Clinical Trial: Complement Inhibition in aHUS Dialysis Patients

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

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

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.

Detailed Summary: 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.
Sponsor: Mario Negri Institute for Pharmacological Research

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

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Complement component 3 serum levels. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  • Complement component 4 serum levels. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  • Complement component 5 serum levels. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  • Complement Factor H. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  • Complement component 5a. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  • Soluble thrombomodulin. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  • Fibrin split products.. [ Time Frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal). ]
  • Ex vivo C5b-9 deposition on microvascular endothelial cells [ Time Frame: At baseline. ]
  • 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. ]
  • Changes in heart rate. [ Time Frame: The participants will be followed for the duration of the study up to 21 days. ]
  • 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. ]
  • 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. ]
  • 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. ]


Original Secondary Outcome: Same as current

Information By: Mario Negri Institute for Pharmacological Research

Dates:
Date Received: May 26, 2015
Date Started: June 4, 2015
Date Completion: July 2017
Last Updated: March 13, 2017
Last Verified: March 2017