E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Spontaneous bacterial peritonitis infection in patients with advanced liver disease |
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E.1.1.1 | Medical condition in easily understood language |
Spontaneous bacterial peritonitis infection in patients with advanced liver disease |
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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 | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10061135 |
E.1.2 | Term | Spontaneous bacterial peritonitis |
E.1.2 | System Organ Class | 100000004862 |
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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 |
The primary objective is to determine whether primary antibiotic prophylaxis with co-trimoxazole reduces the incidence of spontaneous bacterial peritonitis compared to placebo in adults with cirrhosis and ascites. The time to first incidence of spontaneous bacterial peritonitis up to 24 months following randomisation will be measured. |
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E.2.2 | Secondary objectives of the trial |
The following will be measured up to 24 months from randomisation: 1. All-cause mortality 2. Hospital admission with incidence of spontaneous bacterial peritonitis 3. Hospital admission rates 4. Hospital admission with incidence of C. difficile-associated diarrhoea 5. Documented incidence of antimicrobial resistance defined as infections during hospital admission with bacteria resistant to standard antibiotic treatment 6. Other infections including respiratory tract, urinary tract, cellulitis, bacteraemia, cerebral infections and infections with uncertain sources 7. Other cirrhosis related events (e.g. variceal haemorrhage) 8. Complications relating to SBP including Intensive Care Unit admission and renal dysfunction with creatinine >133 µmol/L (1.5mg/dL) at any point during hospital admission 9. Incidence of liver transplantation 10. Progression of liver disease assessed by Model for End-Stage Liver Disease (MELD) score. The MELD score is a scoring system for assessing the severit |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria: 1. Patients with liver cirrhosis and ascites with ascitic fluid protein count <2.0 g/dL (from sample taken within 12 weeks prior to randomisation) 2. Patients with ascitic polymorphonuclear count <250 cells/mm3 and negative microbial culture at 5 days (on the last sample sent within 12 weeks prior to randomisation) 3. Patient at least 18 years of age 4. Documented informed consent to participate
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E.4 | Principal exclusion criteria |
Exclusion criteria: 1. Patients with previous Spontaneous Bacterial Peritonitis (SBP) 2. Patients receiving palliative care with an expected life expectancy of <8 weeks 3. Allergic to co-trimoxazole, trimethoprim or sulphonamides 4. Pregnant or lactating mothers 5. Patient enrolled in a clinical trial of investigational medicinal products (IMPs) that would impact on their participation in the study 6. Patients with persistent hyperkalaemia (>6.5 mmol/L) related to pre-existing kidney disease that is not possible to reduce 7. Patients receiving antibiotic prophylaxis (except for rifaximin) 8. Patients with long-term ascites drains 9. Women of child bearing potential and males with a partner of child bearing potential without effective contraception for the duration of trial treatment; 10. Severe thrombocytopaenia defined as platelets <30 x109/L 11. Any clinical condition which the investigator considers would make the patient unsuitable for the trial |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome will be the difference in the time to the first incidence of spontaneous bacterial peritonitis (SBP) infecion
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
24 months following randomisation |
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E.5.2 | Secondary end point(s) |
1. All-cause mortality 2. Hospital admission with incidence of spontaneous bacterial peritonitis 3. Hospital admission rates 4. Hospital admission with incidence of C. difficile-associated diarrhoea 5. Documented incidence of antimicrobial resistance defined as infections during hospital admission with bacteria resistant to standard antibiotic treatment. 6. Other infections including respiratory tract, urinary tract, cellulitis, bacteraemia, cerebral infections and infections with uncertain sources 7. Other cirrhosis related events (e.g. variceal haemorrhage) 8. Complications relating to SBP including ICU admission and renal dysfunction with creatinine >133 μmol/L (1.5mg/dL) at any point during hospital admission 9. Incidence of liver transplantation 10. Progression of liver disease assessed by MELD score 11. Safety and treatment-related adverse events 12. Treatment adherence (assessed at dispensing) 13. Health-related quality of life assessed using EQ-5D-5L questionnaire 14. Health and social care resource use assessed using Hospital Episode Statistics (HES) database 15. Mean incremental cost per quality adjusted life year gained (QALY) 16. Resolution of ascites with diuretic treatment not required for 6 months
All the above outcomes are assessed up to 24 months following randomisation. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
As per protocol.
Visit 1 - Month 0 Visit 3 - Month 1 Visit 4 - Month 3 Visit 5 - Mont 6 Visit 7 - Month 12 Visit 8 - Month 15 Visit 9 - Month 18 Visit 10 - Month 21 Visit 11 - Month 24 |
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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 | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
E.6.13 | Others | No |
E.6.13.1 | Other scope of the trial description |
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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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | No |
E.8.1.4 | Double blind | Yes |
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 | 30 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 0 |
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 | No |
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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The end of the trial for individual participants will be the date of last subject last visit (LSLV). Trial closure is defined as the date when all data has been received, cleaned and all queries resolved at all sites. |
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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 | 5 |
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 | 5 |
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 |