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Complement Inhibition in aHUS Dialysis Patients (ACCESS)

Primary Purpose

Atypical Hemolytic Uremic Syndrome

Status

Terminated

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

CCX168

About this trial

This is an interventional treatment trial for Atypical Hemolytic Uremic Syndrome focused on measuring Atypical Hemolytic Uremic Syndrome, CCX168, dialysis, C5aR antagonist

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

A.O. Papa Giovanni XXIII - U.O. Nefrologia e Dialisi/IRCCS IRFMN - Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CCX168

Arm Description

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.

Outcomes

Primary Outcome Measures

Ex vivo thrombogenesis.

Secondary Outcome Measures

Complement component 3 serum levels.

Complement component 4 serum levels.

Complement component 5 serum levels.

Complement Factor H.

Complement component 5a.

Soluble thrombomodulin.

Fibrin split products..

Ex vivo C5b-9 deposition on microvascular endothelial cells

Changes in pre-dialysis and intradialytic blood pressure.

Changes in heart rate.

Safety and tolerability parameters including serious and non serious events

Patient health-related quality of life as measured by administration of EQ-5D-5L questionnaire.

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

Full Information

NCT ID

NCT02464891

First Posted

May 26, 2015

Last Updated

November 13, 2017

Sponsor

Mario Negri Institute for Pharmacological Research

Collaborators

ChemoCentryx

1. Study Identification

Unique Protocol Identification Number

NCT02464891

Brief Title

Complement Inhibition in aHUS Dialysis Patients

Acronym

ACCESS

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2017

Overall Recruitment Status

Terminated

Why Stopped

The study had accomplished its goal with the 6 patients who have been enrolled.

Study Start Date

June 4, 2015 (Actual)

Primary Completion Date

July 13, 2017 (Actual)

Study Completion Date

July 13, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Mario Negri Institute for Pharmacological Research

Collaborators

ChemoCentryx

4. Oversight

Data Monitoring Committee

5. Study Description

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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Atypical Hemolytic Uremic Syndrome

Keywords

Atypical Hemolytic Uremic Syndrome, CCX168, dialysis, C5aR antagonist

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

CCX168

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

CCX168

Primary Outcome Measure Information:

Title

Ex vivo thrombogenesis.

Time Frame