Efficacy of INM004 in Children With STEC-HUS

Official title

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.

Overview

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).

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

Interventions

• 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 minut
• 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

Primary outcome measures

• Time to recovery of renal function during the acute phase [Time frame: 28 days]

Secondary outcome measures (5)

• Short-term recovery of renal function [Time frame: 90 days]
• MAKE 90 [Time frame: 90 days]
• Dialysis longer than 10 days [Time frame: 90 days]
• Dialysis requirement [Time frame: 90 days]
• Mortality [Time frame: 90 days]

Eligibility criteria

Inclusion criteria

• Age ≥ 9 months and < 18 years at the time of randomization.
• In addition, only for subjects < 1 year and ≥ 15 years, confirmation of STEC infection determined by:

• Detection of generic Stx, Stx1, Stx2, or Stx1/Stx2 in stools by enzyme immunoassay (EIA); or
• Detection of stx, stx1, stx2, or stx1/stx2 genes in stools by Polymerase Chain Reaction (PCR); or
• Detection of specific anti-polysaccharide (IgM) antibodies in serum; or
• Fecal culture positive for E. coli O157 confirmed by serogroup-specific seroagglutination.
• Hospitalization at the participating institution.
• History of onset of diarrhea within 10 days prior to STEC-HUS diagnosis at the participating institution.
• Diagnosis of STEC-HUS defined as a subject with signs of renal damage, hemolysis, and platelet consumption:

• 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.
• Presence of hemolysis documented by:

• LDH levels above the ULN for age, and/or
• Presence of schistocytes in peripheral blood smear.
• 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.
• 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.
• Subjects who have already had menarche must have a negative pregnancy test.

Exclusion criteria

• Start of dialysis within 48 hours prior to admission to the participating institution.
• More than 24 hours from diagnosis of STEC-HUS at the participating institution up to randomization.
• History of chronic/recurrent hemolytic anemia, thrombocytopenia, or CKD.
• Personal and/or family history of atypical HUS.
• Suspected HUS secondary to infectious processes other than gastrointestinal (e.g., Streptococcus pneumoniae, HIV).
• Suspected HUS secondary to other etiologies (e.g., drug-associated HUS, neoplasms, bone marrow or solid organ transplantation, autoimmune disorders).
• 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.
• 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.
• Pregnant or breastfeeding woman.
• Impossibility of hospitalization in the participating institution.
• Concurrent participation in another clinical trial or having participated in a clinical trial in the last 3 months.
• Severe malnutrition. Defined when the weight is three standard deviations below the median, according to height, age and sex as per WHO guidelines.
• 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).

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

Quadruple blind

Primary purpose

Treatment

Study locations

Argentina · 25 centers

• Hospital Interzonal Dr. José Penna — Bahía Blanca
• Hospital Penna — Bahía Blanca
• Hospital de niños Sor María Ludovica — La Plata
• Clinica del niño y la madre — Mar del Plata
• Hospital Interzonal Especializado Materno Infantil Don Victorio Tetamanti — Mar del Plata
• Sanatorio de la Trinidad Ramos Mejia — Ramos Mejía
• Hospital El Cruce — San Juan Bautista
• Sanatorio Güemes — Buenos Aires
• … and 17 more centers

France · 8 centers

• CHU De Bordeaux — Bordeaux
• Hospices Civils De Lyon - Hopital Femme Mere Enfant — Lyon
• Centre Hospitalier Universitaire De Montpellier — Montpellier
• CHU Nantes — Nantes
• Hospital Necker Enfants Malades — Paris
• Robert Debre University Hospital — Paris
• Trousseau Hospital — Paris
• CHU Rouen — Rouen

Italy · 5 centers

• University Hospital Consorziale Policlinico — Bari
• IRCCS Sant'Orsola — Bologna
• Istituto Gianina Gaslini — Genova
• Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico — Milan
• Azienda Ospedale Università — Padova

Germany · 3 centers

• Charité - Universitätsmedizin Berlin — Berlin
• University Hospital Cologne AöR — Cologne
• Universitaetsklinikum Heidelberg AöR — Heidelberg

Romania · 3 centers

• Spitalul Clinic de Urgenta pentru Copii Marie Sklodowska Curie — Bucharest
• Spitalul Clinic De Urgenta Pentru Copii Cluj-Napoca — Cluj-Napoca
• Spitalul Clinic de Urgenta pentru Copii Louis Turcanu — Timișoara

Spain · 3 centers

• Hospital Universitario De Cruces — Barakaldo
• Hospital Infantil Universitario Niño Jesus — Madrid
• Hospital Universitario 12 De Octubre — Madrid

United Kingdom · 3 centers

• Bristol Royal Hospital for Children — Bristol
• Royal Hospital for Sick Children — Glasgow
• Great Ormon Street Hospital for Children — London

Belgium · 1 center

• Cliniques universitaires Saint-Luc — Brussels

Ireland · 1 center

• Children's Health Ireland — Dublin

Identifiers

NCT: NCT06389474 · CT-INM004-04

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗