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

Primary Purpose

Hemolytic Uremic Syndrome of Childhood

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Eculizumab
Placebo
Sponsored by
University Hospital, Toulouse
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemolytic Uremic Syndrome of Childhood focused on measuring Eculizumab, Shiga-toxin, hemolytic and uremic syndrome, pediatric

Eligibility Criteria

1 Month - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • University Hospital
  • University Hospital
  • University Hospital
  • Pellegrin Hospital
  • Morvan Hospital
  • University Hospital
  • Jeanne de Flandre Hospital
  • Mother and Child Hospital
  • Women, Mother and Child Hospital
  • La Timone Hospital
  • University Hospital
  • Mother and Child Hospital
  • Robert Debré Hospital
  • Trousseau Hospital
  • Necker Hospital
  • Anne de Bretagne University Hospital
  • Purpan Children Hospital
  • Clocheville Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Eculizumab

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

the duration in days of extrarenal epuration
Extrarenal epuration means peritoneal dialysis or hemodialysis, and is assessed at each visit.

Secondary Outcome Measures

Number of adverse events as a measure of Safety and tolerance of treatment injections (ECZ or placebo)
Adverse reactions related to the treatment (ECZ or placebo)
Duration of Acute Renal Failure (ARF)
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.
Renal sequels
Renal sequels will be evaluated as follow : blood pressure, creatinin clearance, ionogram, proteinuria and microalbuminuria.
Hematological abnormalities
Duration (in days) of the thrombocytopenia Duration (in days) of the hemolytic anemia
Blood parameters of Complement Alternative Pathway (CAP)
Blood parameters of CAP will be evaluated with plasmatic dosages of the complement components C3 and CD46.
Inhibition of the Terminal Complement Complex (TCC)
Inhibition of the TCC will be evaluated trough the CH50 assay and plasmatic free ECZ levels.
Incidence of extrarenal manifestations
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)
Mortality

Full Information

First Posted
July 28, 2014
Last Updated
July 11, 2019
Sponsor
University Hospital, Toulouse
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1. Study Identification

Unique Protocol Identification Number
NCT02205541
Brief Title
Eculizumab in Shiga-toxin Related Hemolytic and Uremic Syndrome Pediatric Patients - ECULISHU
Acronym
ECULISHU
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
June 2015 (Actual)
Primary Completion Date
June 2018 (Actual)
Study Completion Date
June 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Toulouse

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemolytic Uremic Syndrome of Childhood
Keywords
Eculizumab, Shiga-toxin, hemolytic and uremic syndrome, pediatric

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
100 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Eculizumab
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Eculizumab
Other Intervention Name(s)
Soloris®
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Solution with 5% glucose
Intervention Description
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
Primary Outcome Measure Information:
Title
the duration in days of extrarenal epuration
Description
Extrarenal epuration means peritoneal dialysis or hemodialysis, and is assessed at each visit.
Time Frame
From the inclusion date and assessed up to 13 months
Secondary Outcome Measure Information:
Title
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)
Title
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)
Title
Duration of Acute Renal Failure (ARF)
Description
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.
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)
Title
Renal sequels
Description
Renal sequels will be evaluated as follow : blood pressure, creatinin clearance, ionogram, proteinuria and microalbuminuria.
Time Frame
At 1, 6 and 12 months after last injection of ECZ (follow-up visits 7, 8, 9)
Title
Hematological abnormalities
Description
Duration (in days) of the thrombocytopenia Duration (in days) of the hemolytic anemia
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)
Title
Blood parameters of Complement Alternative Pathway (CAP)
Description
Blood parameters of CAP will be evaluated with plasmatic dosages of the complement components C3 and CD46.
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)
Title
Inhibition of the Terminal Complement Complex (TCC)
Description
Inhibition of the TCC will be evaluated trough the CH50 assay and plasmatic free ECZ levels.
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)
Title
Incidence of extrarenal manifestations
Description
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)
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)
Title
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Month
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Arnaud Garnier, MD
Organizational Affiliation
Toulouse University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Karine Brochard
Organizational Affiliation
Toulouse University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital
City
Amiens
ZIP/Postal Code
80054
Country
France
Facility Name
University Hospital
City
Angers
ZIP/Postal Code
49100
Country
France
Facility Name
University Hospital
City
Besançon
ZIP/Postal Code
25030
Country
France
Facility Name
Pellegrin Hospital
City
Bordeaux
ZIP/Postal Code
33000
Country
France
Facility Name
Morvan Hospital
City
Brest
ZIP/Postal Code
29609
Country
France
Facility Name
University Hospital
City
Grenoble
ZIP/Postal Code
60107
Country
France
Facility Name
Jeanne de Flandre Hospital
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
Mother and Child Hospital
City
Limoges
ZIP/Postal Code
87000
Country
France
Facility Name
Women, Mother and Child Hospital
City
Lyon
ZIP/Postal Code
69500
Country
France
Facility Name
La Timone Hospital
City
Marseille
Country
France
Facility Name
University Hospital
City
Montpellier
ZIP/Postal Code
34295
Country
France
Facility Name
Mother and Child Hospital
City
Nantes
ZIP/Postal Code
44000
Country
France
Facility Name
Robert Debré Hospital
City
Paris
ZIP/Postal Code
75019
Country
France
Facility Name
Trousseau Hospital
City
Paris
ZIP/Postal Code
75571
Country
France
Facility Name
Necker Hospital
City
Paris
ZIP/Postal Code
75743
Country
France
Facility Name
Anne de Bretagne University Hospital
City
Rennes
ZIP/Postal Code
35056
Country
France
Facility Name
Purpan Children Hospital
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
Clocheville Hospital
City
Tours
ZIP/Postal Code
37044
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
35123930
Citation
Groussolles M, Winer N, Sentilhes L, Biquart F, Massoud M, Vivanti AJ, Bouchghoul H, Rozenberg P, Olivier P, Desbriere R, Chauleur C, Perrotin F, Coatleven F, Fuchs F, Bretelle F, Tsatsaris V, Salomon LJ, Sananes N, Kayem G, Houflin-Debarge V, Schmitz T, Benoist G, Arnaud C, Ehlinger V, Vayssiere C; Groupe de Recherche en Gynecologie Obstetrique. Arabin pessary to prevent adverse perinatal outcomes in twin pregnancies with a short cervix: a multicenter randomized controlled trial (PESSARONE). Am J Obstet Gynecol. 2022 Aug;227(2):271.e1-271.e13. doi: 10.1016/j.ajog.2022.01.038. Epub 2022 Feb 3.
Results Reference
derived
PubMed Identifier
34219224
Citation
Imdad A, Mackoff SP, Urciuoli DM, Syed T, Tanner-Smith EE, Huang D, Gomez-Duarte OG. Interventions for preventing diarrhoea-associated haemolytic uraemic syndrome. Cochrane Database Syst Rev. 2021 Jul 5;7(7):CD012997. doi: 10.1002/14651858.CD012997.pub2.
Results Reference
derived
PubMed Identifier
33774745
Citation
Matrat L, Bacchetta J, Ranchin B, Tanne C, Sellier-Leclerc AL. Pediatric atypical hemolytic-uremic syndrome due to auto-antibodies against factor H: is there an interest to combine eculizumab and mycophenolate mofetil? Pediatr Nephrol. 2021 Jun;36(6):1647-1650. doi: 10.1007/s00467-021-05025-8. Epub 2021 Mar 28.
Results Reference
derived
PubMed Identifier
33693990
Citation
Muff-Luett M, Sanderson KR, Engen RM, Zahr RS, Wenderfer SE, Tran CL, Sharma S, Cai Y, Ingraham S, Winnicki E, Weaver DJ, Hunley TE, Kiessling SG, Seamon M, Woroniecki R, Miyashita Y, Xiao N, Omoloja AA, Kizilbash SJ, Mansuri A, Kallash M, Yu Y, Sherman AK, Srivastava T, Nester CM. Eculizumab exposure in children and young adults: indications, practice patterns, and outcomes-a Pediatric Nephrology Research Consortium study. Pediatr Nephrol. 2021 Aug;36(8):2349-2360. doi: 10.1007/s00467-021-04965-5. Epub 2021 Mar 10.
Results Reference
derived

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

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