An Open-label, Multi-center Clinical Trial of Eculizumab in Adult Patients With Atypical Hemolytic-uremic Syndrome

The record Primary purpose is to assess the efficacy of eculizumab in adult patients with Atypical Hemolytic- Uremic Syndrome (aHUS) to control Thrombotic Microangiopathy (TMA) as characterized by thrombocytopenia, hemolysis and renal impairment.

Study Overview

• Status: Completed
• Conditions: Atypical Hemolytic-Uremic Syndrome
• Intervention / Treatment: Drug: Eculizumab

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Liège, Belgium, 4020
• France
  • Caen, France, 14033
  • Lille, France, 59037
  • Nantes, France, 44093
  • Nice, France, 6000
  • Paris, France, 75970
  • Paris, France, 75743
  • Toulouse, France, 31059
  • Tours, France, 37044
• Germany
  • Essen, Germany, 45147
  • Hannover, Germany, 30625
• Italy
  • Bergamo, Italy, 24127
  • Firenze, Italy, 50134
• Spain
  • Barcelona, Spain, 14004
  • Cordoba, Spain, 14004
• United Kingdom
  • Exeter, United Kingdom
  • London, United Kingdom
  • Newcastle, United Kingdom
• United States
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
  • New York
    • New York, New York, United States, 10032
  • Ohio
    • Columbus, Ohio, United States, 43210
  • Texas
    • Houston, Texas, United States, 77030

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion:

1. Patient must be willing and able to give written informed consent.
2. Patient's age > 18 years.
3. Patients exhibit thrombocytopenia, hemolysis and elevated Serum Creatinine.
4. Patients with diagnosis of aHUS with or without an identified complement regulatory protein genetic abnormality or anti-complement factor antibody and for whom etiologies of hemolytic uremic syndrome have been ruled out as confirmed in the exclusion criteria
5. 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 must agree to continue to use adequate contraception methods for up to 5 months following discontinuation of eculizumab treatment.
6. Able and willing to comply with study procedures

Exclusion:

1. Chronic dialysis.
2. Prior eculizumab use or hypersensitivity to eculizumab, to murine proteins or to one of the excipients.
3. Known familial a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) deficiency (ADAMTS-13 <5%).
4. Typical Hemolytic-Uremic Syndrome (HUS) (known Shiga toxin +).
5. History of malignancy within 5 years of screening.
6. Known human immunodeficiency virus (HIV) infection.
7. Identified drug exposure-related hemolytic-uremic syndrome (HUS).
8. Infection-related HUS.
9. HUS related to bone marrow transplant (BMT).
10. HUS related to vitamin B12 deficiency.
11. Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody positivity or syndrome.
12. 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.
13. 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.
14. Pregnancy or lactation.
15. Unresolved systemic meningococcal disease.
16. 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.
17. Patients receiving chronic intravenous immunoglobulin (IVIg) within 8 weeks or chronic Rituximab therapy within 12 weeks of screening visit.
18. Patients receiving other immunosuppressive therapies such as steroids, mechanist target of rapamycin (mTOR) inhibitors, calcineurin inhibitors (e.g., cyclosporine or tacrolimus) are excluded unless: [1] part of an established post-transplant anti-rejection regime, or [2] patient has confirmed anti-Complement Factor Antibodies requiring immunosuppressive therapy, or [3] steroids are being used for a condition other than aHUS (example asthma).
19. Participation in any other investigational drug trial or device trial, or procedures beginning 4 weeks prior to screening and throughout the entire trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Eculizumab

Drug: Eculizumab; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With Complete TMA Response	Proportion of Patients with Complete TMA response was determined and defined by normalization of hematological parameters (platelet count and LDH) and preservation of renal function (defined as < 25% increase in serum creatinine from baseline) which were sustained for at least two consecutive measurements obtained at least four weeks apart.	Through 26 weeks
Percentage of Patients With Modified Complete TMA Response	Proportion of Patients with Modified Complete TMA response through 26 weeks of treatment was determined and defined by normalization of hematological parameters (platelet count and LDH) and improvement in renal function (defined as ≥ 25% reduction from the baseline value in serum creatinine, which were sustained for at least two consecutive measurements obtained at least four weeks apart.	Through 26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet Count Change From Baseline to 26 Weeks		Through 26 weeks
Platelet Count Change From Baseline to 52 Weeks		Through 52 Weeks
Percentage of Patients With Complete Hematologic Response	Proportion of Patients with Complete Hematologic response through end of study was determined and defined by normalization of platelet count and LDH sustained for at least two consecutive measurements obtained at least four weeks apart.	Through 26 weeks
Percentage of Patients With Platelet Count Normalization	Proportion of Patients with Platelet Count Normalization through 26 weeks of treatment was determined and defined as the platelet count observed to be ≥ 150 x 109/L on at least two consecutive measurements which span a period of at least four weeks	Through 26 weeks
Percentage of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement	Proportion of Patients with Estimated Glomerular Filtration Rate (eGFR) Improvement was determined and defined as an increase in eGFR by ≥ 15 mL/min/1.73m^2 from baseline, sustained for at least two consecutive measurements obtained at least four weeks apart.	Through 26 weeks
Percentage of Patients With Complete TMA Response	Proportion of Patients with Complete TMA response through end of study was determined and defined by normalization of hematological parameters (platelet count and LDH) and preservation of renal function (defined as < 25% increase in serum creatinine from baseline) which were sustained for at least two consecutive measurements obtained at least four weeks apart.	Through End of Study, Median Exposure 52 Weeks
Percentage of Patients With Modified Complete TMA Response	Proportion of Patients with Modified Complete TMA response through end of study was determined and defined by normalization of hematological parameters (platelet count and LDH) and improvement in renal function (defined as ≥ 25% reduction from the baseline value in serum creatinine, which were sustained for at least two consecutive measurements obtained at least four weeks apart.	Through End of Study, Median Exposure 52 Weeks
Percentage of Patients With Complete Hematologic Response	Proportion of Patients with Complete Hematologic response through end of study of treatment was determined and defined by normalization of platelet count and LDH sustained for at least two consecutive measurements obtained at least four weeks apart.	Through End of Study, Median Exposure 52 Weeks
Percentage of Patients With Platelet Count Normalization	Proportion of Patients with Platelet Count Normalization through end of study of treatment was determined and defined as the platelet count observed to be ≥ 150 x 109/L on at least two consecutive measurements which span a period of at least four weeks	Through End of Study, Median Exposure 52 Weeks
Percentage of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement	Proportion of Patients with Estimated Glomerular Filtration Rate (eGFR) Improvement was determined and defined as an increase in eGFR by ≥ 15 mL/min/1.73m^2 from baseline sustained for at least two consecutive measurements obtained at least four weeks apart	Through End of Study, Median Exposure 52 Weeks

Collaborators and Investigators

• Sponsor: Alexion

Publications and helpful links

General Publications

• 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.
• Cofiell R, Kukreja A, Bedard K, Yan Y, Mickle AP, Ogawa M, Bedrosian CL, Faas SJ. Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS. Blood. 2015 May 21;125(21):3253-62. doi: 10.1182/blood-2014-09-600411. Epub 2015 Apr 1.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: August 31, 2010
• First Submitted That Met QC Criteria: September 2, 2010
• First Posted (Estimate): September 3, 2010

Study Record Updates

• Last Update Posted (Actual): May 30, 2017
• Last Update Submitted That Met QC Criteria: April 20, 2017
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: Atypical Hemolytic-Uremic Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Hematologic Diseases; Anemia; Thrombocytopenia; Blood Platelet Disorders; Anemia, Hemolytic; Thrombotic Microangiopathies; Uremia; Syndrome; Azotemia; Hemolysis; Hemolytic-Uremic Syndrome; Atypical Hemolytic Uremic Syndrome; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab
• Other Study ID Numbers: C10-004