|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|Adolescent patients (from 12 and up to 18 years of age) with plasma therapyresistant Atypical Hemolytic-Uremic Syndrome (aHUS).
|E.1.2 Medical condition or disease under investigation
|E.1.2||Classification code ||10018932
|E.1.2||Term ||Haemolytic uraemic syndrome
|E.1.3||Condition being studied is a rare disease || Yes
|E.2 Objective of the trial
|E.2.1||Main objective of the trial ||
|Assess the effect of eculizumab to reduce thrombotic microangiopathy (TMA) as
indicated by thrombocytopenia as measured by platelet count change from baseline
during the treatment period to the first 26 weeks in patients with PT-resistant aHUS.
|E.2.2||Secondary objectives of the trial ||
|• Evaluate additional efficacy endpoints during the treatment period to the first 26
weeks such as the effect of eculizumab on:
− TMA Intervention Rate (# PT and # Dialysis Events/Patient/Day) during the first
26 weeks of the Treatment Period compared with the TMA Intervention Rate
prior to the first dose of Investigational Product.
− TMA-Event Free status defined as the absence for at least 12 weeks of 
decrease in platelet count of >25% from the Platelet Count Pre-PT Baseline Set-
Point;  PT while the patient is receiving eculizumab, and  new dialysis
− Key Hemolytic measures.
− Quality of Life measures.
− Renal function measures.
− TMA Remission.
• Characterize the overall safety and tolerability of eculizumab.
• Describe the pharmacokinetics (PK) and pharmacodynamics (PD) of eculizumab in
patients with aHUS.
• Perform a series of exploratory efficacy analyses during the treatment period to the
first 26 weeks.
|E.2.3||Trial contains a sub-study || No
|E.3||Principal inclusion criteria ||
|1. Male or female patients between ages from 12 and up to 18 year weighing ≥ 40 kg who
have been diagnosed with aHUS. Patients may be newly diagnosed, experiencing a
relapse of the disease, or having a post-transplant recurrence of the disease.
2. Patients must exhibit a decrease in platelet count despite at least 4 PT treatments in the 1
week immediately prior to screening. At screening, platelet count must be < 150 x
109/L and at least 25% lower than the average of 3 platelet counts obtained during the
most recent TMA remission and at least 1 month apart during that remission prior to
screening (designated the “average remission platelet count”).
3. If historical counts are not available, platelet count at onset of the current aHUS episode
must be ≤ 75 x 109/L, and platelet count at screening must be ≤ 100 x 109/L despite PT
treatment administration of at least 4 PT treatments in the 1 week immediately prior to
4. Known complement regulatory protein genetic abnormality, i.e., a mutation in
Complement Protein 3, factor H or associated factor, factor I, or membrane cofactor
protein (MCP) or known Factor B gain-of-function mutation, or known Anti-CFH
antibody (“aHUS lesions”).
• Patients diagnosed with aHUS with any of these aHUS lesions are eligible and will be assigned to one of the following parallel categories during the treatment period of
− (Category 1) Factor H or factor I functional deficiency, abnormal factor
interaction (CFH/CFI FFP Group), or deletions of the CFHR1 and CFHR3
− (Category 2) Complement Protein 3, abnormal factor interaction (C3) or Factor
B Gain of Function;
− (Category 3) Anti-CFH Antibody (anti-CFH Group);
− (Category 4) MCP deficiency (MCP Group);
5. Patients diagnosed with aHUS without documented complement regulatory protein
genetic abnormality or known anti-CFH antibody are eligible if other etiologies of
hemolytic uremic syndrome (HUS) have been ruled out as confirmed in the Exclusion
Criteria (i.e., including Shiga-toxin negative, non-infectious, non-drug-exposure-related
[e.g., cyclosporine]), no known human immunodeficiency syndrome (HIV) positivity,
and anti-phospholipid antibody negative). Patients meeting these conditions will be
assigned to Category 5. In addition, these patients will undergo genetic testing to
determine if a mutation can be identified. If a mutation is identified, the patient will be
reassigned to the appropriate category.
6. Lactate dehydrogenase (LDH) level ≥ upper limit of normal (ULN) unless the patient
has been receiving plasma exchange (PE) and LDH at the onset of the current aHUS
episode was at least the ULN. If LDH is normal at screening, other markers indicative
of ongoing hemolysis should be evaluated, such as haptoglobin, schistocytes, and
discussed with the Sponsor;
7. Creatinine level ≥ ULN for age (patients requiring acute dialysis for acute renal failure
8. Female patients of childbearing potential must be 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 will be
counseled by the principal investigator (PI) or designated study staff that they must
continue to use adequate contraception methods for up to 5 months following
discontinuation of eculizumab treatment.
9. Patient’s parents/legal guardian must be willing and able to give written informed
consent and patients must be willing to give written informed assent (if applicable as
determined by the IRB/IEC).
10. Able and willing to comply with study procedures.
|E.4||Principal exclusion criteria||
|1. Thrombotic Thrombocytopenic Purpura (TTP), defined as ADAMTS13 activity <5% from an historical observation (prior to initiation of Plasma Therapy) or as tested at the screening visit by the central laboratory.
2. History of malignancy within 5 years of screening.
3. Typical HUS (known Shiga toxin +).
4. Known HIVinfection.
5. Identified drug exposure-related HUS.
6. Infection-related HUS
7. HUS related to bone marrow transplant (BMT)
8. HUS related to vitamin B12 deficiency.
9. Renal function status requiring chronic dialysis (defined as dialysis on a regular basis as
renal replacement therapy).
10. Patients with a confirmed diagnosis of sepsis defined as positive blood cultures within 7
days of the screening visit and not treated with antibiotics to which the organism is
11. 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.
12. Pregnancy or lactation.
13. Unresolved meningococcal disease.
14. Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody positivity or
15. 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
16. Patients who have received previous treatment with eculizumab.
17. Patients receiving intravenous immunoglobulin (IVIg) within 8 weeks or Rituximab
therapy within 12 weeks of the screening visit.
18. Patients receiving other immunosuppressive therapies such as steroids, calcineurin
inhibitors (mTOR) or tacrolimus are excluded unless:  part of an established posttransplant
anti-rejection regime and dose of such medications have been unchanged for at least 4 weeks prior to the screening period, or  patient has confirmed anti-CFH
antibody requiring immunosuppressive therapy and dose of such medications have been
unchanged for at least 4 weeks prior to the screening period or  patient is
experiencing an acute aHUS relapse immediately after transplant.
19. Patients receiving Erythrocyte stimulating agents (ESAs) unless already on a stable dose
for at least 4 weeks prior to the screening period, or a washout period of at least 2 weeks
from the last dose of ESA therapy.
20. Participation in any other investigational drug trial or exposure to other investigational
agent, device, or procedures beginning 4 weeks prior to screening and throughout the
21. Hypersensitivity to eculizumab, to murine proteins or to one of the excipients.
22. Patients between the ages from 12 and up to 18 years weighing < 40 kg.
|E.5 End points
|E.5.1||Primary end point(s)||
|Platelet count change from baseline (Platelet Count Pre-PT Baseline Set-point
value) to the end of the first 26 weeks of treatment with the Investigational Product.
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| No
|E.7||Trial type and phase
|E.7.1||Human pharmacology (Phase I)|| No
|E.7.1.1||First administration to humans|| No
|E.7.1.2||Bioequivalence study|| No
|E.126.96.36.199||Other trial type description||
|E.7.2||Therapeutic exploratory (Phase II)|| Yes
|E.7.3||Therapeutic confirmatory (Phase III)|| No
|E.7.4||Therapeutic use (Phase IV)|| No
|E.8 Design of the trial
|E.8.1.3||Single blind|| No
|E.8.1.4||Double blind || No
|E.8.1.5||Parallel group|| No
|E.8.1.6||Cross over || No
|E.188.8.131.52||Other trial design description||
|The protocol has pre-defined objectives and pre-specified end points to assess eculizumab’s efficacy
|E.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| No
|E.8.2.2||Placebo || No
|In protocol each patient serves as his/her own control as described by the endpoints in the protocol
The trial involves single site in the Member State concerned
|E.8.4|| The trial involves multiple sites in the Member State concerned || Yes
|E.8.4.1||Number of sites anticipated in Member State concerned||3
|E.8.5||The trial involves multiple Member States|| Yes
|E.8.5.1||Number of sites anticipated in the EEA||31
|E.8.6 Trial involving sites outside the EEA
|E.8.6.1||Trial being conducted both within and outside the EEA|| Yes
|E.8.6.2||Trial being conducted completely outside of the EEA|| Information not present in EudraCT
|E.8.6.3||If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned||
|E.8.7||Trial has a data monitoring committee|| Yes
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|The last visit of the last patient
|E.8.9 Initial estimate of the duration of the trial
|E.8.9.1||In the Member State concerned years||1
|E.8.9.1||In the Member State concerned months||0
|E.8.9.1||In the Member State concerned days||0
|E.8.9.2||In all countries concerned by the trial years||1
|E.8.9.2||In all countries concerned by the trial months||0
|E.8.9.2||In all countries concerned by the trial days||0