Clinical Trials Register

Summary
EudraCT Number:	2022-000736-37
Sponsor's Protocol Code Number:	1001
National Competent Authority:	Latvia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-09-01
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Latvia - SAM

A.2

EudraCT number

2022-000736-37

A.3

Full title of the trial

A randomized, placebo-controlled, double-blind, multi-center, phase III trial to assess the efficacy and safety of trimodulin (BT588) in adult hospitalized subjects with moderate or severe COVID-19

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A randomized, placebo-controlled, double-blind, multi-center, phase III trial to assess the efficacy and safety of trimodulin (BT588) in adult hospitalized subjects with moderate or severe COVID-19

A.3.2

Name or abbreviated title of the trial where available

TRICOVID

A.4.1

Sponsor's protocol code number

1001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Biotest AG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Biotest AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Biotest AG
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	Landsteinerstrasse 5
B.5.3.2	Town/ city	Dreieich
B.5.3.3	Post code	63303
B.5.3.4	Country	Germany
B.5.6	E-mail	patrick.langohr@biotest.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Trimodulin
D.3.2	Product code	BT588
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	-
D.3.9.3	Other descriptive name	Trimodulin (human IgM, IgA, IgG solution)
D.3.9.4	EV Substance Code	SUB215556
D.3.10	Strength
D.3.10.1	Concentration unit	g/ml gram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.05
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	Yes
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

moderate or severe Coronavirus Disease 2019 (COVID-19)

E.1.1.1

Medical condition in easily understood language

moderate or severe Coronavirus Disease 2019 (COVID-19)

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	PT
E.1.2	Classification code	10084268
E.1.2	Term	COVID-19
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objectives of the trial are to assess the efficacy and safety of trimodulin as adjunctive treatment to standard of care (SoC) compared to placebo plus SoC in adult hospitalized subjects with moderate or severe COVID-19.

E.2.2

Secondary objectives of the trial

Other objectives are to determine pharmacokinetic (PK) and pharmacodynamic (PD) properties of trimodulin.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent obtained from the subject or legally acceptable/authorized representative (LAR) or informed verbal consent in case of pandemic restrictions, in compliance with all local legal requirements.
2. Hospitalized, adult (≥ 18 years of age) subject (any gender).
3. Laboratory-confirmed acute SARS-CoV-2 infection within 5 days prior to screening.
4. Receiving oxygen supply via low-flow oxygen (LFO, by mask or nasal prongs) or on non-invasive ventilation (NIV) or high-flow oxygen (HFO) at start of treatment.
5. Fulfilling at least one of the following clinical respiratory parameters within 24 hours prior to start of treatment:
- SpO2 ≤ 94% (on room air, and without preceding chronic lung disease);
- 100 mm Hg < PaO2/FiO2 ≤ 300 mm Hg under HFO or NIV;
- Radiologic evidence of COVID-19 pneumonia.
6. C-reactive protein ≥ 50 mg/L and ≤ 150 mg/L within 24 hours prior to start of treatment.
7. D-dimer ≤ 3 mg/L and platelets ≥ 130 x109/L within 24 hours prior to start of treatment.
8. Treatment with investigational medicinal product (IMP) has to be started within 7 days after first hospital-admission for COVID-19.
9. Subject must receive SoC treatment for COVID-19 according to Section 6.9 in the protocol.

E.4

Principal exclusion criteria

1. Pregnant or lactating women.
2. Subject on invasive mechanical ventilation (IMV) and/or extracorporeal membrane oxygenation (ECMO) or predicted to be on IMV and/or ECMO at start of treatment.
3. Subject with sustained improvement in any form of oxygen supply (e.g. change from IMV to NIV/HFO/LFO, or change from HFO to LFO) during the last 7 days or with predicted cessation of oxygen supply at start of treatment.
4. Severe neutropenia (neutrophil count < 0.5 x109/L) assessed within 24 hours prior to start of treatment.
5. Hemoglobin < 7g/dL assessed within 24 hours prior to start of treatment.
6. Known hemolytic disease.
7. Known thrombosis or acute 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 3 months before entering the trial. Subjects particularly at risk for TEEs caused by other reasons than the current COVID-19 infection (e.g. history of thrombophilia).
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. COPD (GOLD stage III-IV / Group D), 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. Morbid obesity with high body mass index ≥ 40 kg/m², or malnutrition with low body mass index < 16 kg/m².
19. Known treatment with polyvalent immunoglobulin preparations, plasma, or albumin preparations during the last 21 days before entering the trial.
20. Known treatment with exploratory selective immune suppressors (cytokine inhibitors, cytokine receptor inhibitors, kinase inhibitors) during the last 10 days before entering the trial.
21. Known treatment with fluoroquinolone preparations, during the last 5 days before entering the trial.
22. Known treatment with any type of interferon during the last 21 days before entering the trial.
23. Known treatment with immunosuppressants other than guideline recommended immunosuppressants for treatment of acute COVID-19.
24. Participation in another interventional clinical trial within 30 days before entering, or previous participation in this clinical trial.
25. Employee or direct relative of an employee of the contract research organization, the trial site, or Biotest.

E.5 End points

E.5.1

Primary end point(s)

Composite primary endpoint: Deterioration / mortality rate

E.5.1.1

Timepoint(s) of evaluation of this end point

- Clinical deterioration (increment of at least 1 category on the 9-category ordinal-scale from baseline) between day 6 and day 29
- 28-day all-cause mortality between day 1 and day 29

E.5.2

Secondary end point(s)

Secondary efficacy endpoints:
- Clinical deterioration rate (day 6-29)
- Clinical deterioration rate (day 1-29)
- 28-days all-cause mortality rate on day 29
- 90-days all-cause mortality rate on day 91
- Time to recovery to score ≤ 2 until day 29
- Proportion of subjects with score ≤ 2 on day 29
- Proportion of subjects improved, unchanged, and deteriorated/died compared to baseline at several days
- Proportion of subjects with PaO2/FiO2 ratio < 100, 100 to < 200, 200 to < 300 or ≥ 300 on days 7, 14, 21, 29
- Days of IMV/ECMO until day 29
- Proportion of subjects on IMV/ECMO until day 29
- Days with oxygen supply until day 29
- Proportion of subjects with oxygen supply on days 7, 14, 21, 29
- Days in intensive care unit (ICU) until day 29
- Proportion of subjects in ICU until day 29
- Days of hospitalization until day 29

Secondary safety endpoints:
- Number, severity, causality, outcome, and seriousness of all adverse events (AEs), treatment-emergent AEs (TEAEs), AEs of special interest (AESIs), infusional TEAEs, TEAEs that led to permanent withdrawal of IMP, and TEAEs that led to discontinuation of the trial through day 29 [+3]
- Number of all infusion-related TEAEs through day 29 [+3]
- Number, severity, causality, and outcome of all serious adverse events (SAEs) through day 29 [+3]
- Dose modifications (incl. reductions and changes in infusion rate)
- Distribution and changes over time for safety, laboratory, vital signs parameters, and ECG

Secondary PK endpoints:
Changes from baseline, during and after treatment:
- Serum concentration of IgM, IgA, and IgG

Secondary PD endpoints:
Changes from baseline, during and after treatment:
- Factors and markers of coagulation
- Markers of inflammation
- Complement factors
- Biomarkers
- Anti-SARS-CoV-2 titers

E.5.2.1

Timepoint(s) of evaluation of this end point

Included in E.5.2

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Brazil

Chile

Colombia

Israel

Mexico

Peru

South Africa

Turkey

Austria

Belgium

Denmark

Estonia

France

Germany

Hungary

Italy

Latvia

Lithuania

Poland

Portugal

Slovakia

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of this clinical trial (Study 1001) is defined as the Last Visit of the Last Subject. The Last Visit is the closing visit done on day 91 [+10], or a telephone interview on day 91 [+10] in case the Last Subject is discharged before day 91, or has been transferred to another hospital.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

134

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2022-09-01.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

181

F.4.2.2

In the whole clinical trial

334

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-10-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-10-19

P. End of Trial
P.	End of Trial Status	Ongoing

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