Cirrhosis, Liver
Conditions
Brief summary
In this pilot study, the investigators aim to assess feasibility of subject identification and data collection, including specimen processing, as well as the rate of enrollment for a future, larger study of the effect of empiric antibiotics for all patients with advanced cirrhosis admitted to the hospital without an existing indication for new antibiotic use. Specifically, the investigators will assess the incidence of infection after the time of enrollment and associated outcomes. Subjects will be randomly assigned to receive antibiotics vs placebo.
Detailed description
Cirrhosis is associated with a state of immune-compromise and progressive decompensation, acute on chronic liver failure (ACLF), and death are often caused by bacterial infections. Different sub-groups of patients with cirrhosis at increased risk, i.e. active upper gastrointestinal hemorrhage, low protein ascites, history of spontaneous bacterial peritonitis (SBP), are known to benefit from prophylactic antibiotics. The investigators hypothesize that hospitalized patients with advanced cirrhosis are also at increased risk and thus may benefit from preventive treatment. Subjects will be randomly assigned to receive an antibiotic vs placebo.
Interventions
DRUGCeftriaxone
Antibiotic
DRUGNormal saline
50cc intravenous once daily
Sponsors
American Association for the Study of Liver Diseases
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blinded placebo-controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* MELD-Na \>= 18 * Cirrhosis as defined by liver biopsy or a composite assessment of available results from imaging, elastography, prior records, and laboratory studies
Exclusion criteria
* Inability to obtain consent (from subject or next of kin/legal authorized representative (LAR) * Allergy to cephalosporins * Pregnancy (due to limited prospective data regarding safety of ceftriaxone) * Existing indication for new antibiotics, e.g. upper gastrointestinal hemorrhage or apparent infection * Use of major immunosuppressive medications (e.g. prednisone 20 mg/day or greater, immunosuppression for solid organ transplant) * H/o recurrent C difficile infection within the past year (\>2) or requiring fecal microbiota transplant (FMT) * Enrollment in the study protocol during a previous admission
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Infections | For 7 days or until end of hospital stay | Incident bacterial infection after enrollment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Length of Stay | Up to 30 days | Days in hospital after randomization |
| Mortality | Up to 30 days | In-hospital |
| 30-day Mortality | Up to 30-days | Includes f/u after discharge |
Other
| Measure | Time frame | Description |
|---|---|---|
| Fungal Infection | During hospital admission up to 30 days | Incident fungal infection (by culture data or requirement for new anti-fungal medication) |
| Incident C Difficile Colitis | 30 days | Positive stool toxin/PCR with new onset diarrhea |
| Biomarker of Infection | Once at time of randomization | Procalcitonin |
| Incident ACLF | During hospital admission up to 30 days | (by NACSELD) or change in CLIF-C ACLF score |
| Incident Variceal Hemorrhage | During hospital admission up to 30 days | Incident variceal hemorrhage |
| Increase in MELD-Na | Upon discharge (or at 30 days) | \>2 pts |
Countries
United States
Participant flow
Recruitment details
Enrolled inpatients only. Enrollment proceeded with intermittent interruption due to COVID pandemic.
Participants by arm
| Arm | Count |
|---|---|
| Treatment 1 gram intravenous ceftriaxone once daily for up to one week or until end of hospitalization
Ceftriaxone: Antibiotic | 17 |
| Placebo Normal saline (50cc) once daily for up to one week or until end of hospitalization
Normal saline: 50cc intravenous once daily | 15 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Treatment | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 54 years | 62 years | 59 years |
| Race/Ethnicity, Customized Hispanic/Latino | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Non-Hispanic | 13 Participants | 11 Participants | 24 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 14 Participants | 11 Participants | 25 Participants |
| Region of Enrollment United States | 17 participants | 15 participants | 32 participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 17 | 5 / 15 |
| other Total, other adverse events | 4 / 17 | 1 / 15 |
| serious Total, serious adverse events | 3 / 17 | 5 / 15 |
Outcome results
Primary
Infections
Incident bacterial infection after enrollment
Time frame: For 7 days or until end of hospital stay
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Infections | 2 Participants |
| Placebo | Infections | 5 Participants |
Secondary
30-day Mortality
Includes f/u after discharge
Time frame: Up to 30-days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | 30-day Mortality | 2 Participants |
| Placebo | 30-day Mortality | 5 Participants |
Secondary
Length of Stay
Days in hospital after randomization
Time frame: Up to 30 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment | Length of Stay | 9 days |
| Placebo | Length of Stay | 10 days |
Secondary
Mortality
In-hospital
Time frame: Up to 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Mortality | 1 Participants |
| Placebo | Mortality | 4 Participants |
Other Pre-specified
Biomarker of Infection
C-reactive protein
Time frame: Once at time of randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment | Biomarker of Infection | 9.7 mg/L |
| Placebo | Biomarker of Infection | 11.0 mg/L |
Other Pre-specified
Biomarker of Infection
Procalcitonin
Time frame: Once at time of randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment | Biomarker of Infection | 0.25 ng/mL |
| Placebo | Biomarker of Infection | 0.44 ng/mL |
Other Pre-specified
Fungal Infection
Incident fungal infection (by culture data or requirement for new anti-fungal medication)
Time frame: During hospital admission up to 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Fungal Infection | 0 Participants |
| Placebo | Fungal Infection | 0 Participants |
Other Pre-specified
Incident ACLF
(by NACSELD) or change in CLIF-C ACLF score
Time frame: During hospital admission up to 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Incident ACLF | 5 Participants |
| Placebo | Incident ACLF | 3 Participants |
Other Pre-specified
Incident C Difficile Colitis
Positive stool toxin/PCR with new onset diarrhea
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Incident C Difficile Colitis | 0 Participants |
| Placebo | Incident C Difficile Colitis | 1 Participants |
Other Pre-specified
Incident Variceal Hemorrhage
Incident variceal hemorrhage
Time frame: During hospital admission up to 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Incident Variceal Hemorrhage | 0 Participants |
| Placebo | Incident Variceal Hemorrhage | 0 Participants |
Other Pre-specified
Increase in MELD-Na
\>2 pts
Time frame: Upon discharge (or at 30 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Increase in MELD-Na | 3 Participants |
| Placebo | Increase in MELD-Na | 3 Participants |