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Complement Inhibition in aHUS Dialysis Patients (ACCESS)

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ClinicalTrials.gov Identifier: NCT02464891
Recruitment Status : Terminated (The study had accomplished its goal with the 6 patients who have been enrolled.)
First Posted : June 8, 2015
Last Update Posted : November 14, 2017
Sponsor:
Collaborator:
ChemoCentryx
Information provided by (Responsible Party):
Mario Negri Institute for Pharmacological Research

Brief Summary:
This study evaluates the effect of CCX168, a C5aR Antagonist, Oral Administration on Ex Vivo Thrombus Formation and Disease Activity in ten patients with diagnosis of Atypical Hemolytic Uremic Syndrome with or without genetic abnormalities in the complement system or thrombomodulin, on stable chronic extracorporeal or peritoneal dialysis therapy since at least 6 months.

Condition or disease Intervention/treatment Phase
Atypical Hemolytic Uremic Syndrome Drug: CCX168 Phase 2

Detailed Description:
Inherited defects that determine uncontrolled activation of the alternative complement pathway have been well documented in atypical Hemolytic Uremic Syndrome (aHUS) patients. Research in recent years has identified more than 120 different mutations, accounting for around 40%-60% of cases, in the genes encoding complement factor H (CFH), membrane cofactor protein (MCP), complement factor I (CFI), C3, complement factor B (CFB), and thrombomodulin (THBD). A therapeutic approach could be the administration of molecules that pharmacologically target complement activation, which is the primary common pathogenic mechanism in all genetic forms of aHUS. Eculizumab has been successfully used as prophylaxis of aHUS recurrences in subjects with plasma dependent or plasma resistant disease or in renal transplant recipients at high risk of recurrence due to CFH, CFI, or C3 complement gene mutations. However the drug must be administered chronically and drug spacing or discontinuance was associated with disease recurrence in the graft. The C5aR receptor antagonist CCX168 could present an appealing alternative to eculizumab for post-transplant prophylaxis of aHUS recurrences since it is orally administrable with lower cost of goods. In addition, CCX168 is theoretically associated with lower risk of infections than eculizumab since the former does not target C5b and leaves the terminal complement pathway intact.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Phase 2 Study to Assess the Effect of C5aR Antagonist Therapy by CCX168 Oral Administration on ex Vivo Thrombus Formation and Disease Activity in ESRD Patients With Atypical Hemolytic Uremic Syndrome
Actual Study Start Date : June 4, 2015
Actual Primary Completion Date : July 13, 2017
Actual Study Completion Date : July 13, 2017


Arm Intervention/treatment
Experimental: CCX168
Study medication will be administered as hard gelatin capsules containing 10 mg CCX168. Patients will take 30 mg CCX168, given as 3 x 10 mg capsule, twice daily for 15 days.
Drug: CCX168



Primary Outcome Measures :
  1. Ex vivo thrombogenesis. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]

Secondary Outcome Measures :
  1. Complement component 3 serum levels. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  2. Complement component 4 serum levels. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  3. Complement component 5 serum levels. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  4. Complement Factor H. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  5. Complement component 5a. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  6. Soluble thrombomodulin. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  7. Fibrin split products.. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  8. Ex vivo C5b-9 deposition on microvascular endothelial cells [ Time Frame: At baseline. ]
  9. Changes in pre-dialysis and intradialytic blood pressure. [ Time Frame: The participants will be followed for the duration of the study up to 21 days. ]
  10. Changes in heart rate. [ Time Frame: The participants will be followed for the duration of the study up to 21 days. ]
  11. Safety and tolerability parameters including serious and non serious events [ Time Frame: The participants will be followed for the duration of the study up to 21 days. ]
  12. Patient health-related quality of life as measured by administration of EQ-5D-5L questionnaire. [ Time Frame: Changes from baseline at 14 and 21 day. ]
  13. Characterization of CCX168 pharmacokinetic profile after oral administration by determining by maximum plasma concentration, time of maximum plasma concentration and area under the plasma concentration-time curve from time 0 to hour 6 [ Time Frame: Changes from Baseline at 4,9,11 and 15 day. ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age >18 years;
  • Diagnosis of aHUS with or without identified genetic abnormalities in the complement system or thrombomodulin;
  • Stable chronic extracorporeal or peritoneal dialysis therapy since at least 6 months;
  • Written informed consent.

Exclusion Criteria:

  • Women of childbearing potential or women who are breastfeeding;
  • Shiga toxin-associated HUS or secondary forms of thrombotic microangiopathy;
  • ADAMTS13 activity <10 % or circulating anti ADAMTS13 autoantibodies consistent with the diagnosis of thrombotic thrombocytopenic purpura;
  • Need for specific intervention with plasma therapy and/or complement inhibitors as deemed clinically appropriate;
  • Plasma therapy or treatment with complement inhibitors or antiplatelet and antithrombotic agents over the last two weeks;
  • Liver function impairment (serum liver enzymes or bilirubin levels >3 x upper limit of normal);
  • Neutrophil count < 2000/μL or lymphocyte count < 1000/μL;
  • Infection requiring antibiotic treatment within the previous 4 weeks prior to screening;
  • Participated in any clinical study of an investigational product within 30 days prior to screening or within 5 half-lives after taking the last dose;
  • History or presence of any medical condition or disease which, in the opinion of the Investigator may place the subject at unacceptable risk for study participation;
  • Inability to understand the potential risks and benefits of the study;
  • Legal incapacity.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02464891


Locations
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Italy
A.O. Papa Giovanni XXIII - U.O. Nefrologia e Dialisi/IRCCS IRFMN - Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò
Bergamo, Italy
Sponsors and Collaborators
Mario Negri Institute for Pharmacological Research
ChemoCentryx
Investigators
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Study Chair: Giuseppe Remuzzi, MD IRCCS - Mario Negri Institute for Pharmacological Research/A.O. Papa Giovanni XXIII- BG
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier: NCT02464891    
Other Study ID Numbers: CL006_168
2014-004261-24 ( EudraCT Number )
First Posted: June 8, 2015    Key Record Dates
Last Update Posted: November 14, 2017
Last Verified: November 2017
Keywords provided by Mario Negri Institute for Pharmacological Research:
Atypical Hemolytic Uremic Syndrome
CCX168
dialysis
C5aR antagonist
Additional relevant MeSH terms:
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Azotemia
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