E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Infection of the blood caused by the Staphylococcus aureus bug |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058887 |
E.1.2 | Term | Staphylococcus aureus bacteremia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054638 |
E.1.2 | Term | Staphylococcus aureus septicemia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058863 |
E.1.2 | Term | Staphylococcus aureus bacteraemia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10041943 |
E.1.2 | Term | Staphylococcus aureus septicaemia |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058867 |
E.1.2 | Term | Methicillin-resistant staphylococcal aureus sepsis |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Does the addition of 14 days rifampicin to initial standard antibiotic therapy reduce (i) all-cause mortality through 14 days and (ii) bacteriological failure/death through 12 weeks from randomisation in adults with Staphylococcus aureus bacteraemia? |
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E.2.2 | Secondary objectives of the trial |
1. To determine whether rifampicin reduces the duration bacteria survive in the blood, and reduces treatment failure and death by 12 weeks from randomisation. 2. To determine the incidence of rifampicin-related drug toxicity, clinically significant interactions with other drugs, and the development of rifampicin resistant bacteria. 3. To estimate the costs of S. aureus bacteraemia treatment within the NHS, and the and cost-effectiveness of additional rifampicin. 4. To define the relationship between plasma concentrations of the common standard antibiotics (flucoloxacillin and vancomycin) and rifampicin in individual patients and their clinical effect. 5. To determine whether the genetic make-up of the bacteria or the patients influences the clinical outcome from the infection. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study 1 (version 1.0). A population pharmacokinetic (PK) and pharmacodynamic (PD) study of rifampicin, flucloxacillin and vancomycin for the treatment of S. aureus bacteraemia. Our aim is to determine the pharmacological parameters of rifampicin which best predict treatment success and provide a rational basis from which optimal dose, frequency, and route of administration can be modelled statistically and/or explored in future studies. If the trial results are negative, these data will be able to identify whether this is because of issues with the dosing schedule or the susceptibility of the bacteria, or both. If results are positive, these data will identify whether greater benefits could be achieved, either overall or in some groups of patients (personalised medicine). Necessarily, the study will also include PK models of the primary antibiotic treatment given with rifampicin (flucloxacillin or vancomycin); comparison of the PK/PD parameters between the control and rifampicin-treated groups will determine the relative contributions rifampicin makes to patients treated with either flucloxcillin or vancomycin. Sub-study 2 (version 1.0). The influence of host and bacterial genetics on disease severity and outcome from S. aureus bacteraemia. Our aim is to identify host and bacterial genetic factors which influence disease severity (for example, the development of metastatic complications) and poor outcome from S. aureus bacteraemia. The well-characterised patients enrolled into the trial provide a unique opportunity to assess these factors and thereby provide important insights into disease pathogenesis which may benefit patients in the future. Additional consent will be sought to extract and store DNA from each participant and their infecting bacteria for these investigations. Bacteria genetic variation will be assessed by multi-locus sequence and spa-typing and, when greater resolution is required, whole genome sequencing. Host genetic determinants of infection phenotype will be investigated though a candidate gene approach and, if funds are obtained, whole genome association studies. These data will identify targets for future therapeutic strategies, and may also identify patients at greater or lesser risk of poor outcomes. |
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E.3 | Principal inclusion criteria |
1. Adults (18 years or older) 2. Staphylococcus aureus (meticillin-susceptible or resistant) grown from at least one blood culture 3. Less than 96 hours of active antibiotic therapy for the current infection 4. Patient or legal representative (LR) provides written informed consent |
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E.4 | Principal exclusion criteria |
1. Infection not caused by S. aureus alone in the opinion of the infection specialist (e.g. S. aureus is considered a blood culture contaminant, or polymicrobial culture with another organism likely to be contributing clinically to the current infection) 2. Sensitivity results already available and demonstrate rifampicin resistant S. aureus (defined by British Society for Antimicrobial Chemotherapy in vitro disc susceptibility testing) 3. Infection specialist considers rifampicin is contraindicated for any reason 4. Infection specialist considers rifampicin treatment is mandatory for any reason 5. Suspected active infection with Mycobacterium tuberculosis 6. Previously been randomised in ARREST for a prior episode of S. aureus bacteraemia |
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E.5 End points |
E.5.1 | Primary end point(s) |
The co-primary outcome measures are: (i) all-cause mortality through 14 days from randomisation (ii) bacteriological failure/death through 12 weeks from randomisation |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
(i) through 14 days (ii) through 12 weeks |
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E.5.2 | Secondary end point(s) |
death or clinically defined treatment failure or disease recurrence by 12 weeks (clinical failure being assessed by an independent endpoint review committee blind to the treatment allocation) duration of bacteraemia (blood cultures will be taken on days 3 and 7 following randomisation) development of rifampicin resistant S. aureus grade 3/4 adverse events serious adverse events modification of any treatment (including concomitant medications) due to drug interactions. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |