 12-40% across NHS Trusts), in those treated for longer than 28 days (range 13-54%), and in those given combination antimicrobial therapy (range 14-94%). Twenty four percent of patients died during admission, 72% within the first 14 days of treatment. Older age, longer time in hospital before bacteraemia, and an unidentified infection focus were independent predictors of in-hospital death (p<0.001). Our literature review and observational study confirm S. aureus to be a common, frequently fatal blood infection within NHS Hospitals - yet the optimal management remains uncertain and practice highly variable. In particular, key questions concerning the most effective antimicrobial regimen are unanswered, and will remain so until they have been addressed by large, well-conducted RCTs. For reasons described below, one major clinical research priority is to assess the role of adjuvant antibiotic therapy.
    Evidence for comparator
    Three properties make rifampicin an attractive, if unproven, antibiotic for S. aureus bacteraemia treatment. First, it has good oral bioavailability. Second, it penetrates cells, tissues, and biofilms better than beta-lactam and glycopeptide antibiotics (the current mainstays of S. aureus bacteraemia treatment) and, therefore, in combination with these agents, may resolve serious S. aureus infections faster and more effectively. And third, it is cheap: a daily 600mg dose costs £0.73 by mouth and £7.67 intravenously. There are three important potential problems with using rifampicin for the treatment of S. aureus bacteraemia: the development of rifampicin resistant bacteria, interactions with other drugs, and hepatic toxicity. Resistance can be acquired rapidly when rifampicin is used alone in treatment, resulting from mutations in the drug’s binding site (the β-subunit of the bacterial DNA-dependent RNA polymerase). Interactions with other drugs are mediated by rifampicin’s ability to increase their metabolism through the potent induction of the hepatic cytochrome p450 system. Lastly, rifampicin can cause hepatic toxicity, although the enormous worldwide experience of using rifampicin for the prevention and 6-month treatment of tuberculosis confirms the drug is extremely well-tolerated and causes clinically significant hepatitis in <1% of patients.
    Actual start date of recruitment
    10 Dec 2012
    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
    United Kingdom: 758
    Worldwide total number of subjects
    758
    EEA total number of subjects
    758
    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)
    376
    From 65 to 84 years
    313
    85 years and over
    69

    Subject disposition

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    Recruitment
    Recruitment details
    Adults (≥18 years) were recruited from 29 hospitals from around the United Kingdom. Subjects were recruited by the study team and in consultation with the hospital team responsible for the patient’s in-hospital care. Subjects, or their legal representatives (in the case of incapacity), gave written informed consent. Main eligibility criteria below.

    Pre-assignment
    Screening details
    INCLUSION CRITERIA S aureus (meticillin-susceptible/resistant) grown from ≥1 blood culture <96h active antibiotic therapy for current infection, not including rifampicin EXCLUSION CRITERIA Infection not caused by S aureus alone Sensitivity results already available and demonstrate rifampicin resistant S aureus Rifampicin contraindicated TB

    Pre-assignment period milestones
    Number of subjects started
    2884 [1]
    Number of subjects completed
    758

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Non-randomisation: 2126
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 2884 subjects were screened, but 758 randomised.
    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, Carer, Assessor
    Blinding implementation details
    Rifampicin can turn urine orange-red. This is variable both within and between subjects, but a potential source of unblinding, particularly of subjects. The opportunity for doctors/nurses to examine urine at the bedside only occurred in subjects with catheters, removed at the earliest opportunity. Rifampicin capsules were overencapsulated to make them indistinguishable from placebo. In those needing IV treatment, pharmacists dispensed rifampicin for infusion or saline, with an opaque cover.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Treatment with placebo for 14 days from randomisation (oral and/or IV according to patient status) (plus standard backbone antibiotic therapy as chosen by the physician):  Placebo oral 300 mg capsules containing cellulose  Standard saline for intravenous injection Additional intravenous catheters were not required to administer the study drug as standard antibiotic therapy (with a beta-lactam or glycopeptide) is always given intravenously. The dose of placebo was prescribed according to the patient’s weight:  those <60kg received 600mg every 24h  those ≥60kg received 900mg every 24h Oral doses could be given once or twice daily, according to clinician and patient preference. If taken twice daily, 900mg daily (3 capsules) was taken as unequal divided doses (600mg am, 300mg pm). The study treatment was given for 14 days, unless fewer than 14 days of standard antibiotic therapy was planned, in which case placebo was given until standard antibiotic treatment ended.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Solution for infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Placebo was given by oral or intravenous route, according to the attending physician’s preference and the patient’s status. Additional intravenous catheters were not required to administer the study drug as standard antibiotic therapy (with a beta-lactam or glycopeptide) is always given intravenously. Patients may start taking IV placebo and then move to the oral formulation when they could swallow safely. We anticipated around 90% of doses would be given by mouth.

    Arm title
    Rifampicin
    Arm description
    Active treatment with rifampicin for 14 days from randomisation (oral and/or IV according to patient status) (plus standard antibiotic):  Rifampicin oral 300 mg capsules  Rifampicin 600 mg for intravenous injection Additional intravenous catheters were not required to administer the study drug as standard antibiotic therapy is always given intravenously. The dose of rifampicin was prescribed according to the patient’s weight:  those <60kg received 600mg every 24h  those ≥60kg received 900mg every 24h Oral doses could be given once or twice daily, according to clinician and patient preference. If taken twice daily, 900mg daily (3 capsules) was taken as unequal divided doses (600mg am, 300mg pm): as rifampicin can also be taken once daily, this provided adequate exposure. The study treatment was given for 14 days, unless fewer than 14 days of standard antibiotic therapy was planned, in which case rifampicin was given until standard antibiotic treatment ended.
    Arm type
    Experimental

    Investigational medicinal product name
    Rifampicin
    Investigational medicinal product code
    Other name
    Rifampin
    Pharmaceutical forms
    Capsule, Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Rifampicin was given by oral or intravenous route, according to the attending physician’s preference and the patient’s status. Oral rifampicin has excellent bioavailabilty with oral administration achieving comparable plasma concentrations to the intravenous route. Therefore, provided a patient can swallow safely, most physicians will elect to use rifampicin orally. We anticipated around 90% of doses would be given by mouth. Patients may start taking IV rifampicin and then move to the oral formulation when they could swallow safely. It is important, however, to allow intravenous administration to very sick patients who may not be able to swallow or absorb tablets. Additional intravenous catheters were not required to administer the study drug as standard antibiotic therapy (with a beta-lactam or glycopeptide) is always given intravenously.

    Number of subjects in period 1
    Placebo Rifampicin
    Started
    388
    370
    Completed
    360
    333
    Not completed
    28
    37
         Consent withdrawn by subject
    7
    15
         Lost to follow-up
    21
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Treatment with placebo for 14 days from randomisation (oral and/or IV according to patient status) (plus standard backbone antibiotic therapy as chosen by the physician):  Placebo oral 300 mg capsules containing cellulose  Standard saline for intravenous injection Additional intravenous catheters were not required to administer the study drug as standard antibiotic therapy (with a beta-lactam or glycopeptide) is always given intravenously. The dose of placebo was prescribed according to the patient’s weight:  those <60kg received 600mg every 24h  those ≥60kg received 900mg every 24h Oral doses could be given once or twice daily, according to clinician and patient preference. If taken twice daily, 900mg daily (3 capsules) was taken as unequal divided doses (600mg am, 300mg pm). The study treatment was given for 14 days, unless fewer than 14 days of standard antibiotic therapy was planned, in which case placebo was given until standard antibiotic treatment ended.

    Reporting group title
    Rifampicin
    Reporting group description
    Active treatment with rifampicin for 14 days from randomisation (oral and/or IV according to patient status) (plus standard antibiotic):  Rifampicin oral 300 mg capsules  Rifampicin 600 mg for intravenous injection Additional intravenous catheters were not required to administer the study drug as standard antibiotic therapy is always given intravenously. The dose of rifampicin was prescribed according to the patient’s weight:  those <60kg received 600mg every 24h  those ≥60kg received 900mg every 24h Oral doses could be given once or twice daily, according to clinician and patient preference. If taken twice daily, 900mg daily (3 capsules) was taken as unequal divided doses (600mg am, 300mg pm): as rifampicin can also be taken once daily, this provided adequate exposure. The study treatment was given for 14 days, unless fewer than 14 days of standard antibiotic therapy was planned, in which case rifampicin was given until standard antibiotic treatment ended.

    Reporting group values
    Placebo Rifampicin Total
    Number of subjects
    388 370 758
    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)
    185 191 376
        From 65-84 years
    166 147 313
        85 years and over
    37 32 69
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    66 (51 to 76) 64 (49 to 76) -
    Gender categorical
    Units: Subjects
        Female
    142 121 263
        Male
    246 249 495
    Mode of acquisition of infection
    Units: Subjects
        Community acquired
    240 245 485
        Nosocomial infection (onset >=48h after admission)
    76 56 132
        Healthcare associated (all other)
    72 68 140
        Not recorded
    0 1 1
    Was the patient admitted to ITU before enrolment?
    Units: Subjects
        No
    352 335 687
        Yes
    36 34 70
        Not recorded
    0 1 1
    Was the patient transferred from another hospital?
    Units: Subjects
        No
    358 343 701
        Yes - date known
    30 26 56
        Yes - date not known
    0 1 1
    S. aureus isolated from blood within the 12 weeks preceding this episode
    Units: Subjects
        No
    364 355 719
        Yes
    5 5 10
        Not recorded
    19 10 29
    Intention to give IV study drug
    Units: Subjects
        No
    325 305 630
        Yes
    63 64 127
        Not recorded
    0 1 1
    Likely portal of entry
    Incorporating any changes of opinion of the Infectious Diseases physician since Day 0. Although this includes post-baseline information, the most meaningful categorisation is the one closest to the truth and this includes some post-baseline information
    Units: Subjects
        Skin/soft tissue infection unrelated to surgery
    131 124 255
        Infected surgical wound within last 3 months
    19 19 38
        Peripheral vascular catheter (inc. arterial line)
    23 26 49
        Central vascular catheter (including PICC line)
    50 42 92
        Other implanted vascular device
    15 12 27
        Respiratory
    16 13 29
        Per-urethral urinary catheter
    6 6 12
        Supra-pubic urinary catheter
    1 2 3
        Urological surgery within 1 week of bacteraemia
    1 3 4
        Not known (absence of any of the above)
    110 108 218
        Other
    14 14 28
        Not recorded
    2 1 3
    Active intravenous drug use
    Units: Subjects
        No
    342 326 668
        Yes
    41 42 83
        Not recorded
    5 2 7
    End stage renal disease having peritoneal dialysis
    Units: Subjects
        No
    384 368 752
        Yes
    4 1 5
        Not recorded
    0 1 1
    End stage renal disease having haemodialysis
    Units: Subjects
        No
    347 336 683
        Yes
    40 33 73
        Not recorded
    1 1 2
    Systemic corticosteroid therapy
    Units: Subjects
        No
    381 363 744
        Yes
    6 5 11
        Not recorded
    1 2 3
    Neutropenia
    Units: Subjects
        No
    381 362 743
        Yes
    6 7 13
        Not recorded
    1 1 2
    Currently receiving anti-neoplastic chemotherapy
    Units: Subjects
        No
    374 349 723
        Yes
    14 20 34
        Not recorded
    0 1 1
    Any other immune suppressive therapy?
    Units: Subjects
        No
    362 352 714
        Yes
    22 17 39
        Not recorded
    4 1 5
    Organ or marrow transplant
    Units: Subjects
        No
    381 362 743
        Yes
    7 6 13
        Not recorded
    0 2 2
    Any surgery in 30 days before blood culture?
    Units: Subjects
        No
    335 331 666
        Yes
    53 37 90
        Not recorded
    0 2 2
    Vascular catheter in situ at time of bacteraemia?
    Units: Subjects
        No
    278 275 553
        Yes
    102 89 191
        Not recorded
    8 6 14
    BMI
    Not recorded for 11 placebo subjects, 10 rifampicin.
    Units: kilogram(s)/square meter
        median (inter-quartile range (Q1-Q3))
    26.4 (22.6 to 31.2) 26.3 (22.5 to 30.7) -
    Time between drawing of first positive blood culture and randomisation
    Units: day
        median (inter-quartile range (Q1-Q3))
    3.0 (2.0 to 3.0) 3.0 (2.0 to 4.0) -
    Number of days between admission to current hospital and randomisation
    Units: day
        median (inter-quartile range (Q1-Q3))
    3.0 (3.0 to 6.0) 3.0 (2.0 to 5.0) -
    Time between first new symptom caused by S. aureus and randomisation
    Not recorded for 1 placebo subject, 3 rifampicin.
    Units: day
        median (inter-quartile range (Q1-Q3))
    4.0 (3.0 to 6.0) 4.0 (3.0 to 6.0) -
    CRP measured closest to first positive culture
    Mean (standard deviation) estimated using normal interval regression to account for values above limit of quantification in one centre (that is, CRP only reported as >156 mg/L if above this threshold). Not recorded for 2 placebo subjects.
    Units: milligram(s)/litre
        arithmetic mean (standard deviation)
    173 ± 111.5 167 ± 103.8 -
    White cell count measured closest to first positive culture
    Not recorded for 3 placebo subjects, 1 rifampicin.
    Units: 10^9/L
        median (inter-quartile range (Q1-Q3))
    10.1 (7.1 to 14.2) 9.9 (7.3 to 14.3) -
    Neutrophil count measured closest to first positive culture
    Not recorded for 5 placebo subjects.
    Units: 10^9/L
        median (inter-quartile range (Q1-Q3))
    8.2 (5.1 to 12.0) 7.9 (5.4 to 12.2) -
    Lymphocyte count measured closest to first positive culture
    Not recorded for 5 placebo subjects, 1 rifampicin.
    Units: 10^9/L
        median (inter-quartile range (Q1-Q3))
    1.0 (0.6 to 1.4) 0.8 (0.6 to 1.3) -
    CRP at randomisation
    Mean (standard deviation) estimated using normal interval regression to account for values above limit of quantification in one centre (that is, CRP only reported as >156 mg/L if above this threshold). Not recorded for 2 placebo subjects, 1 rifampicin.
    Units: milligram(s)/litre
        arithmetic mean (standard deviation)
    163 ± 101.9 166 ± 101.2 -
    White cell count at randomisation
    Not recorded for 3 placebo subjects, 3 rifampicin.
    Units: 10^9/L
        median (inter-quartile range (Q1-Q3))
    9.5 (6.7 to 13.4) 9.5 (7.1 to 13.1) -
    Neutrophil count at randomisation
    Not recorded for 5 placebo subjects, 1 rifampicin.
    Units: 10^9/L
        median (inter-quartile range (Q1-Q3))
    7.3 (4.7 to 11.0) 7.4 (4.9 to 10.7) -
    Lymphocyte count at randomisation
    Not recorded for 5 placebo subjects, 2 rifampicin.
    Units: 10^9/L
        median (inter-quartile range (Q1-Q3))
    1.0 (0.7 to 1.5) 1.0 (0.7 to 1.5) -
    Charlson comorbidity index score
    Not recorded for 1 rifampicin subject.
    Units: Charlson comorbidity index score
        median (inter-quartile range (Q1-Q3))
    2 (0 to 3) 1 (0 to 3) -
    Sepsis related organ failure assessment (SOFA) score
    Not recorded for 68 placebo subjects, 50 rifampicin.
    Units: SOFA score
        median (inter-quartile range (Q1-Q3))
    2.0 (1.0 to 4.0) 2.0 (1.0 to 4.0) -
    Days between first new symptom caused by S. aureus and starting active antibiotics
    Not recorded for 1 placebo subject, 3 rifampicin.
    Units: day
        median (inter-quartile range (Q1-Q3))
    1 (0 to 3) 1 (0 to 3) -
    Duration of active antibiotic therapy before randomisation
    Units: day
        median (inter-quartile range (Q1-Q3))
    2.6 (1.8 to 3.1) 2.5 (1.7 to 3.2) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Treatment with placebo for 14 days from randomisation (oral and/or IV according to patient status) (plus standard backbone antibiotic therapy as chosen by the physician):  Placebo oral 300 mg capsules containing cellulose  Standard saline for intravenous injection Additional intravenous catheters were not required to administer the study drug as standard antibiotic therapy (with a beta-lactam or glycopeptide) is always given intravenously. The dose of placebo was prescribed according to the patient’s weight:  those <60kg received 600mg every 24h  those ≥60kg received 900mg every 24h Oral doses could be given once or twice daily, according to clinician and patient preference. If taken twice daily, 900mg daily (3 capsules) was taken as unequal divided doses (600mg am, 300mg pm). The study treatment was given for 14 days, unless fewer than 14 days of standard antibiotic therapy was planned, in which case placebo was given until standard antibiotic treatment ended.

    Reporting group title
    Rifampicin
    Reporting group description
    Active treatment with rifampicin for 14 days from randomisation (oral and/or IV according to patient status) (plus standard antibiotic):  Rifampicin oral 300 mg capsules  Rifampicin 600 mg for intravenous injection Additional intravenous catheters were not required to administer the study drug as standard antibiotic therapy is always given intravenously. The dose of rifampicin was prescribed according to the patient’s weight:  those <60kg received 600mg every 24h  those ≥60kg received 900mg every 24h Oral doses could be given once or twice daily, according to clinician and patient preference. If taken twice daily, 900mg daily (3 capsules) was taken as unequal divided doses (600mg am, 300mg pm): as rifampicin can also be taken once daily, this provided adequate exposure. The study treatment was given for 14 days, unless fewer than 14 days of standard antibiotic therapy was planned, in which case rifampicin was given until standard antibiotic treatment ended.

    Primary: Bacteriological failure

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    End point title
    Bacteriological failure
    End point description
    In the protocol, bacteriological failure is defined as death or microbiologically confirmed treatment failure or disease recurrence. Microbiologically confirmed treatment failure is defined as symptoms and signs of infection for longer than 14 days from randomisation with the isolation of the same strain of S. aureus (confirmed by genotyping) from a sterile site. Disease recurrence is defined as the isolation of the same strain of S. aureus from a sterile site after at least 7 days of apparent clinical improvement. The same strain will be defined as one with the same genotype by multi-locus sequence and spa-typing. Because of failure to locate bacteriological isolates/missing samples, the primary analysis of the primary endpoint includes all bacteriological failures/recurrences confirmed by the Endpoint Review Committee and a secondary analysis counts as events only those with samples and the same genotype by whole genome sequencing and spa-typing (or who died).
    End point type
    Primary
    End point timeframe
    Up to 12 weeks from randomisation.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: Subjects
        Died without suffering bacteriological failure
    50
    55
        Suffered bacteriological failure
    21
    7
    Attachments
    Kaplan-Meier curves
    Statistical analysis title
    Logrank test (unstratified) (primary analysis)
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.81
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Logrank test (stratified by site) (2ndry analysis)
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.77
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Cox model (unstratified) (primary analysis)
    Statistical analysis description
    Hazard ratio is for Rifampicin v Placebo (i.e. a hazard ratio of more than one implies a greater hazard in the Rifampicin group).
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.81
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    1.35
    Statistical analysis title
    Cox model (stratified by site) (2ndry analysis)
    Statistical analysis description
    Hazard ratio is for Rifampicin v Placebo.
    Comparison groups
    Rifampicin v Placebo
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.77
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    1.34
    Statistical analysis title
    Logrank test (unstratified) (sensitivity analysis)
    Statistical analysis description
    Counting as events only those with samples and the same genotype by whole genome sequencing and spa-typing (or who died).
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.79
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Logrank test (stratified by site) (sensitivity)
    Statistical analysis description
    Counting as events only those with samples and the same genotype by whole genome sequencing and spa-typing (or who died).
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.87
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Cox model (unstratified) (sensitivity analysis)
    Statistical analysis description
    Counting as events only those with samples and the same genotype by whole genome sequencing and spa-typing (or who died). Hazard ratio is for Rifampicin v Placebo.
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.79
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    1.5
    Statistical analysis title
    Cox model (stratified by site) (sensitivity)
    Statistical analysis description
    Counting as events only those with samples and the same genotype by whole genome sequencing and spa-typing (or who died). Hazard ratio is for Rifampicin v Placebo.
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.87
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    1.48

    Secondary: All-cause mortality to 2 weeks

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    End point title
    All-cause mortality to 2 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 2 weeks from randomisation.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: Subjects
        All-cause mortality to 2 weeks
    17
    25
    Statistical analysis title
    Logrank test (unstratified) (primary analysis)
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.13
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Logrank test (stratified by site) (2ndry analysis)
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.18
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Cox model (unstratified) (primary analysis)
    Statistical analysis description
    Hazard ratio is for Rifampicin v Placebo.
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    2.95
    Statistical analysis title
    Cox model (stratified by site) (2ndry analysis)
    Statistical analysis description
    Hazard ratio is for Rifampicin v Placebo.
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.18
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    2.82

    Secondary: All-cause mortality to 12 weeks

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    End point title
    All-cause mortality to 12 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks from randomisation.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: Subjects
        All-cause mortality to 12 weeks
    56
    56
    Attachments
    Kaplan-Meier curves
    Statistical analysis title
    Logrank test (unstratified) (primary analysis)
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Logrank test (stratified by site) (2ndry analysis)
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.77
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Cox model (unstratified) (primary analysis)
    Statistical analysis description
    Hazard ratio is for Rifampicin v Placebo.
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.61
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.6
    Statistical analysis title
    Cox model (stratified by site) (2ndry analysis)
    Statistical analysis description
    Hazard ratio is for Rifampicin v Placebo.
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.77
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    1.53

    Secondary: Clinical failure

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    End point title
    Clinical failure
    End point description
    Clinical failure is defined as death, treatment failure or disease recurrence (whether or not microbiologically confirmed).
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks from randomisation.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: Subjects
        Died without suffering clinical failure
    38
    45
        Suffered clinical failure
    48
    31
    Attachments
    Kaplan-Meier curves
    Statistical analysis title
    Logrank test (unstratified) (primary analysis)
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.84
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Logrank test (stratified by site) (2ndry analysis)
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.78
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    Cox model (unstratified) (primary analysis)
    Statistical analysis description
    Hazard ratio is for Rifampicin v Placebo.
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.84
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.32
    Statistical analysis title
    Cox model (stratified by site) (2ndry analysis)
    Statistical analysis description
    Hazard ratio is for Rifampicin v Placebo.
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.78
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.31

    Secondary: Development of rifampicin resistant S. aureus

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    End point title
    Development of rifampicin resistant S. aureus
    End point description
    This endpoint is only applicable to the subset of patients with S. aureus susceptible to rifampicin at randomisation (as the underlying hypothesis is that rifampicin may improve outcomes by increasing the rate of early bacterial killing, results of in vitro sensitivity testing were not required before randomisation).
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks from randomisation.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: Subjects
        Not developed rifampicin resistant S. aureus
    388
    368
        Developed rifampicin resistant S. aureus
    0
    2
    Attachments
    Cumulative incidence
    Statistical analysis title
    Analysis
    Statistical analysis description
    Risk difference is for Rifampicin - Placebo.
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.24
    Method
    Fisher exact
    Parameter type
    Risk difference (%)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    1.3

    Secondary: Serious adverse events

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    End point title
    Serious adverse events
    End point description
    Safety analyses include all subjects, regardless of whether or not study drug was actually received. Non-fatal events related to S. aureus bacteraemia are not considered SAEs.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks from randomisation.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: Subjects
        Number of subjects with one or more SAE
    94
    101
    Attachments
    Kaplan-Meier curves
    Statistical analysis title
    Time to first serious adverse event
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.17
    Method
    Logrank
    Confidence interval

    Secondary: Grade 3 and 4 adverse events

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    End point title
    Grade 3 and 4 adverse events
    End point description
    Safety analyses include all subjects, regardless of whether or not study drug was actually received. Non-fatal events related to S. aureus bacteraemia are not considered AEs.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks from randomisation.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: Subjects
        Number of subjects with one or more grade 3/4 AE
    131
    129
    Attachments
    Kaplan-Meier curves
    Statistical analysis title
    Time to first grade 3 or 4 adverse event
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.36
    Method
    Logrank
    Confidence interval

    Secondary: Drug-modifying adverse events

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    End point title
    Drug-modifying adverse events
    End point description
    Safety analyses include all subjects, regardless of whether or not study drug was actually received. A drug-modifying adverse event is defined by a stop or other change (e.g. dose) of antibiotic treatment (study drug or other antibiotic) that is due to an adverse event. Death and discontinuation of active antibiotic therapy for the current infection treated as competing risks.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks from randomisation.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: Subjects
        Number of subjects with one or more event
    39
    63
    Attachments
    Cumulative incidence
    Statistical analysis title
    Time to first drug-modifying adverse event
    Statistical analysis description
    Death and discontinuation of active antibiotic therapy for the current infection treated as competing risks.
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    Subhazard regression
    Confidence interval

    Secondary: CRP

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    End point title
    CRP
    End point description
    Mean (standard deviation) estimated using normal interval regression to account for values above limit of quantification in one centre (that is, CRP only reported as >156 mg/L if above this threshold).
    End point type
    Secondary
    End point timeframe
    Assessments were scheduled on days 0, 3, 10 and 14. Means (standard deviations) below are for day 3. Respective values for day 10 are: placebo 56.7 (56.32), rifampicin 70.2 (66.81); day 14 51.4 (49.15), 73.2 (75.60). Numbers with information as per chart.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: milligram(s)/litre
        arithmetic mean (standard deviation)
    90.7 ± 73.87
    100.5 ± 82.59
    Attachments
    Mean CRP
    Statistical analysis title
    CRP
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [1]
    Method
    Normal generalized linear regression GEE
    Confidence interval
    Notes
    [1] - Change in CRP from baseline was analysed using a normal generalized linear regression model (using GEE) for a global test of difference between treatment groups across days 3, 10, 14 (independent correlation structure).

    Secondary: Bilirubin

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    End point title
    Bilirubin
    End point description
    End point type
    Secondary
    End point timeframe
    Assessments were scheduled on days 0, 3 and 10. Means (standard deviations) below are for day 3. Respective values for day 10 are: placebo 6.7 (6.98), rifampicin 11.0 (12.12). Numbers with information as per chart.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: micromole(s)/litre
        arithmetic mean (standard deviation)
    8.1 ± 9.24
    18.1 ± 16.70
    Attachments
    Mean bilirubin
    Statistical analysis title
    Bilirubin
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Generalized linear regression GEE
    Confidence interval
    Notes
    [2] - Change in bilirubin from baseline was analysed using a normal generalized linear regression model (using GEE) for a global test of difference between treatment groups across days 3, 10 (independent correlation structure).

    Secondary: ALT

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    End point title
    ALT
    End point description
    End point type
    Secondary
    End point timeframe
    Assessments were scheduled on days 0, 3 and 10. Means (standard deviations) below are for day 3. Respective values for day 10 are: placebo 23.9 (19.85), rifampicin 23.3 (19.41). Numbers with information as per chart.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: international unit(s)/litre
        arithmetic mean (standard deviation)
    43.4 ± 59.51
    38.4 ± 40.27
    Attachments
    Mean ALT
    Statistical analysis title
    ALT
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.18 [3]
    Method
    Normal generalized linear regression GEE
    Confidence interval
    Notes
    [3] - Change in ALT from baseline was analysed using a normal generalized linear regression model (using GEE) for a global test of difference between treatment groups across days 3, 10 (independent correlation structure).

    Secondary: ALP

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    End point title
    ALP
    End point description
    End point type
    Secondary
    End point timeframe
    Assessments were scheduled on days 0, 3 and 10. Means (standard deviations) below are for day 3. Respective values for day 10 are: placebo 140.8 (108.60), rifampicin 144.9 (98.51). Numbers with information as per chart.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: international unit(s)/litre
        arithmetic mean (standard deviation)
    166.9 ± 254.95
    154.0 ± 136.57
    Attachments
    Mean ALP
    Statistical analysis title
    ALP
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.11 [4]
    Method
    Normal generalized linear regression GEE
    Confidence interval
    Notes
    [4] - Change in ALP from baseline was analysed using a normal generalized linear regression model (using GEE) for a global test of difference between treatment groups across days 3, 10 (independent correlation structure).

    Secondary: Duration of bacteraemia

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    End point title
    Duration of bacteraemia
    End point description
    End point type
    Secondary
    End point timeframe
    Only applicable to the subset of patients with repeated blood cultures following randomisation. Numbers below are for day 3. Respective values for day 7 are: placebo 245 not bacteraemic, 1 bacteraemic; rifampicin 211 not bacteraemic, 3 bacteraemic.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: Subjects
        Not bacteraemic
    254
    243
        Bacteraemic
    12
    7
    Attachments
    Proportions bacteraemic over time
    Statistical analysis title
    Duration of bacteraemia
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.66 [5]
    Method
    GEE with logistic link
    Confidence interval
    Notes
    [5] - The proportion of patients who were bacteraemic over time was analysed using generalized estimating equations (GEE) with a logistic link for a global test of difference between treatment groups over time (independent correlation structure).

    Secondary: Interactions between other medications and study drug

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    End point title
    Interactions between other medications and study drug
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 2 weeks from randomisation.
    End point values
    Placebo Rifampicin
    Number of subjects analysed
    388
    370
    Units: Subjects
        No
    366
    325
        Yes
    6
    24
        Not recorded
    16
    21
    Statistical analysis title
    Analysis
    Comparison groups
    Placebo v Rifampicin
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005
    Method
    Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 12 weeks from randomisation.
    Adverse event reporting additional description
    Safety analyses include all subjects, regardless of whether or not study drug was actually received. Non-fatal events related to S. aureus bacteraemia are not considered AEs/SAEs.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Rifampicin
    Reporting group description
    -

    Serious adverse events
    Placebo Rifampicin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    94 / 388 (24.23%)
    101 / 370 (27.30%)
         number of deaths (all causes)
    56
    56
         number of deaths resulting from adverse events
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    2 / 388 (0.52%)
    4 / 370 (1.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (inc cysts and polyps)
         subjects affected / exposed
    7 / 388 (1.80%)
    11 / 370 (2.97%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 12
         deaths causally related to treatment / all
    0 / 5
    0 / 8
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    12 / 388 (3.09%)
    11 / 370 (2.97%)
         occurrences causally related to treatment / all
    0 / 12
    2 / 11
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    2 / 388 (0.52%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisining and procedural complications
         subjects affected / exposed
    5 / 388 (1.29%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Investigations
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    13 / 388 (3.35%)
    5 / 370 (1.35%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 6
         deaths causally related to treatment / all
    0 / 3
    0 / 6
    Congenital, familial and genetic disorders
    Congenital, familial and genetic disorders
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    1 / 388 (0.26%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    12 / 388 (3.09%)
    6 / 370 (1.62%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    5 / 388 (1.29%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    7 / 388 (1.80%)
    10 / 370 (2.70%)
         occurrences causally related to treatment / all
    0 / 7
    2 / 12
         deaths causally related to treatment / all
    0 / 2
    0 / 5
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    0 / 388 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    4 / 388 (1.03%)
    10 / 370 (2.70%)
         occurrences causally related to treatment / all
    0 / 4
    3 / 10
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    1 / 388 (0.26%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    1 / 388 (0.26%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    39 / 388 (10.05%)
    37 / 370 (10.00%)
         occurrences causally related to treatment / all
    2 / 40
    0 / 38
         deaths causally related to treatment / all
    0 / 34
    0 / 33
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo Rifampicin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 388 (14.95%)
    66 / 370 (17.84%)
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    5 / 388 (1.29%)
    2 / 370 (0.54%)
         occurrences all number
    5
    2
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 370 (0.27%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
         subjects affected / exposed
    2 / 388 (0.52%)
    1 / 370 (0.27%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    1 / 388 (0.26%)
    4 / 370 (1.08%)
         occurrences all number
    1
    4
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    3 / 388 (0.77%)
    4 / 370 (1.08%)
         occurrences all number
    3
    5
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 370 (0.27%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    2 / 388 (0.52%)
    4 / 370 (1.08%)
         occurrences all number
    2
    4
    Investigations
    Investigations
         subjects affected / exposed
    6 / 388 (1.55%)
    11 / 370 (2.97%)
         occurrences all number
    6
    15
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    2 / 388 (0.52%)
    2 / 370 (0.54%)
         occurrences all number
    2
    2
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    2 / 388 (0.52%)
    4 / 370 (1.08%)
         occurrences all number
    2
    4
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    5 / 388 (1.29%)
    5 / 370 (1.35%)
         occurrences all number
    5
    5
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    6 / 388 (1.55%)
    3 / 370 (0.81%)
         occurrences all number
    8
    3
    Eye disorders
    Eye disorders
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 370 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    17 / 388 (4.38%)
    23 / 370 (6.22%)
         occurrences all number
    20
    30
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    0 / 388 (0.00%)
    3 / 370 (0.81%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    5 / 388 (1.29%)
    7 / 370 (1.89%)
         occurrences all number
    5
    7
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    6 / 388 (1.55%)
    4 / 370 (1.08%)
         occurrences all number
    6
    4
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    2 / 388 (0.52%)
    0 / 370 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    3 / 388 (0.77%)
    1 / 370 (0.27%)
         occurrences all number
    3
    2
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    12 / 388 (3.09%)
    8 / 370 (2.16%)
         occurrences all number
    12
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jun 2013
    (i) Remove King’s College London (KCL) as Co-Sponsor, and (ii) Add four new trial sites.
    14 Aug 2014
    Addition of substudy – Experiences of being approached for trial participation, the consenting process and trial participation.
    01 Oct 2015
    Sample size reduced and co-primary endpoint (all cause mortality up to 14 days) reassigned as a secondary endpoint at the request of the funder

    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/23249501
    http://www.ncbi.nlm.nih.gov/pubmed/29249276
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