An Open-Label, Multi-Center Clinical Trial of Eculizumab in Pediatric Patients With Atypical Hemolytic-Uremic Syndrome

Study Overview
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Brief Summary
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The primary purpose is to assess the efficacy and safety of eculizumab in pediatric patients with aHUS to control TMA as characterized by thrombocytopenia, hemolysis and renal impairment.

Official Title
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An Open-Label, Multi-Center Clinical Trial of Eculizumab in Pediatric Patients With Atypical Hemolytic-Uremic Syndrome

Conditions
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Atypical Hemolytic-Uremic Syndrome

Intervention / Treatment
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* Drug: Eculizumab


Participation Criteria
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Eligibility Criteria
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Inclusion: Patient's parent/legal guardian must have been willing and able to give written informed consent and the patient must have been willing to give written informed assent (if applicable as determined by the central IRB/IEC). Pediatric patients with aHUS: Patients could have been newly diagnosed, or with previously diagnosed disease, or post-kidney transplant with the disease. Patients one month to 18 years and body weight ≥ 5kg. Platelet count at screening and baseline visit must have been below lower limit of normal (<LLN). If screening visit and baseline visit are combined into one day, an additional platelet count value obtained at least 24 hours before screening/baseline sample must also be <LLN. Exhibited signs or symptoms of hemolysis at start of current aHUS event (i.e., lactate dehydrogenase (LDH) ≥1.5 x Upper Limit of Normal [ULN] and hemoglobin ≤LLN), fragmented RBC with a negative Coombs test. Serum Creatinine level ≥97 percentile for age at screening (patients requiring dialysis for acute renal failure are also eligible). Patients with aHUS due to complement regulatory protein genetic abnormality or anti-complement factor antibody or those in whom known etiologies of hemolytic uremic syndrome (HUS) have been ruled out as confirmed in the Exclusion Criteria. Patients must have been vaccinated against N. meningitidis, pneumococcus and haemophilus (per the vaccine label) at least 14 days prior to study drug initiation or otherwise be protected by prophylactic antibiotics. Patients under age two years were to receive antibiotic prophylaxis throughout the treatment period. Female patients of childbearing potential (female patients who have achieved menarche) must have been practicing an effective, reliable and medically approved contraceptive regimen during the entire duration of the study, including the follow-up period. At the time of the last follow-up visit, patients must have agreed to continue to use adequate contraception methods for up to five months following discontinuation of eculizumab treatment. Able and willing to comply with study procedures Exclusion: Any of the following was regarded as a criterion for exclusion from the study: Known familial ADAMTS-13 deficiency (ADAMTS-13 <5%). Shiga toxin E.coli-related hemolytic uremic syndrome (STEC-HUS [known Shiga toxin + E.coli]). History of malignancy within five years of screening. Known human immunodeficiency virus (HIV) infection. Identified drug exposure-related HUS. Infection-related HUS. HUS related to bone marrow transplant (BMT). HUS related to vitamin B12 deficiency. Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody positivity or syndrome. Plasma Therapy for >5 weeks prior to enrollment. Chronic dialysis (defined as dialysis on a regular basis as renal replacement therapy for end-stage renal disease [ESRD]). Patients with a confirmed diagnosis of sepsis defined as positive blood cultures within seven days of the screening visit and not treated with antibiotics to which the organism is sensitive. Presence or suspicion of active and untreated systemic bacterial infection that, in the opinion of the Investigator confounds an accurate diagnosis of aHUS or impedes the ability to manage the aHUS disease. Pregnancy or lactation. History of meningococcal/pneumococcal/gonococcal disease. Any medical or psychological condition that, in the opinion of the investigator, could increase the patient's risk by participating in the study or confound the outcome of the study. Patients receiving chronic intravenous immunoglobulin (IVIg) within eight weeks unless for unrelated medical condition (e.g., Hypogammaglobinemia), or chronic Rituximab therapy within 12 weeks of the screening visit. Patients receiving other immunosuppressive therapies such as steroids, mTOR inhibitors, calcineurin inhibitors (e.g., cyclosporine or tacrolimus are excluded unless: [1] part of an established post-transplant anti-rejection regime, or [2] patient has confirmed anti-Complement Factor antibodies antibody requiring immunosuppressive therapy or [3] steroids are being used for a condition other than aHUS (example asthma). Participation in any other investigational drug trial or device trial, or procedures beginning four weeks prior to screening and throughout the entire trial Prior use of eculizumab, hypersensitivity to eculizumab, to murine proteins or to one of the excipients.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eculizumab<br> | Drug: Eculizumab<br>* Fixed dosing is based on body weight cohorts. Adjustment of dose to accommodate patient growth is possible.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Complete TMA Response | Proportion of Patients with Complete TMA response was determined and defined by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline which was sustained for at least two consecutive measurements obtained at least four weeks apart). | Through 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Complete Hematologic Response | Proportion of Patients with Complete Hematologic response through 26 weeks of treatment was determined and defined by normalization of platelet count and LDH sustained for at least two consecutive measurements obtained at least four weeks apart. | Through 26 weeks | 
| Proportion of Patients With Platelet Count Normalization | Proportion of Patients with Platelet Count Normalization through 26 weeks of treatment was determined and defined as the platelet count observed to be ≥ 150 x 109/L on at least two consecutive measurements which span a period of at least four weeks. | Through 26 weeks | 
| Proportion of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement | Proportion of Patients with Estimated Glomerular Filtration Rate (eGFR) Improvement was determined and defined as an increase in eGFR by ≥ 15 mL/min/1.73m2 from baseline, sustained for at least two consecutive measurements obtained at least four weeks apart. | Through 26 weeks | 
| Platelet Count Change From Baseline to 26 Weeks |  | Through 26 weeks | 
| Proportion of Patients With Complete TMA Response | Proportion of Patients with Complete TMA response was determined and defined by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline which was sustained for at least two consecutive measurements obtained at least four weeks apart). | Through End of Study, Median Exposure 55 Weeks | 
| Proportion of Patients With Complete Hematologic Response | Proportion of Patients with Complete Hematologic response through end of study was determined and defined by normalization of platelet count and LDH sustained for at least two consecutive measurements obtained at least four weeks apart. | Through End of Study, Median Exposure 55 Weeks | 
| Proportion of Patients With Platelet Count Normalization | Proportion of Patients with Platelet Count Normalization through end of study was determined and defined as the platelet count observed to be ≥ 150 x 109/L on at least two consecutive measurements which span a period of at least four weeks | Through End of Study, Median Exposure 55 Weeks | 
| Proportion of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement | Proportion of Patients with Estimated Glomerular Filtration Rate (eGFR) Improvement was determined and defined as an increase in eGFR by ≥ 15 mL/min/1.73m2 from baseline, sustained for at least two consecutive measurements obtained at least four weeks apart. | Through End of Study, Median Exposure 55 Weeks | 
| Platelet Count Change From Baseline to 52 Weeks |  | Through 52 Weeks | 
| Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 5 - <10kg) N=3 |  | Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort.Maintenance Phase was started 1 week after induction phase and dosing of eculizumab administration was every 2 weeks or every 3 weeks depending on patient weight cohort | 
| Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 10 - <20kg) N=7 |  | Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort.Maintenance Phase was started 1 week after induction phase and dosing of eculizumab administration was every 2 weeks or every 3 weeks depending on patient weight cohort | 
| Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 20 - <30kg) |  | Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort. Maintenance Phase was started either 2 weeks or 3 weeks after induction phase depending on patient weight cohort | 
| Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 30 - <40kg) N=1 |  | Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort. Maintenance Phase was started either 2 weeks or 3 weeks after induction phase depending on patient weight cohort | 
| Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort ≥40kg) N=5 |  | Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort. Maintenance Phase was started either 2 weeks or 3 weeks after induction phase depending on patient weight cohort | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atypical Hemolytic-Uremic Syndrome