Eculizumab in Hypertensive Emergency-associated Hemolytic Uremic Syndrome

Phase

Condition

Renal Failure

Kidney Failure (Pediatric)

Platelet Disorders

Treatment

Renin angiotensin system blockers

Soliris®

Clinical Study ID

NCT05726916

APHP211039

Ages > 18
All Genders

Study Summary

Hemolytic and uremic syndrome (HUS) is a clinic-biological syndrome related to thrombotic microangiopathy affecting predominantly the kidney. Atypical HUS (aHUS) has been historically defined as HUS occurring in the absence of infectious event. The role of complement dysregulation in aHUS pathophysiology has been largely demonstrated, since C genetic rare variants are present in 60-70% aHUS patients. In line with the frequency of C dysregulation in aHUS, Eculizumab, an anti-C5 monoclonal antibody, has dramatically improved aHUS patients prognosis.

Numerous conditions have been associated with aHUS, including hypertensive emergency (HE), a syndrome of acute blood pressure flare associated with end-organ damage. In cases of HE-aHUS, whether primary aHUS is complicated by secondary HE, or primary HE leads to secondary aHUS is still debated.

The investigators recently demonstrated that C genetic variants frequency was similar in patients with HE-aHUS and patients with aHUS without HE, suggesting a major role for C dysregulation in HE-aHUS. Consequently, the investigators propose to evaluate, in HE-aHUS patients, the benefit of a strategy with early Eculizumab therapy (used within its marketing authorization and its conditions of refunding by the health insurance in usual care), compared to standard of care including tight blood pressure control.

The hypothesis suggests that C dysregulation may impact renal prognosis of HE-aHUS patients. The investigator's aim to demonstrate that early Eculizumab therapy improves prognosis of HE-aHUS patients.

Method

The HYPERSHU study is a randomized, controlled, open-labelled study including HE-aHUS patients with severe AKI and no evidence of other conditions associated with HUS (infections, autoimmunity, drugs, pregnancy). The investigators plan to include 62 patients. Patients will be randomized in 2 arms:

Early Eculizumab therapy (for 3 months) added to standard of care (tight blood pressure control).
Standard of care alone with tight blood pressure control. Renal function after 6 months is the primary evaluation criterium.

HE is a frequently associated with aHUS, and strongly impacts patient renal prognosis. Efficient therapeutic strategies are still lacking for this condition. The HYPERSHU study will allow to evaluate the benefit of early Eculizumab therapy in patients with HE-aHUS and severe renal dysfunction.

Eligibility Criteria

Inclusion

Inclusion Criteria:

≥ 18years
Hospitalization for HE-aHUS within prior 10 days:
Presume acute renal failure (renal replacement therapy or serum creatinine ≥ 354µM)
Mechanical hemolysis including: anemia, thrombopenia, and: low haptoglobin (<LNL), or elevated LDH (>1,5UNL), or presence of schistocytes
Severe hypertension with systolic blood pressure >180mmHg or diastolic bloodpressure>110mmHg
Target organ damage, including neurological involvement (notably hypertensiveencephalopathy, headache, confusion, nausea, posterior reversible encephalopathysyndrome), or cardiovascular involvement (notably acute left ventricular failure,acute pulmonary edema, acute cardiac ischemia, chest pain, dyspnea,palpitations), or ophtalmological involvement (notably ischemic retinopathy orblurred vision)
Effective contraception during the study and for at least 5 months after the last doseof treatment with eculizumab
Subject affiliated to a social security regimen
Subject having signed written informed consent.

Exclusion

Exclusion Criteria:

Atrophic kidneys with maximum length<8cm on recent (<1 month) renal ultrasound, CTscan, or renal MRI
High clinical suspicion of Complement-mediated aHUS (including familial history ofaHUS)
High clinical suspicion of typical HUS (including Shiga Toxin-producing E. Coliinfection) or Thrombotic thrombocytopenic purpura
High clinical suspicion of secondary HUS related to autoimmune disease (includinglupus, scleroderma, antiphospholipid syndrome, ANCA vasculitis), or C3 glomerulopathy.
High clinical suspicion of recent hemorrhagic or ischemic stroke.
ADAMTS 13<10%, HIV or HCV infection, positivity of 2 markers among: anticardiolipinIgG/antiBeta2 GP1 IgG/lupus anticoagulant, positivity of ANCA (ELISA PR3 or MPO)
Active infection
Subjects with unresolved Neisseria meningitidis infection
Subjects refusing Neisseria meningitidis vaccination or refusing antibioprophylaxiswith oracillin (In case of penicillin allergy, antibioprophylaxis with macrolidecouldbeproposed according to ANSM recommendations (azithromycin or roxithromycin)).
Contra-indication to eculizumab or renin angiotensin system blockers
Solid organ or haematopoietic transplant
History (<1year) of active cancer or exposition to drugs associated with aHUS (< 3months)
Severe cognitive or psychiatric disorders, patients unable to give an informedconsent.
PCR SARS-CoV2 positive
Pregnant or breastfeeding woman or ineffective contraception
Persons deprived of their liberty by judicial or administrative decision,
Persons under legal protection (guardianship, curatorship)
Participation in another interventional study involving human participants or being inthe exclusion period at the end of a previous study involving human participants.

Study Design

Renin angiotensin system blockers

November 09, 2023

November 09, 2027

Connect with a study center

Tenon Hospital
Paris, 75020
France
Active - Recruiting

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