Eculizumab to Cemdisiran Switch in aHUS (NCT03999840) | Clinical Trial Compass
WithdrawnPhase 2
Eculizumab to Cemdisiran Switch in aHUS
Stopped: Due to the COVID global pandemic Sponsor has not received the economic support necessary for the study conduction.
Italy0Started 2021-01
Plain-language summary
Atypical Hemolytic Uremic Syndrome (aHUS) is a rare, lifethreatening, chronic disease of complement-mediated thrombotic microangiopathy (TMA) characterized by acute onset of renal impairment, thrombocytopenia, and microangiopathic hemolytic anemia. The estimated incidence of aHUS is approximately 0.5 per million per year. aHUS affects both adults and children, but is observed primarily in children and young adults.
Atypical HUS commonly develops due to dysregulation of the alternative complement pathway and can be sporadic (80%) or familial(20%).
The clinical course of aHUS is often unpredictable and can be dependent upon the specific genetic abnormality present within the complement system, if any, and/or triggering events associated with complement activation or inflammation, including autoimmune disease, transplant, pregnancy, infection, metabolic conditions, and drug use. In patients with dysregulated complement activity, such as those with complement mutations commonly observed in aHUS, the kidney vasculature is often the site of thrombosis stemming from endothelial injury.
Cemdisiran has been designed to reduce the level of C5 mRNA in the liver, thereby reducing levels of circulating C5 protein, inhibiting terminal complement pathway activity, and preventing formation and deposition of the MAC (C5-b9) on endothelial cells in the kidney. As a result, complement-mediated endothelial cell damage in patients with aHUS and subsequent progression to End Stage Renal Disease (ESRD) may be reduced.
Who can participate
Age range12 Years
SexALL
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Inclusion criteria
✓. 12 years and older at the time of consent;
✓. Written informed consent (of parents or the guardian in case of underage participants) to enter the study;
✓. Consent to stop eculizumab therapy during the whole study period and to resume eculizumab therapy in case of disease recurrence
✓. \>40 kg body weight;
✓. On stable disease status with eculizumab continuous therapy for aHUS for ≥ 12 consecutive months (stability assessed on the basis of hematological/biochemical parameters by the Investigator)
✓. Hematological remission at screening and inclusion;
✓. Estimated GFR (by the simplified MDRD equation) \> 30/ml/min 1.73 m2;
✓. Known high risk of aHUS recurrence due to at least one of the following criteria;
Exclusion criteria
✕. Solid organ or bone marrow/stem cell transplantation;
What they're measuring
1
Ex vivo complement activation on the surface of cultured microvascular endothelial cells exposed to patient sera
Timeframe: Changes from baseline and 16,32,44,60, 84 and 108 weeks after randomization.
Trial details
NCT IDNCT03999840
SponsorMario Negri Institute for Pharmacological Research
. Alanine transaminase (ALT) \>3×ULN, INR \>2 (or \>3.5 if on anticoagulants), or total bilirubin \>3×ULN (unless bilirubin elevation is due to Gilbert's syndrome);
✕. Clinical or biochemical evidence of active thrombotic; microangiopathy or flare of aHUS at the time of enrolment
✕. Evidence of Shigatoxin associated HUS;
✕. Patients who required intensified eculizumab therapy because of uncontrolled disease (these patients could be at very high risk of relapse after the shift, even in the cemdisiran treatment arm and their inclusion could be unsafe);
✕. Patients who did not relapse despite prolonged (\>3 months) interruption of eculizumab therapy (these would probably be low risk patients that are expected to be event-free throughout the whole study period independent of treatment allocation and could have a dilution effect for event analyses);
✕. Patients with a confirmed diagnosis of sepsis, defined as positive blood cultures within 7 days of the screening visit and not treated with antibiotics to which the organism is sensitive;
✕. 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;