|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 therapysensitive 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 on 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, or  new dialysis.
|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.
− Reduction of thrombotic microangiopathy (TMA) as indicated by
thrombocytopenia as measured by platelet count change from baseline during the first 26 weeks of the treatment period.
− 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.
2. Patients must be receiving PT for aHUS and must be observed to (i) receive ≥1 PT
treatment every two weeks and no more than 3 PT treatments/week (at an unchanged
frequency) for at least 8 weeks before the first dose of Investigational Product.
3. Platelet Count Pre-PT Baseline Set-Point (collected in the hours before the
Qualifying PT Episode) is within 75% of the average of the pre-PT platelet counts
collected at Screening and during the Observation Period.
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 the trial:
• (Category 1) Factor H or factor I functional deficiency, abnormal factor
interaction (CFH/CFI FFP Group), or deletions of the CFHR1 and CFHR3 genes;
• (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-drugexposure-
related [e.g., cyclosporine]), no known HIV positivity, and antiphospholipid
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) at screening or at the onset of the current aHUS
episode was ≥ 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.
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 PI or designated study staff that they must continue to use
adequate contraception methods for up to 5 months following discontinuation of
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 human immunodeficiency virus (HIV) infection.
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. 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 sensitive.
10. 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.
11. Pregnancy or lactation.
12. Unresolved meningococcal disease.
13. Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody
positivity or syndrome.
14. 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
15. Patients who have received previous treatment with eculizumab.
16. Patients receiving intravenous immunoglobulin (IVIg) within 8 weeks or Rituximab
therapy within 12 weeks of the screening visit.
17. 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 and
throughout the Observation Period or  patient is experiencing an acute aHUS
relapse immediately after transplant.
18. 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.
19. 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 entire trial.
20. Hypersensitivity to eculizumab, to murine proteins, or to one of the excipients.
21. 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)||
|The primary efficacy endpoint for this protocol is to assess the effect of
eculizumab on 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. Dialysis events occurring within the 14 days after the first dose of
Investigational Product will not be considered as a new Treatment Period dialysis event. In addition, dialysis events that commence within the 14 days before the
first dose of Investigational Product and continue up to 14 days after the first
dose of Investigational Product will not be considered a new Treatment Period
|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.220.127.116.11||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.18.104.22.168||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