Clinical trial NCT04576728: Efficacy and Safety of Trimodulin in Subjects With Severe COVID-19
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Covid19
Keywords: Covid19
Severe community acquired pneumonia
Acute Respiratory Distress Syndrome
SARS-CoV-2
Severe Corona Virus Disease
Lead sponsor: Biotest
Sponsor class: INDUSTRY
First posted: 2020-10-06
Enrollment: 166
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subjects will be randomized on a 1:1 basis either to trimodulin or to placebo treatment stratified by center.
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.
5. 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.

Primary outcomes:
measure: Clinical detoriation rate
timeFrame: Between day 6 and day 29
measure: 28-day all-cause mortality rate
timeFrame: Between day 1 and day 29
Secondary outcomes:
measure: Clinical deterioration rate
timeFrame: Days 1-29 and days 6-29
measure: 28-days all-cause mortality rate on day 29
timeFrame: Day 29
measure: Time to clinical deterioration
timeFrame: Time Frame: between Days 1-29 and days 6-29
measure: Time to Mortality
timeFrame: Time Frame: between Day 1 and day 29
measure: Proportion of subjects in each of the 9-categories of the ordinal scale
timeFrame: Days 7, 14, 21, 29
measure: Time to clinical improvement
timeFrame: Day 29
measure: Proportion of subjects with score ≤2
timeFrame: Day 29
measure: Days on IMV
timeFrame: Until day 29
measure: Days without oxygen supply
timeFrame: Until day 29
measure: Time to discontinuation from any form of oxygen supply
timeFrame: Until day 29
measure: Proportion of subjects without any form of oxygen supply
timeFrame: Day 29
measure: Hospital-free-days
timeFrame: Until day 29
measure: SARS-CoV-2 status
timeFrame: Until day 29
measure: Adverse events (AEs), treatment-emergent AEs (TEAEs), AEs of special interest, infusional TEAEs
timeFrame: Until day 29
measure: TEAEs
timeFrame: Until day 29
measure: SAEs
timeFrame: Until day 29
measure: Dose modifications
timeFrame: Day 1-5
measure: Time to recovery
timeFrame: Day 29
measure: Change over time in ECG parameters
timeFrame: Until day 29
measure: Change over time in vital signs
timeFrame: Until day 29
Other outcomes:
measure: Pharmacokinetic assessment of immunoglobulins
timeFrame: Day 1(baseline) to day 29
measure: Pharmacodynamic assessment of disease related serum proteins
timeFrame: Day 1(baseline) to day 29
Locations:
city: Porto Alegre
country: Brazil
facility: Investigational site # 5503
city: Santo André
country: Brazil
facility: Investigational site # 5502
city: Santo André
country: Brazil
facility: Investigational site # 5505
city: São Paulo
country: Brazil
facility: Investigational site # 5501
city: Paris
country: France
facility: Investigational site # 3304
city: Paris
country: France
facility: Investigational Site # 3301
city: Saint-Étienne
country: France
facility: Investigational site # 3305
city: Kemerovo
country: Russian Federation
facility: Investigational site # 0707
city: Krasnoyarsk
country: Russian Federation
facility: Investigational site # 0709
city: Moscow
country: Russian Federation
facility: Investigational site # 0702
city: Moscow
country: Russian Federation
facility: Investigational site # 0706
city: Moscow
country: Russian Federation
facility: Investigational site # 0711
city: Moscow
country: Russian Federation
facility: Investigational Site # 0704
city: Moscow
country: Russian Federation
facility: Investigational site # 0708
city: Saint Petersburg
country: Russian Federation
facility: Investigational site # 0701
city: Barcelona
country: Spain
facility: Investigational Site # 3401
city: Madrid
country: Spain
facility: Investigational Site # 3402
Study officials:
affiliation: University of Barcelona Hospital Clinic of Barcelona Spain
name: Antoni Torres, MD
role: PRINCIPAL_INVESTIGATOR
References: