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Azithromycin in Post Diarrheal Haemolytic and Uremic Syndrome (ZITHROSHU)

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ClinicalTrials.gov Identifier: NCT02336516
Recruitment Status : Recruiting
First Posted : January 13, 2015
Last Update Posted : November 18, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:
Post diarrheal hemolytic and uremic syndrome (D+HUS) is the first etiology of acute renal failure in children less than 5 years old in France. Previous works highlighted a mortality rate of 2 % and a prevalence of renal sequelae at one year after D+HUS onset in 25 % of patients D+HUS is a consequence of a gastrointestinal infection with shiga toxin (Stx) producing E.coli (STEC). The most frequent straight is E.coli O157H7. The sequence of STEC induced HUS is now well known. Typically, digestive symptoms appear five days following STEC ingestion. STEC colonize the intestinal mucosa, adhere to the enterocyte and cause a typical attaching/effacing lesion and inflammation. Then, diarrhea and vomiting occurred. D+HUS occurs in about 10% of patients and is a consequence of Stx systemic absorption. Indeed, Stx are released in the gastrointestinal tract, then after transferred to the systemic circulation. At the cellular level, Stx binds the globotriosylceramide (Gb3Cer) localized at the surface of the endothelial and epithelial cells of target organs. Following binding to Gb3Cer, the A subunits of Stx are internalized and trigger the activation of the apoptotic program leading to cell death. In addition, Stx are also able to enhance the production and the release of pro inflammatory factor (IL-1, TNFα, IL-6). Cytokines locally produced by Stx-stimulated cells can amplify the inflammatory processes and the prothrombotic state leading to the constitution of the microangiopathic lesions of HUS. To this day, management of D+HUS involves supportive care mainly based on fluid management, dialysis and red blood cells transfusions. Specific therapies used in D+HUS (plasma infusion, antithrombotic and anti inflammatory agents) failed to improve the course of D+HUS. The use of antibiotics remains not recommended while meta-analysis clearly showed that the use of bactericidal antibiotics could worse the course of D+HUS. In vitro experimentations highlighted that some classes of antibiotics like fluoroquinolones dramatically increase the production and the release of Stx before bacterial lysis and worsen the outcome of D+HUS in animal models. By contrast, azythromycin, a bacteriostatic antibiotic of the macrolides family blocking the protein synthesis in bacteria, has a strong inhibitory effect on Stx production and release by STEC as well as it inhibits the in vitro growth of STEC strains. In addition, azithromycin is able to inhibit the Stx-induced production of inflammatory cytokines which are considered to be essential for the development of D+HUS. Consistently the use of azithromycin in animal models of D+HUS dramatically improved the survival rate. Preliminary data on humans with D+HUS treated with azithromycin highlighted a lower prevalence of severe gastrointestinal involvement than in control patients. All these data supported the hypothesis that azithromycin should have a beneficial effect on D+HUS and should improve the short and long term outcome and deserves to be formally demonstrated in human with D+HUS.

Condition or disease Intervention/treatment Phase
Haemolytic and Uremic Syndrome Drug: Azithromycin Drug: Placebo (glucose solution 10%) Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 148 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Azithromycin in Post Diarrheal Haemolytic and Uremic Syndrome
Actual Study Start Date : July 2015
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Azithromycin
ZITHROMAX ® 40mg/ml solution. DCI : Azithromycin . Pfizer ®
Drug: Azithromycin
ZITHROMAX ® 40mg/ml solution. DCI : Azithromycin . Pfizer ® 20mg/kg dose with a maximum dose of 500mg per day for three days

Placebo Comparator: Glucose solution 10%
Glucose solution 10%
Drug: Placebo (glucose solution 10%)



Primary Outcome Measures :
  1. Glomerular filtration rate (GFR ) assessed with Schwartz formula 2009 [ Time Frame: 1 month ]
    GFR ( ml/min/1.73m ² ) = 39.1 [ Height (m) / Serum creatinine (mg / dl) ] x 0.516 [ 1.8 / cystatin C ( mg / l) ] 0.294 [ 30/urea (mg / dl ) ] x 0.169 [ 1.099 ] x man [ Height (m) / 1.4 ] .188


Secondary Outcome Measures :
  1. Hematologic impairment [ Time Frame: 1 month ]
    Hemolysis time defined by the time between the date of diagnosis of D + HUS and the recovery of a normal platelets level (> 150000/mm3 ) Number of packed red blood cells transfusion required during the initial phase of D+HUS

  2. Digestive tract impairment [ Time Frame: 1 month ]
    Occurrence of pancreatitis (defined by a lipase higher than 3 times the upper limit) Occurrence of severe colitis (severe digestive symptoms with bloody diarrhea and ultrasound or CT diagnosis of colitis) Need for parenteral nutrition for more than 72 hours. If yes, duration of parenteral nutrition. Occurence of hepatitis (defined by a SGPT level higher than 3 times the upper limit)

  3. Neurological involvement [ Time Frame: 1 month ]
    Presence or absence of neurological impairment defined by the presence of impaired consciousness and / or confusion and / or convulsions. In the presence of one or more of these signs, neurological impairment must be documented by the completion of a brain imaging (MRI) and electroencephalogram.

  4. Renal impairment [ Time Frame: 1 month ]
    Dialysis, duration of dialysis, anuria, glomerular filtration rate at 1 month, presence of proteinuria and / or a significant microalbuminuria. Blood pressure assessement (according to the standards defined by the Task Force for the size and age of the patient). Time to return to plasma creatinine level < 60μmol/l if the delay is less than one month

  5. One month Survival [ Time Frame: 1 month ]
    occurrence of death or not at 1 month



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Ages Eligible for Study:   6 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient aged from 6 months to 18 years old, residing in France, with a D+HUS according to the definition used by the National Institute for Public Health Surveillance (InVS) :
  • Renal impairment with a serum creatinine > 60μmol/l in children less than 2 years old and > 75μmol/l over 2 years old
  • AND hemolytic anemia defined by hemoglobin < 10g/dl associated with schizocytes ≥ 2%
  • Collection of free and informed consent of the holders of parental authority

Exclusion Criteria:

  • Age < 6 months and > 18 years.
  • Administration of antibiotics in the 15 days preceding the diagnosis of D+HUS.
  • Personal or family history of atypical HUS .
  • More than 15 days between the onset of diarrhea and the diagnosis of D+HUS.
  • Hypersensitivity to azithromycin, erythromycin, or any macrolide
  • patient treated with dihydroergotamine, ergotamine or cisapride
  • Severe hepatic impairment
  • No affiliation to a social security scheme (beneficiary or legal)
  • Pregnancy
  • Breastfeeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02336516


Contacts
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Contact: Marc Fila, MD +33467336428 m-fila@chu-montpellier.fr
Contact: Georges Deschenes, MD, PhD +33140031242 georges.deschenes@rdb.aphp.fr

Locations
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France
Arnaud de Villeneuve Hospital Recruiting
Montpellier, France, 34295 Montpellier cedex 5
Contact: Marc Fila, MD    +33467336428    m-fila@chu-montpellier.fr   
Contact: Georges Deschenes, MD, PhD    +33140031242    georges.deschenes@rdb.aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Marc Fila, MD Assistance Publique - Hôpitaux de Paris

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02336516    
Other Study ID Numbers: P130910 / AOM13540
2014-001740-38 ( EudraCT Number )
First Posted: January 13, 2015    Key Record Dates
Last Update Posted: November 18, 2019
Last Verified: November 2019
Additional relevant MeSH terms:
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Azotemia
Syndrome
Disease
Pathologic Processes
Uremia
Kidney Diseases
Urologic Diseases
Pharmaceutical Solutions