ESsCOVID: Efficacy and Safety of Trimodulin in Subjects With Severe COVID-19

Sponsor
Biotest (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT04576728
Collaborator
(none)
164
Enrollment
17
Locations
2
Arms
8.8
Anticipated Duration (Months)
9.6
Patients Per Site
1.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The objectives of the trial are to evaluate the efficacy and safety of trimodulin as add-on therapy to standard of care (SoC) compared to placebo treatment in adult hospitalized subjects with severe COVID-19.

Additionally, pharmacodynamic (PD) and pharmacokinetic (PK) properties of trimodulin will be evaluated in all subjects.

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

Detailed Description

This is a randomized, placebo-controlled, double-blind, multi-center, phase II trial investigating the efficacy and safety of trimodulin compared to placebo treatment, as add-on therapy to SoC in adult subjects with severe COVID-19. Severe COVID-19 patients with need for non-invasive ventilation or high flow oxygen and with dysregulated inflammatory responses demonstrated by an elevated CRP level, will be enrolled.

Subjects will be randomized to receive either trimodulin or placebo on a 1:1 basis, stratified by center. Investigational Medicinal Product (IMP) treatments will be blinded. Subjects will be administered IMP once daily on five consecutive days (day 1 through day 5) as add-on therapy to SoC. The subsequent follow-up phase comprises 23 [+3] days (day 6 through day 28) followed by an end-of-trial visit/ telephone call on day 29 [+3]. For evaluation of this trial, a 9-category ordinal scale will be used. The primary aim of trimodulin treatment in the enrolled severely ill patients with a score of 5, is to prevent their clinical deterioration to a critical disease stage (score 6-7, e.g. requiring invasive mechanical ventilation or ECMO) and death (score 8). Accordingly, a composite primary efficacy endpoint reflecting the deterioration / mortality rate is used.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
164 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Subjects will be randomized on a 1:1 basis either to trimodulin or to placebo treatment stratified by center.Subjects will be randomized on a 1:1 basis either to trimodulin or to placebo treatment stratified by center.
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
All bottles will be indistinguishable.
Primary Purpose:
Treatment
Official Title:
A Randomized, Placebo-controlled, Double-blind, Multi-center, Phase II Trial Investigating the Efficacy and Safety of Trimodulin (BT588) as add-on Therapy to Standard of Care in Adult Subjects With Severe COVID-19
Actual Study Start Date :
Oct 6, 2020
Anticipated Primary Completion Date :
Jul 1, 2021
Anticipated Study Completion Date :
Jul 1, 2021

Arms and Interventions

ArmIntervention/Treatment
Experimental: Trimodulin

Trimodulin (human IgM, IgA, IgG solution) for intravenous (IV) administration.

Drug: Trimodulin
IMP will be administered via IV infusion on 5 consecutive days.
Other Names:
  • BT588
  • Placebo Comparator: Placebo

    Human albumin 1%

    Other: Placebo (human albumin 1%)
    IMP will be administered via IV infusion on 5 consecutive days.

    Outcome Measures

    Primary Outcome Measures

    1. Clinical detoriation rate [Between day 6 and day 29]

      Percentage of subjects with a change of clinical status to score 6 or 7 on the 9-category ordinal scale

    2. 28-day all-cause mortality rate [Between day 1 and day 29]

      Percentage of subjects with a change to score 8 on the 9-category ordinal scale

    Secondary Outcome Measures

    1. Clinical deterioration rate [Days 1-29 and days 6-29]

      Percentage of subjects with a change to score 6-7

    2. 28-days all-cause mortality rate on day 29 [Day 29]

      Percentage of subjects with score=8, assessed at the end-of-trial visit on day 29 [+3].

    3. Time to clinical deterioration [Time Frame: between Days 1-29 and days 6-29]

      Number of days to first change from score 5 (enrollment) to score 6-7

    4. Time to Mortality [Time Frame: between Day 1 and day 29]

      Number of days to change to score =8

    5. Proportion of subjects in each of the 9-categories of the ordinal scale [Days 7, 14, 21, 29]

      Number of patients by score on specific study days

    6. Time to clinical improvement [Day 29]

      Number of days to change to score 4 (mild disease, with supplemental oxygen) or score 3 (mild disease, no supplemental oxygen)

    7. Proportion of subjects with score ≤2 [Day 29]

      Proporation of subjects that improved to score ≤2

    8. Days on IMV [Until day 29]

      Number of calendar days on IMV until day 29

    9. Days without oxygen supply [Until day 29]

      Number of calendar days without any form of oxygen support until day 29

    10. Time to discontinuation from any form of oxygen supply [Until day 29]

      Time to definite stop of any form of additional oxygenation, irrespective of short interruptions

    11. Proportion of subjects without any form of oxygen supply [Day 29]

      Proportion of subjects that improved to not requiring supplemental oxygen.

    12. Hospital-free-days [Until day 29]

      Calendar days between hospital discharge and day 29

    13. SARS-CoV-2 status [Until day 29]

      Time to SARS-CoV-2 negative status

    14. Adverse events (AEs), treatment-emergent AEs (TEAEs), AEs of special interest, infusional TEAEs [Until day 29]

      Number, severity, causality, outcome, and seriousness of all. AE, TEAEs that led to permanent withdrawal of IMP, and TEAEs that led to discontinuation of the trial.

    15. TEAEs [Until day 29]

      Number of all infusion related TEAEs

    16. SAEs [Until day 29]

      Number, severity, causality, and outcome of all SAEs

    17. Dose modifications [Day 1-5]

      Dose modifications (incl. reductions and changes in infusion rate)

    18. Time to recovery [Day 29]

      Number of days to change to score ≤2 (hospital discharged or meets discharge criteria)

    19. Change over time in ECG parameters [Until day 29]

      ECG recordings, (including heart rate, PR interval, RR interval, QRS interval, QT-interval, QTcF) showing abnormal, clinically relevant findings will be reported as adverse event.

    20. Change over time in vital signs [Until day 29]

      Changes in recordings of vital sign parameters (including systolic and diastolic blood pressure, Arterial oxygen saturation, heart rate, respiratory rate and body temperature) showing clinically significant measurements outside the normal range will be reported as adverse event.

    Other Outcome Measures

    1. Pharmacokinetic assessment of immunoglobulins [Day 1(baseline) to day 29]

      Assessment of changes in serum concentrations (g/L) of IgM, IgA, and IgG before, during and after treatment.

    2. Pharmacodynamic assessment of disease related serum proteins [Day 1(baseline) to day 29]

      Assessment of relative changes in serum concentrations from baseline before, during and after treatment including inflammation markers (e.g. % change in CRP, PCT, Ferritin, TNF-alpha, IL-6, IL-8 and IL-10), biomarkers (e.g. % change in p-selectin) and complement factors (e.g. % change in C3, C4).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Written informed consent obtained from the subject or legally authorized representative or informed verbal or administration consent due to pandemic situation, in compliance with all local legal requirements.

    2. Male or female subject ≥18 years of age.

    3. Laboratory-confirmed SARS-CoV-2 infection from a test done in a respiratory tract sample within the last 5 days at screening.

    4. Diagnosis of community-acquired severe COVID-19 within 10 days after hospital-admission, with severe defined as:

    Need for non-invasive ventilation (NIV), or high-flow oxygen therapy (score =5 on the 9-category ordinal scale).

    At least one of the following clinical respiratory parameters is fulfilled: dyspnea, respiratory frequency ≥30/min, SpO2 ≤93%, 100 mmHg < PaO2/FiO2 ≤300 mmHg, and/or lung infiltrates >50% within 24 to 48 hours.

    At least one measurement of C-reactive protein ≥50 mg/L within 36 hours prior to start of treatment.

    1. Subject must receive SoC treatment for COVID-19.
    Exclusion Criteria:
    1. Pregnant or lactating women.

    2. Subjects that deteriorated to score >5 on the 9-category ordinal scale (e.g. receiving invasive mechanical ventilation (IMV), and/or extracorporeal membrane oxygenation (ECMO)) or subjects that improved to score <5 prior to randomization.

    3. Severe neutropenia (neutrophil count <500/mm³) assessed within 24 hours prior to start of treatment.

    4. Thrombocytopenia (platelet count <30,000/mm³) assessed within 24 hours prior to start of treatment.

    5. Hemoglobin <7g/dL assessed within 24 hours prior to start of treatment.

    6. Known hemolysis.

    7. Known thrombosis or thromboembolic events (TEEs) or known medical history of TEEs (e.g. cerebrovascular accidents, transient ischemic attack, myocardial infarction, pulmonary embolism, and deep vein thrombosis) within the previous 3 months or those subjects particularly at risk for TEEs (e.g. history of thrombophilia, permanent immobilization, or permanent paralysis of the lower extremities) caused by other reasons than COVID-19.

    8. Subject on dialysis or with severe renal impairment, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² assessed within 24 hours prior to start of treatment (details in Appendix 3: Estimated Glomerular Filtration Rate).

    9. Subject with end stage renal disease (ESRD), or known primary focal segmental glomerulosclerosis (FSGS).

    10. Known severe lung diseases interfering with COVID-19 therapy (e.g. severe interstitial lung disease, cystic fibrosis, idiopathic pulmonary fibrosis, active tuberculosis, chronically infected bronchiectasis, or active lung cancer).

    11. Known decompensated heart failure (New York Heart Association class III-IV).

    12. Known pre-existing hepatic cirrhosis, severe hepatic impairment (Child Pugh C score ≥9 points), or hepatocellular carcinoma.

    13. Known intolerance to proteins of human origin or known allergic reactions to components of trimodulin.

    14. Selective, absolute immunoglobulin A (IgA) deficiency with known antibodies to IgA.

    15. Known treatment for thorax/head/neck/hematologic malignancies in the last 12 months.

    16. Known human immunodeficiency virus infection.

    17. Life expectancy of less than 90 days, according to the Investigator's clinical judgment, because of medical conditions neither related to COVID-19 nor to associated medical complications.

    18. Obesity (body mass index ≥40 kg/m²), a body weight of more than 123 kg, or anorexia (body mass index <16 kg/m²).

    19. Known immunosuppressive treatment other than acute treatment for COVID-19 (e.g. transplant recipient, subject with autoimmune disease).

    20. Known treatment with polyvalent immunoglobulin preparations, any type of blood product, or any type of interferon during the last 21 days before entering the trial.

    21. Participation in another interventional clinical trial within 30 days before entering, or during the trial, or previous participation in this clinical trial.

    22. Employee or direct relative of an employee of the contract research organization, the trial site, or Biotest.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Investigational site # 5503Porto AlegreBrazil90020-090
    2Investigational site # 5502Santo AndréBrazil09030-010
    3Investigational site # 5505Santo AndréBrazil09080-110
    4Investigational site # 5501São PauloBrazil05403-000
    5Investigational site # 3304ParisFrance75020
    6Investigational Site # 3301ParisFrance75877
    7Investigational site # 3305Saint-ÉtienneFrance42 055
    8Investigational site # 0707KemerovoRussian Federation650066
    9Investigational site # 0709KrasnoyarskRussian Federation660062
    10Investigational site # 0702MoscowRussian Federation111539
    11Investigational site # 0706MoscowRussian Federation119048
    12Investigational site # 0711MoscowRussian Federation125015
    13Investigational Site # 0704MoscowRussian Federation125367
    14Investigational site # 0708MoscowRussian Federation129301
    15Investigational site # 0701Saint PetersburgRussian Federation197706
    16Investigational Site # 3401BarcelonaSpain
    17Investigational Site # 3402MadridSpain

    Sponsors and Collaborators

    • Biotest

    Investigators

    • Principal Investigator: Antoni Torres, MD, University of Barcelona Hospital Clinic of Barcelona Spain

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Biotest
    ClinicalTrials.gov Identifier:
    NCT04576728
    Other Study ID Numbers:
    • 998
    First Posted:
    Oct 6, 2020
    Last Update Posted:
    Jun 16, 2021
    Last Verified:
    Jun 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Biotest
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jun 16, 2021