Clinical trial NCT04132375: Phase 2/3 Study to Evaluate PK, Safety & Efficacy of INM004 in STEC Positive Pediatric Patients for Prevention of HUS
Official title: A Double-blind, Placebo-controlled, Adaptive, Phase 2/3 Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of INM004 in Pediatric Patients With Shiga Toxin-positive Bloody Diarrhea for Prevention of Hemolytic Uremic Syndrome
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Bloody Diarrhea
STEC, Unspecified
Hemolytic-Uremic Syndrome
Pediatric Kidney Disease
Lead sponsor: Inmunova S.A.
Sponsor class: OTHER
Collaborators: name: Exeltis
First posted: 2019-10-18
Enrollment: 11
Sex: ALL
Minimum age (years): 1
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This study will be an adaptive seamless design (ASD) phase 2/3 investigation using an "inferentially seamless" platform.

Stage 1 In Stage 1, subjects will be randomly assigned to receive 1 of the 3 treatment regimens (high treatment regimen, low treatment regimen, or placebo) in a 1:1:1 ratio.

Review for Dose Selection The Data Monitoring Committee will conduct a blinded safety review at the end of Stage 1 to determine the best active dose based on safety.

Stage 2 Stage 2 is considered the efficacy portion of the study. The randomization ratio for subjects in Stage 2 will be 1:1 (active treatment regimen of INM004: placebo).

Interim Analysis The intent of the unblinded interim analysis is to demonstrate superiority of INM004 versus the placebo, based on 80% reduction in the incidence of HUS in the treated cohort to stop study due to overwhelming efficacy, or declare futility, or re-estimate sample.
Primary purpose: PREVENTION

Brief summary: The investigational medicinal product (IMP), INM004, proposes to neutralize the toxin in the bloodstream to prevent the interaction of the Stx with the specific receptor, by means of a polyclonal antibody to be administered upon the appearance of symptoms (bloody diarrhea) and diagnosis of infection by STEC, thereby preventing the action of the toxin in the body. Thus, the initial hypothesis for examination is for the prevention of the full expression of HUS, based upon presumptive clinical, biochemical, and other biological evidence suggesting a risk of HUS at the time of treatment application. The polyclonal antibody (F(ab')2 fragment) is obtained by processing the serum of equine animals previously immunized against engineered Stx1B and Stx2B immunogens.

INM004 could be administered at the earlier stages of STEC disease since subjects with STEC diarrhea are more likely to benefit from Stx neutralizing antibodies before the development of extra-intestinal manifestations and HUS. Neutralizing equine anti-Stx F(ab')2 antibodies (INM004) have the objective of preventing the development of HUS by blocking the circulating toxins in patients infected with STEC. Therefore, INM004 may be used in patients with a clinical manifestation of bloody diarrhea and a positive Stx result in feces. Early interruption of the Stx mediated cascade is expected to prevent the development of HUS, alleviate the severity of the illness, the rate of complications and the incidence/duration of hospitalizations. Therefore, patients in the early phases of the disease will be targeted in this study, ie, children who seek medical care due to diarrhea associated with STEC infection before HUS development.

Detailed description: Hemolytic uremic syndrome (HUS) is a form of thrombotic microangiopathy, characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal impairment of varying severity, which may be preceded by an episode of diarrhea with or without blood. Karmali et al. showed the relationship between this syndrome and diarrhea caused by Shiga toxin-producing bacteria such as Escherichia coli. These cytotoxins, called Shiga-like toxins or Shiga toxins (Stx), are also called verotoxins, due to the characteristic cytopathic effect they cause on Vero cell cultures.

HUS is often classified into 3 primary types: 1) HUS due to infections associated with Shiga-toxin producing E. coli (STEC) or Shigella dysenteriae Type 1, often associated with diarrhea, with the rare exception of HUS due to a severe disseminated infection caused by Streptococcus pneumoniae, 2) HUS related to complement abnormalities or related to factor ADAMTS13 deficit, such HUS is also known as "atypical HUS" and is not associated with diarrhea, and 3) HUS of unknown etiology that usually occurs in the course of systemic diseases or physio-pathologic conditions such as pregnancy, after transplantation or after drug use.

E. coli bacteria normally live in the intestines of people and animals. Cattle and sheep are the main reservoirs of STEC, and the major transmission route is believed to be food contaminated with animal feces. Contaminated water has also been recognized as a source, and direct human-to-human and animal-to-human transmission have been reported.

E. coli consists of a diverse group of bacteria. Most of them are harmless and an important part of a healthy human intestinal tract. However, some E. coli are pathogenic, that can cause either diarrhea or illness outside of the intestinal tract. Diarrheagenic E. coli strains are categorized into 6 pathotypes: 1) Enterotoxigenic E. coli, 2) Enteropathogenic E. coli, 3) Enteroaggregative E. coli, 4) Enteroinvasive E. coli, 5) diffusely adherent E. coli, and 6) STEC. STEC may also be referred to as verocytotoxin-producing E. coli (VTEC). This last pathotype is the one most commonly associated with foodborne outbreaks.

Treatment of STEC HUS renal damage caused by Stx is available. The investigational medicinal product (IMP), INM004, proposes to neutralize the toxin in the bloodstream to prevent the interaction of the Stx with the specific receptor, by means of a polyclonal antibody to be administered upon the appearance of symptoms (bloody diarrhea) and diagnosis of infection by STEC, thereby preventing the action of the toxin in the body. Thus, the initial hypothesis for examination is for the prevention of the full expression of HUS, based upon presumptive clinical, biochemical, and other biological evidence suggesting a risk of HUS at the time of treatment application. The polyclonal antibody (F(ab')2 fragment) is obtained by processing the serum of equine animals previously immunized against engineered Stx1B and Stx2B immunogens.

INM004 could be administered at the earlier stages of STEC disease since subjects with STEC diarrhea are more likely to benefit from Stx neutralizing antibodies before the development of extra-intestinal manifestations and HUS. Neutralizing equine anti-Stx F(ab')2 antibodies (INM004) have the objective of preventing the development of HUS by blocking the circulating toxins in patients infected with STEC. Therefore, INM004 may be used in patients with a clinical manifestation of bloody diarrhea and a positive Stx result in feces. Early interruption of the Stx mediated cascade is expected to prevent the development of HUS, alleviate the severity of the illness, the rate of complications and the incidence/duration of hospitalizations. Therefore, patients in the early phases of the disease will be targeted in this study, ie, children who seek medical care due to diarrhea associated with STEC infection before HUS development.

Pediatric subjects between 1 and 10 years (y) of age at the time of screening with an increased risk for development of HUS defined by the presence of bloody diarrhea based upon history or presentation and positive screen for Stx2 in the stool will be enrolled.

Bloody diarrhea and positive screen for Stx2 have been included as inclusion criteria as these factors have been identified as risk factor for HUS development and will serve to enrich the patient population within the study to those most likely to benefit from this therapy.

Case of Bloody Diarrhea Any person with an increase in the number of daily stools and alteration in the stool consistency, with presence of visible blood, which may include episodes of stool formed with blood in the form of streaks on its surface or blood visible only under a microscope, which may be accompanied by other symptoms such as vomiting, nausea, abdominal pain, or fever.

Case of Shiga Toxin producing Escherichia coli Infection

Identification of the etiological agent by at least 1 of the following laboratory criteria:

* Isolation of an E. coli strain that produces Stx or harbors stx1 or stx2 gene(s);
* Direct detection of stx1 or stx2 gene(s) nucleic acid (without strain isolation);
* Direct detection of free Stx in feces (without strain isolation). The surveillance of the STEC strains is performed using subtyping techniques: 1) genotyping of stx and eae by polymerase chain reaction (PCR)-restriction fragment length polymorphism and 2) pulsed-field gel electrophoresis. STEC O157 and non O157 strains are recovered from the clinic, animal, food and environmental samples, and E. coli O157:H7, a Stx2a/Stx2c producer, harboring eae and ehxA genes, is the most common serotype.

Case of Hemolytic Uremic Syndrome Patient of any age who presents in an acute form with microangiopathic hemolytic anemia, thrombocytopenia, and renal compromise.

Case of Hemolytic Uremic Syndrome with Confirmed Diagnosis of Shiga Toxin producing Escherichia coli

Case of HUS with identification of the etiological agent by at least 1 of the laboratory criteria:

* Screening of stx1 and/or stx2 by PCR/isolation of STEC
* Detection of free Stx in stool
* Detection of serogroup-specific O antigen antibodies O157, O145, O121

Eligibility criteria: Inclusion Criteria:

1. Age of ≥ 1 to \< 10 y.
2. Signed informed consent from the parent(s)/legal guardian with assent from the subject as appropriate by age and regulatory guidance.
3. Bloody diarrhea based upon history or presentation (by visual inspection).
4. Detection of Stx2 in stool based on enzyme immunoassay (EIA) and/or stx2 based on PCR before randomization.

   NOTE: The basis for accepting a positive test for stx2 by EIA is based on taking as valid the results yielded from an EIA whose sensitivity and specificity are greater than 98.7% and 100%, respectively (according to the description in the insert) as per recommendation given by the NRL. The Sponsor will select the investigational sites that have in their laboratory such EIA test used in the STEC diagnostic routine algorithm. (Appendix 6).
5. For children between 1 to 5 years old: weight for length/height between percentiles 3 (\< 2 z score) and 97 (\> 2 z score) corresponding to age (according to the reference tables "WHO Child Growth Standards".
6. For children ≥ 5 years: Body mass index (BMI) between percentiles 3 (\<2 z score) and 97 (\> 2 z score) corresponding to age (according to the reference tables "WHO Child Standards, Appendix 4)

Exclusion Criteria:

1. Any laboratory findings compatible with the development of HUS:

   * Microangiopathic hemolytic anemia defined as LDH above the ULN for age with the finding of schistocytes on peripheral smear and a negative Coomb's test, and/or
   * Thrombocytopenia: platelet count \< 150 × 103/μL, and/or
   * Renal failure: serum creatinine \> ULN adjusted for age and gender criteria despite correction of hypovolemia, and/or hematuria, and/or proteinuria (Table 7.1)11 NOTE: Laboratory results must be obtained within 24 h before the 1st study drug administration; there must be no clinical signs and symptoms of HUS at the time laboratory assessments are obtained. If there is any change in clinical presentation in the 24 h before the 1st study drug administration, laboratory assessments are to be repeated and results reviewed before study drug administration.

   NOTE: Laboratory and physical examination results must indicate normal hydration before the 1st study drug administration.
2. A history of chronic/recurrent hemolytic anemia, thrombocytopenia, or chronic renal failure.
3. A family history of aHUS.
4. Anuria or oliguria after hypovolemia is corrected.
5. Evidence of clinically significant chronic active disease not medically controlled.
6. History of anaphylaxis, prior administration of equine serum (eg, antitetanus serum or anti-ophidic serum, or anti-arachnid toxin serum), or allergic reaction to contact with, or exposure to, horses.
7. Family relation or work relation with a member of the personnel of the research group.

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Primary outcomes:
measure: Incidence of HUS development
timeFrame: 4 weeks
Secondary outcomes:
measure: Frequency of subjects with treatment-emergent adverse event (TEAEs) to assess the safety of 2 doses of INM004 in children through evaluation of safety data in Stage 1
timeFrame: 12 weeks
measure: Frequency of subjects with treatment-emergent adverse event (TEAEs) to assess the safety of the administration on INM004 in all treated patients
timeFrame: 12 weeks
measure: Incidence of secondary endpoints through Week 4 and Week 12 (short term complications).
timeFrame: by Week 4; by Week 12
measure: Incidence in long-term sequelae from Week 12 through Week 48 in those who develop HUS (long-term complications).
timeFrame: From Week 12 through Week 48
measure: Time after the administration of INM004 in which peak plasma concentration is reached (Tmax)
timeFrame: 5 days
measure: Peak Plasma Concentration (Cmax) of INM004
timeFrame: 5 days
measure: Area under the plasma concentration of INM004 versus time curve (AUC)
timeFrame: 5 days
Other outcomes:
measure: Length of the hospital stay in subjects who developed HUS
timeFrame: 4 weeks
measure: Other observed or derived estimates of staff and resource utilization in subjects who developed HUS
timeFrame: 4 weeks
measure: Incidence of predictors of mortality in subjects who developed HUS.
timeFrame: 4 weeks
measure: Serotype and genotype of E. coli strains isolated from all subjects
timeFrame: 4 weeks
measure: Changes from baseline in laboratory parameters following study drug administration in all subjects.
timeFrame: 4 weeks
measure: immunogenicity of INM004 by measuring anti-INM004 antibodies at day 30 post drug administration.
timeFrame: 4 weeks
measure: Investigator submitted events (ie, confirmed HUS, incomplete HUS, or signs and symptoms which may represent neither) for hypothesis generation.
timeFrame: 4 weeks
Locations:
city: Bahia Blanca
country: Argentina
facility: Hospital Penna
state: Buenos Aires
city: La Plata
country: Argentina
facility: Hospital Sor Maria Ludovica
state: Buenos Aires
city: Santa Rosa
country: Argentina
facility: Hospital Lucio Molas
state: LA Pampa
city: Neuquén
country: Argentina
facility: Hospital Castro Rendon
state: Neuquen
city: Ciudad Autonoma de Buenos aires
country: Argentina
facility: Hospital Elizalde
city: Ciudad Autonoma de Buenos Aire
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Santa Fe
country: Argentina
facility: Hospital Orlando Alassia
Study officials:
affiliation: Inmunova S.A.
name: SANTIAGO SANGUINETI, PhD
role: STUDY_DIRECTOR
References:
citation: Imdad A, Mackoff SP, Urciuoli DM, Syed T, Tanner-Smith EE, Huang D, Gomez-Duarte OG. Interventions for preventing diarrhoea-associated haemolytic uraemic syndrome. Cochrane Database Syst Rev. 2021 Jul 5;7(7):CD012997. doi: 10.1002/14651858.CD012997.pub2.