Efficacy of INM004 in Children With STEC-HUS

A Phase III Study to Evaluate the Efficacy of INM004 (Shiga Antitoxin) in Pediatric Patients With Shiga Toxin-producing Escherichia Coli-associated Hemolytic Uremic Syndrome.

The objectives of this study are to evaluate the efficacy, safety, and pharmacokinetics of INM004 in pediatric patients with Hemolytic Uremic Syndrome associated to infection by Shiga toxin-producing Escherichia coli (STEC-HUS).

Study Overview

• Status: Not yet recruiting
• Conditions: Hemolytic-Uremic Syndrome
• Intervention / Treatment: Biological: INM004; Other: Placebo

Detailed Description

The primary objective will be to evaluate the efficacy of INM004, added to the standard of care, as a treatment for STEC-HUS in the amelioration of renal function.

Secondary objectives

• To evaluate the efficacy of INM004 in the reduction of mortality.
• To evaluate the efficacy of INM004 in the prevention and reduction of extrarenal complications.
• To evaluate the efficacy of INM004 in the improvement of TMA laboratory parameters.
• To evaluate the efficacy of INM004 in the reduction of hospital stay days.
• To evaluate the safety of INM004
• To evaluate the pharmacokinetics of INM004
• To evaluate the kinetics of Stx

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Santiago Sanguineti, Ph.D; Phone Number: 6184 +541120331455; Email: ssanguineti@inmunova.com
• Study Contact Backup: Name: Mariana Colonna, Bioch; Email: mcolonna@inmunova.com

Study Locations

• Argentina
  • Ciudad Autonoma de Buenos Aire, Argentina
    • Hospital de Niños Dr. Ricardo Gutierrez
  • Ciudad Autonoma de Buenos Aire, Argentina
    • Clínica Zabala
  • Córdoba, Argentina
    • Sanatorio Allende
  • Córdoba, Argentina
    • Hospital de Niños de la Santísima Trinidad
  • Mendoza, Argentina
    • Hospital Pediátrico Dr. Humberto Notti
  • Buenos Aires
    • Florencio Varela, Buenos Aires, Argentina
      • Hospital El Cruce - Néstor Kirchner
    • Mar Del Plata, Buenos Aires, Argentina
      • Hospital Interzonal Especializado Materno Infantil Don Victorio Tetamanti
  • Santa Fe
    • Rosario, Santa Fe, Argentina
      • Sanatorio de Niños

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 9 months and < 18 years at the time of randomization.

2. In addition, only for subjects < 1 year and ≥ 15 years, confirmation of STEC infection determined by:

   1. Detection of generic Stx, Stx1, Stx2, or Stx1/Stx2 in stools by enzyme immunoassay (EIA); or
   2. Detection of stx, stx1, stx2, or stx1/stx2 genes in stools by Polymerase Chain Reaction (PCR); or
   3. Detection of specific anti-polysaccharide (IgM) antibodies in serum; or
   4. Fecal culture positive for E. coli O157 confirmed by serogroup-specific seroagglutination.
3. Hospitalization at the participating institution.
4. History of onset of diarrhea within 10 days prior to STEC-HUS diagnosis at the participating institution.

5. Diagnosis of STEC-HUS defined as a subject with signs of renal damage, hemolysis, and platelet consumption:

   1. Signs of renal damage defined as:

      • Serum creatinine value above the ULN for age and sex, and GFR below the LLN for age, sex, and height.

   2. Presence of hemolysis documented by:

      • LDH levels above the ULN for age, and/or
      • Presence of schistocytes in peripheral blood smear.

   3. Platelet consumption according to any of the following laboratory criteria:

      • Peripheral blood platelet count < 150 × 103/μL, and/or
      • A ≥50% decrease in peripheral blood platelet count compared to a sample collected within the previous 24 hours.
6. Informed consent form signed and dated by the subject or, the legal guardian(s), with the subject's assent as appropriate based on age and regulatory guidelines in the region.
7. Subjects who have already had menarche must have a negative pregnancy test.

Exclusion Criteria:

1. Start of dialysis within 48 hours prior to admission to the participating institution.
2. More than 24 hours from diagnosis of STEC-HUS at the participating institution up to randomization.
3. History of chronic/recurrent hemolytic anemia, thrombocytopenia, or CKD.
4. Personal and/or family history of atypical HUS.
5. Suspected HUS secondary to infectious processes other than gastrointestinal (e.g., Streptococcus pneumoniae, HIV).
6. Suspected HUS secondary to other etiologies (e.g., drug-associated HUS, neoplasms, bone marrow or solid organ transplantation, autoimmune disorders).
7. Any other acute or chronic medical condition that, in the opinion of the investigator, may interfere with the evaluation of the efficacy and/or safety of the study medication.
8. History of: a) anaphylaxis of any kind; b) prior administration of equine serum (e.g., antivenom, anti-arachnid serum, anti-SARS-CoV-2 serum, etc.) or an allergic reaction from contact or exposure to horses.
9. Pregnant or breastfeeding woman.
10. Impossibility of hospitalization in the participating institution.
11. Concurrent participation in another clinical trial or having participated in a clinical trial in the last 3 months.
12. Severe malnutrition. Defined when the weight is three standard deviations below the median, according to height, age and sex as per WHO guidelines.

13. Medical conditions that may affect kidney function or cause/enhance neurological symptoms or signs:

    • Congenital or acquired anomalies that may affect functioning renal mass.
    • Epilepsy or structural abnormalities of the brain that may increase the risk of seizures.
    • Trisomy 21.
    • Prematurity (born before 28 weeks gestation).
    • Other (according to investigator criteria).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: INM004; Two doses of Anti-Shiga Toxin Hyperimmune Equine Immunoglobulin F(ab´)2 fragment at a dosage of 4 mg/kg of body weight, 24 hours apart.	Biological: INM004; Two doses of Anti-Shiga Toxin Hyperimmune Equine Immunoglobulin F(ab´)2 fragments at a dosage of 4 mg/kg of body weight, 24 hours apart. Each vial contains 25 mg of protein/ml. Therefore, each subject must receive 0.16 ml/kg per dose. The vial volume will be reconstituted in a 100 ml (for subjects with a body weight of 20 kg or more) or 50 ml (for subjects under 20 kg of body weight) infusion bag. It will be administered as an intravenous infusion using an infusion pump over a period of 50 minutes. In subjects with a BMI over 30 kg/m2, infusion will be performed over a period of 100 minutes; Other Names: Active
Placebo Comparator: Placebo; Two doses of saline solution, 24 hours apart.	Other: Placebo; Two doses of placebo, 24 hours apart. The placebo solution has the same composition of excipients as INM004 without the active pharmaceutical ingredient, and its appearance is identical. Each subject must receive 0.16 ml/kg of placebo solution per dose. The vial volume will be reconstituted in a 100 ml (for subjects with a body weight of 20 kg or more) or 50 ml (for subjects under 20 kg of body weight) infusion bag. It will be administered as an intravenous infusion using an infusion pump over a period of 50 minutes. In subjects with a BMI over 30 kg/m2, infusion will be performed over a period of 100 minutes; Other Names: Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to recovery of renal function during the acute phase	Time (days) to achieve a glomerular filtration rate greater than or equal to the lower limit of normal (according to age, height, and sex) and a serum creatinine lower than or equal to the upper limit of normal (according to age and sex), both measured in the absence of dialysis.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Short-term recovery of renal function	Proportion of subjects with a glomerular filtration rate ≥ lower limit of normal (according to age, height and sex) and serum creatinine ≤ upper limit of normal (according to age and sex), both measured in the absence of dialysis.	90 days
MAKE 90	Proportion of subjects meeting any of the following criteria at day 90: death, dialysis requirement after 24 hours post-randomization, dialysis of more than 10 days, or persistent decline in renal function (without recovery of glomerular filtration rate according to age, height, and sex).	90 days
Dialysis longer than 10 days	Proportion of dialyzed subjects requiring more than 10 days of dialysis	90 days
Dialysis requirement	Proportion of subjects requiring dialysis after 24 hours post-randomization	90 days
Mortality	Proportion of subjects who die from any cause.	90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Incidence of adverse events	90 days
CKD Risk Assessment According to Kidney Disease Improving Global Outcomes (KDIGO) Categories	Proportion of subjects in each CKD category (low, medium, high, very high) according to GFR and albuminuria at day 90	90 days
Evolution of renal function at 7 days (GFR_AUC1-7)	Area under the curve of glomerular filtration rate from Day 1 to Day 7	7 days
Evolution of renal function at 28 days (GFR_AUC1-28)	Area under the curve of glomerular filtration rate from Day 1 to Day 28	28 days
Evolution of renal function at 90 days (GFR_AUC1-90)	Area under the curve of glomerular filtration rate from Day 1 to Day 90	90 days
Incidence of anuria	Proportion of subjects with anuria onset after 24 hours post-randomization	90 days
Extrarenal composite endpoint	Proportion of subjects who develop at least one severe extrarenal event including neurological events (coma, seizure, stroke), cardiovascular (hemodynamic instability, heart failure, acute myocardial infarction, myocarditis), respiratory (respiratory distress), gastrointestinal (hemorrhagic colitis, intestinal necrosis, intussusception, pancreatitis, severe hepatitis) or death.	90 days
Recovery of the thrombotic microangiopathy (TMA), thrombocytopenia	Normalization of thrombocytopenia (platelet count ≥150,000/mm3), measured as time to recovery.	90 days
Recovery of the thrombotic microangiopathy (TMA), hemolytic anemia	Proportion of subjects with recovery from hemolytic anemia (Hemoglobin ≥ lower limit of normal and Lactate Dehydrogenase ≤ upper limit of normal).	90 days
Duration of hospitalization	Time from randomization to hospital discharge.	90 days
Incidence of adverse events of special interest	Incidence of injection site reactions.; Incidence of hypersensitivity (i.e., allergic reaction, anaphylaxis and serum sickness)	28 days
Pharmacokinetic - AUC0-t	Area under the curve of INM004 concentration from time 0 to the last measurable concentration	144 hours
Pharmacokinetic - AUC0-inf	Area under the curve of INM004 concentration as a function of time extrapolated to infinity	144 hours
Pharmacokinetic - Cmax	Maximum concentration of INM004 in plasma after administration	144 hours
Pharmacokinetic - Tmax	Time in which INM004 reaches the maximum concentration in plasma after administration	144 hours
Pharmacokinetic - λz	Terminal velocity constant via linear logit regression	144 hours
Pharmacokinetic - t1/2	Terminal half-life of INM004	144 hours
Pharmacokinetic - Vz	Volume of distribution of INM004	144 hours
Pharmacokinetic - Cl	INM004 clearence	144 hours
Pharmacokinetic - AUC/dose	Area under the curve of INM004 normalized for the administered dose	144 hours
Pharmacokinetic - Cmax/dose	Maximum concentration of INM004 in plasma normalized for the administered dose	144 hours
Baseline Shiga toxin serum levels	Baseline serum Stx2 concentration in all subjects	Baseline
Kinetics of Shiga toxin in serum	Serum Stx2 concentration at different time-points in placebo subjects.	144 hours

Collaborators and Investigators

• Sponsor: Inmunova S.A.
• Collaborators: Chemo Research; KLIXAR; Linical; Crovelis
• Investigators: Study Director: Santiago Sanguineti, Ph.D, Inmunova S.A.

Study record dates

Study Major Dates

• Study Start (Estimated): May 16, 2024
• Primary Completion (Estimated): July 28, 2025
• Study Completion (Estimated): September 28, 2025

Study Registration Dates

• First Submitted: April 25, 2024
• First Submitted That Met QC Criteria: April 25, 2024
• First Posted (Actual): April 29, 2024

Study Record Updates

• Last Update Posted (Actual): May 10, 2024
• Last Update Submitted That Met QC Criteria: May 8, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: STEC-HUS; Typical Hemolytic Uremic Syndrome; Diarrhea asociated-Hemolytic Uremic Syndrome; Shiga toxin-producing Escherichia coli; Shiga toxin
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Hematologic Diseases; Anemia; Thrombocytopenia; Blood Platelet Disorders; Anemia, Hemolytic; Thrombotic Microangiopathies; Uremia; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Cytopenia; Syndrome; Azotemia; Hemolysis; Hemolytic-Uremic Syndrome
• Other Study ID Numbers: CT-INM004-04

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No