Clinical Trials Register

Summary
EudraCT Number:	2020-002130-33
Sponsor's Protocol Code Number:	ZILU-COV
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-05-06
Trial results	View 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

Belgium - FPS Health-DGM

A.2

EudraCT number

2020-002130-33

A.3

Full title of the trial

A prospective, randomized, open-label, interventional study to investigate the efficacy of complement C5 inhibition with Zilucoplan® in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure.

A.3.1

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

Zilucoplan® in patients with acute hypoxic respiratory failure due to COVID-19

A.3.2

Name or abbreviated title of the trial where available

ZILU-COV

A.4.1

Sponsor's protocol code number

ZILU-COV

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	University Hospital Ghent
B.1.3.4	Country	Belgium
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	Ra Pharmaceuticals, Inc., a member of the UCB group of companies
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospital Ghent
B.5.2	Functional name of contact point	HIRUZ CTU
B.5.3	Address:
B.5.3.1	Street Address	C. Heymanslaan 10
B.5.3.2	Town/ city	Ghent
B.5.3.3	Post code	9000
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+3293320500
B.5.5	Fax number	+3293320520
B.5.6	E-mail	hiruz.ctu@uzgent.be

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	Zilucoplan
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ZILUCOPLAN
D.3.9.1	CAS number	1841136-73-9
D.3.9.2	Current sponsor code	RA101495
D.3.9.4	EV Substance Code	SUB194709
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	Yes
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	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

COVID-19 patients with acute hypoxic respiratory failure.

E.1.1.1

Medical condition in easily understood language

COVID-19 patients with acute hypoxic respiratory failure.

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

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

The primary objective of this intervention is to study if Zilucoplan® affects the the median and/or mean change in oxygenation between enrolment (baseline) and at predose day 6 and day 15 (or discharge, whichever comes first) through assessment of the PaO2/FiO2 ratio and through measurement of the P(A-a)O2 gradient, which can easily be performed in the setting of clinical observation of patients admitted to the COVID-19 ward or ICU COVID-19 unit. For patients on ECMO the PaO2/FiO2 ratio and Aa-gradient cannot be calculated as in this case the FiO2 will be missing. Therefore, the last available value of PaO2/FiO2 ratio and Aa gradient prior to ECMO can be used at that timepoint.

E.2.2

Secondary objectives of the trial

-to study if early intervention with Zilucoplan® is safe (number of AEs/SAEs)
-to study if early intervention with Zilucoplan® affects clinical outcome defined by duration of hospital stay, 6-point ordinal scale, time to defervescence, supplemental oxygen use and SOFA score
- to study if early intervention with Zilucoplan® affects progression to mechanical ventilation and/or ARDS and duration of ICU stay
-to study if early intervention with Zilucoplan® affects the rate of nosocomial infection
-to study if treatment with Zilucoplan® has a favourable effect on long term at follow up 12-22 weeks post-randomization
-to study if treatment with Zilucoplan® affects all-cause mortality rate at day 28 and at 12-22 weeks post-randomization

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Recent (≥6 days and ≤16 days of flu-like symptoms or malaise prior to randomization) infection with COVID-19.
-COVID-19 diagnosis confirmed by antigen detection test and/or PCR and/or positive serology, or any emerging and validated diagnostic laboratory test for COVID-19 within this period. For patients with a negative SARS-CoV-2 PCR and either a positive SARS-CoV-2 antigen or antibody test, the presence of suggestive lesions for COVID-19 on chest-CT scan is mandatory.
-In some patients, it may be impossible to get a confident laboratory confirmation of COVID-19 diagnosis after 24h of hospital admission because viral load is low and/or problems with diagnostic sensitivity. In those cases, in absence of an alternative diagnosis, and with highly suspect bilateral ground glass opacities on recent (<24h) chest-CT scan (confirmed by a radiologist and pulmonary physician as probable COVID-19), and a typical clinical and chemical diagnosis with signs of cytokine release syndrome, a patient can be enrolled as probable SARS-CoV-2-infected. In all cases, this needs confirmation by later seroconversion.
-Presence of hypoxia defined as
1)O2 saturation below 93% on minimal 2l/min O2 therapy;
and/or 2) Patient on ECMO or PaO2/FiO2 below 350 mmHg (Strongly recommended: patient in upright position, after minimal 3 minutes without supplemental oxygen; In ventilated patients PaO2 can be taken from invasive arterial line and FiO2 taken directly from mechanical ventilation settings).
-Signs of acute lung injury and/or cytokine release syndrome defined as
ANY of the following
-serum ferritin concentration >1000 mcg/L and rising since last 24h
-single ferritin above 2000 mcg/L in patients requiring immediate high flow oxygen device (Optiflow) or non-invasive or invasive mechanical ventilation
-lymphopenia defined as <800 lymphocytes/microliter and two of the following extra criteria
-Ferritin > 700 mcg/L and rising since last 24h
-increased LDH (above 300 IU/L) and rising since last 24h
-D-Dimers > 1000 ng/mL and rising since last 24h
-CRP above 70 mg/L and rising since last 24h and absence of bacterial infection
-if three of the above are present at admission, no need to document 24h rise
-Low dose Chest CT or HRCT or Angio Chest CT scan showing bilateral infiltrates within last 2 days prior to randomization
-Admitted to specialized COVID-19 ward or an ICU ward taking care of COVID-19 patients
-Age ≥ 18 years
- Women of childbearing potential must have a negative serum pregnancy test pre-dose on day 1. Women of childbearing potential must consistently and correctly use (during the entire treatment period and 4weeks after last Zilucoplan® administration ) at least 1 highly effective method for contraception.
Male subjects (who have not been surgically sterilized by vasectomy) must agree to use effective contraception during the study.
-Willing and able to provide informed consent or legal representative willing to provide informed consent

E.4

Principal exclusion criteria

-Patients with known history of serious allergic reactions, including anaphylaxis, to Zilucoplan® or inability to receive antibiotic prophylaxis due to allergy to ALL of the antibiotics that can be given for prophylaxis of meningococcal disease
-History of active or past meningococcal disease
-Invasive mechanical ventilation > 24 h at randomization
-Patient on ECMO at screening
-Clinical frailty scale above 3 before onset of the COVID-19 episode
-Weight below 54 kg as measured max 1 week prior to inclusion
-Weight above 150 kg as measured max 1 week prior to inclusion
-Active bacterial or fungal infection
-Unlikely to survive beyond 48h
-Neutrophil count below 1500 cells/microliter
-Platelets below 50.000/microliter
-Patients enrolled in another investigational drug study
-Patients on high dose systemic steroids (> 8 mg methylprednisolone or equivalent for more than 1 month) or other moderately immunosuppressive drugs (in the opinion of the investigator) for COVID-19 unrelated disorder
-Patients on current complement inhibiting drugs
-Serum transaminase levels >5 times upper limit of normal, unless there are clear signs of cytokine release syndrome defined by LDH >300 IU/L and ferritin >700 ng/ml
-Pregnant or breastfeeding females (all female subjects deemed of childbearing potential by the investigator must have negative pregnancy test at screening)

E.5 End points

E.5.1

Primary end point(s)

To measure the effectiveness of SC Zilucoplan® treatment on restoring lung homeostasis, the primary endpoint of this intervention is measuring oxygenation at predose day 6 and day 15 (or at discharge, whichever comes first) through assessment of the mean and/or median change from pretreatment (day 1) to post-treatment (day 6 and 15 or at discharge, whichever comes first) PaO2/FiO2 ratio, P(A-a)O2 gradient and a/A pO2 ratio, which can easily be performed in the setting of clinical observation of patients admitted to the COVID-19 ward or ICU COVID-19 unit. These measurements derived from an arterial blood gas sampling are taken when the patient is sitting upright and breathing room air. Since supplemental oxygen will be indispensable in some patients, the A-a gradient will be normalized against age and FiO2 expected A-a gradient, according to validated formulas. If patients leave hospital between day 6 and day 15, that day of discharge will be taken as measurement point for primary endpoint instead of day 15. For patients on ECMO the PaO2/FiO2 ratio and Aa-gradient cannot be calculated as in this case the FiO2 will be missing. Therefore, the last available value of PaO2/FiO2 ratio and Aa gradient prior to ECMO can be used at that timepoint.

E.5.1.1

Timepoint(s) of evaluation of this end point

day 6
day 15
at discharge

E.5.2

Secondary end point(s)

-To study if early intervention with Zilucoplan® is safe (number of AEs/SAEs)
-To study if early intervention with Zilucoplan® affects clinical outcome
defined by 6-point ordinal scale change between day 1 and respectively day 6, day 15 (or discharge,
whichever comes first) and day 28 (by phone call). 6-point ordinal scale defined as
1. Death
2. Hospitalized, on invasive mechanical ventilation or ECMO;
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
4. Hospitalized, requiring supplemental oxygen
5. Hospitalized, not requiring supplemental oxygen
Not hospitalized
-Number of days requiring supplemental oxygen after randomization to Day 28 (or discharge,
whichever comes first)
-Number of days with fever (defined as 37.1°C or more) during 28-day assessment period
- change from baseline in SOFA score to D6, D15 (or on discharge, whichever is first)
- Time to at least a 2-point improvement or discharge sustained up to D28 on the 6-point ordinal
scale during 28-day assessment period
-Incidence of nosocomial bacterial or invasive fungal infection during 28-day assessment period
Patients with viral respiratory infection are at risk of secondary bacterial infections. As part of routine
clinical care, sputum or BAL samples will be collected in patients suspected of secondary bacterial
pneumonia, and checked for the presence of bacteria. Measurements of procalcitonin levels will be
performed at least three times per week until day 14 or hospital discharge.
- All-cause mortality rate at 28 days post randomization (all treated participants)
-All-cause mortality rate at 28 days post randomization (excluding participants that required invasive
mechanical ventilation or ECMO, non-invasive mechanical ventilation or high-flow oxygen devices
within 24 hours prior to or after randomization)
-All-cause mortality rate at 28 days post randomization (excluding participants that required invasive
mechanical ventilation or ECMO within 24 hours prior to or after randomization)
-All-cause mortality rate at 28 days post randomization (only including patients that required
invasive mechanical ventilation or ECMO within 24 hours prior to or after randomization)
-Incidence of patients in each category of the 6-point Ordinal Scale at follow up 12-22 weeks postrandomization
-All cause mortality at follow up 12-22 weeks post-randomization for all treated participants
- Results from 6 minute walking test
- Incidence of participants in each category of the WHO performance scale

E.5.2.1

Timepoint(s) of evaluation of this end point

day 6
day 15
day 28
follow up 12-22 weeks

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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

Yes

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

standard of 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

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

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

If a potential subject ends up in the intensive care unit very quickly after admission, and is mechanically ventilated, permission will be sought from a family member.

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

2020-05-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-05-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-05-27

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