Clinical Trials Register

Summary
EudraCT Number:	2008-006953-41
Sponsor's Protocol Code Number:	C08-002B
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-04-14
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2008-006953-41

A.3

Full title of the trial

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

A.4.1

Sponsor's protocol code number

C08-002B

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	ALEXION PHARMACEUTICALS, INC.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	SOLIRIS
D.2.1.1.2	Name of the Marketing Authorisation holder	ALEXION EUROPE
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/09/653
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	eculizumab
D.3.9.2	Current sponsor code	h5G1.1-mAb
D.3.9.3	Other descriptive name	Anti-C5 antibody
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

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).

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
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 [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
− 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

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 screening.
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-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 also eligible).
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)
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 sensitive.
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 syndrome.
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 study.
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: [1] part of an established post-transplant 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 or [3] 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 entire trial.
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.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

In protocol each patient serves as his/her own control as described by the endpoints in the protocol

E.8.3

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last visit of the last subject undergoing the trial

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Non Adult Subjects

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients will be allowed to continue to receive the investigational product for an additional two years after completing the 26 week treatment period. Patients who prematurely discontinue investigational product during the study will require follow-up visits for 8 weeks after the last dose of eculizumab.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2009-03-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-05-28

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2011-10-17

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