Clinical Trials Register

Summary
EudraCT Number:	2020-001310-38
Sponsor's Protocol Code Number:	CAPSID2020-DRK-BSD
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2020-03-31
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

Germany - PEI

A.2

EudraCT number

2020-001310-38

A.3

Full title of the trial

A randomized, prospective, open label clinical trial on the use of convalescent plasma compared to best supportive care in patients with severe COVID-19

Randomisierte, prospektive, offene klinische Studie von Rekonvaleszentenplasma verglichen mit bestmöglicher supportiver Behandlung bei Patienten mit schwerer COVID-19-Erkrankung

A.3.1

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

Clinical Study to assess positive value of blood plasma from donors having built immunity against the new corona virus (SARS-CoV-2) transfused to patients suffering from SARS-CoV-2 infection

Klinische Studie zur Überprüfung der positiven Wirkung der Übertragung von Blutplasma von Spendern mit nachgewiesener Immunität gegen das neuartige Coronavirus (SARS-CoV-2) auf Patienten mit Infektion durch SARS-CoV-2

A.3.2

Name or abbreviated title of the trial where available

Convalescent Plasma against COVID-19

Rekonvaleszentenplasma gegen COVID-19

A.4.1

Sponsor's protocol code number

CAPSID2020-DRK-BSD

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	DRK-Bluspendedienst Baden-Württemberg - Hessen gGmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Ministry of Health
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	IKT Ulm
B.5.2	Functional name of contact point	Sixten Körper
B.5.3	Address:
B.5.3.1	Street Address	Helmholtzstr. 10
B.5.3.2	Town/ city	Ulm
B.5.3.3	Post code	89081
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049731150519
B.5.5	Fax number	0049731150509
B.5.6	E-mail	s.koerper@blutspende.de

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	Yes
D.2.1.1.1	Trade name	Fresh frozen plasma (FFP) with marketing authorisation in Germany issued by PEI
D.2.1.1.2	Name of the Marketing Authorisation holder	German marketing authorization holders for FFPs participating in this study
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	For example "Gefrorenes Frischplasma / Apherese DRK Blutspendedienst"
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.3.11 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)	Yes
D.3.11.7	Plasma derived medicinal product	No
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with SARS-CoV-2 infection and:
1. age ≥ 18 years and ≤ 75 years
2. SARS-CoV-2 infection confirmed by PCR (BAL, sputum, nasal and/or pharyngeal
swap)
3. severe disease defined by at least one of the following:
a. respiratory rate ≥ 30 breaths / minute under ambient air
b. requirement of any type of ventilation support
c. needs ICU treatment

Patienten mit SARS-CoV-2-Infektion und:
1. Alter ≥ 18 und ≤ 75 Jahre
2. SARS-CoV-2-Infektion bestätigt durch PCR (BAL, Sputum, Nasen-/Rachenabstrich)
3. schwere Erkrankung definiert durch eines der folgenden Kriterien:
a. Atemfrequenz ≥ 30/Minute unter Umgebungsluft
b. Notwendigkeit jeglicher Beatmungsunterstützung
c. Notwendigkeit intensivmedizinischer Betreuung

E.1.1.1

Medical condition in easily understood language

COVID-19 can cause pneumonias, which in severe cases can require automated assisted ventilation. In this context potentially fatal multiorgan dysfunction and circulatory failure may occur as well.

COVID-19 kann Lungenentzündungen auslösen. In schweren Fällen ist eine maschinelle Beatmung erforderlich. Es können auch potentiell tödliches Kreislaufversagen und Multiorganversagen auftreten.

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10047475
E.1.2	Term	Viral pneumonia, unspecified
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	LLT
E.1.2	Classification code	10070267
E.1.2	Term	SARS virus test positive
E.1.2	System Organ Class	100000004848

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10021433
E.1.2	Term	Immunization
E.1.2	System Organ Class	100000004865

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10054540
E.1.2	Term	Passive immunization
E.1.2	System Organ Class	100000004865

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To improve survival

AND

remove criteria of severe COVID-19 (CoV-2 infection) within 21 days after randomization

Verlängerung des Überlebens

UND

Wegfallen der Kriterien für eine schwere COVID-19-Erkrankung (CoV-2-Infektion) innerhalb von 21 Tagen nach Randomisierung

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

E.4

Principal exclusion criteria

1. Accompanying diseases other than COVID-19 with an expected survival time of
less than 12 months
2. In the opinion of the clinical team, progression to death is imminent and
inevitable within the next 48 hours, irrespective of the provision of treatment
3. Interval > 72 hours since start of ventilation support
4. Not considered eligible for extracorporeal oxygenation support (even in case of
severe ARDS according to Berlin classification with Horovitz-Index < 100 mg Hg)
5. Chronic obstructive lung disease (COPD), stage 4
6. Lung fibrosis with UIP pattern in CT and severe emphysema
7. Chronic heart failure NYHA ≥ 3 and/or pre-existing reduction of left ventricular
ejection fraction to ≤ 30%
8. Cardiovascular failure requiring ≥ 0.5 µg/kg/min noradrenaline (or equivalent) or
requiring more than two types of vasopressor medication
9. Liver cirrhosis Child C
10. Liver failure: Bilirubin > 5 x ULN and elevation of ALT or AST (> 10 x ULN)
11. Any history of adverse reactions to plasma proteins
12. Known deficiency of immunoglobulin A
13. Pregnancy
14. Breastfeeding women
15. Volume overload until sufficiently treated
16. Pulmonary edema
17. Participation in another clinical trial for treatment of COVID-19

1. Begleiterkrankungen neben COVID-19 mit einer Lebenserwartung < 12 Monaten
2. Behandlungsunabhängige, infauste Prognose innerhalb der nächsten 48 Stunden
3. Zeitintervall > 72 Stunden seit Beginn der maschinellen Beatmung
4. Nicht geeignet für ECMO
5. COPD Stadium 4
6. Lungenfibrose und schweres Emphysem
7. Chronische Herzinsuffizienz (NYHA ≥ 3) und/oder vorbestehende Reduktion der
linksventrikulären Ejektionsfraktion ≤ 30%
8. Herzkreislaufversagen mit Bedarf von ≥ 0.5 µg/kg/min Noradrenalin (oder
Äquivalent) oder Bedarf von mehr als 2 vasopressorisch aktiven Substanzen
9. Leberzirrhose Child C
10. Leberversagen: Erhöhung des Bilirubins (> 5 x oberer Normwert) und Erhöhung
der ALT oder der AST (> 10 x oberer Normwert)
11. Anamnestisch unerwünschte Arzneimittelwirkungen gegenüber Plasmaproteinen
12. Bekannte Immunoglobulin A-Defizienz
13. Schwangerschaft
14. Stillzeit
15. Volumenüberladung
16. Lungenödem
17. Teilnahme an einer anderen Studie zur Behandlung von COVID-19

E.5 End points

E.5.1

Primary end point(s)

Composite endpoint of:

- Survival

AND

- no longer fulfilling criteria of severe COVID-19 within 21 days after randomization

All criteria must be met in order to fulfill the primary endpoint.

Kombinierter Endpunkt bestehend aus:

- Überleben

UND

- Wegfallen der Kriterien für eine schwere COVID-19-Erkrankung (CoV-2-Infektion) innerhalb von 21 Tagen nach Randomisierung

Beide Kriterien müssen gegeben sein, um den kombinierten primären Endpunkt zu erfüllen.

E.5.1.1

Timepoint(s) of evaluation of this end point

Treatment group: Day 21

Control group: Days 14 and 21

Behandlungsgruppe: Tag 21

Kontrollgruppe: Tage 14 und 21

E.5.2

Secondary end point(s)

- Time to clinical improvement on WHO R&D Blueprint seven-category ordinal scale by 2
- Adverse events
- Case fatality rate on days 21, 35 and 60
- Length of hospital stay
- Length of ICU stay
- Duration of ventilation Support / ECMO
- Time until negative SARS-CoV-2 PCR
- Predictive value of comorbidities and inflammation markers
- Feasibility of collection of plasma units
- Kinetics of anti-SARS-CoV-2 antibodies in plasma of patients = plasma donors who recovered
from a SARS-CoV-2 infection
- Titer of anti-SARS-CoV-2 in transfused plasma units
- Impact of donor characteristics on anti-SARS-CoV-2 humoral response
- Course of anti-SARS-CoV-2 titer in patients
- Effect of timing of plasma transfusions on outcome

Endpoints relating to the extended observation phase:
- Long term survival* up to 15 months after randomisation (patients in CCP group* compared to control group) or first plasma donation (CCP donors).
- Frequency, severity and duration of long COVID-19* up to 540 days after randomisation (patients in CCP group* compared to control group) or first plasma donation (CCP donors)
- Resolution of pneumonia and functional recovery* in patients (CCP group compared to control group and donors)
- Fatigue* (in patients CCP group compared to control group and donors)
- QoL* (in patients: CCP group compared to control group and donors)
- Utilization of health care resources* (in patients: CCP group compared to control group and donors)
- Anti-SARS-CoV-2 immunity and inflammation* (in patients: CCP group compared to control group and donors).
- Effect of SARS-CoV-2 vaccination* in control group, CCP group and CCP donors

For the endpoints mentioned above (*) also a subgroup analysis by the cumulative amount of transfused neutralizing units in the CCP is planned.

- Dauer bis zur klinischen Verbesserung auf siebenstufiger WHO R&D Blueprint-Skala um 2
- Unerwünschte Wirkungen
- Todesfallraten an den Tagen 21, 35 und 60
- Dauer des Krankenhausaufenthaltes
- Dauer des Aufenthaltes auf Intensivstation
- Dauer der apparativen Beatmung / ECMO
- Zeitdauer bis SARS-CoV-2-PCR negativ
- Prädiktiver Wert von Begleiterkrankungen und Entzündungsparametern
- Verfügbarkeit der notwendigen Plasmapräparate
- Kinetik von Anti-SARS-CoV-Antikörpern im Plasma von Patienten = Plasmaspender, die von
einer SARS-CoV-2-Infektion genesen sind
- Anti-SARS-CoV-2-Antikörpertiter in transfundierten Plasmapräparaten
- Einfluss von Spendercharakteristika auf die humorale Anti-SARS-CoV-2-Antwort
- Verlauf der anti-SARS-CoV-2-Antikörpertiter in Patienten
- Einfluss des Zeitpunkts der Plasmatransfusionen auf den Krankheitsverlauf

Endpunkte der erweiterten Beobachtungsphase:
- Langzeitüberleben* bis zu 15 Monate nach der Randomisierung (Patienten in der CCP-Gruppe* im Vergleich zur Kontrollgruppe) oder der ersten Plasmaspende (CCP-Spender).
- Häufigkeit, Schwere und Dauer des Long-COVID-19* bis zu 540 Tage nach der Randomisierung (Patienten der CCP-Gruppe* im Vergleich zur Kontrollgruppe) oder der ersten Plasmaspende (CCP-Spender)
- Abklingen der Lungenentzündung und funktionelle Erholung* bei Patienten (CCP-Gruppe im Vergleich zur Kontrollgruppe und zu den Spendern)
- Müdigkeit* (bei Patienten der CCP-Gruppe im Vergleich zur Kontrollgruppe und zu den Spendern)
- Lebensqualität* (bei Patienten: CCP-Gruppe im Vergleich zur Kontrollgruppe und zu Spendern)
- Inanspruchnahme von Gesundheitsressourcen* (bei Patienten: CCP-Gruppe im Vergleich zur Kontrollgruppe und zu Spendern)
- Anti-SARS-CoV-2-Immunität und Entzündung* (bei Patienten: CCP-Gruppe im Vergleich zur Kontrollgruppe und zu Spendern).
- Wirkung der SARS-CoV-2-Impfung* in der
Kontrollgruppe, CCP-Gruppe und CCP-Spendern

Für die oben genannten Endpunkte (*) ist auch eine
Untergruppenanalyse nach der kumulativen Menge der transfundierten neutralisierenden Einheiten in der CCP geplant.

E.5.2.1

Timepoint(s) of evaluation of this end point

Treatment group: Prior to transfusion of convalescent plasma on days 1, 3 and 5 and one day after infusion (days 2, 4 and 6) and every week thereafter up to day 21.

Cross-over group: Prior to transfusion of convalescent plasma on days 15, 17 and 19 and one day after infusion (days 16, 18 and 20) and every week thereafter up to day 35.

Timepoint relating endpoints in extended observation phase: up to 15 months after randomisation

Behandlungsgruppe: Vor Transfusion des Konvaleszentenplasmas an den Tagen 1, 3 and 5 und einen Tag nach Infusion (Tage 2, 4 and 6) sowie danach einmal wöchentlich bis Tag 21

Cross-over-Gruppe: Vor Transfusion des Konvaleszentenplasmas an den Tagen 15, 17 und 19 und einen Tag nach Infusion (Tage 16, 18 und 20) sowie danach einmal wöchentlich bis Tag 35

Zeitpunkt der Endpunkte in der erweiterten Beobachtungsphase: bis zu 15 Monate nach Randomisierung

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Cross-over erlaubt bei Patienten mit fortschreitender COVID-19-Erkrankung

Cross-over allowed for patients with progressive COVID-19

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Beste supportive Therapie

Best supportive care

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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 2020-03-31.

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Legal representative

OR

Combination of alleged patient will PLUS opinion of a physician independent of the clinical trial team

Gesetzlicher Vertreter

ODER

Kombination aus mutmaßlichem Patientenwillen PLUS Meinung eines nicht an der Studie beteiligten Arztes

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

120

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

Keine

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

2020-04-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-06

P. End of Trial
P.	End of Trial Status	Restarted

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