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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
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
|
|
|||||||||||||||||||
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.
|
||||||||||||||||||
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
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. |
|
||||||||||||||||
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.
|
|||||||||||||||
|
||||||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
||||||||||||||||
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.
|
|||||||||||||||
|
||||||||||||||||
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 |
|
||||||||||||||||
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.
|
|||||||||||||||
|
||||||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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 |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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). |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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). |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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). |
|
|||||||||||||
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.
|
||||||||||||
|
|||||||||||||
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). |
|
||||||||||||||||
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.
|
|||||||||||||||
|
||||||||||||||||
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). |
|
|||||||||||||||||||
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.
|
||||||||||||||||||
|
|||||||||||||||||||
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 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 |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
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 |