Working…
Help guide our efforts to modernize ClinicalTrials.gov.
Send us your comments by March 14, 2020.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Eculizumab in Shiga-toxin Related Hemolytic and Uremic Syndrome Pediatric Patients - ECULISHU (ECULISHU)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02205541
Recruitment Status : Completed
First Posted : July 31, 2014
Last Update Posted : July 12, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital, Toulouse

Brief Summary:

The investigators aim to perform the first controlled randomized prospective study using ECZ in pediatric STEC-HUS. This is of great interest as there is still no efficient specific therapy in that potentially devastating disease.

Furthermore, published data concerning the use of ECZ in STEC-HUS are controversial, reflecting statistical bias in retrospective or uncontrolled studies, thus emphasizing the need for prospective studies.


Condition or disease Intervention/treatment Phase
Hemolytic Uremic Syndrome of Childhood Drug: Eculizumab Drug: Placebo Phase 3

Detailed Description:

Hemolytic and uremic syndrome (HUS), characterized by thrombocytopenia, hemolytic anemia and acute renal failure (ARF), mainly affects children younger than 5 years old. Shiga-toxin (Stx) related HUS (STEC-HUS) is due to Stx secreting bacteria (mainly enterohemorrhagic Escherichia Coli strains). Acute phase of STEC-HUS is severe with at least 50% of affected children requiring dialysis, 20% presenting neurological involvement and 5% cardiac involvement. Mortality rates can reach 5% in pediatric series and long-term renal sequels have been reported in at least 30% of surviving patients. Apart from supportive care, no specific treatment (such as plasma exchange) has proven its efficacy in this life-threatening disease.

Recently, activation of the complement alternative pathway (CAP) has been demonstrated in STEC-HUS patients and experimental studies have highlighted that Stx induce CAP activation on human endothelial cells and platelet-leucocytes complexes, in addition to its direct cell toxicity inducing apoptosis, both processes ending up in microvasculature thrombosis. CAP activation has been demonstrated as the cause of atypical HUS (aHUS) and ECZ, a monoclonal C5 antibody, which inhibits the terminal complement complex (TCC) formation, can efficiently prevent evolution to end stage renal disease in aHUS patients. In 2011, Lapeyraque et al. reported its possible efficacy in 3 severe STEC-HUS pediatric patients. Nevertheless, in STEC-HUS, ECZ has only been used in uncontrolled studies, mostly during the 2011 German outbreak, with conflicting results. Considering the lack of therapy to prevent life-threatening complications and renal sequels in STEC-HUS and the logically expected efficacy of ECZ, controlled studies are mandatory. In recruiting centers, STEC-HUS patients with ARF will be proposed to enroll the trial with the exception of patients with multiorgan. After parental consent, patients will be randomized to receive either ECZ or a dextrose-based placebo in a single blinded fashion. According to the patient body weight, there will be 3 to 5 injections at day (D) 0, D7, D14, D21 and D28. According to the length of initial hospital stay, patients may have the remaining injections in the day ward of the recruiting center. Dosage of ECZ will be based on previous trials using ECZ in pediatric aHUS patients. We designed a single blinded study because patients treated with placebo who will develop severe multiorgan involvement will be switched to the ECZ arm. ECZ or placebo will be administrated intravenously as a 30-minute injection. In patients receiving hemodialysis, ECZ injection will be performed after a dialysis session. Before first injection, patients will receive a tetravalent meningococcal vaccine and an oral antibiotic prophylaxis to be continued up to 14 days after last injection.

This is a single blinded, phase III, randomized, multi-center controlled versus placebo clinical trial of eculizumab in STEC-HUS patients.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Early Treatment With the Monoclonal C5 Antibody Eculizumab in Pediatric Patients Affected by Shiga-toxin Related Hemolytic and Uremic Syndrome: A Phase III Prospective Randomized Controlled Therapeutic Trial Versus Placebo
Actual Study Start Date : June 2015
Actual Primary Completion Date : June 2018
Actual Study Completion Date : June 2018


Arm Intervention/treatment
Experimental: Eculizumab

300mg concentrate for solution for infusion. According to the patient body weight, there will be 3 to 5 injections administered in IV infusion at D0, D7, D14, D21 and D28.

Eculizumab (ECZ) will be administrated intravenously as a 30-minute injection.

Drug: Eculizumab

According to the patient body weight, there will be 3 to 5 injections at D0, D7, D14, D21 and D28. According to the length of initial hospital stay, patients may have the remaining injections in the day ward of the recruiting center. Dosage of ECZ will be based on previous trials using ECZ in pediatric aHUS patients.

ECZ or placebo will be administrated intravenously as a 30-minute injection

Other Name: Soloris®

Placebo Comparator: Placebo

Infusion of a solution with 5% glucose. The administration scheme will be the same as the Eculizumab arm : there will be 3 to 5 injections at D0, D7, D14, D21 and D28.

Placebo will be administrated intravenously as a 30-minute injection.

Drug: Placebo

According to the patient body weight, there will be 3 to 5 injections at D0, D7, D14, D21 and D28.

ECZ or placebo will be administrated intravenously as a 30-minute injection

Other Name: Solution with 5% glucose




Primary Outcome Measures :
  1. the duration in days of extrarenal epuration [ Time Frame: From the inclusion date and assessed up to 13 months ]
    Extrarenal epuration means peritoneal dialysis or hemodialysis, and is assessed at each visit.


Secondary Outcome Measures :
  1. Number of adverse events as a measure of Safety and tolerance of treatment injections (ECZ or placebo) [ Time Frame: At each injection (treatment visits 2, 3, 4, 5, 6 at respectively day 0, 7, 14, 21, 28) and at each follow-up visit (7, 8, 9 respectively at month 2, 7, 13) ]
  2. Adverse reactions related to the treatment (ECZ or placebo) [ Time Frame: At each injection (treatment visits 2, 3, 4, 5, 6 at respectively day 0, 7, 14, 21, 28) and at each follow-up visit (7, 8, 9 respectively at month 2, 7, 13) ]
  3. Duration of Acute Renal Failure (ARF) [ Time Frame: Inclusion Visit (1 at day -3 to -1 ), treatment period (visits 2, 3, 4, 5, 6 respectively at day 0, 7, 14, 21, 28), follow-up period (visits 7, 8, 9 respectively at month 2, 7, 13) ]
    Duration of ARF will be evaluated as follow : urine output measurement, creatinin clearance estimated with the Schwartz 2009 assay (based on creatinin plasma levels), ionogram, proteinuria.

  4. Renal sequels [ Time Frame: At 1, 6 and 12 months after last injection of ECZ (follow-up visits 7, 8, 9) ]
    Renal sequels will be evaluated as follow : blood pressure, creatinin clearance, ionogram, proteinuria and microalbuminuria.

  5. Hematological abnormalities [ Time Frame: Inclusion Visit (1 at day -3 to -1), treatment period (visits 2, 3, 4, 5, 6 respectively at day 0, 7, 14, 21, 28), follow-up period (visits 7, 8, 9 respectively at month 2, 7, 13) ]
    • Duration (in days) of the thrombocytopenia
    • Duration (in days) of the hemolytic anemia

  6. Blood parameters of Complement Alternative Pathway (CAP) [ Time Frame: Inclusion visit (1 at day -3 to -1), Treatment visits (3, 4, 5, 6 at day 7, 14, 21, 28), follow-up visit (7 at month 2) ]
    Blood parameters of CAP will be evaluated with plasmatic dosages of the complement components C3 and CD46.

  7. Inhibition of the Terminal Complement Complex (TCC) [ Time Frame: Inclusion visit (1 at day -3 to -1), Treatment visits (3, 4, 5, 6 at day 7, 14, 21, 28), follow-up visit (7 at month 2) ]
    Inhibition of the TCC will be evaluated trough the CH50 assay and plasmatic free ECZ levels.

  8. Incidence of extrarenal manifestations [ Time Frame: Inclusion Visit (1 at day -3 to -1), treatment period (visits 2, 3, 4, 5, 6 respectively at day 0, 7, 14, 21, 28) ]
    • Neurological involvement (seizures, coma, focal deficit)
    • Cardiac involvement (cardiac failure, ischemic myocarditis, conduction or rhythm troubles)
    • Digestive involvement (pancreatitis, hepatitis, hemorrhagic colitis, bowel perforation, rectal prolapsus)

  9. Mortality [ Time Frame: Inclusion Visit (1 at day -3 to -1), treatment period (visits 2, 3, 4, 5, 6 respectively at day 0, 7, 14, 21, 28), follow-up period (visits 7, 8, 9 respectively at month 2, 7, 13) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   1 Month to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pediatric patient (1 month-18 years old)
  • Affected by STEC-HUS defined by :
  • Thrombocytopenia (<150 000/mm3)
  • Mechanic hemolytic anemia (Hemoglobin < 10g/dL, haptoglobin <LLN, lactate dehydrogenase (LDH) >upper limit of normal (ULN) and/or bilirubin > ULN, presence of schizocytes)
  • ARF defined by an estimated Schwartz 2009 creatinin clearance <75ml/min/1,73m²
  • With prodromal diarrhea and/or presence of an enterohemorrhagic strain of Escherichia Coli and/or identification of the Stx 1 or 2 genes in the stool sample or rectal swab
  • Written consent of the 2 parents
  • Female patients of childbearing potential must be practicing an effective, reliable and medically acceptable contraceptive regimen during the entire duration of the study and 5 months after the end of the participation.

Exclusion Criteria:

  • Neonatal HUS
  • Malignancy
  • Known HIV infection
  • Pregnancy or lactation
  • Identified drug exposure-related HUS
  • Infection-related HUS
  • Known systemic lupus erythematosus or antiphospholipid antibody positivity or syndrome
  • Patient already enrolled in a drug trial
  • Patient with ongoing meningococcal infection
  • Patient affected by aHUS or family history of aHUS
  • STEC-HUS patient with severe multiorgan involvement at diagnostic:

    • Neurological involvement (seizures, coma, focal deficit) with signs of microangiopathy on cerebral Magnetic Resonance Imaging.
    • Cardiac involvement (cardiac failure, ischemic myocarditis, conduction or rhythm troubles)
    • Digestive involvement (severe pancreatitis defined by lipasemia>500UI/L, severe hepatitis defined by transaminase >x10ULN and/or prothrombin time<60%, hemorrhagic colitis, bowel perforation, rectal prolapsus)

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): NCT02205541


Locations
Layout table for location information
France
University Hospital
Amiens, France, 80054
University Hospital
Angers, France, 49100
University Hospital
Besançon, France, 25030
Pellegrin Hospital
Bordeaux, France, 33000
Morvan Hospital
Brest, France, 29609
University Hospital
Grenoble, France, 60107
Jeanne de Flandre Hospital
Lille, France, 59037
Mother and Child Hospital
Limoges, France, 87000
Women, Mother and Child Hospital
Lyon, France, 69500
La Timone Hospital
Marseille, France
University Hospital
Montpellier, France, 34295
Mother and Child Hospital
Nantes, France, 44000
Robert Debré Hospital
Paris, France, 75019
Trousseau Hospital
Paris, France, 75571
Necker Hospital
Paris, France, 75743
Anne de Bretagne University Hospital
Rennes, France, 35056
Purpan Children Hospital
Toulouse, France, 31059
Clocheville Hospital
Tours, France, 37044
Sponsors and Collaborators
University Hospital, Toulouse
Investigators
Layout table for investigator information
Principal Investigator: Arnaud Garnier, MD Toulouse University Hospital
Principal Investigator: Karine Brochard Toulouse University Hospital

Layout table for additonal information
Responsible Party: University Hospital, Toulouse
ClinicalTrials.gov Identifier: NCT02205541    
Other Study ID Numbers: RC31/13/7052
PHRC 13-0060 ( Other Grant/Funding Number: French Ministry of Health, PHRC 2013 )
2014-001169-28 ( EudraCT Number )
First Posted: July 31, 2014    Key Record Dates
Last Update Posted: July 12, 2019
Last Verified: July 2019
Keywords provided by University Hospital, Toulouse:
Eculizumab
Shiga-toxin
hemolytic and uremic syndrome
pediatric
Additional relevant MeSH terms:
Layout table for MeSH terms
Azotemia
Hemolytic-Uremic Syndrome
Syndrome
Hemolysis
Disease
Pathologic Processes
Uremia
Kidney Diseases
Urologic Diseases
Anemia, Hemolytic
Anemia
Hematologic Diseases
Thrombotic Microangiopathies
Thrombocytopenia
Blood Platelet Disorders
Pharmaceutical Solutions
Shiga Toxins
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action