Eculizumab in Hypertensive Emergency-associated Hemolytic Uremic Syndrome

Official title

Eculizumab in Hypertensive Emergency-associated Hemolytic Uremic Syndrome: a Randomized Multicenter Controlled Trial

Overview

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.

Interventions

• Drug Soliris®
  Eculizumab IV administration (900mg/w during 4w then 1200 mg at w5 and 1200mg/2w for 8w) + Blood pressure control with renin angiotensin system blockers
• Drug Renin angiotensin system blockers
  Blood pressure control with renin angiotensin system blockers

Primary outcome measures

• 6-month response to therapy [Time frame: 6 month]

Secondary outcome measures (9)

• Frequency of Complement genetic rare variants [Time frame: up to 12 months]
• Rate of renal replacement therapy [Time frame: Week 13 and 12 months]
• Frequency of severe infections [Time frame: up to 12 months]
• Time to resolution of hemolysis [Time frame: up to 12 months]
• Frequency of kidney lesions [Time frame: up to 12 months]
• Costs relating to renal replacement therapy (or lack of) [Time frame: up to 12 months]
• Costs relating to Eculizumab therapy [Time frame: up to 12 months]
• Costs relating to other antihypertensive treatments [Time frame: up to 12 months]
• Costs relating to hospitalizations [Time frame: up to 12 months]

Eligibility criteria

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 blood pressure>110mmHg
• Target organ damage, including neurological involvement (notably hypertensive encephalopathy, headache, confusion, nausea, posterior reversible encephalopathy syndrome), or cardiovascular involvement (notably acute left ventricular failure, acute pulmonary edema, acute cardiac ischemia, chest pain, dyspnea, palpitations), or ophtalmological involvement (notably ischemic retinopathy or blurred vision)
• Effective contraception during the study and for at least 5 months after the last dose of treatment with eculizumab
• Subject affiliated to a social security regimen
• Subject having signed written informed consent.

Exclusion criteria

• Atrophic kidneys with maximum length<8cm on recent (<1 month) renal ultrasound, CT scan, or renal MRI
• High clinical suspicion of Complement-mediated aHUS (including familial history of aHUS)
• High clinical suspicion of typical HUS (including Shiga Toxin-producing E. Coli infection) or Thrombotic thrombocytopenic purpura
• High clinical suspicion of secondary HUS related to autoimmune disease (including lupus, 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: anticardiolipin IgG/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 antibioprophylaxis with oracillin (In case of penicillin allergy, antibioprophylaxis with macrolide couldbeproposed 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 (< 3 months)
• Severe cognitive or psychiatric disorders, patients unable to give an informed consent.
• 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 in the exclusion period at the end of a previous study involving human participants.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 1 center

• Tenon Hospital — Paris

Identifiers

NCT: NCT05726916 · APHP211039

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗