Phase 2/3 Study to Evaluate PK, Safety & Efficacy of INM004 in STEC Positive Pediatric Patients for Prevention of HUS

NCT04132375 | Terminated Phase 2 DMC

• 1 other identifier: CT-INM004-02
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 7

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.

Conditions

Bloody Diarrhea; STEC, Unspecified; Hemolytic-Uremic Syndrome; Pediatric Kidney Disease

Outcome Measures

Primary Outcomes (1)

• Incidence of HUS development

  The primary endpoint is a binary (Y/N) endpoint defined as having confirmed HUS by week 4. This endpoint will be centrally adjudicated by a Clinical Endpoint Committee. This committee will classify all potential events into one of the following categories: * Confirmed HUS * Probable HUS * No HUS The proportion of children with HUS by week 4 confirmed by central adjudication will be reported for each treatment arm (optimal dose of INM004 vs placebo).

  4 weeks

Secondary Outcomes (7)

• 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

  12 weeks

• Frequency of subjects with treatment-emergent adverse event (TEAEs) to assess the safety of the administration on INM004 in all treated patients

  12 weeks

• Incidence of secondary endpoints through Week 4 and Week 12 (short term complications).

  by Week 4; by Week 12

• Incidence in long-term sequelae from Week 12 through Week 48 in those who develop HUS (long-term complications).

  From Week 12 through Week 48

• Time after the administration of INM004 in which peak plasma concentration is reached (Tmax)

  5 days

Other Outcomes (7)

• Length of the hospital stay in subjects who developed HUS

  4 weeks

• Other observed or derived estimates of staff and resource utilization in subjects who developed HUS

  4 weeks

• Incidence of predictors of mortality in subjects who developed HUS.

  4 weeks

Study Arms (5)

Stage 1 - high treatment arm

ACTIVE COMPARATOR

Subjects will receive a 1st intravenous dose of 4 mg/kg INM004 (Anti-Stx hyperimmune equine immunoglobulin F\[ab'\]2 fragments) and a 2nd intravenous dose of 4 mg/kg of INM004. Each dose will be separated by 24 h (± 2 h).

Drug: INM004

Stage 1 - Low treatment arm

ACTIVE COMPARATOR

Subjects will receive a 1st intravenous dose of 4 mg/kg INM004 (Anti-Stx hyperimmune equine immunoglobulin F\[ab'\]2 fragments) and a 2nd intravenous dose of Placebo. Each dose will be separated by 24 h (± 2 h).

Drug: INM004

Stage 1 - Placebo arm

PLACEBO COMPARATOR

Subjects will receive a 1st intravenous dose of Placebo and a 2nd intravenous dose of Placebo. Each dose will be separated by 24 h (± 2 h).

Drug: Placebo

Stage 2 - Selected active treatment arm

ACTIVE COMPARATOR

In the case, the high treatment regime is selected, subjects will receive a 1st intravenous dose of 4 mg/kg INM004 and a 2nd intravenous dose of 4 mg/kg of INM004. Each dose will be separated by 24 h (± 2 h). In the case, the low treatment regime is selected subjects will receive an intravenous dose of 4 mg/kg INM004

Drug: INM004

Stage 2 - Placebo arm

ACTIVE COMPARATOR

In the case, the high treatment regime is selected, subjects will receive a 1st intravenous dose of Placebo and a 2nd intravenous dose of Placebo, each dose separated by 24 h (± 2 h) In the case, low treatment regime is selected subjects will receive a single intravenous dose of Placebo

Drug: Placebo

Interventions

INM004 DRUG

The IMP dose to be studied will be 4 mg of protein/kg of subject's weight. Each vial contains 25 mg protein/mL. Therefore, each subject must receive 0.16 mL/kg. The IMP will be added to the 100 mL infusion bag of saline solution. Doses will be administered as an infusion at 2.0 mL/min over 50 min with an interval of 24 h between doses.

Also known as: active

Stage 1 - Low treatment arm; Stage 1 - high treatment arm; Stage 2 - Selected active treatment arm

Placebo DRUG

The IMP dose to be studied will be 4 mg of protein/kg of subject's weight. Each vial contains 25 mg protein/mL. Therefore, each subject must receive 0.16 mL/kg. The IMP will be added to the 100 mL infusion bag of saline solution. Doses will be administered as an infusion at 2.0 mL/min over 50 min with an interval of 24 h between doses.

Stage 1 - Placebo arm; Stage 2 - Placebo arm

Eligibility Criteria

• Age: 1 Year - 10 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Age of ≥ 1 to \< 10 y.
• Signed informed consent from the parent(s)/legal guardian with assent from the subject as appropriate by age and regulatory guidance.
• Bloody diarrhea based upon history or presentation (by visual inspection).
• 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).
• 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".
• 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)

You may not qualify if:

• 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.
• A history of chronic/recurrent hemolytic anemia, thrombocytopenia, or chronic renal failure.
• A family history of aHUS.
• Anuria or oliguria after hypovolemia is corrected.
• Evidence of clinically significant chronic active disease not medically controlled.
• 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.
• Family relation or work relation with a member of the personnel of the research group.

Sponsors & Collaborators

• Inmunova S.A.: lead
• Exeltis: collaborator

Study Sites (7)

Hospital Penna

Bahía Blanca, Buenos Aires, 8000, Argentina

Location

Hospital Sor Maria Ludovica

La Plata, Buenos Aires, Argentina

Location

Hospital Lucio Molas

Santa Rosa, La Pampa Province, Argentina

Location

Hospital Castro Rendon

Neuquén, Neuquén Province, Argentina

Location

Hospital Elizalde

Buenos Aires, 1270, Argentina

Location

Hospital Italiano de Buenos Aires

Ciudad Autonoma de Buenos Aire, 1199, Argentina

Location

Hospital Orlando Alassia

Santa Fe, Argentina

Location

Related Publications (2)

• Imdad A, Nelson JR, Tanner-Smith EE, Huang D, Gomez-Duarte OG. Interventions for preventing diarrhoea-associated haemolytic uraemic syndrome. Cochrane Database Syst Rev. 2025 Apr 25;4(4):CD012997. doi: 10.1002/14651858.CD012997.pub3.

  PMID: 40277027 DERIVED

• 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.

  PMID: 34219224 DERIVED

MeSH Terms

Conditions

Hemolytic-Uremic Syndrome

Interventions

Exercise

Condition Hierarchy (Ancestors)

Uremia; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Cytopenia

Intervention Hierarchy (Ancestors)

Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• SANTIAGO SANGUINETI, PhD

  Inmunova S.A.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: A Double-blind, Placebo-controlled, IWRS based. access to unblinded interim results will be limited to the DMC and unblinded statistician
• Purpose: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 19, 2019
• First Posted: October 18, 2019
• Study Start: July 17, 2019
• Primary Completion: May 4, 2022
• Study Completion: July 19, 2022
• Last Updated: July 19, 2023

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

AR (7)