COVID-19
Conditions
Brief summary
This study aims to analyze the efficacy and safety of passive immunotherapy by administering an equine hyperimmune serum (INM005) against the SARS-CoV-2 receptor binding domain (RBD) to COVID-19 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-CoV-2 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-CoV-2 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.
Interventions
DRUGINM005
The investigational medicinal product (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.
DRUGPlacebo
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.
Sponsors
Inmunova S.A.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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
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".
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects of both sexes aged 18 to 79 years of age 2. SARS-CoV-2 infection confirmed by polymerase chain reaction (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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Improvement in at Least Two Categories in WHO 8-point Ordinal Clinical Scale at Day 28 or Discharge | Discharge or up to Day 28 | 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 World Health Organization (WHO) ordinal scale of clinical status or a subject who is discharged. The ordinal scale measures illness severity over time, the minimum value is 0 and the maximum value is 8. The higher is the score, the worse is the outcome. Detailed scale: 0 = no evidence of infection, 1. = outpatient, with no activities limitation; 2. = outpatient, with activities limitation; 3. = hospitalised with no oxygen therapy required; 4. = oxygen therapy employing a mask; 5. = non-invasive ventilation or high flow oxygen; 6. = Mechanical ventilation; 7. = mechanical ventilation and organ support (vasopressors, extracorporeal membrane oxygenation (ECMO), renal replacement therapy (RRT); 8. = Death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK) Evaluation of INM005 (Cmax) | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose | INM005 product concentration in serum at different time points after dosing. The following PK parameters were measured: * Cmax after (mg/L) Dose 1 * Cmax (mg/L) after Dose 2 |
| Pharmacokinetics (PK) Evaluation of INM005 (Clearance) | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose | INM005 product concentration in serum at different time points after dosing. The following PK parameters were measured: \- Clearance (mL/h) after Dose 1 |
| Pharmacokinetics (PK) Evaluation of INM005 (Weight-adjusted Clearance) | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose | INM005 product concentration in serum at different time points after dosing. The following PK parameters were measured: \- Weight-adjusted Clearance (mL/h/kg) after Dose 1 |
| Pharmacokinetics (PK) Evaluation of INM005 (AUC0) | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose | INM005 product concentration in serum at different time points after dosing. The following PK parameters were measured: * AUC0-t (mg/L\*h) after Dose 1 * AUC0-I (mg/L\*h) after Dose 1 * AUC0-I (mg/L\*h) -Normalized- after Dose 1 * AUC0-t (mg/L\*h) after Dose 2 * AUC0-I (mg/L\*h) after Dose 2 * AUC0-I (mg/L\*h) -Normalized- after Dose 2 |
| Pharmacokinetics (PK) Evaluation of INM005 (Elimination Half-time) | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose | INM005 product concentration in serum at different time points after dosing. The following PK parameters were measured: * Elimination half-time (hs) after Dose 1 * Elimination half-time (hs) after Dose 2 * Mean Residence Time (hs) after Dose 1 |
| Pharmacokinetics (PK) Evaluation of INM005 (Elimination Rate) | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose | INM005 product concentration in serum at different time points after dosing. The following PK parameters were measured: * Elimination rate after Dose 1 * Elimination rate after Dose 2 |
| Pharmacokinetics (PK) Evaluation of INM005 (Distribution Volume) | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose | INM005 product concentration in serum at different time points after dosing. The following PK parameters were measured: \- Distribution Volume (L) after Dose 1 |
| Pharmacokinetics (PK) Evaluation of INM005 (Weight-adjusted Distribution Volumen) | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose | INM005 product concentration in serum at different time points after dosing. The following PK parameters were measured: \- Weight-adjusted Distribution volumen (L/kg) after Dose 1 |
| Time to Progression of Disease | 28 days | Time to achieve decrease 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). |
| Clinical Improvement at Day 7 and Day 14 | up to 2 weeks | Percentage of patients who present a decrease 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. |
| Patients Discharged at 28 Days | up to 4 weeks | Rate of discharged patients at 28 days |
| Participants Who Require (ICU) Hospitalization | up to 4 weeks | Cumulative percentage of patients who require Intensive care unit (ICU) hospitalization |
| Participants Who Require Mechanical Ventilation Assistance (MVA) | up to 4 weeks | Rate of participants who require Mechanical ventilation assistance |
| Mortality at Day 28 | up to 4 weeks | Mortality rate due to complications from COVID-19 at day 28 |
| Changes in Viral Load | up to 3 weeks | Percentage of participants with detectable viral load at baseline, day 7 and day 21 after the start of the treatment.. GeneFinder ™ COVID-19 PLUS RealAmp Kit was used for detection of COVID-19 virus through reverse Transcription and Real-Time Polymerase Chain Reaction from RNA extracted from Respiratory specimens such as throat swab. This product can qualitatively detect COVID-19 using One-Step Reverse Transcription Real-Time polymerase chain reaction to confirm the presence of SARS-COV-2 by amplification of the genes RdRp (RNA-dependent RNA polymerase), E (Envelope) and N (Nucleocapsid). |
Countries
Argentina
Contacts
STUDY_DIRECTORSantiago Sanguineti, Ph.D.
Inmunova S.A.
Participant flow
Recruitment details
Between August 1st and October 26th, 2020, a total of 243 patients were randomized. Among these, 119 received the active treatment, and 124 received placebo which constituted the safety population. Of those, 1 patient in each group had protocol deviations, thus 118 in the INM005 and 123 participants in the placebo group constituted the mITT. The number of randomized subjects was increased to compensate for patients with protocol deviations.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 31 Participants |
| Age, Categorical Between 18 and 65 years | 188 Participants |
| Age, Continuous | 54 years |
| Body Mass Index Patients with BMI <30 | 59 Participants |
| Body Mass Index Patients with BMI 30-35 | 27 Participants |
| Body Mass Index Patients with BMI >35 | 26 Participants |
| Body Mass Index | 30.1 kg/m^2 |
| COVID-19 classification by NIH Moderate | 73 Participants |
| COVID-19 classification by NIH Severe | 94 Participants |
| Days from symptoms onset to study treatment | 6 days |
| Number of coexisting conditions None | 24 Participants |
| Number of coexisting conditions One | 78 Participants |
| Number of coexisting conditions Two or more | 55 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 103 Participants |
| Race/Ethnicity, Customized Hispanic / Latino | 9 Participants |
| Race/Ethnicity, Customized Native american | 6 Participants |
| Region of Enrollment Argentina | 241 participants |
| Score on WHO 8-point ordinal scale | 4 units on a scale |
| Score on WHO 8-point ordinal scale - Categorized Hospitalized, not requiring oxygen (category 3) | 55 Participants |
| Score on WHO 8-point ordinal scale - Categorized Hospitalized, receiving noninvasive mechanical ventilation or high-flow oxygen devices (category 5) | 4 Participants |
| Score on WHO 8-point ordinal scale - Categorized Hospitalized, requiring supplemental oxygen (category 4) | 61 Participants |
| Sex: Female, Male Female | 46 Participants |
| Sex: Female, Male Male | 77 Participants |
| Use of dexamethasone for COVID-19 Moderate patients Did not used dexamethasone | 38 Participants |
| Use of dexamethasone for COVID-19 Moderate patients Used dexamethasone | 35 Participants |
| Use of dexamethasone for COVID-19 Severe patients Did not used dexamethasone | 12 Participants |
| Use of dexamethasone for COVID-19 Severe patients Used dexamethasone | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 119 | 16 / 124 |
| other Total, other adverse events | 22 / 119 | 24 / 124 |
| serious Total, serious adverse events | 16 / 119 | 25 / 124 |
Outcome results
None listed