Primary Antibiotic Prophylaxis Using Co-trimoxazole to Prevent Spontaneous Bacterial Peritonitis in Cirrhosis

Study Overview
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Brief Summary
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A multicentre, interventional, double-blind, placebo-controlled, parallel-arm, phase 3, randomised controlled trial to evaluate the use of co-trimoxazole as primary prophylaxis for spontaneous bacterial peritonitis to improve overall survival

Detailed Description
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See above

Official Title
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Primary Antibiotic Prophylaxis Using Co-trimoxazole to Prevent Spontaneous Bacterial Peritonitis in Cirrhosis

Conditions
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Spontaneous Bacterial Peritonitis

Intervention / Treatment
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* Drug: Co-Trimoxazole 960Mg Dispersible Tablet
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with Child-Pugh Class B or C cirrhosis and presence of ascites requiring any diuretic treatment or at least 1 or more paracentesis within 3 months prior to enrolment. Patient at least 18 years of age Documented informed consent to participate Exclusion criteria: Patients with current or previous Spontaneous Bacterial Peritonitis (defined as ascitic polymorphonuclear (PMN) cell count >250/mm3 with either positive or negative ascitic fluid culture without evident intra-abdominal surgically treatable source of infection. A white cell count >500 cell/mm2 or positive microbial culture may be considered as evidence of previous SBP if the site PI considers this was in the context of a likely clinical diagnosis of SBP). Patients receiving palliative care with an expected life expectancy of <8 weeks Allergic to co-trimoxazole, trimethoprim or sulphonamides Pregnant or lactating mothers Patient enrolled in a clinical trial of investigational medicinal products (IMPs) that would impact on their participation in the study Patients with serum potassium (>5.5 mmol/L) related to pre-existing kidney disease which cannot be reduced* Patients receiving antibiotic prophylaxis (except for rifaximin)* Patients with long-term ascites drains* Women of child-bearing potential and males with a partner of child-bearing potential without effective contraception for the duration of trial treatment Patients with pathological blood count changes Patients with haemoglobin (Hb) <70g/L* Granulocytopenia defined as absolute neutrophil counts of less than 500 cells per microliter* Severe thrombocytopenia with a platelet count <30 x109 /L* Patients with severe renal impairment, with eGFR <15 ml/min* Patients with skin conditions: exudative erythema multiform, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug eruption with eosinophilia and systemic symptoms Patients with congenital conditions: congenital glucose-6-Phosphate dehydrogenase deficiency of the erythrocytes, haemoglobin anomalies such as Hb Köln and Hb Zürich Patients with acute porphyria Any clinical condition which the investigator considers would make the patient unsuitable for the trial. It is common for these investigations to change in patients with cirrhosis and long-term ascitic drains may be removed. Patients can be re-screened for eligibility if this occurs.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Co-trimoxazole<br>Co-trimoxazole, 960mg capsule oral tablet, to be taken daily for 18 months | Drug: Co-Trimoxazole 960Mg Dispersible Tablet<br>* Antibiotic prophylaxis of Spontaneous Bacterial Peritonitis<br>|
| Placebo Comparator: Placebo<br>Placebo, 960mg capsule oral tablet, to be taken daily for 18 months | Drug: Placebo oral tablet<br>* Placebo<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall Survival | The maximum possible period of follow up will be 48 months (assuming a recruitment period of 30 months and 18 months treatment period for final patient recruited) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spontaneous Bacterial peritonitis | Time to first incidence of spontaneous bacterial peritonitis (SBP) | Minimum period of 18 months from randomisation | 
| Hospital admissions | Hospital admission rates | Minimum period of 18 months from randomisation | 
| C. difficile-associated diarrhoea | Incidence of C. difficile-associated diarrhoea | Minimum period of 18 months from randomisation | 
| Infections other than spontaneous bacterial peritonitis with hospital admission | Incidence of infections other than spontaneous bacterial peritonitis with hospital admission. | Minimum period of 18 months from randomisation | 
| Cirrhosis related events | Incidence of other cirrhosis related events (e.g. variceal haemorrhage) | Minimum period of 18 months from randomisation | 
| Renal dysfunction | Incidence of renal dysfunction with creatinine >133 μmol/L (1.5mg/dL) at any point during hospital admission | Minimum period of 18 months from randomisation | 
| Anti-microbial resistance | Incidence of anti-microbial resistance | Minimum period of 18 months from randomisation | 
| Liver transplantation | Incidence of liver transplantation | Minimum period of 18 months from randomisation | 
| Liver disease assessed by increase in MELD score | Progression of liver disease assessed by increase in MELD score between baseline and end of trial follow up. | Minimum period of 18 months from randomisation | 
| Safety and treatment-related serious adverse events | Safety and treatment-related serious adverse events | Minimum period of 18 months from randomisation | 
| Treatment adherence | Treatment adherence (assessed by MARS questionnaire) | Minimum period of 18 months from randomisation | 
| Health-related quality of life | Health-related quality of life assessed using EQ-5D-5L questionnaire | Minimum period of 18 months from randomisation | 
| Health and social care | Health and social care resource use assessed using Hospital Episode Statistics (HES) database | Minimum period of 18 months from randomisation | 
| Mean incremental cost per quality adjusted life year gained (QALY) | Mean incremental cost per quality adjusted life year gained (QALY) | Minimum period of 18 months from randomisation | 
| Incidence of resolution of ascites with diuretic treatment not required for 6 months | Incidence of resolution of ascites with diuretic treatment not required for 6 months | Minimum period of 18 months from randomisation | 
| Transjugular intrahepatic portosystemic shunt (TIPS) insertion | Incidence of Transjugular intrahepatic portosystemic shunt (TIPS) insertion | Minimum period of 18 months from randomisation |