Primary Objective:To evaluate the efficacy potential, safety and tolerability of intravenously administered ANXV, in ascending doses, and two different dosing regimens, in patients with confirmed moderate to severe COVID-19.Secondary Objectives:To…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Viral infectious disorders
- Pulmonary vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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)
Secondary outcome
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 (*z)
• Terminal half-life (T*)
• Clearance (CL)
• Volume of distribution (Vz)
• Dose proportionality after a single dose, based on AUC and Cmax
Background summary
Within the past 14 months over 3,0 million people have been reported deceased
due to COVID-19, a novel clinical entity caused by severe acute respiratory
syndrome due to infection with the coronavirus-2 (SARS CoV-2). No specific
anti-viral treatment is available against SARS CoV-2.
We recently demonstrated that the pathogenesis of severe COVID-19 involves the
innate immune system and the coagulation cascade, explaining the high incidence
of thrombotic complications and vasculopathy1. The crosstalk between activated
neutrophils and the coagulation cascade, also coined immuno-thrombosis,
appeared to amplify thrombogenesis and injury of blood vessels.
Recently the DAMP PS has indeed been linked to the pathogenic mechanisms
involved in COVID-19. Hence, PS is a promising therapeutic target for treatment
of COVID-19.
Annexin A5 is a human anticoagulant protein that was discovered at the
Maastricht University.
ANXV is a recombinant human Annexin A5 currently in development for treatment
of acute immuno-thrombotic vascular disease, including retinal vein occlusion.
ANXV suppresses the catalytic activity of phosphatidylserine (PS). PS is
exposed by activated, injured and dying cells and, thereby, functions as a
danger associated molecular pattern (DAMPs), which are immunomodulatory
molecules, activating proinflammatory and prothrombotic signaling cascades.
ANXV binds PS with high affinity, and thereby dampens this downstream
immuno-thrombotic cascade.
We hypothesize that ANXV administered to patients with moderate to severe
COVID-19 infection will prevent clinical deterioration and reduce the need for
invasive ventilation, and thereby mortality. To address this hypothesis, a
single centre proof of concept clinical trial is proposed to assess the safety,
tolerability and efficacy potential of ANXV in hospitalised adult patients with
moderate to severe COVID-19 who are receiving high flow nasal oxygen (HFNO).
Observations from this study, including efficacy indicators, will be
informative for and thus guide near future randomised controlled studies with
multiple dosing, which will be considered immediately pending the results from
this study.
Study objective
Primary Objective:
To evaluate the efficacy potential, safety and tolerability of intravenously
administered ANXV, in ascending doses, and two different dosing regimens, in
patients with confirmed moderate to severe COVID-19.
Secondary Objectives:
To determine the PK profile of intravenously administered ANXV, in ascending
doses, and two different dosing regimens, in patients with confirmed moderate
to severe COVID-19.
Study design
The trial aims to enroll 12 patients who are admitted with moderate to severe
COVID-19, over a 6-month inclusion period.
It is an interventional, open-label, standard of care-controlled trial, to
evaluate the safety, tolerability, pharmacokinetics and clinical efficacy of
multiple intravenous dosing with ANXV, and two dosing regimens, in patients
with confirmed moderate to severe COVID-19.
Recruitment takes place among the patients who are admitted to the medium care
or intensive care unit of our referral hospital because of moderate to severe
COVID-19. All patients for the purpose of this study are receiving high flow
nasal oxygen (optiflow). After admission the treating physician will inform the
patient about the study. Depending on the patient*s acceptance to hear more
about this study, a member of the research or study team will further inform
the patient about the outline of the study. The patient will receive a written
patient information brochure and will be given a maximum of 48 hours to decide
whether or not to participate.
Baseline measurements will be performed and baseline blood samples will be
taken. All patients will receive optimal COVID-19 related treatment, according
to the local protocol.
Directly following the completion of all baseline measurements, the first
intravenous dose of ANXV will be administered. The following doses are proposed
to be tested in Cohort 1 in the study: 1 mg total dose/60 min (starting dose),
1 mg total dose/15 min, 2 mg total dose /60 min, 2 mg total dose/ 15 min. Only
after the evaluation of the safety data, the study will be extended to Cohort 2
with 4 mg total dose/60 min and 4 mg total dose/15 min.
The study aims to evaluate 6 subjects in Cohort 1 and 6 subjects in Cohort 2.
As control group for we will include data from 16 subjects with moderate to
severe COVID-19 wo received standard of care with no ANXV nor placebo
administration. In these patients we previously collected blood samples as part
of our biomarker study in COVID-19. (Annexin and extracellular histon3 are
novel biomarkers for the progression of COVID-19. A bridging opportunity
towards new treatment strategies. METC 2020-1325)
Safety evaluation and dose escalation will be done per subject. The starting
dose will be 1 mg per subject administered intravenously as a slow (60 min),
and subsequently after eight hours fast (15 min) infusion. This first and the
second dose level of ANXV are expected to be well tolerated based on the NOAEL
obtained in pre-clinical toxicology studies and on safety and tolerability data
from in human healthy volunteers. The dose will be incrementally escalated to
6.0 mg and 8.0 mg total dose per subject, in Cohort 1 and Cohort 2,
respectively.
Intervention
The first 6 consecutive patients will receive 1 mg ANXV i.v. in 60 minutes,
(t=0) and 1 mg ANXVV i.v. in 15 minutes (t=8h), on day 1.
The next day these 6 patients, in case there have been no safety issues, will
receive 2 mg ANXV i.v. in 60 minutes (t=0), followed by 2 mg ANXV i.v. in 15
minutes (t=8h).
In case no safety issues arise, a second cohort of 6 patients will be included.
They will receive 4 mg ANXV i.v. in 60 minutes on day 1, followed by 4 mg ANXV
i.v. on day 2.
Study burden and risks
The current study potentially contributes to the development of a novel and
promising class of medication to treat patients with moderate to severe damage
caused by the immuno-thrombotic cascade incited by the SARS-CoV-2 virus
infection. ANXV is based on the cellular protein Annexin A5, that binds the
danger molecule PS. Participation in this study, based on the above-mentioned
mode of action of the test compound, could result (being the leading
hypothesis) in dampening of the inflammatory cascade, also described as
immuno-thrombosis, which in its turn may result in a better clinical outcome.
However, as this is the first administration of ANXV in COVID-19 patients, the
optimal dosing regimen is presently unknown. All patients will receive optimal
standard care. Based on the available data, the dose of ANXV that is chosen in
this study is considered safe.
During the study there will be more sampling of blood than anticipated during
usual care, but the total volume of blood taken will be safe.
ANXV could potentially induce side effects, including headache, dizziness,
heartburn, tremor, muscle ache and spasms.
During this study, several invasive sample collections will be performed,
including blood sample collection. These measurements could be associated with
local hematoma or bruise development. However, due to the state-of-the-art
techniques, risks for infection or prolonged bleeding will be minimized.
All non-invasive measurements performed in this study are part of standard
clinical care for patients with COVID-19, in their particular stage of disease.
Blood pressure and heart rate measurements will be performed by means of an
automatic inflat-able cuff. These measurements might feel a bit uncomfortable,
but do not induce detrimental health effects.
P.Debyelaan 25
Maastricht 6229HX
NL
P.Debyelaan 25
Maastricht 6229HX
NL
Listed location countries
Age
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)
6. Mentally Competent
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-002200-12-NL |
| CCMO | NL77746.068.21 |
| Other | nog niet bekend |