Clinical trial NCT06389474: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Hemolytic-Uremic Syndrome
Keywords: STEC-HUS
Typical Hemolytic Uremic Syndrome
Diarrhea asociated-Hemolytic Uremic Syndrome
Shiga toxin-producing Escherichia coli
Shiga toxin
Lead sponsor: Inmunova S.A.
Sponsor class: OTHER
Collaborators: name: Exeltis
name: Chemo Research
name: Linical
name: KLIXAR
First posted: 2024-04-29
Enrollment: 220
Sex: ALL
Minimum age (years): 9
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Adaptive design. IA will be done when approximately 50% of the enrollment is reached and the participants have completed 28 days of follow-up. This analysis will not be blinded and will be carried out to declare futility or re-estimate the sample size. The re-estimation of the sample size will allow a maximum of 300 randomized subjects in total, but a reduction in the initial item size of 220 subjects is not expected. In case of re-estimating the sample size, the smallest sample size under 300 will be selected, which allows a power of ≥ 80%. %. If with 300 subjects, a power of 80% is not reached, but it is ≥ 50%, then the sample size is re-estimated to 300 subjects, as long as the conditional power of the IA is ≥ 50% (promising results)
Primary purpose: TREATMENT

Brief summary: 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

Eligibility criteria: 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).

Primary outcomes:
measure: Time to recovery of renal function during the acute phase
timeFrame: 28 days
Secondary outcomes:
measure: Short-term recovery of renal function
timeFrame: 90 days
measure: MAKE 90
timeFrame: 90 days
measure: Dialysis longer than 10 days
timeFrame: 90 days
measure: Dialysis requirement
timeFrame: 90 days
measure: Mortality
timeFrame: 90 days
Other outcomes:
measure: CKD Risk Assessment According to Kidney Disease Improving Global Outcomes (KDIGO) Categories
timeFrame: 90 days
measure: Evolution of renal function at 7 days (GFR_AUC1-7)
timeFrame: 7 days
measure: Evolution of renal function at 28 days (GFR_AUC1-28)
timeFrame: 28 days
measure: Evolution of renal function at 90 days (GFR_AUC1-90)
timeFrame: 90 days
measure: Incidence of anuria
timeFrame: 90 days
measure: Extrarenal composite endpoint
timeFrame: 90 days
measure: Recovery of the thrombotic microangiopathy (TMA), thrombocytopenia
timeFrame: 90 days
measure: Recovery of the thrombotic microangiopathy (TMA), hemolytic anemia
timeFrame: 90 days
measure: Duration of hospitalization
timeFrame: 90 days
measure: Incidence of adverse events of special interest
timeFrame: 28 days
measure: Incidence of adverse events
timeFrame: 90 days
measure: Pharmacokinetic - AUC0-t
timeFrame: 144 hours
measure: Pharmacokinetic - AUC0-inf
timeFrame: 144 hours
measure: Pharmacokinetic - Cmax
timeFrame: 144 hours
measure: Pharmacokinetic - Tmax
timeFrame: 144 hours
measure: Pharmacokinetic - λz
timeFrame: 144 hours
measure: Pharmacokinetic - t1/2
timeFrame: 144 hours
measure: Pharmacokinetic - Vz
timeFrame: 144 hours
measure: Pharmacokinetic - Cl
timeFrame: 144 hours
measure: Pharmacokinetic - AUC/dose
timeFrame: 144 hours
measure: Pharmacokinetic - Cmax/dose
timeFrame: 144 hours
measure: Baseline Shiga toxin serum levels
timeFrame: Baseline
measure: Kinetics of Shiga toxin in serum
timeFrame: 144 hours
Locations:
city: Bahia Blanca
country: Argentina
facility: Hospital Interzonal Dr. José Penna
state: Buenos Aires
city: La Plata
country: Argentina
facility: Hospital de niños Sor María Ludovica
state: Buenos Aires
city: Mar Del Plata
country: Argentina
facility: Clinica del niño y la madre
state: Buenos Aires
city: Mar Del Plata
country: Argentina
facility: Hospital Interzonal Especializado Materno Infantil Don Victorio Tetamanti
state: Buenos Aires
city: Caba
country: Argentina
facility: Sanatorio Anchorena
state: Ciudad Autónoma De Buenos Aires
city: Ciudad Autonoma De Buenos Aires
country: Argentina
facility: Sanatorio Güemes
state: Ciudad Autónoma De Buenos Aires
city: Ciudad Autonoma De Buenos Aires
country: Argentina
facility: Hospital de Pediatría S.A.M.I.C. "Prof. Dr. Juan P. Garrahan"
state: Ciudad Autónoma De Buenos Aires
city: Ciudad Autonoma De Buenos Aires
country: Argentina
facility: Hospital General de Niños Pedro de Elizalde
state: Ciudad Autónoma De Buenos Aires
city: Río Cuarto
country: Argentina
facility: Hospital "San Antonio de Padua" Río Cuarto
state: Córdoba
city: San Rafael
country: Argentina
facility: Hospital Teodoro J. Schestakow
state: Mendoza
city: Rosario
country: Argentina
facility: Hospital de Niños Zona Norte "Dr. Roberto M. Carra"
state: Santa Fe
city: Rosario
country: Argentina
facility: Sanatorio de Niños
state: Santa Fe
city: San Miguel De Tucumán
country: Argentina
facility: Hospital De Clínicas Pte. Nicolás Avellaneda
state: Tucumán
city: Ciudad Autonoma de Buenos Aire
country: Argentina
facility: Clínica Zabala
city: Ciudad Autonoma de Buenos Aire
country: Argentina
facility: Hospital de Niños Dr. Ricardo Gutierrez
city: Córdoba
country: Argentina
facility: Hospital Privado Centro Médico de Córdoba
city: Córdoba
country: Argentina
facility: Hospital de Niños de la Santísima Trinidad
city: Córdoba
country: Argentina
facility: Sanatorio Allende
city: Mendoza
country: Argentina
facility: Hospital Pediátrico Dr. Humberto Notti
city: Neuquén
country: Argentina
facility: Clínica Pediátrica San Lucas
city: Salta
country: Argentina
facility: Hospital Público Materno Infantil
city: San Luis
country: Argentina
facility: Hospital Pediátrico San Luis
city: Brussel
country: Belgium
facility: Cliniques universitaires Saint-Luc
city: Bordeaux
country: France
facility: CHU De Bordeaux
city: Lyon
country: France
facility: Hospices Civils De Lyon - Hopital Femme Mere Enfant
city: Montpellier
country: France
facility: Centre Hospitalier Universitaire De Montpellier
city: Paris
country: France
facility: Hospital Necker Enfants Malades
city: Paris
country: France
facility: Robert Debre University Hospital
city: Paris
country: France
facility: Trousseau Hospital
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg AöR
city: Dublin
country: Ireland
facility: Children's Health Ireland
city: Milano
country: Italy
facility: Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
city: Cluj-Napoca
country: Romania
facility: Spitalul Clinic De Urgenta Pentru Copii Cluj-Napoca
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Sick Children
city: London
country: United Kingdom
facility: Great Ormon Street Hospital for Children
Study officials:
affiliation: Inmunova S.A.
name: Santiago Sanguineti, Ph.D
role: STUDY_DIRECTOR
References: