Open Label Controlled Trial of Eculizumab in Adult Patients With Plasma Therapy-Resistant aHUS (aHUS)

• ClinicalTrials.gov Identifier: NCT00844545
• Recruitment Status: Completed
• First Posted: February 16, 2009
• Results First Posted: December 1, 2014
• Last Update Posted: July 23, 2015
• Sponsor: Alexion Pharmaceuticals
• Information provided by (Responsible Party): Alexion Pharmaceuticals

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-resistant Atypical Hemolytic-Uremic Syndrome (aHUS).

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 16 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multi-Center Controlled Clinical Trial of Eculizumab in Adult Patients With Plasma Therapy-Resistant Atypical Hemolytic Uremic Syndrome (aHUS)
• Study Start Date: May 2009
• Actual Primary Completion Date: September 2010
• Actual Study Completion Date: July 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Platelet Count Change From Baseline to 26 Weeks [ Time Frame: From Baseline to 26 weeks ]
2. Percentage of Patients With Platelet Count Normalization [ Time Frame: 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.
3. Percentage of Patients With Hematologic Normalization [ Time Frame: 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 :

1. Percentage of Patients With Complete TMA Response [ Time Frame: Through 26 weeks ]
   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 as ≥25% reduction from baseline in serum creatinine), which was sustained for two consecutive measurements over a period of at least four weeks.
2. TMA Intervention Rate [ Time Frame: Through 26 weeks ]
   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.
3. Platelet Count Change From Baseline to 156 Weeks [ Time Frame: From Baseline to 156 Weeks ]
4. Percentage of Patients With Platelet Count Normalization [ Time Frame: 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.
5. Percentage of Patients With Hematologic Normalization [ Time Frame: 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.
6. Percentage of Patients With Complete TMA Response [ Time Frame: 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.
7. TMA Intervention Rate [ Time Frame: 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.
8. 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. ]

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Georgia

Atlanta, Georgia, United States, 30322

United States, Indiana

Fort Wayne, Indiana, United States, 46804

United States, New York

New York, New York, United States, 10032

New York, New York, United States, 10065

United States, Texas

Grapevine, Texas, United States, 76051

Houston, Texas, United States, 77030

Austria

Innsbruck, Austria, 6020

France

Bordeaux, France, 33076

Lyon, France, 69437

Nantes, France, 44093

Paris, France, 75743

Quimper, France, 29107

Saint Priest en Jarez, France, 42270

Tours, France, 37044

Germany

Aachen, Germany, 52074

Essen, Germany, 45147

United Kingdom

Newcastle, United Kingdom, NE7 7DN

Sponsors and Collaborators

Alexion Pharmaceuticals

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:CD012862. doi: 10.1002/14651858.CD012862.pub2.

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, Nürnberger 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.

• Responsible Party: Alexion Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00844545
• Other Study ID Numbers: C08-002A; BB-IND-11075; EudraCT Number 2008-006952-23
• First Posted: February 16, 2009
• Results First Posted: December 1, 2014
• Last Update Posted: July 23, 2015
• Last Verified: June 2015

Keywords provided by Alexion Pharmaceuticals:

aHUS

Additional relevant MeSH terms:

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