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Open Label Controlled Trial of Eculizumab in Adult Patients With Plasma Therapy-sensitive Atypical Hemolytic Uremic Syndrome (aHUS) (aHUS)

Primary Purpose

Atypical Hemolytic Uremic Syndrome

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
eculizumab
Sponsored by
Alexion
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Atypical Hemolytic Uremic Syndrome focused on measuring aHUS

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Critera:

  1. Male or female patients' ≥18 years of age who have been diagnosed with Atypical Hemolytic-Uremic Syndrome (aHUS).
  2. Patients must be receiving PT for aHUS and must be observed to 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 first dose of IP.
  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.
  5. Lactate dehydrogenase (LDH) level 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 such as haptoglobin, schistocytes should be evaluated and discussed with Sponsor.
  6. Creatinine level ≥ ULN for age.
  7. 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 eculizumab treatment discontinuation.
  8. Able to give written informed consent.
  9. 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. Patients with a confirmed diagnosis of sepsis.
  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 IVIg within 8 weeks or Rituximab therapy within 12 weeks of the screening visit.
  17. 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 and throughout the Observation Period or [4] 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.

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

eculizumab

Arm Description

Outcomes

Primary Outcome Measures

Percentage of Patients With TMA Event-free Status
TMA Event-free status is 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.
Percentage of Patients With Hematologic Normalization
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.
Percentage of Patients With Complete TMA Response
The proportion of patients who achieved a Complete TMA Response from baseline through 26 weeks of treatment with eculizumab 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.

Secondary Outcome Measures

TMA Intervention Rate
TMA Intervention Rate (# PE/PI and # Dialysis Events/Patient/Day) in the eculizumab treatment period (from baseline through 26 weeks) for PE/PI and (from the fifteenth day following the first eculizumab dose through 26 weeks) for new dialysis events was compared with the TMA Intervention Rate during the pre-eculizumab treatment period.
Platelet Count Change From Baseline to 26 Weeks
Percentage of Patients With Platelet Count Normalization
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 TMA Event-free Status
TMA Event-free status is 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.
Percentage of Patients With Hematologic Normalization
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.
Percentage of Patients With Complete TMA Response
The proportion of patients who achieved a Complete TMA Response from baseline through end of study with eculizumab 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
TMA Intervention Rate (# PE/PI and # Dialysis Events/Patient/Day) in the eculizumab treatment period (from baseline through end of study) for PE/PI and (from the fifteenth day following the first eculizumab dose through end of 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
Percentage of Patients With Platelet Count Normalization
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 Not specified.
Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration

Full Information

First Posted
February 3, 2009
Last Updated
June 30, 2015
Sponsor
Alexion
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1. Study Identification

Unique Protocol Identification Number
NCT00838513
Brief Title
Open Label Controlled Trial of Eculizumab in Adult Patients With Plasma Therapy-sensitive Atypical Hemolytic Uremic Syndrome (aHUS)
Acronym
aHUS
Official Title
An Open-label, Multi-center Controlled Clinical Trial of Eculizumab in Adult Patients With Plasma Therapy-sensitive Atypical Hemolytic Uremic Syndrome (AHUS)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2015
Overall Recruitment Status
Completed
Study Start Date
July 2009 (undefined)
Primary Completion Date
October 2010 (Actual)
Study Completion Date
December 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alexion

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Atypical Hemolytic Uremic Syndrome
Keywords
aHUS

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
eculizumab
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
eculizumab
Intervention Description
All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Primary Outcome Measure Information:
Title
Percentage of Patients With TMA Event-free Status
Description
TMA Event-free status is 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.
Time Frame
Through 26 weeks
Title
Percentage of Patients With Hematologic Normalization
Description
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.
Time Frame
Through 26 weeks
Title
Percentage of Patients With Complete TMA Response
Description
The proportion of patients who achieved a Complete TMA Response from baseline through 26 weeks of treatment with eculizumab 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.
Time Frame
Through 26 weeks
Secondary Outcome Measure Information:
Title
TMA Intervention Rate
Description
TMA Intervention Rate (# PE/PI and # Dialysis Events/Patient/Day) in the eculizumab treatment period (from baseline through 26 weeks) for PE/PI and (from the fifteenth day following the first eculizumab dose through 26 weeks) for new dialysis events was compared with the TMA Intervention Rate during the pre-eculizumab treatment period.
Time Frame
Through 26 weeks
Title
Platelet Count Change From Baseline to 26 Weeks
Time Frame
From Baseline to 26 Weeks
Title
Percentage of Patients With Platelet Count Normalization
Description
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
Time Frame
Through 26 Weeks
Title
Percentage of Patients With TMA Event-free Status
Description
TMA Event-free status is 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.
Time Frame
Through End of Study, Median Exposure 156 Weeks
Title
Percentage of Patients With Hematologic Normalization
Description
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.
Time Frame
Through End of Study, Median Exposure 156 Weeks
Title
Percentage of Patients With Complete TMA Response
Description
The proportion of patients who achieved a Complete TMA Response from baseline through end of study with eculizumab 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.
Time Frame
Through End of Study, Median Exposure 156 Weeks
Title
TMA Intervention Rate
Description
TMA Intervention Rate (# PE/PI and # Dialysis Events/Patient/Day) in the eculizumab treatment period (from baseline through end of study) for PE/PI and (from the fifteenth day following the first eculizumab dose through end of study) for new dialysis events was compared with the TMA Intervention Rate during the pre-eculizumab treatment period.
Time Frame
Through End of Study, Median Exposure 156 Weeks
Title
Platelet Count Change From Baseline to 156 Weeks
Time Frame
From Baseline to 156 Weeks
Title
Percentage of Patients With Platelet Count Normalization
Description
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 Not specified.
Time Frame
Through End of Study, Median Exposure 156 Weeks
Title
Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration
Time Frame
Induction Phase for 4 weeks followed by Maintenance Phase starting on Week 5 through 26 weeks or longer.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Critera: Male or female patients' ≥18 years of age who have been diagnosed with Atypical Hemolytic-Uremic Syndrome (aHUS). Patients must be receiving PT for aHUS and must be observed to 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 first dose of IP. 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. Known complement regulatory protein genetic abnormality. Lactate dehydrogenase (LDH) level 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 such as haptoglobin, schistocytes should be evaluated and discussed with Sponsor. Creatinine level ≥ ULN for age. 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 eculizumab treatment discontinuation. Able to give written informed consent. Able and willing to comply with study procedures. Exclusion Criteria: 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. Malignancy within 5 years of screening. Typical HUS (Shiga toxin +). Known HIV infection. Identified drug exposure-related HUS. Infection-related HUS. HUS related to bone marrow transplant. HUS related to vitamin B12 deficiency. Patients with a confirmed diagnosis of sepsis. 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. Pregnancy or lactation. Unresolved meningococcal disease. Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody positivity or syndrome. 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. Patients who have received previous treatment with eculizumab. Patients receiving IVIg within 8 weeks or Rituximab therapy within 12 weeks of the screening visit. 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 and throughout the Observation Period or [4] patient is experiencing an acute aHUS relapse immediately after transplant. 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. 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. Hypersensitivity to eculizumab, to murine proteins or to one of the excipients.
Facility Information:
City
Toronto
Country
Canada
City
Bois-Guillaume
ZIP/Postal Code
76230
Country
France
City
Bordeaux
ZIP/Postal Code
33076
Country
France
City
Lyon
ZIP/Postal Code
69437
Country
France
City
Nantes
ZIP/Postal Code
44093
Country
France
City
Paris
ZIP/Postal Code
75743
Country
France
City
Strasbourg
ZIP/Postal Code
67091
Country
France
City
Hannover
ZIP/Postal Code
30625
Country
Germany
City
Genova
ZIP/Postal Code
16147
Country
Italy
City
Nijmegen
ZIP/Postal Code
6525
Country
Netherlands
City
Stockholm
ZIP/Postal Code
14186
Country
Sweden
City
Exeter
Country
United Kingdom
City
Glasgow
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
33783815
Citation
Pugh D, O'Sullivan ED, Duthie FA, Masson P, Kavanagh D. Interventions for atypical haemolytic uraemic syndrome. Cochrane Database Syst Rev. 2021 Mar 23;3(3):CD012862. doi: 10.1002/14651858.CD012862.pub2.
Results Reference
derived
PubMed Identifier
23738544
Citation
Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, Karpman D, Lebranchu Y, Mariat C, Menne J, Moulin B, Nurnberger J, Ogawa M, Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship T, Loirat C. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013 Jun 6;368(23):2169-81. doi: 10.1056/NEJMoa1208981.
Results Reference
derived

Learn more about this trial

Open Label Controlled Trial of Eculizumab in Adult Patients With Plasma Therapy-sensitive Atypical Hemolytic Uremic Syndrome (aHUS)

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