A Study to Assess Safety, Efficacy, and Pharmacokinetics of INM004 in Pediatric Patients With STEC-HUS
Condition: Diarrhea-Associated Hemolytic Uremic Syndrome; Pediatric Kidney Disease; Hemolytic-Uremic Syndrome
MeSH terms: Kidney Diseases; Azotemia; Hemolytic-Uremic Syndrome; Syndrome; Diarrhea; Hemolysis
Study type: Interventional
Phase: Phase 2

Summary: 
      Hemolytic Uremic Syndrome (HUS) is a foodborne disease which mainly affects children. It is
      caused by Escherichia coli bacteria, which release a toxin called Shiga toxin within the
      body. This infectious form of HUS, defined as STEC-HUS, can cause sporadic cases or
      outbreaks, as observed in different countries. Argentina has the highest incidence of
      STEC-HUS worldwide. The disease is endemic, representing approximately 95% of all HUS cases
      nationwide.

      STEC-HUS generally begins with diarrhea (with or without blood), and can also cause fever,
      abdominal pain, and cramps. Then the child may have pallor, altered consciousness, decreased
      urine output, seizures, and other symptoms. Although death is uncommon (it occurs in 2-4% of
      cases), it is a very serious disease that mainly affects the kidneys, and also other organs
      such as the brain. About half of children need to undergo a risky procedure such as dialysis
      (due to malfunctioning kidneys); and most of them also receive blood transfusions.

      Around 30% of the patients are left with lifelong consequences that can range from permanent
      kidney damage to the need for a transplant.

      So far there is no drug, antibiotic or vaccine to prevent or treat HUS. Current treatment
      protocols include hospitalization for all patients with HUS, and supportive therapy such as
      hydration and salt intake. Support therapy is not a specific treatment, but rather helps the
      body better defend itself against the disease.

      The purpose of this study is to establish whether it is safe and effective to treat patients
      who are diagnosed with STEC-HUS, with INM004 (study drug). INM004 is an investigational
      product "Fraction F(ab')2 of Equine Shiga Antitoxin Immunoglobulin". It is a concentrated and
      sterile serum obtained from healthy horses immunized against Shiga toxin that contains
      antibodies capable of neutralizing it.

      The initial hypothesis is that INM004 would neutralize the entry of Shiga toxin into the
      body's cells thus preventing the consequent toxic damage. With the proposed treatment, INM004
      would eliminate the Shiga toxin, preventing the progression of HUS symptoms and its serious
      complications (such as the need for and duration of dialysis, duration of hospital stays, as
      well as neurological, cardiovascular, intestinal complications, among others) which are
      associated with high morbidity and mortality. This treatment could then have an impact in
      health costs of STEC-HUS as well as the social costs.
    

Detailed description: 
      Hemolytic uremic syndrome (HUS) is a form of thrombotic microangiopathy characterized by
      microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS of
      infectious origin, associated with infection by Shiga toxin (Stx)-producing Escherichia coli.

      This disease can cause sporadic cases or outbreaks. Argentina is the country with the highest
      incidence of STEC-HUS worldwide. The disease is endemic, representing approximately 95% of
      all HUS cases.

      There is no specific treatment capable of preventing or controlling renal and extrarenal
      damage caused by Stx. The treatment is mainly symptomatic. Therapy for patients with acute
      kidney injury is supportive and includes hydric and electrolyte management; thus, most cases
      require red blood cell transfusions and approximately half of cases require dialysis.

      INM004 is a neutralizing serum consisting of the F(ab')2 fragment of equine immunoglobulins
      with specificity against the B subunits of Stx1 and Stx2. The F(ab')2 fragments are obtained
      through the processing of serum from horses immunized with Stx1B and Stx2B immunogens,
      obtained through genetic engineering techniques. A polyclonal therapy based on INM004 offers
      the advantage that the different subtypes of Stx could be recognized by multiple antibodies
      simultaneously, even when the toxin circulates bound to neutrophils or microvesicles derived
      from them.

      The objective of this study is to evaluate the efficacy, safety, and pharmacokinetics of
      INM004 administered in patients between 1 and 12 years of age who are in the early stage of
      the disease.

      The initial hypothesis is that INM004 would reduce the complications associated with STEC-HUS
      by neutralizing the harmful effect of Stx on the body. Intravenous administration of INM004
      is expected to interrupt the Stx-mediated cascade, reducing the occurrence of renal and
      extrarenal complications (such as the need for and duration of dialysis, number of
      transfusions, CNS complications, and length of hospitalization).

      Two doses of 4 mg/kg of INM004 will be administered as an intravenous infusion over a period
      of 50 min, with an interval of 24 h (± 2 h) from each other. The selection of the exposure
      level is based on preclinical in vitro data regarding the affinity of INM004, its
      neutralizing capacity for both Stx toxins, and clinical data obtained from the previous Phase
      I study in adult volunteers and the Phase 2/3 study in children with STEC bloody diarrhea.

      Study design: A Phase II, multicenter, controlled study, with a prospective open "treatment
      group" (with INM004 and Standard of Care -SoC-), and a retrospective "control group" (only
      treated with SoC). Considering that STEC-HUS is an orphan disease currently without
      treatment, the design with retrospective control has been chosen.

      The treatment group will enroll 100 patients hospitalized in 16 healthcare centers in
      Argentina, between September 2022 and May 2023, time of highest incidence of STEC-HUS. The
      data of the control group will be obtained retrospectively from 200 cases of STEC-HUS treated
      in the same centers, in the same seasonal period in the years 2018, 2019 and until March 2020
      (COVID-19 pre-pandemic), with the same screening criteria as the subjects in the treatment
      group.

      Primary Objectives: To assess: 1) the efficacy of INM004, plus SoC, in the treatment of
      STEC-HUS, in terms of improvement of renal involvement; 2) the safety of the administration
      of INM004; 3) the pharmacokinetics (PK) of INM004.

      Secondary Objectives: To assess the efficacy of INM004: 1) in the mortality reduction; 2) in
      the improvement of the STEC-HUS associated thrombotic microangiopathy, plus SoC; 3) in the
      treatment of STEC-HUS, in the prevention and reduction of renal involvement in the short
      term, plus SoC; 4) in the treatment of STEC-HUS, in the prevention and reduction of
      extrarenal involvement in the short term, plus SoC; 5) the in the prevention and reduction of
      the complications not associated to thrombotic microangiopathy, plus SoC; 6) in terms of the
      length of hospital stay; and 7) the evolution of laboratory parameters of interest after the
      administration of INM004.

      Exploratory Objectives: To assess: 1) the immunogenicity of INM004; 2) the presence of
      circulating Stx before the administration of INM004; 3) the immune response to STEC infection
      over 4 weeks follow-up; 4) the correlation between serotype/ genotype of isolated STEC
      strains and disease severity.

      Study Procedures:

      For the control group: Data will be collected from the medical records of the subjects who
      have been eligible from the "Potential Subjects Selection List" of the year's corresponding
      to this population. The data to be collected for this group will be the same as for the
      treatment group, except for that related to the specific procedure of the intervention: basal
      ECG and post dose control; 1st dose and 2nd dose, and associated controls (vital signs and
      AESI evaluation); blood samples for biological and/or pharmacokinetic studies; adverse
      events.

      The inclusion of subjects in the treatment group will be conducted in two stages: Stage 1
      (Safety): A safety analysis will be performed by the Data Safety Monitoring Board (DSMB)
      after the first 12 subjects have been enrolled and 24 h after the administration of the
      second dose of INM004 have occurred. Stage 2 (Safety and Efficacy): Enrollment will continue
      until May 2023, and it is estimated that 88 more subjects will enroll in this stage.

      Once the participant was included the following data will be collected:

      Demographic data, medical history data, data of the current illness (related to the prodromal
      period of STEC-HUS and to the clinical features compatible with STEC-HUS at the time of
      diagnosis); Complications associated with STEC-HUS at the time of diagnosis and before:
      renal, neurological, cardiovascular, gastrointestinal, endocrinological, hematologic, lung
      involvement, infectious compromise. The follow up will continue to the day 28 after
      diagnosis.

      For statistical analyses, the following populations will be considered:

        -  Full Analysis Set (FAS): For the treatment group, defined as all subjects who received
           at least 1 dose of INM004 with available follow-up evaluation on at least one efficacy
           parameter. This population will be used for all main efficacy analyses. All subjects
           included in the control group will be part of the FAS for the comparative analyses.

        -  Population by Correct Protocol (PCP): includes all the subjects in the FAS who did not
           present major deviations from the protocol that could affect the measures of efficacy.
           This population will be analyzed as a sensitivity evaluation for the main analyzes of
           the study.

        -  Safety Population (SP): For the treatment group, it is defined as all subjects who have
           received at least one dose of INM004.

      Statistical methods:

      Statistical analyzes will be mainly descriptive. For continuous variables, mean, median,
      standard deviation, quartiles, maximum and minimum will be presented. Categorical variables
      will be described by absolute frequencies and percentages.

      Baseline parameters, demographics, clinical history and previous treatments will be described
      in a cross-sectional manner prior to the start of treatment. The continuous evaluations
      carried out throughout the study will be described longitudinally by the change from
      baseline. For categorical variables, shift tables can be generated.

      In the treatment group, the last measure performed prior to the administration of the first
      dose of INM004 will be considered as the baseline measure of efficacy and safety. If a
      generalized delay in the administration of the INM004 treatment is observed, the closest
      measurement available to the diagnosis of symptoms compatible with STEC-HUS may be considered
      as the baseline measurement. For the control group, the baseline assessments will be those at
      the time of diagnosis of symptoms compatible with STEC-HUS.

      Multivariate analyzes will be assessed to identify risk factors related to the evolution and
      severity of the disease.

      Safety will be assessed throughout the study describing subjects with at least one AE,
      serious adverse events (SAE) and AESI, and subjects with at least one major safety deviation
      for each of the parameters: ECG, vital signs, clinical laboratory evaluations, including
      liver function tests.

      Efficacy and sensitivity analyzes will be performed to detect possible subjects who could
      benefit more from treatment in subgroups defined according to levels of severity at admission
      Comparative multivariate analyzes of the main efficacy variables against the control group
      will be performed. These comparisons will be duly adjusted using propensity scoring
      techniques in order to minimize any confusion bias between both groups. Among the potential
      confounders to consider as adjustment variables in the model will be age, sex and severity
      levels at admission. Due to the exploratory nature of the comparisons, no adjustments will be
      made for multiple comparisons.

      Due to the exploratory nature of this study, a sample of approximately 100 evaluable subjects
      in the treatment group would be sufficient to detect any existing trends regarding the
      efficacy and safety of INM004. In the control group, 200 subjects are expected to be
      evaluated.

      With 100 evaluable subjects we will obtain a precision (distance from the mean to the end of
      the bilateral confidence interval at 95%) of ±1.2 for the days on dialysis (SD 6.1 days) and
      ±2.4 for the days of admission (SD 12 days).
    

Intervention name(s): INM004; SoC
Intervention type(s): Drug; Other
Intervention description(s): Two 4 mg/kg doses of INM004, 24 h (±2 h) apart, will be assessed. Each dose will be administered as an intravenous infusion during 50 min.; Standard of care
Other intervention name(s): Equine immunoglobulin fragment F(ab')2 anti-Shiga toxin
Intervention MeSH terms: Immunoglobulins; Immunoglobulin Fragments; Shiga Toxins
Intervention model: Single Group Assignment
Intervention model description: A Phase II, multicenter, controlled study, with a prospective open "treatment group" (with INM004 added to Standard of Care) and a retrospective "control group" (only treated with Standard of Care).
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: STEC-HUS