Efficacy Evaluation of Equine Immunoglobulin F(ab')2 Fragments Targeting Shiga Toxin in Pediatric Hemolytic Uremic Syndrome Induced by Shiga Toxin-Producing E. coli

The primary objective of this Phase III study is to evaluate the **efficacy** of INM004, an anti-Shiga toxin, when added to the standard of care (SoC), in ameliorating renal involvement in pediatric patients with Hemolytic Uremic Syndrome (HUS) associated with infection by Shiga toxin-producing Escherichia coli. This is clinically relevant as HUS is a serious condition that can lead to acute kidney injury, and improving renal outcomes is crucial for patient recovery and long-term health.

Secondary objectives include:

• Evaluating the efficacy of INM004 in reducing mortality.
• Assessing its efficacy in the prevention and reduction of extrarenal complications associated with STEC-HUS.
• Improving hematological parameters of microangiopathic thrombocytopenic anemia (MAT).
• Reducing the number of days of hospital stay.
• Evaluating the safety of INM004.
• Assessing the pharmacokinetics (PK) of INM004.
• Evaluating the kinetics of the Shiga toxin (Stx).

The clinical trial involves a total of **145 participants** diagnosed with **Hemolytic Uremic Syndrome**. The study population includes both male and female subjects, with an age range of greater than 9 months and less than 18 years at the time of randomization. Participants were selected based on specific inclusion criteria, including a clinical diagnosis of STEC-HUS, hospitalization at the participating institution, and a history of diarrhea onset within 10 days prior to diagnosis. The trial population is considered vulnerable, and informed consent was obtained from the subjects or their legal guardians. Lifestyle considerations such as diet and physical activity were not specified. The study aims to evaluate the efficacy of INM004, in addition to the standard of care, in improving renal involvement in the participants.

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the efficacy of INM004, an **anti Shiga toxin** solution for infusion, in pediatric patients diagnosed with **Hemolytic Uremic Syndrome** associated with infection by Shiga toxin-producing **Escherichia coli**. The trial will involve the administration of the investigational product, INM004, and a placebo, Sodium Chloride 0.9%, both delivered via **intravenous infusion**. The study is set to commence recruitment on October 1, 2024, and is expected to conclude by October 1, 2026.

Participants will be involved in the study for a maximum treatment period of 2 days, with a follow-up period extending up to 90 days post-randomization. The trial will include several key visits: an initial screening visit to confirm eligibility based on inclusion criteria such as age, confirmation of STEC infection, and clinical diagnosis of STEC-HUS, followed by randomization. Subsequent visits will include regular follow-up assessments to monitor renal function recovery, with primary endpoints focusing on the time to recovery of renal function during the acute phase. Secondary endpoints will assess the recovery of kidney function at day 90, incidence of dialysis, and mortality rates.

The expected length of participant involvement is approximately 90 days, with conditions for early termination including adverse events, withdrawal of consent, or any significant protocol deviations. The study aims to provide comprehensive data on the efficacy of INM004 in improving renal outcomes in the target population, contributing valuable insights into the management of Hemolytic Uremic Syndrome in pediatric patients.

The clinical trial involves the administration of **ANTI SHIGA TOXIN**, an experimental medication formulated as a **solution for infusion**. The active substance in this medication is **equine immunoglobulin F(ab')2 fragments targeting Shiga toxin**, which is a protein derived from equine sources. The medication is administered via **intravenous infusion**. The dosing regimen includes a maximum daily dose of 4 mg/kg and a total maximum dose of 8 mg/kg over a treatment period of up to 2 days. The medication is identified by the sponsor product code INM004 and is designated as an orphan drug under the number EMA/OD/248/17. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The study also includes a **placebo** treatment, which is a **sterile normal saline solution** containing sodium chloride at 0.9%. This placebo is packaged in glass vials and is administered by **intravenous infusion**. The placebo serves as a comparator to the experimental medication, allowing for the assessment of the efficacy of ANTI SHIGA TOXIN in the treatment of Hemolytic Uremic Syndrome associated with infection by Shiga toxin-producing Escherichia coli. The placebo is identified as PLACEBO INM004 and is used to maintain blinding in the trial.

The efficacy of the investigational product, INM004 (Shiga antitoxin), will be assessed in a Phase III clinical trial involving pediatric patients with **Hemolytic Uremic Syndrome** associated with infection by Shiga toxin-producing Escherichia coli. The primary endpoint for evaluating efficacy is the time to recovery of renal function during the acute phase. This is defined as the time in days to achieve a glomerular filtration rate (GFR) greater than or equal to the lower limit of normal (LLN) and a serum creatinine (sCr) level less than or equal to the upper limit of normal (ULN), measured in the absence of dialysis within a 28-day follow-up period.

Secondary endpoints include the recovery of kidney function at the short-term, assessed by the proportion of subjects with GFR ≥ LLN and sCr ≤ ULN at day 90, measured without dialysis. Additional secondary endpoints are the MAKE 90 criteria, which include the proportion of subjects experiencing death, dialysis requirement after 24 hours post-randomization, dialysis for more than 10 days, or persistent decline in renal function. Other secondary measures include the incidence of dialysis, defined as the proportion of subjects requiring dialysis after 24 hours post-randomization, and mortality, defined as the proportion of subjects who die due to any cause.