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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04132375
Recruitment Status : Recruiting
First Posted : October 18, 2019
Last Update Posted : October 18, 2019
Sponsor:
Collaborator:
Exeltis
Information provided by (Responsible Party):
Inmunova S.A.

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.


Condition or disease Intervention/treatment Phase
Bloody Diarrhea STEC, Unspecified Hemolytic-Uremic Syndrome Pediatric Kidney Disease Drug: INM004 Drug: Placebo Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 396 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
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.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: A Double-blind, Placebo-controlled, IWRS based. access to unblinded interim results will be limited to the DMC and unblinded statistician
Primary Purpose: Prevention
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
Actual Study Start Date : July 17, 2019
Estimated Primary Completion Date : March 1, 2022
Estimated Study Completion Date : September 1, 2022


Arm Intervention/treatment
Active Comparator: Stage 1 - high treatment arm
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

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.

Other Name: active

Active Comparator: Stage 1 - Low treatment arm
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

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.

Other Name: active

Placebo Comparator: Stage 1 - Placebo arm
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

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.


Active Comparator: Stage 2 - Selected active treatment arm

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

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.

Other Name: active

Active Comparator: Stage 2 - Placebo arm

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

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.





Primary Outcome Measures :
  1. Incidence of HUS development [ Time Frame: 4 weeks ]

    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).



Secondary Outcome Measures :
  1. 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 [ Time Frame: 12 weeks ]

    Frequency of subjects with TEAEs will be summarized by treatment group providing the number of subjects with event, the proportion subjects with event and the number of events

    The statistics above will also be provided for the following events:

    • Serious TEAEs
    • TEAEs leading to study withdrawal
    • Treatment related TEAEs
    • Serious and treatment related TEAEs
    • Severe TEAEs
    • TEAEs leading to death
    • treatment emergent adverse events of special interest (TEAESI)
    • treatment-emergent adverse events related to background disease (TEAEBD) The frequency of TEAEs will also be reported by System Organ Class (SOC), and will also be reported by severity and relationship to study drug.

    AEs will be coded by Preferred Term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) classification


  2. Frequency of subjects with treatment-emergent adverse event (TEAEs) to assess the safety of the administration on INM004 in all treated patients [ Time Frame: 12 weeks ]

    Frequency of subjects with TEAEs will be summarized by treatment group providing the number of subjects with event, the proportion subjects with event and the number of events

    The statistics above will also be provided for the following events:

    • Serious TEAEs
    • TEAEs leading to study withdrawal
    • Treatment related TEAEs
    • Serious and treatment related TEAEs
    • Severe TEAEs
    • TEAEs leading to death
    • treatment emergent adverse events of special interest (TEAESI)
    • treatment-emergent adverse events related to background disease (TEAEBD) The frequency of TEAEs will also be reported by System Organ Class (SOC), and will also be reported by severity and relationship to study drug.

    AEs will be coded by Preferred Term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) classification


  3. Incidence of secondary endpoints through Week 4 and Week 12 (short term complications). [ Time Frame: by Week 4; by Week 12 ]
    • the time to death will be calculated in order to assess overall survival,
    • The time to the first serious extrarenal events will be calculated (in days) for the following events:

      • Major neurological involvement
      • Cardiovascular involvement
      • Gastrointestinal involvement
      • Pancreatic involvement
      • Hepatic involvement

  4. Incidence in long-term sequelae from Week 12 through Week 48 in those who develop HUS (long-term complications). [ Time Frame: From Week 12 through Week 48 ]

    The time to long-term sequelae will be calculated for the following events:

    • Long-term renal sequelae
    • Neurological sequelae
    • Cardiovascular sequelae
    • Pancreatic sequelae
    • Gastrointestinal sequelae
    • Overall survival

  5. Time after the administration of INM004 in which peak plasma concentration is reached (Tmax) [ Time Frame: 5 days ]
    Pharmacokinetic profile will be assessed by measuring serum INM004 concentration at different timepoints. Serum INM004 concentration will be followed by a specific ELISA. Concentration of INM004 will be plotted as a function of time and pharmacokinetic profile will be defined.

  6. Peak Plasma Concentration (Cmax) of INM004 [ Time Frame: 5 days ]
    Pharmacokinetic profile will be assessed by measuring serum INM004 concentration at different timepoints. Serum INM004 concentration will be followed by a specific ELISA. Concentration of INM004 will be plotted as a function of time and pharmacokinetic profile will be defined.

  7. Area under the plasma concentration of INM004 versus time curve (AUC) [ Time Frame: 5 days ]
    Pharmacokinetic profile will be assessed by measuring serum INM004 concentration at different timepoints. Serum INM004 concentration will be followed by a specific ELISA. Concentration of INM004 will be plotted as a function of time and pharmacokinetic profile will be defined.


Other Outcome Measures:
  1. Length of the hospital stay in subjects who developed HUS [ Time Frame: 4 weeks ]
    Length of the hospital stay will be calculated as the discharge date minus the admission date + 1 as collected in the HUS admission/ discharge forms .

  2. Other observed or derived estimates of staff and resource utilization in subjects who developed HUS [ Time Frame: 4 weeks ]
    The following resources, measured in duration of days, utilized during the entire hospitalization for HUS will be collected: peritoneal dialysis, hemodialysis, transfusions, antibiotics, erythropoietin, plasmapheresis, diuretics, frozen plasma, hypotensors, mechanical ventilation, insulin duration in the intensive care unit, duration in the general ward and abdominal surgery

  3. Incidence of predictors of mortality in subjects who developed HUS. [ Time Frame: 4 weeks ]

    For each subject hospitalized for HUS, the following binary (Y/N) variables will be created:

    • White blood cell (WBC) value > 20,000/mL
    • Hemoglobin (Hb) value > 10.8 g/dL
    • Sodium (Na) < 128 mEq/L
    • Neurological involvement

  4. Serotype and genotype of E. coli strains isolated from all subjects [ Time Frame: 4 weeks ]
    All E. coli strains isolated from patients will be Serotyped and genotyped. A correlation between a certain type of strain and the development of HUS will be investigated. Strains will be aggregated by serotype and/or genotype and a correlation between a specific combination and development of HUS will be explored.

  5. Changes from baseline in laboratory parameters following study drug administration in all subjects. [ Time Frame: 4 weeks ]

    Descriptive statistics will be produced for the values and the changes from baseline at each assessment time point by treatment arm.

    The absolute frequency (n) and percentage (%) of subjects with clinically significant abnormalities by visit and at any post-baseline moment during the study will be reported by treatment arm.


  6. immunogenicity of INM004 by measuring anti-INM004 antibodies at day 30 post drug administration. [ Time Frame: 4 weeks ]
    Assessment of the immunogenicity of INM004 determined by the presence of anti-drug antibodies (ADA) in serum samples by a specific ELISA test. This will be evaluated at baseline and at day 30 post drug administration

  7. Investigator submitted events (ie, confirmed HUS, incomplete HUS, or signs and symptoms which may represent neither) for hypothesis generation. [ Time Frame: 4 weeks ]
    • A secondary binary endpoint defined as having either probable or confirmed HUS by week 4 will be defined using the CEC assessment.
    • A secondary qualitative endpoint defined as having either mild, moderate or severe HUS (probable or confirmed) by week 4 will be defined using the CEC assessment.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 10 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

    -


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04132375


Contacts
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Contact: MARIANA COLONNA, BIOCH + 54 9 1161718697 mcolonna@inmunova.com
Contact: SANTIAGO SANGUINETI, PhD +54 9 11 4564-3625 ssanguineti@inmunova.com

Locations
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Argentina
Hospital Penna Recruiting
Bahia Blanca, Buenos Aires, Argentina, 8000
Contact: LAURA ALCONCHER, M.D         
Hospital Sor Maria Ludovica Recruiting
La Plata, Buenos Aires, Argentina
Contact: ANGELA SUAREZ       'Angela del Carmen Suarez' <angelasuarez@intramed.net>   
Hospital Lucio Molas Recruiting
Santa Rosa, LA Pampa, Argentina
Contact: SUSANA PEREZ, M.D       Susana Pérez <susanaperezk@gmail.com>   
Hospital Castro Rendon Not yet recruiting
Neuquén, Neuquen, Argentina
Contact: FLAVIA RAMIREZ, M.D       flavia ramirez <ramirezfb@yahoo.com.ar>   
Hospital Elizalde Recruiting
Ciudad Autonoma de Buenos aires, Argentina, 1270
Contact: ALEJANDRO BALESTRACCI, M.D       Alejandro Balestracci <abalestracci@yahoo.com.ar>   
Hospital Italiano de Buenos Aires Recruiting
Ciudad Autonoma de Buenos Aire, Argentina, 1199
Contact: LIDIA GHEZZI, M.D         
Hospital Orlando Alassia Not yet recruiting
Santa Fe, Argentina
Contact: JOSE PALADINI, M.D       jose hugo paladini <josehugo_1958@hotmail.com>   
Sponsors and Collaborators
Inmunova S.A.
Exeltis
Investigators
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Study Director: SANTIAGO SANGUINETI, PhD Inmunova S.A.

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Responsible Party: Inmunova S.A.
ClinicalTrials.gov Identifier: NCT04132375    
Other Study ID Numbers: CT-INM004-02
First Posted: October 18, 2019    Key Record Dates
Last Update Posted: October 18, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Kidney Diseases
Hemolytic-Uremic Syndrome
Syndrome
Diarrhea
Hemolysis
Disease
Pathologic Processes
Urologic Diseases
Signs and Symptoms, Digestive
Signs and Symptoms
Uremia
Anemia, Hemolytic
Anemia
Hematologic Diseases
Thrombotic Microangiopathies
Thrombocytopenia
Blood Platelet Disorders