Open Label Controlled Trial of Eculizumab in Adolescent Patients With Plasma Therapy-Resistant aHUS

Phase 2

Completed

• Conditions: Atypical Hemolytic Uremic Syndrome
• Interventions: Drug: Eculizumab

• Registration Number: NCT00844844
• Lead Sponsor: Alexion Pharmaceuticals, Inc.

Brief Summary

The purpose of this study is to determine whether eculizumab is safe and effective in the treatment of adolescent patients with plasma therapy-resistant Atypical Hemolytic-Uremic Syndrome (aHUS).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2009-02-13
• Study First Submitted QC: 2009-02-13
• Study First Posted: 2009-02-16
• Study Start: 2009-05
• Primary Completion: 2010-09
• Study Completion: 2013-07
• Results First Submitted: 2014-10-21
• Results First Submitted QC: 2014-11-26
• Results First Posted: 2014-12-03
• Status Verified: 2015-06
• Last Update Submitted: 2015-06-30
• Last Update Posted: 2015-07-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1

Inclusion Criteria

1. Male or female patients from 12 and up to 18 years weighing ≥ 40 kg who have been diagnosed with Atypical Hemolytic-Uremic Syndrome (aHUS).

2. Decrease in platelet count despite at least 4 plasma therapy (PT) treatments in the 1 week immediately prior to screening.

   1. Screening platelet count , < 150 x10^9/L and at least 25% lower than the average remission platelet count or
   2. If remission counts not available, platelet count at onset of the current aHUS episode must be ≤75x10^9/L and platelet count at screening must be ≤ 100 x 10^9/L despite PT treatment administration of at least 4 PT treatments in the 1 week immediately prior to screening

3. Known complement regulatory protein genetic abnormality

4. Lactate dehydrogenase (LDH) level ≥ ULN unless the patient has been receiving plasma exchange 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 such as haptoglobin, schistocytes should be evaluated and discussed with Sponsor

5. Creatinine level ≥ ULN for age

6. 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 and for up to 5 months following of eculizumab treatment discontinuation.

7. Patient's parents/legal guardian must be willing and able to give written informed consent and patient must be willing to give written informed assent.

8. Able and willing to comply with study procedures.

Exclusion Criteria

1. TTP, (defined as ADAMTS-13 activity <5%) from an historical observation (prior to initiation of plasma therapy) or as tested at the screening visit by the central laboratory
2. Malignancy within 5 years of screening.
3. Typical HUS (Shiga toxin +).
4. Known HIV infection.
5. Identified drug exposure-related HUS.
6. Infection-related HUS.
7. HUS related to bone marrow transplant
8. HUS related to vitamin B12 deficiency
9. Renal function status requiring chronic dialysis
10. Patients with a confirmed diagnosis of sepsis
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 IVIG within 8 weeks or Rituximab therapy within 12 weeks of screening.
18. Patients receiving other immunosuppressive therapies such as steroids, mTOR inhibitors or tacrolimus are excluded unless: [1] part of an established post-transplant anti-rejection regime, [2] patient has confirmed anti-CFH antibody requiring immunosuppressive therapy, and [3] dose of such medications have been unchanged for at least 4 weeks prior to the screening period or [4] 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 ages from 12 and up to 18 years weighing < 40 kg

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Eculizumab	Eculizumab	-

Primary Outcome Measures

Name	Time	Method
Platelet Count Change From Baseline to 26 Weeks	From Baseline to 26 weeks
Percentage of Patients With Platelet Count Normalization	Through 26 weeks	The primary objective of the study (per protocol) was to assess the effect of eculizumab to reduce TMA as measured by platelet count change from baseline (BL) during the Treatment Period (26 weeks) in patients with plasma therapy (PT)-resistant aHUS (protocol defined), including assessment of the proportion of patients who achieved Platelet Count Normalization from baseline through 26 weeks. Platelet Count Normalization was defined as the platelet count observed to be ≥150 x 10\^9/L on at least two consecutive measurements which span a period of at least four weeks.
Percentage of Patients With Hematologic Normalization	Through 26 weeks	Hematologic Normalization was defined as normalization of both platelet count and lactic dehydrogenase (LDH) sustained for at least two consecutive measurements which spanned a period of at least four weeks.

Secondary Outcome Measures

Name	Time	Method
Percentage of Patients With Complete TMA Response	Through End of Study, Median Exposure 100.29 Weeks	The proportion of patients who achieved a Complete TMA Response from baseline through end of the study was determined. Complete TMA Response was defined as Hematologic Normalization plus improvement in renal function (defined as ≥25% reduction from baseline in serum creatinine), which was sustained for two consecutive measurements over a period of at least four weeks.
TMA Intervention Rate	Through End of Study, Median Exposure 100.29 Weeks	TMA Intervention Rate (# PE/PI and # Dialysis Events/Patient/Day) in the eculizumab treatment period (from baseline through end of the study) for PE/PI and (from the fifteenth day following the first eculizumab dose through end of the study) for new dialysis events was compared with the TMA Intervention Rate during the pre-eculizumab treatment period.
Platelet Count Change From Baseline to 156 Weeks	From Baseline to 156 Weeks
Percentage of Patients With Platelet Count Normalization	Through End of Study, Median Exposure 100.29 Weeks	Platelet Count Normalization was defined as the platelet count observed to be ≥150 x 10\^9/L on at least two consecutive measurements which span a period of at least four weeks.
Percentage of Patients With Hematologic Normalization	Through End of Study, Median Exposure 100.29 Weeks	Hematologic Normalization was defined as normalization of both platelet count and lactic dehydrogenase (LDH) sustained for at least two consecutive measurements which spanned a period of at least four weeks.
Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration	Induction Phase for 4 weeks followed by Maintenance Phase starting on Week 5 through 26 weeks or longer