Efficacy of Eculizumab in Hypertensive Emergency-Associated Hemolytic Uremic Syndrome with Severe Renal Impairment: A Randomized Multicenter Controlled Trial

The primary objective of this study is to demonstrate the efficacy of early **Eculizumab** administration, in addition to standard blood pressure control, on reducing dialysis-dependence at six months in patients with hypertensive emergency-associated hemolytic uremic syndrome (HE-aHUS) who have severely impaired initial renal function. This is clinically relevant as it aims to improve renal outcomes and reduce the need for long-term dialysis in this patient population.

Secondary objectives include:

• Evaluating the role of complement biomarkers in predicting therapeutic response.
• Assessing the frequency of complement genetic rare variants in the study population.
• Determining the efficacy of early Eculizumab administration on the risk of renal replacement therapy at 3 and 12 months.
• Evaluating the frequency of severe infections in both treatment groups.
• Assessing the time to resolution of hemolysis and acute dialysis.
• Evaluating the frequency and prognosis of histological lesions, if a kidney biopsy is performed.
• Assessing the medico-economic impact of Eculizumab.
• Conducting a pangenomic analysis to identify new genetic variants associated with HE-aHUS in an ancillary study.
• Storing residual samples for a biological collection to identify new potential genetic and pathophysiological determinants of HE-aHUS in any other ancillary studies.

The clinical trial involves **adult patients** diagnosed with atypical hemolytic uremic syndrome (aHUS) associated with hypertensive emergencies (HE) and severe kidney involvement, characterized by the need for dialysis or a serum creatinine level of 354 μM or higher. The study population includes both male and female participants aged 18 years and older. Participants were selected based on recent hospitalization for HE-aHUS within the prior 10 days, with conditions such as presumed acute renal failure, mechanical hemolysis, severe hypertension, and target organ damage, including neurological, cardiovascular, or ophthalmological involvement. Women of childbearing potential are required to use effective contraception during the study and for at least five months after the last dose of treatment with eculizumab. Participants must be affiliated with a social security regimen and have provided written informed consent. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified.

The clinical trial is designed to evaluate the efficacy of **eculizumab** in adult patients with atypical hemolytic uremic syndrome (aHUS) associated with hypertensive emergency (HE) and severe kidney involvement. This is a randomized, multicenter, controlled trial with a double-blind design. The primary objective is to assess the impact of early administration of eculizumab, in addition to standard blood pressure control, on dialysis dependence at six months in patients with severely impaired renal function. The trial is expected to commence recruitment on February 13, 2024, and conclude by February 13, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), recent hospitalization for HE-aHUS, and severe hypertension. The study will include follow-up visits at specified intervals, including weeks 1, 2, 4, and 13, to monitor response to therapy and collect data on secondary endpoints such as complement biomarkers and renal replacement therapy rates. The end-of-study visit will occur at the six-month mark, where the primary endpoint will be evaluated, defined by the absence of persistent renal replacement therapy, eGFR <15 ml/min/1.73m², or patient death.

The expected duration of participant involvement is approximately 13 weeks, with the possibility of early termination if criteria such as persistent hemolysis despite well-conducted antihypertensive therapy are met. The trial will also assess secondary endpoints, including the frequency of severe infections, time to resolution of hemolysis, and the prognostic role of kidney lesions. Participants will receive eculizumab intravenously, with a maximum daily dose of 1200 mg and a total dose not exceeding 9600 mg over the treatment period. The trial is categorized as a Phase III study, focusing on the therapeutic efficacy and safety of eculizumab in this patient population.

The clinical trial involves the administration of **Eculizumab**, a monoclonal antibody, as the experimental medication. **Eculizumab** is provided in the pharmaceutical form of a **concentrate for solution for infusion**. The active substance is derived from a protein of other origin. The medication is administered intravenously, with a maximum daily dose of 1200 mg and a total maximum dose of 9600 mg over a treatment period of up to 13 weeks. The trial aims to assess the efficacy of early **Eculizumab** administration in patients with hypertensive emergency-associated hemolytic uremic syndrome (HEaHUS) who have severely impaired initial renal function.

In addition to the experimental treatment, the study includes standard-of-care blood pressure control as a non-experimental treatment. This standard-of-care therapy is essential for managing the condition and is used in conjunction with **Eculizumab** to evaluate its added efficacy. The trial does not utilize a placebo or comparator treatment. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of **Eculizumab** in the treatment of hypertensive emergency-associated hemolytic uremic syndrome (HEaHUS) will be assessed through a randomized multicenter controlled trial. The primary endpoint for evaluating efficacy is the response to therapy, defined by the absence of specific adverse events at the 6-month follow-up. These events include persistent renal replacement therapy, an estimated glomerular filtration rate (eGFR) of less than 15 ml/min/1.73 m², or patient death. Additionally, at week 2, persistent hemolysis despite well-conducted antihypertensive therapy will be considered a failure, as will any Eculizumab rescue in the control group.

Secondary endpoints include the prognostic role of repeat complement biomarkers measured at weeks 1, 4, and 13, the frequency of complement genetic rare variants, and renal replacement therapy rates at months 3 and 12 follow-up. Other secondary measures include the frequency of severe infections requiring hospitalization, time to resolution of hemolysis, time to resolution of renal replacement therapy, and the frequency and prognostic role of kidney lesions, glomerulosclerosis, and kidney fibrosis if a kidney biopsy is performed. Additionally, costs related to renal replacement therapy, Eculizumab, other antihypertensive treatments, and hospitalizations will be evaluated.