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

CT-INM004-02

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.

2019-07-17

2022-05-04

2022-07-19

Terminated

Early phase I

11

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. -

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE2', 'PHASE3'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'SEQUENTIAL', 'interventionModelDescription': 'This study will be an adaptive seamless design (ASD) phase 2/3 investigation using an "inferentially seamless" platform.\n\nStage 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.\n\nReview 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.\n\nStage 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).\n\nInterim 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.', 'primaryPurpose': 'PREVENTION', 'maskingInfo': {'masking': 'QUADRUPLE', 'maskingDescription': 'A Double-blind, Placebo-controlled, IWRS based. access to unblinded interim results will be limited to the DMC and unblinded statistician', 'whoMasked': ['PARTICIPANT', 'CARE_PROVIDER', 'INVESTIGATOR', 'OUTCOMES_ASSESSOR']}}, 'enrollmentInfo': {'count': 11, 'type': 'ACTUAL'}}

2023-07-19