A Study to Investigate the Pharmacokinetics, Efficacy and Safety of INM005 in Patients With COVID-19.

• ClinicalTrials.gov Identifier: NCT04494984
• Recruitment Status: Completed
• First Posted: July 31, 2020
• Last Update Posted: February 11, 2021
• Sponsor: Inmunova S.A.
• Information provided by (Responsible Party): Inmunova S.A.

Tracking Information

• First Submitted Date: July 29, 2020
• First Posted Date: July 31, 2020
• Last Update Posted Date: February 11, 2021
• Actual Study Start Date: July 27, 2020
• Actual Primary Completion Date: November 23, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 31, 2020)

Clinical changes in COVID-19 symptoms [ Time Frame: 4 weeks ]

The primary endpoint will be the proportion of patients who show a change in symptoms 28 days after the administration of the first dose. A responding subject is defined as a subject with improvement in at least 2 categories on the 8-point World Health Organization (WHO) ordinal scale of clinical status or a subject who is discharged.

Original Primary Outcome Measures (submitted: July 30, 2020)

Clinical improvement of COVID-19 symptoms [ Time Frame: 4 weeks ]

The primary endpoint will be the proportion of patients who showed improvement 28 days after the administration of the first dose. A responding subject is defined as a subject with improvement in at least 2 categories on the 8-point WHO ordinal scale of clinical status or a subject who is discharged.

Current Secondary Outcome Measures (submitted: July 31, 2020)

• Pharmacokinetics evaluation of INM005 [ Time Frame: 1 week ]
  INM005 product concentration in serum at different time points after dosing
• Time to progression of disease [ Time Frame: 4 weeks ]
  Time to achieve a change in at least 2 categories on the 8-point WHO ordinal scale of clinical status. Time to discharge (days). Time to intensive care unit (ICU) discharge (days).
• Disease progression [ Time Frame: up to 2 weeks ]
  Proportion of patients who present change in at least 2 categories on the 8-point WHO ordinal scale of clinical status at 7 and 14 days after the start of the treatment.
• Discharge [ Time Frame: up to 4 weeks ]
  Proportion of patients discharged at 28 days
• Intensive care unit (ICU) hospitalization [ Time Frame: up to 4 weeks ]
  Proportion of patients who require ICU hospitalization
• Mechanical ventilation assistance (MVA) [ Time Frame: up to 4 weeks ]
  Proportion of patients who require MVA
• Mortality [ Time Frame: up to 4 weeks ]
  Proportion of patients who die due to complications from COVID19
• Changes in viral load [ Time Frame: up to 3 weeks ]
  Change in viral load from baseline to 7 and 21 days after the start of the treatment.

Original Secondary Outcome Measures (submitted: July 30, 2020)

• Pharmacokinetics evaluation of INM005 [ Time Frame: 1 week ]
  INM005 product concentration in serum at different time points after dosing
• Time to progression of disease [ Time Frame: 4 weeks ]
  Time to achieve improvement in at least 2 categories on the 8-point WHO ordinal scale of clinical status. Time to discharge (days). Time to intensive care unit (ICU) discharge (days).
• Disease progression [ Time Frame: 4 weeks ]
  Proportion of patients who present an improvement in at least 2 categories on the 8-point WHO ordinal scale of clinical status at 7 and 14 days after the start of the treatment. Proportion of patients with discharge at 28 days. Proportion of patients who require ICU hospitalization Proportion of patients who require mechanical ventilation assistance (MVA). Proportion of patients who died.
• Changes in viral load [ Time Frame: 3 weeks ]
  Change in viral load from baseline to 7 and 21 days after the start of the treatment.

Current Other Pre-specified Outcome Measures (submitted: July 31, 2020)

• Anti SARS-CoV2 antibodies levels [ Time Frame: 3 weeks ]
  Measurement of anti SARS-CoV2 antibodies titer levels. IgG (0, 21 days)
• Changes in Troponin T levels [ Time Frame: 3 weeks ]
  Changes in Troponin T levels will be evaluated at 7 and 21 days as a measurement of disease progression
• Changes in D-dimer levels [ Time Frame: 3 weeks ]
  Changes in D-dimer levels will be evaluated at 7 and 21 days as a measurement of disease progression
• Changes in Ferritin levels [ Time Frame: 3 weeks ]
  Changes in Ferritin levels will be evaluated at 7 and 21 days as a measurement of disease progression
• Changes in LDH levels [ Time Frame: 3 weeks ]
  Changes in LDH levels will be evaluated at 7 and 21 days as a measurement of disease progression
• Changes in C-reactive protein levels [ Time Frame: 3 weeks ]
  Changes in C-reactive protein levels will be evaluated at 7 and 21 days as a measurement of disease progression
• Immunogenicity [ Time Frame: 3 weeks ]
  Measurement of anti-INM005 antibodies: baseline and 21 days

Original Other Pre-specified Outcome Measures (submitted: July 30, 2020)

• Anti SARS-CoV2 antibodies levels [ Time Frame: 3 weeks ]
  Measurement of anti SARS-CoV2 antibodies titer levels. IgG (0, 21 days)
• Changes in laboratory variables that predict disease progression [ Time Frame: 3 weeks ]
  Evaluable laboratory variables baseline, 7 and 21 days: Troponin T, D-dimer, ferritin, LDH, C-reactive protein
• Immunogenicity [ Time Frame: 3 weeks ]
  Measurement of anti-INM005 antibodies: baseline and 21 days

Descriptive Information

• Brief Title: A Study to Investigate the Pharmacokinetics, Efficacy and Safety of INM005 in Patients With COVID-19.
• Official Title: A Stage 2/3, Adaptive, Randomized, Controlled, Double-blind Study to Investigate the Pharmacokinetics, Efficacy and Safety of the Hyperimmune Equine Serum (INM005) in Adult Patients With Moderate to Severe Confirmed SARS-CoV2 Disease.
• Brief Summary: This study aims to analyze the efficacy and safety of passive immunotherapy by administering an equine hyperimmune serum (INM005) against the SARS-CoV2 RBD to Covid19 patients. Improvement of the clinical course 28 days after the start of treatment will be evaluated.
• Detailed Description: The pandemic caused by the new coronavirus has generated a situation unprecedented in recent history, with several million infected and hundreds of thousands of deaths. This disease is easily transmissible by air. Although a high percentage of cases present mild clinical presentation, approximately 15% of patients present moderate to severe cases and 5% require critical care, with respiratory assistance and a high risk of mortality. No effective therapies for the treatment or prevention of SARS.CoV2 have been identified yet. Preliminary evidence indicates that passive immunotherapy with convalescent plasma could alter the clinical course of this infection in a favorable manner. This strategy, even if confirmed as successful, requires voluntary donation by patients who have recovered, not all of whom are eligible as donors, since the antibody response varies in magnitude in different patients. This adaptive stage II/III study aims to analyze the efficacy and safety of passive immunotherapy by administering a purified Fab fraction of equine hyperimmune serum (INM005) generated from antigenic stimulation with the SARS-CoV2 RBD protein, with the objective of neutralizing the interaction of SARS-CoV-2 with its cellular receptor, thus preventing the multiplication of the virus. The safety of this type of equine hyperimmune sera has already been demonstrated in previous and ongoing protocols with a biologically equivalent product against the E. Coli shiga toxin to treat patients with Hemolytic Uremic Syndrome (CT-INM004-01 and CT-INM004-02). In the present study, eligible patients will with moderate to severe symptoms of COVID-19 that require hospitalization will receive two 4 mg/kg doses of INM005, two days apart, with the aim of improving the clinical course of COVID-19 28 days after the start of treatment with the study drug.
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

This study will be an adaptive phase 2/3 investigation. First, 12 subjects will be randomly assigned to receive 1 of the 2 treatment regimens (study drug or placebo) in a 1:1 ratio. After the first 6 subjects have been enrolled and have completed 24 hours post treatment of 2nd dose, the IDMC will review the safety data and will inform whether to continue with staggered enrollment. Randomization ratio for subjects in the following stage will be 1:1. The independent data monitoring committee (IDMC) will review safety data after 12, 24, 48 and 96 patients have been enrolled in each arm. The study will then enroll a total of 121 patients in each arm. An interim analysis will be performed after 80% of recruitment has been reached (n=194). The IDMC will analyze the rate of events in the group under "standard of care".

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

A Double-blind, Placebo-controlled, sealed-envelope based. Access to unblinded interim results will be limited to the DMC and unblinded statistician

Primary Purpose: Treatment

• Condition: Covid19

Intervention

• Drug: INM005
  The IMP dose to be studied will be 4 mg of protein/kg of subject's weight. 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 48 h between doses.
• Drug: Placebo
  Placebo substance 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 48 h between doses.

Study Arms

• Active Comparator: Active
  Subjects will receive a 1st intravenous dose of 4 mg/kg INM005 (Anti-SARS-CoV-2 hyperimmune equine immunoglobulin F[ab']2 fragments) and a 2nd intravenous dose of 4 mg/kg of INM005. Each dose will be separated by 48 h (± 2 h).
  Intervention: Drug: INM005
• Placebo Comparator: Placebo
  Subjects will receive a 1st intravenous dose of Placebo and a 2nd intravenous dose of Placebo. Each dose will be separated by 48 h (± 2 h).
  Intervention: Drug: Placebo

Publications *

• Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
• Piechotta V, Iannizzi C, Chai KL, Valk SJ, Kimber C, Dorando E, Monsef I, Wood EM, Lamikanra AA, Roberts DJ, McQuilten Z, So-Osman C, Estcourt LJ, Skoetz N. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021 May 20;5(5):CD013600. doi: 10.1002/14651858.CD013600.pub4.
• Lopardo G, Belloso WH, Nannini E, Colonna M, Sanguineti S, Zylberman V, Munoz L, Dobarro M, Lebersztein G, Farina J, Vidiella G, Bertetti A, Crudo F, Alzogaray MF, Barcelona L, Teijeiro R, Lambert S, Scublinsky D, Iacono M, Stanek V, Solari R, Cruz P, Casas MM, Abusamra L, Luciardi HL, Cremona A, Caruso D, de Miguel B, Lloret SP, Millan S, Kilstein Y, Pereiro A, Sued O, Cahn P, Spatz L, Goldbaum F; INM005 Study Group. RBD-specific polyclonal F(ab )2 fragments of equine antibodies in patients with moderate to severe COVID-19 disease: A randomized, multicenter, double-blind, placebo-controlled, adaptive phase 2/3 clinical trial. EClinicalMedicine. 2021 Apr;34:100843. doi: 10.1016/j.eclinm.2021.100843. Epub 2021 Apr 11.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 30, 2020): 242
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: December 30, 2020
• Actual Primary Completion Date: November 23, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Subjects of both sexes aged 18 to 79 years of age
2. SARS-CoV-2 infection confirmed by PCR for virus detection
3. Patients with moderate or severe disease by NIH definition, which requires hospitalization.
4. Acceptance to participate in the study by the signature of the informed consent by a subject or their relative, if applicable
5. Be within 10 days of the onset of symptoms at the time of the Screening visit according to a case definition from the National Ministry of Health
6. Female patients of child-bearing age with negative pregnancy test

Exclusion Criteria:

1. Patients who have received treatment with plasma from COVID-19 convalescents.
2. Patients who are participating in other therapeutic clinical trials
3. Patients who require mechanical respiratory assistance or are hospitalized in the ICU at the time of the screening visit.
4. History of anaphylaxis, prior administration of equine serum (por example, anti-tetanus serum or anti-ophidic serum or anti-arachnid toxin serum) or allergic reaction due to contact or exposure to horses.
5. Pregnant or breastfeeding women
6. Patients who, at the doctor's discretion, are likely to die within the next 30 days due to a concomitant disease other than the study disease
7. Patients who are expected to be referred to another institution within 72 hours of enrollment, which prevents proper follow-up of that patient.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 79 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina

Administrative Information

• NCT Number: NCT04494984
• Other Study ID Numbers: CT-INM005-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Inmunova S.A.
• Original Responsible Party: Same as current
• Current Study Sponsor: Inmunova S.A.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Santiago Sanguineti, Ph.D.; Inmunova S.A.

• PRS Account: Inmunova S.A.
• Verification Date: February 2021