AN OPEN-LABEL, MULTI-CENTER CONTROLLED CLINICAL TRIAL OF ECULIZUMAB IN ADULT PATIENTS WITH PLASMA THERAPY-SENSITIVE ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS)

• Register: EUCTR
• Last refreshed on: 24 February 2014
• Main ID: EUCTR2008-006954-17-DE
• Date of registration: 19/02/2009
• Prospective Registration: Yes
• Primary sponsor: ALEXION PHARMACEUTICALS, INC.
• Public title: AN OPEN-LABEL, MULTI-CENTER CONTROLLED CLINICAL TRIAL OF ECULIZUMAB IN ADULT PATIENTS WITH PLASMA THERAPY-SENSITIVE ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS)
• Scientific title: AN OPEN-LABEL, MULTI-CENTER CONTROLLED CLINICAL TRIAL OF ECULIZUMAB IN ADULT PATIENTS WITH PLASMA THERAPY-SENSITIVE ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUS)
• Date of first enrolment: 18/06/2009
• Target sample size: 15
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-006954-17
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: yes Other trial design description: The protocol has pre-defined objectives and pre-specified end points to assess eculizumab’s efficacy If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: In protocol each patient serves as his/her own control as described by the endpoints in the protocol

Countries of recruitment

Austria, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female patients = 18 years of age 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
eculizumab treatment.
9. Able to give written informed consent.
10. Able and willing to comply with study procedures.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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 the study.
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: [1] 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 [2] 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 [3] 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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Adult patients with plasma therapy-sensitive Atypical Hemolytic-Uremic Syndrome (aHUS)
MedDRA version: 9.1 Level: LLT Classification code 10018932 Term: Haemolytic uraemic syndrome

Intervention(s)

Trade Name: SOLIRIS
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: eculizumab
Current Sponsor code: h5G1.1-mAb
Other descriptive name: Anti-C5 antibody
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

Main Objective: Assess the effect of eculizumab on TMA-Event Free status defined as the absence for at least 12 weeks of [1] decrease in platelet count of >25% from the Platelet Count Pre-PT Baseline Set-Point; [2] PT while the patient is receiving eculizumab, or [3] new dialysis.

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 [1] decrease in platelet count of >25% from the Platelet Count Pre-PT Baseline Set-Point; [2] PT while the patient is receiving eculizumab, and [3] 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 dialysis event.

Secondary Objective: • 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.

Secondary ID(s)

C08-003A