TerminatedNCT02464891ACCESSUpdated Nov 14, 2017

Complement Inhibition in aHUS Dialysis Patients

A Phase 2 interventional study of CCX168 in Atypical Hemolytic Uremic Syndrome, sponsored by Mario Negri Institute for Pharmacological Research. Terminated at 1 site in Italy. Open to participants aged 18 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2017-11-14.

Sponsored by Mario Negri Institute for Pharmacological Research · Phase 2, Interventional, and Treatment

Why this study was terminated

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

Phase: Phase 2
Study type: Interventional
Enrollment: 6
Allocation: Not applicable
Ages: 18 Years and older
Sex: All

Study 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.

Read the 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.

Conditions studied

Atypical Hemolytic Uremic Syndrome

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Keywords

Atypical Hemolytic Uremic Syndrome
CCX168
dialysis
C5aR antagonist

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: Yes

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

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.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 6 participants (actual)

Study arms

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

Interventions

DrugCCX168

What researchers measure

Primary outcomes

Ex vivo thrombogenesis.
Time frame: Changes from baseline at day 2,14 (during CCX168 treatment), 16 and 21 (after treatment withdrawal).

Secondary outcomes

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.

Study locations

1 site

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

References and documents

Publications

Aiello S, Gastoldi S, Galbusera M, Ruggenenti P, Portalupi V, Rota S, Rubis N, Liguori L, Conti S, Tironi M, Gamba S, Santarsiero D, Benigni A, Remuzzi G, Noris M. C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19. Blood Adv. 2022 Jan 8;6(3):866-881. doi: 10.1182/bloodadvances.2021005246. Erratum In: Blood Adv. 2022 May 10;6(9):2812. doi: 10.1182/bloodadvances.2022007722. PubMed 34852172 ↗

Registry details

Key details

Study ID: NCT02464891
Lead sponsor: Mario Negri Institute for Pharmacological Research
Collaborators: Amgen
Responsible party: Sponsor
First posted: Jun 8, 2015
Start date: Jun 4, 2015
Primary completion: Jul 13, 2017
Completion: Jul 13, 2017
Last update: Nov 14, 2017

Study contacts

Giuseppe Remuzzi, MD

study chair · IRCCS - Mario Negri Institute for Pharmacological Research/A.O. Papa Giovanni XXIII- BG

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

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