Trial document





This trial has been registered retrospectively.
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  DRKS00006359

Trial Description

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Title

Minimal hepatic encephalopathy (MHE) – influence of therapy with rifaximin on MHE and on the intestinal microbiome in patients with liver cirrhosis – the RiMINI-Trial

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Trial Acronym

RiMINI

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URL of the Trial

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Brief Summary in Lay Language

Primary objectives:
to compare continuous antibiotic therapy with rifaximin combined with lactulose with continuous therapy with rifaximin alone in patients with MHE concerning neurocognitive function

Secondary objectives:
to analyze the intestinal microbiome of the upper GI-tract in cirrhotic patients with minimal hepatic encephalopathy before, during and after therapy with rifaximin alone and before, during and after therapy with rifaximin combined with lactulose

60 Patients with minimal hepatic encephalopathy will receive either a treatment with continuous rifaximin or a combination of continuos rifaximin and lactulose and will be compared with respect to neurocognitive function

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Brief Summary in Scientific Language

Background

Minimal hepatic encephalopathy (MHE) is present in 30 to 84% of patients with liver cirrhosis (1). 531 patients with liver cirrhosis were treated in our department within 12 months and, based on clinical tests +/- hyperammonemia, 16,4 % ( n= 87) of these patients suffered from manifest hepatic encephalopathy. HE significantly affects neurocognitive functions leading to impaired quality of life, already if present in subclinical stages.
Diagnosis of MHE is established by psychometric tests (e.g. number connection test, figure connection test, picture completion test). Objective and sensitive methods to assess MHE are visual evoked potentials and critical flicker frequency analysis (CFF).

A continuous therapy with rifaximin in combination with lactulose significantly reduces the risk of overt HE, recurrence and HE-related hospitalisations in randomized double-blind placebo-controlled clinical trials (1-3). The drug is approved for the therapy of overt HE in Germany. A therapy with lactulose has been shown to improve cognitive functions in patients with liver cirrhosis. It has not been addressed in prospective clinical trials so far, if a monotherapy with rifaximin is as effective as a combination therapy with rifaximin and lactulose in the treatment of MHE.
Rifaximin is a minimally absorbed gut-selective antibiotic and thus impacts on gut microbiome. The role of the gut microbiome in the pathophysiology of hepatic encephalopathy is still little understood. Changes in gut microbiome of the upper gastrointestinal tract as result of therapy with rifaximin have not been addressed in clinical studies so far.


Primary objective: To compare continuous antibiotic therapy with rifaximin combined with lactulose with continuous therapy with rifaximin alone in patients with MHE concerning neurocognitive function
Secondary objective:To analyze the intestinal microbiome of the upper GI-tract in cirrhotic patients with minimal hepatic encephalopathy before, during and after therapy with rifaximin alone and before, during and after therapy with rifaximin combined with lactulose

References
(1) Bajaj JS, Saeian K, Schubert CM, et al. Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. Hepatology 2009;50:1175-83.
(2) Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362:1071-1081.
(3) Neff GW, Kemmer N, Zacharias VC, et al. Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy. Transplant Proc 2006;38:3552-3555.

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Organizational Data

  •   DRKS00006359
  •   2015/11/25
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  •   yes
  •   Approved
  •   172/14, Ethikkommission der Medizinischen Fakultät der Otto-von-Guericke-Universität Magdeburg
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Secondary IDs

  •   U1111-1163-9410 
  •   2013-004414-18 
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Health Condition or Problem studied

  •   K72.7 -  [generalization K72: Hepatic failure, not elsewhere classified]
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Interventions/Observational Groups

  •   Rifaximin 550mg 1-0-1 per os for 90 days
  •   550mg rifaximin bid 1-0-1 po for 90 days in combination with lactulose three to four times 7,5 - 15 ml up to 30-60 ml daily (to pass 2-3 semisoft stools/day) for 3 months
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   IV
  •   Yes
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Primary Outcome

Primary efficacy variable: neurocognitive function measured in CFF( Critical Flicker Test), NCT(Number Cancellation Test),VEP (Visually Evoked Potentials)


Treatment Phase (EOT):
Screening,
Visit1 after 30 days +/-3 days,
Visit 2 after 60 days +/-3 days,
Visit 3 after 90 days +/-3 days,


Follow up after 120 days:
Visit 5 6 weeks after end of Treatment (EOT)
Visit 6 12 weeks after end of Treatment (EOT) = end of study

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Secondary Outcome

Secondary efficacy variable: - EEG, quality of life and Health-Related Quality of Life (ECOG performance status and HR-QOL - EORTC QLQ C30)- changes in gut microbiome - influence of infection with H. pylori


Visite:4 120 Tagen after end of Treatment (EOT)

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2015/03/17
  •   60
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   90   Years
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Additional Inclusion Criteria

1. Male and female individuals 18 - 90 years of age at the time of enrollment who are mentally competent, willing and able to understand the nature and risks of the proposed study, and able to sign the consent form prior to study entry;
2. Individuals with a projected life expectancy of 6 months or longer;
3. Individuals who are able to comply with all study procedures and requirements;
4. Female subjects with childbearing potential who have negative pregnancy test during screening period.
5. diagnosis of liver cirrhosis, established either by histology or by typical signs in transabdominal ultrasound in combination with signs of portal hypertension (ascites, enlarged spleen, fundic or esophageal varices)
6. presence of minimal hepatic encephalopathy (MHE)

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Exclusion Criteria

Individuals with one of the following medical conditions:
1. Documented underlying allergic condition against rifaximin or lactulose
2. Underlying blindness or eye axis deviation or red- green- color- blindness
3. Individuals with a projected life expectancy of less than 6 months
4. overt hepatic encephalopathy
5. antibiotic treatment within 28 days before study entry or during the study
6. Individuals who are not in sufficient health status as determined by the outcome of medical history, physical assessment, and clinical judgment of the investigator.
7. Individuals who are not able to follow the required study procedures for the whole period of the study.
8. Individuals with behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the subject´s ability to participate in the trial.
9. Individuals who are planned to be hospitalized or undergo surgery during the study period.
10. Individuals who have participated in another clinical study within 30 days prior enrollment into the study.
11. Individuals with ongoing drug- or alcohol abuse that, in the opinion of the investigator, would interfere with the safety of the subject or the evaluation of the study objectives.
12. Individuals who are member of the research staff or have relatives who are member of the research staff.
13. Female subjects with childbearing potential who have positive pregnancy test during screening period. Female subjects no use of common contraceptive methods. Pregnant and lactating women.
14. Individuals with a medical history or any illness that may, in the opinion of the investigator, pose additional risk to the subject due to participation in the study.

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Addresses

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    • Medizinische Fakultät der Otto-von-Guericke Universität
    • Mr.  Prof. Dr. med   Hermann-Josef  Rothkötter 
    • Leipziger Str.44
    • 39218  Magdeburg
    • Germany
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    • Medizinische Fakultät der Otto-von-Guericke-Universität, Klinik für Gastroenterologie, Hepatologie und Infektiologie
    • Ms.  Dr. med.  Kerstin  Schütte 
    • Leipziger Str. 44
    • 39120  Magdeburg
    • Germany
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    • Medizinische Fakultät der Otto-von-Guericke-Universität, Klinik für Gastroenterologie, Hepatologie und Infektiologie
    • Mr.  Dr. med.  Christian  Schulz 
    • Leipziger Str. 44
    • 39120  Magdeburg
    • Germany
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Sources of Monetary or Material Support

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    • NORGINE
    • Im Schwarzenborn 4
    • 35041  Schwarzenborn
    • Germany
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Status

  •   Recruiting stopped after recruiting started
  •   2016/11/05
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Trial Publications, Results and other Documents

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