Clinical Trials Register

Summary
EudraCT Number:	2021-002200-12
Sponsor's Protocol Code Number:	ANN-002
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-12-17
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

Netherlands - Competent Authority

A.2

EudraCT number

2021-002200-12

A.3

Full title of the trial

A multiple dosing study to demonstrate the safety, tolerability, pharmacokinetics and efficacy potential of
intravenously administered ANXV (a recombinant human Annexin A5) in patients with confirmed moderate to
severe COVID-19; The CO-ANNEXIN Study.

Meervoudig dosering studie om aan te tonen de veiligheid, verdraagbaarheid, farmacokinetiek en effectiviteit van
intraveneus toegediend ANXV (een recombinant humaan Annexine A5) aan patiënten met matig tot ernstige
COVID-19; De CO-ANNEXIN studie.

A.3.1

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

The CO-ANNEXIN study; assessing the efficacy and safety of ANXV (recombinant Annexin A5) in moderate to
severe COVID-19.

De CO-ANNEXIN studie; onderzoek naar de effectiviteit en veiligheid van ANXV (recombinant Annexine A5) in
matig tot ernstige COVID-19.

A.3.2

Name or abbreviated title of the trial where available

The CO-ANNEXIN Study

De CO-ANNEXIN Studie

A.4.1

Sponsor's protocol code number

ANN-002

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	MUMC AZm
B.1.3.4	Country	Netherlands
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	Annexinpharmaceuticals
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CTCM
B.5.2	Functional name of contact point	clinical trial centre maastricht
B.5.3	Address:
B.5.3.1	Street Address	oxfordlaan 70
B.5.3.2	Town/ city	Maastricht
B.5.3.3	Post code	6229EV
B.5.3.4	Country	Netherlands
B.5.6	E-mail	johan.vanden.oever@mumc.nl

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.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Annexin A5
D.3.2	Product code	ANXV
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Not mentioned (Noncurrent)
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	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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

moderate to severe COVID-19 pneumonia

patiënten met matig tot ernstige COVID-19 oneumonie

E.1.1.1

Medical condition in easily understood language

patients with moderate to severe covid-19 pneumoniae

patiënten met matig tot ernstige COVID-19 pneumonie

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluation of the potential efficacy, safety, and tolerance of intravenous ANXV, in ascending doses, and two
different dosing schedules, in patients with proven moderate to severe COVID-19

Evaluatie van de potentiele effectiviteit, veiligheid, en tolerantie van intraveneus toegediend ANXV, in opklimmende doses, en twee
verschillende doseringsschema's, in patiënten met bewezen matig tot ernstige COVID-19

E.2.2

Secondary objectives of the trial

Determination of the pharmacokinetic profile of intravenous ANXV, in ascending dose, and two different
rates of administration, in patients with moderate to severe COVID-19.

Bepalen van het farmacokinetische profiel van intravenous toegediend ANXV, in opklimmende dosering, en twee verschillende
snelheden van toediening , in patiënten met matig tot ernstig COVID-19.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must be at least 18 years of age or older, with clinically evident or otherwise confirmed moderate to severe COVID-19
pneumonia, with PCR-confirmed presence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
They have to be in need for oxygen supply, via high flow nasal oxygen (optiflow).
Inclusion criteria
1. Patients hospitalized for laboratory documented SARS-CoV2 infection (qRT-PCR).
2. Males between 18 and 75 years or Females of non-reproductive age or capacity, i.e post-menopausal or sterile, and between 18
and 75 years.
3. Signed informed consent by patient
4. Hospitalized with a resting oxygen saturation on room air of <92 %, AND receiving high flow nasal oxygen.
5. Elevated LDH (>350U/L, n=97-247 U/l)

Patiënten moeten ten minste 18 jaar oud zijn, en er moet bewijs zijn voor de diagnose matig tot ernstige COVID-19 pneumonie,
met een middels PCR bewezen aanwezigheid van het SARS-CoV-2 virus. Zij dienen zuurstof toediening afhankelijk te zijn, via
optiflow.

1. Patient op medium- of intensive care in verband met SARS-CoV2 infection (qRT-PCR).
2. Mannen tussen 18 en 75 jaar of vrouwen die niet zwanger zijn, of kunnen worden,dus post-menopausaal, of steriel of door
adequaat gebruik van anticonceptie.
3. Getekend geïnformeerde toestemming.
4. Opgenomen in het ziekenhuis, met zuurstof saturatie in rust en in kamerlucht <92 %, EN met toediening van hoge flow nasaal
zuurstof (optieflow).
5. Verhoogd LDH (>350U/L, n=97-247 U/l)

E.4

Principal exclusion criteria

1. Subject requiring mechanical ventilation/ extracorporeal membrane oxygenation and in-tubated for mechanical ventilation.
2. Severe COPD, defined by continuous use of long-acting bronchodilators or inhaled/oral corticosteroids for > 2 months in the
home situation.
3. Subject with severe renal impairment (eGFR < 30 ml/min)
4. Subjects on chronic dialysis.
5. Subject with an active malignancy within the last three months, and/or a risk of mortality >50% within 6 months.
6. Bleeding Risk:
a. Clinical: Active bleeding; head trauma, intracranial surgery or stroke within 3 months; history of intracerebral arteriovenous
malformation, cerebral aneurysm or mass lesions of the central nervous system; cerebral haemorrhage; history of a bleeding
diatheses; gastrointestinal bleeding within 6 weeks; presence of an epidural or spinal catheter; contraindication for IV therapeutic
UFH.
b. Laboratory: Platelet count <50 x109/L, INR >3.0 or baseline aPTT ≥45 seconds prior to enrolment.
7. Use of any of the following treatments: UFH to treat a thrombotic event within 12 hours before enrolment; thrombolytic therapy
within 3 previous days;
8. Confirmed antiphospholipid syndrome, systemic lupus erythematosus and other auto-immune diseases (at discretion of PI)
9. Confirmed thalassemias (e.g sickle cell disease)
10. Cardiopulmonary resuscitation in previous 7 days.
11. Liver failure defined as Child-Pugh Score Class C.
12. Abnormal liver function (AST >5xULN, ALT >5xULN)
13. Life expectancy of <24 hours
14. Treating physician refusal.
15. Any other clinical condition which, in the opinion of the investigator, would not allow safe completion of the protocol.
16. Participation in any other investigational drug study

1. De noodzaak tot mechanische ventilatie/extracorporele membraan oxygenatie en geïntubeerd.
2. Ernstig COPD, gedefinieerd door het gebruik op chronische basis van langwerkend bronchodilatatie of inhalatie steroïden in de
thuissituatie.
3. Ernstige nierinsufficiëntie. (eGFR< 30 ml/min)
4. Chronische dialyse.
5. Aanwezigheid van een actieve maligniteit binnen de laatste drie maanden, en/of risico op overlijden> 50% binnen 6 maand.
6. Verhoogd bloedingsrisico:
a. Klinisch: actieve bloeding; schedeltrauma, intracraniële chirurgie of bloedig CVA in de laatste drie maanden; voorgeschiedenis
van intracerebrale arterioveneuze malformatie,cerebraal aneurysma; aanwezigheid van een ruimte innemend proces met
massawerking intracerebraal; aanwezigheid van verhoogd bloedingsneiging; gastrointestinale bloeding binnen de laatste 6 weken;
aanwezigheid van een epidurale of spinale catheter. Aanwezigheid van contraindicatie voor het gebruik van therapeutisch LMWH,
of iv UFH.
b. Laboratorium: trombocyten getal <50 x109/L, INR >3.0 of baseline aPTT ≥45 seconden vooraf aan de inclusie in de studie.
7. Gebruik van therapeutische dosering UFH in kader van bewezen nieuwe trombose dat optreedt binnen 12 uur voor de inclusie;
trombolyse binnen de drie dagen voor inclusie in de studie.
8. Bewezen antifosfolipide syndroom; Tevens actieve systemische lupus erythrmatosus of andere auto-immuunziekte indien dit
niet schikt naar het oordeel van de PI.
9. Bevestigde diagnose van thalassemia en/of sikkelcelziekte.
10. Cardiopulmonale reanimatie in de voorafgaande 7 dagen.
11. Leverfalen gedefineerd als Child-Pugh Score klasse C.
12. Abnormale lever functie (AST >5xULN, ALT >5xULN)
13. Levensverwachting < 24 uur.
14. Weigering of ontraden van deelname door hoofdbehandelaar.
15. Elke andere situatie waardoor naar het oordeel van de onderzoeker een veilige afronding van het protocol niet mogelijk is.
16. Deelname aan andere geneesmiddelen studie.

E.5 End points

E.5.1

Primary end point(s)

Main study parameter/endpoint:
Efficacy potential:
• Assessment of activated coagulation factors in complex with antithrombin before each ANXV administration, and at 5, 20, 90, 240
and 480 min after the ending of each ANXV administration. Complexes are FXIa:AT, FIXa:AT and FXa:AT.
• Assessment of cytokine and inflammatory profile at baseline, at 16 and 32 hours after last ANXV administration. (CRP, IFN-��,
TNF��, IL-1��, IL- 6, IL-10 and IL-18).
• Assessment of coagulation profile at baseline, and at 16 and 32 hours after the start of the first ANXV administration. Endpoints:
Absolute D-dimer - (Fibrin Equivalent units); aPTT (Activated Partial Thromboplastin time) - seconds; fibrinogen (g/L); INR
• Assessment of complement C5a levels at baseline, and at 16 and 32 hours after the start of the first ANXV administration
• Assessment of the presence or absence of free histones in plasma.
• 28-day all cause mortality
• Patient free of shortness of breath (respiratory rate <20/min) and in absence of oxygen supply.
• Patient free of fever (fever > 37,50°C)
• Change from baseline in ALT and AST
• Change from baseline in lymphocyte count
• Change from baseline in neutrophil count
Frequency, intensity and seriousness of adverse events (AEs):
• Infusion reactions to IMP, including hypersensitivity or anaphylactic reactions.
• Clinically relevant changes from baseline in:
• Vital signs (blood pressure, pulse, body temperature, respiratory rate, pulse oximetry, FiO2)
• Physical examination
• Safety laboratory parameters
• ADA
• Electrocardiogram (ECG)
• Imaging (on indication, for instance in case suspicion of thromboembolic-or hemorrhagic event)

E.5.1.1

Timepoint(s) of evaluation of this end point

after each administration

na ieder toediening

E.5.2

Secondary end point(s)

Pharmaco-kinetic parameters:
• Area under the plasma concentration vs time curve from time zero extrapolated to infinity (AUCinf)
• AUC from time zero to time of last quantifiable analyte concentration (AUClast)
• Observed maximum concentration (Cmax)
• Time to Cmax (Tmax)
• Terminal slope of a semi-logarithmic concentration-time curve (λz)
• Terminal half-life (T½)
• Clearance (CL)
• Volume of distribution (Vz)
• Dose proportionality after a single dose, based on AUC and Cmax

E.5.2.1

Timepoint(s) of evaluation of this end point

after each administration

na iedere toediening

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

Yes

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

E.8.1.1

Randomised

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

It is an interventional, open-label, standard of care-controlled trial

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

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

CTCM

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)

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

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

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.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

2021-12-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-10

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

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