Eculizumab in Hypertensive Emergency-associated Hemolytic Uremic Syndrome

NCT05726916 | Recruiting Phase 3

• 1 other identifier: APHP211039
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hypertensive Emergency-associated Hemolytic Uremic Syndrome

Keywords

Eculizumab; Hypertensive emergency; atypical hemolytic uremic syndrome; complement; acute kidney injury; end stage renal disease

Outcome Measures

Primary Outcomes (1)

• 6-month response to therapy

  6-month response to therapy, as defined by the absence of any of the following events: i) lack of renal efficacy at 6-month follow-up: persistent renal replacement therapy, eGFR \<15ml/mn/1,73m2, or patient death; ii) lack of early hemolysis control with persistent hemolysis at W2 despite well conducted antihypertensive therapy. Any Eculizumab rescue in the control group will be considered as a failure.

  6 month

Secondary Outcomes (9)

• Frequency of Complement genetic rare variants

  up to 12 months

• Rate of renal replacement therapy

  Week 13 and 12 months

• Frequency of severe infections

  up to 12 months

• Time to resolution of hemolysis

  up to 12 months

• Frequency of kidney lesions

  up to 12 months

Study Arms (2)

Experimental group

EXPERIMENTAL

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: Soliris®

Control group

ACTIVE COMPARATOR

Blood pressure control with renin angiotensin system blockers

Drug: Renin angiotensin system blockers

Interventions

Soliris® DRUG

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

Also known as: Eculizumab

Experimental group

Renin angiotensin system blockers DRUG

Blood pressure control with renin angiotensin system blockers

Control group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥ 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Tenon Hospital

Paris, 75020, France

RECRUITING

MeSH Terms

Conditions

Hypertensive Crisis; Atypical Hemolytic Uremic Syndrome; Acute Kidney Injury; Kidney Failure, Chronic

Interventions

eculizumab

Condition Hierarchy (Ancestors)

Hypertension; Vascular Diseases; Cardiovascular Diseases; Hemolytic-Uremic Syndrome; Uremia; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Cytopenia; Renal Insufficiency; Renal Insufficiency, Chronic; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The present proposal is a randomized, controlled, multicenter, open-labelled study. In the experimental group, Ecu will be administered at randomization according to usual recommendations in aHUS (4 intravenous administrations, 900mg/w until W4 then 1200mg/2w starting at W5, until W13). In both experimental and control group, BP control with systematic maximum tolerated dose of RAS blockers will be administered.

Study Record Dates

• First Submitted: December 16, 2022
• First Posted: February 14, 2023
• Study Start: November 9, 2023
• Primary Completion (Estimated): May 9, 2026
• Study Completion (Estimated): November 9, 2027
• Last Updated: January 5, 2024

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)