Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04736836 |
| Other study ID # |
CL(1173) |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
January 2015 |
| Est. completion date |
June 2019 |
Study information
| Verified date |
February 2021 |
| Source |
National Hepatology & Tropical Medicine Research Institute |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Aims and Objectives: To determine the safety and efficacy of rifaximin plus lactulose as
secondary prophylaxis of HE compared to lactulose alone. To evaluate the effect of long-term
administration of rifaximin on development of resistant mutants and investigating its
correlation with its efficacy.
Methods: An open label parallel, prospective interventional study was conducted. One hundred
patients experienced at least one attack of hepatic encephalopathy were included in the
study. Patients were randomly allocated either to receive rifaximin plus lactulose or
lactulose alone for 6 months. Conn score, Model of End stage Liver Disease (MELD) score,
asterixis grade, complete blood count (CBC), liver function tests, kidney function tests,
urine and stool analysis and abdominal ultrasonography were compared in both groups. The
primary efficacy endpoint was the time to the first breakthrough. The secondary efficacy
endpoint was the time to the first hospitalization involving HE. Safety assessment was done
by reporting any adverse events, serious adverse events and by repeating biochemical
evaluation every 2 weeks. Determination of the minimum inhibitory concentration (MIC) of
rifaximin for lactose fermenter isolates was done for the entire patients before starting
treatment and at the end of treatment.
Description:
Methodology Inclusion and exclusion criteria Fully conscious patients were enrolled from the
National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo, Egypt between
January 2015 and December 2018. The inclusion criteria were cirrhosis due to HCV infection,
age 18 to 75 years, experiencing at least one episode of OHE, and a MELD score ≤ 25.13
Patients with neurological or communication problems, hepatocellular carcinoma, diabetes
mellitus, active infection, serum creatinine > 2 mg/dl, Hg < 8 g/dL, serum Na < 125 mmol/L or
serum K < 2.5 mmol/L were excluded. Patients with previous intake of rifaximin as prophylaxis
or any antibiotic within the last month were also excluded.
Study Design The protocol of this open label, parallel, prospective interventional study was
approved by the institutional review board (IRB) of NHTMRI and that of the Faculty of
Pharmacy, Cairo University (CL(1173)). All patients and/or patients' caregivers for those
with weak/impaired cognitive and/or thinking ability due to previous episode of HE were
consulted and explained for provided written informed consent before study enrolment.
The patients were randomly assigned into either intervention group (rifaximin group) or
control group (lactulose only group). Both groups received lactulose syrup 30-45 ml three
times daily while rifaximin 400 mg three times daily was added to the intervention group for
6 months. Other conventional therapy including diuretics, proton pump inhibitors,
ursodeoxycholic acid and silymarin were given to the patients in both groups according to the
hospital protocol.
Study Follow-up All recruited patients were assessed clinically and biochemically at baseline
and every 2 weeks for 6 months. Conn score, asterixis grade, complete blood picture with
differential, serum bilirubin (total and direct), serum aspartate transaminase (AST) and
alanine transaminase (ALT), alkaline phosphatase, gamma-glutamyltransferase (GGT), serum
albumin, prothrombin time and concentration, urea and serum creatinine, serum sodium (Na) and
potassium (K), urine and stool analysis were measured.
Efficacy outcomes The primary efficacy endpoint was the time to the first breakthrough
episode of OHE (defined as the time from the first dose of the study drug to an increase from
a baseline Conn score of 0 or 1 to a score of 2 or more or from a baseline Conn score of 0 to
a Conn score of 1 plus a 1-unit increase in the asterixis grade.13 The secondary efficacy
endpoint was the time to the first hospitalization involving HE (defined as hospitalization
because of the disorder or hospitalization during which an episode of HE occurred).14 The
percentage of patient's survival during the study was also considered a secondary outcome.
Safety Outcomes All recruited patients were requested to report any adverse event(s)
experienced during the study period. Clinic visits occurred every 2 weeks till end of the
treatment period. On weeks with no clinical visits, patients were followed-up by phone calls.
Rifaximin Microbial Resistance Isolation of Gram negative bacteria from clinical stool
samples Stool samples were collected from all the participants before commencing treatment
and at the end of the study. One gram of stool was suspended in 10 ml saline and vortexed
vigorously. One ml aliquot of the stool suspension was streaked on the surface of MacConkey
agar plates to isolate Gram-negative lactose-fermenters. The plates were then incubated at
37⁰C for 24 hours. Pink colonies were picked and re-streaked one more time then suspended in
30% glycerol (vol/vol) in Brain Heart Infusion broth (BHI) and stored at -80 ⁰C till further
analyses.
Determination of the minimum inhibitory concentration (MIC) of rifaximin for lactose
fermenter isolates A sequential two-fold serial dilution broth procedure was adopted
according to the Clinical and Laboratory Standards Institute (CLSI) guidelines.15 Ten
dilutions of rifaximin were prepared starting from 256 μg/ml in Muller Hinton broth (MHB) and
aliquoted in 200 μl aliquots in the wells of a round bottom 96-well plate. A control well was
included that was prepared using 200 μl MHB inoculated with 20 μl of the prepared bacterial
inoculum.
The inoculum was prepared by adjusting cells from an overnight culture to match the McFarland
standard 0.5 (OD600 = 0.125). The suspension was further diluted 1:20 in MHB and 20 μl of the
adjusted inoculum were added to each well. The plates were then incubated at 37°C for 24
hours. The experiment was repeated twice and the lowest concentration of rifaximin that
resulted in complete inhibition of visible growth represented the MIC value. The MIC values
were considered different if they differed by more than a two-fold dilution.16
