An Open-Label, Multi-Center Clinical Trial of Eculizumab in Pediatric Patients With Atypical Hemolytic-Uremic Syndrome (aHUS)

• ClinicalTrials.gov Identifier: NCT01193348
• Recruitment Status: Completed
• First Posted: September 1, 2010
• Results First Posted: April 29, 2015
• Last Update Posted: April 29, 2015
• Sponsor: Alexion
• Information provided by (Responsible Party): Alexion

Study Description

Brief Summary:

The primary purpose is to assess the efficacy and safety of eculizumab in pediatric patients with aHUS to control TMA as characterized by thrombocytopenia, hemolysis and renal impairment.

Condition or disease	Intervention/treatment	Phase
Atypical Hemolytic-Uremic Syndrome	Drug: Eculizumab	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 22 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multi-Center Clinical Trial of Eculizumab in Pediatric Patients With Atypical Hemolytic-Uremic Syndrome
• Study Start Date: September 2010
• Actual Primary Completion Date: January 2014
• Actual Study Completion Date: April 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Eculizumab	Drug: Eculizumab; Fixed dosing is based on body weight cohorts. Adjustment of dose to accommodate patient growth is possible.

Outcome Measures

Primary Outcome Measures :

1. Proportion of Patients With Complete TMA Response [ Time Frame: Through 26 weeks ]
   Proportion of Patients with Complete TMA response was determined and defined by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline which was sustained for at least two consecutive measurements obtained at least four weeks apart).

Secondary Outcome Measures :

1. Proportion of Patients With Complete Hematologic Response [ Time Frame: Through 26 weeks ]
   Proportion of Patients with Complete Hematologic response through 26 weeks 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.
2. Proportion of Patients With Platelet Count Normalization [ Time Frame: Through 26 weeks ]
   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.
3. Proportion of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement [ Time Frame: Through 26 weeks ]
   Proportion of Patients with Estimated Glomerular Filtration Rate (eGFR) Improvement was determined and defined as an increase in eGFR by ≥ 15 mL/min/1.73m2 from baseline, sustained for at least two consecutive measurements obtained at least four weeks apart.
4. Platelet Count Change From Baseline to 26 Weeks [ Time Frame: Through 26 weeks ]
5. Proportion of Patients With Complete TMA Response [ Time Frame: Through End of Study, Median Exposure 55 Weeks ]
   Proportion of Patients with Complete TMA response was determined and defined by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline which was sustained for at least two consecutive measurements obtained at least four weeks apart).
6. Proportion of Patients With Complete Hematologic Response [ Time Frame: Through End of Study, Median Exposure 55 Weeks ]
   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.
7. Proportion of Patients With Platelet Count Normalization [ Time Frame: Through End of Study, Median Exposure 55 Weeks ]
   Proportion of Patients with Platelet Count Normalization through end of study 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
8. Proportion of Patients With Estimated Glomerular Filtration Rate (eGFR) Improvement [ Time Frame: Through End of Study, Median Exposure 55 Weeks ]
   Proportion of Patients with Estimated Glomerular Filtration Rate (eGFR) Improvement was determined and defined as an increase in eGFR by ≥ 15 mL/min/1.73m2 from baseline, sustained for at least two consecutive measurements obtained at least four weeks apart.
9. Platelet Count Change From Baseline to 52 Weeks [ Time Frame: Through 52 Weeks ]
10. Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 5 - <10kg) N=3 [ Time Frame: Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort.Maintenance Phase was started 1 week after induction phase and dosing of eculizumab administration was every 2 weeks or every 3 weeks depending on patient weight cohort ]
11. Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 10 - <20kg) N=7 [ Time Frame: Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort.Maintenance Phase was started 1 week after induction phase and dosing of eculizumab administration was every 2 weeks or every 3 weeks depending on patient weight cohort ]
12. Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 20 - <30kg) [ Time Frame: Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort. Maintenance Phase was started either 2 weeks or 3 weeks after induction phase depending on patient weight cohort ]
13. Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort 30 - <40kg) N=1 [ Time Frame: Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort. Maintenance Phase was started either 2 weeks or 3 weeks after induction phase depending on patient weight cohort ]
14. Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration (Body Weight Cohort ≥40kg) N=5 [ Time Frame: Induction Phase was between 1 and 4 weeks in length depending on patient weight cohort. Maintenance Phase was started either 2 weeks or 3 weeks after induction phase depending on patient weight cohort ]

Eligibility Criteria

• Ages Eligible for Study: 1 Month to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion:

1. Patient's parent/legal guardian must have been willing and able to give written informed consent and the patient must have been willing to give written informed assent (if applicable as determined by the central IRB/IEC).
2. Pediatric patients with aHUS: Patients could have been newly diagnosed, or with previously diagnosed disease, or post-kidney transplant with the disease.
3. Patients one month to 18 years and body weight ≥ 5kg.
4. Platelet count at screening and baseline visit must have been below lower limit of normal (<LLN). If screening visit and baseline visit are combined into one day, an additional platelet count value obtained at least 24 hours before screening/baseline sample must also be <LLN.
5. Exhibited signs or symptoms of hemolysis at start of current aHUS event (i.e., lactate dehydrogenase (LDH) ≥1.5 x Upper Limit of Normal [ULN] and hemoglobin ≤LLN), fragmented RBC with a negative Coombs test.
6. Serum Creatinine level ≥97 percentile for age at screening (patients requiring dialysis for acute renal failure are also eligible).
7. Patients with aHUS due to complement regulatory protein genetic abnormality or anti-complement factor antibody or those in whom known etiologies of hemolytic uremic syndrome (HUS) have been ruled out as confirmed in the Exclusion Criteria.
8. Patients must have been vaccinated against N. meningitidis, pneumococcus and haemophilus (per the vaccine label) at least 14 days prior to study drug initiation or otherwise be protected by prophylactic antibiotics. Patients under age two years were to receive antibiotic prophylaxis throughout the treatment period.
9. Female patients of childbearing potential (female patients who have achieved menarche) must have been 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 have agreed to continue to use adequate contraception methods for up to five months following discontinuation of eculizumab treatment.
10. Able and willing to comply with study procedures

Exclusion:

Any of the following was regarded as a criterion for exclusion from the study:

1. Known familial ADAMTS-13 deficiency (ADAMTS-13 <5%).
2. Shiga toxin E.coli-related hemolytic uremic syndrome (STEC-HUS [known Shiga toxin + E.coli]).
3. History of malignancy within five years of screening.
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. Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody positivity or syndrome.
10. Plasma Therapy for >5 weeks prior to enrollment.
11. Chronic dialysis (defined as dialysis on a regular basis as renal replacement therapy for end-stage renal disease [ESRD]).
12. Patients with a confirmed diagnosis of sepsis defined as positive blood cultures within seven 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. History of meningococcal/pneumococcal/gonococcal 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 eight weeks unless for unrelated medical condition (e.g., Hypogammaglobinemia), or chronic Rituximab therapy within 12 weeks of the screening visit.
18. Patients receiving other immunosuppressive therapies such as steroids, 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 antibody 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 four weeks prior to screening and throughout the entire trial
20. Prior use of eculizumab, hypersensitivity to eculizumab, to murine proteins or to one of the excipients.

Contacts and Locations

Locations

United States, Georgia

Atlanta, Georgia, United States, 30322

United States, New Jersey

Hackensack, New Jersey, United States, 07601

United States, Texas

Corpus Christi, Texas, United States, 78411

United States, Washington

Spokane, Washington, United States, 99204

Australia, South Australia

North Adelaide, South Australia, Australia, 5006

Belgium

Gent, Belgium, 9000

Canada, Ontario

Toronto, Ontario, Canada, M5G1X8

France

Lille, France, 59800

Marseille, France, 13385

Paris, France, 75935

Rouen, France, 76000

Germany

Hannover, Germany, 30625

Italy

Milano, Italy

Palermo, Italy, 90134

Netherlands

Nijmegen, Netherlands, 6525

United Kingdom

London, United Kingdom

Nottingham, United Kingdom

Sponsors and Collaborators

Alexion

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Tschumi S, Gugger M, Bucher BS, Riedl M, Simonetti GD. Eculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findings. Pediatr Nephrol. 2011 Nov;26(11):2085-8. doi: 10.1007/s00467-011-1989-4. Epub 2011 Aug 30.

• Responsible Party: Alexion
• ClinicalTrials.gov Identifier: NCT01193348
• Other Study ID Numbers: C10-003
• First Posted: September 1, 2010
• Results First Posted: April 29, 2015
• Last Update Posted: April 29, 2015
• Last Verified: April 2015

Keywords provided by Alexion:

Atypical Hemolytic-Uremic Syndrome

Additional relevant MeSH terms:

Azotemia; Hemolytic-Uremic Syndrome; Atypical Hemolytic Uremic Syndrome; Syndrome; Hemolysis; Disease; Pathologic Processes; Uremia; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Anemia, Hemolytic; Anemia; Hematologic Diseases; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Eculizumab; Complement Inactivating Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs