Clinical Trials Register

Summary
EudraCT Number:	2020-005104-20
Sponsor's Protocol Code Number:	N-003-CRD008
National Competent Authority:	Croatia - MIZ
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-12-06
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

Croatia - MIZ

A.2

EudraCT number

2020-005104-20

A.3

Full title of the trial

A randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ambrisentan in patients with severe COVID-19

Randomizirano, dvostruko slijepo, placebo kontrolirano kliničko ispitivanje procjene učinkovitosti i sigurnosti ambrisentana u bolesnika s teškim oblikom bolesti COVID-19

A.3.1

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

A randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ambrisentan in patients with severe COVID-19

Randomizirano, dvostruko slijepo, placebo kontrolirano kliničko ispitivanje procjene učinkovitosti i sigurnosti ambrisentana u bolesnika s teškim oblikom bolesti COVID-19

A.4.1

Sponsor's protocol code number

N-003-CRD008

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	Noorik Biopharmaceuticals AG
B.1.3.4	Country	Switzerland
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	Noorik Biopharmaceuticals AG.
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Noorik Biopharmaceuticals AG
B.5.2	Functional name of contact point	CEO
B.5.3	Address:
B.5.3.1	Street Address	Lange Gasse15
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4052
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41763987007
B.5.6	E-mail	iker.navarro@noorik.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	N-003 (Ambrisertan)
D.3.2	Product code	N-003
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ambrisentan
D.3.9.1	CAS number	177036-94-1
D.3.9.4	EV Substance Code	SUB25424
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	2.5
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	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	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	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment for respiratory complications of COVID-19 disease

Liječenje respiratornih komplikacija uzrokovanih bolešću COVID-19

E.1.1.1

Medical condition in easily understood language

Treatment for respiratory complications of COVID-19 disease

Liječenje respiratornih komplikacija uzrokovanih bolešću 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	23.1
E.1.2	Level	LLT
E.1.2	Classification code	10084401
E.1.2	Term	COVID-19 respiratory infection
E.1.2	System Organ Class	100000004862

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 determine whether N-003 (ambrisentan) can prevent the progression to respiratory failure or death.

Utvrditi može li ambrisentan spriječiti napredovanje bolesti do respiratornog zatajenja ili smrti.

E.2.2

Secondary objectives of the trial

To determine:
• Whether ambrisentan can delay progression to respiratory failure or death.
• Whether ambrisentan can reduce dependency on oxygen supplementation and mechanical ventilation.
• Whether ambrisentan can reduce the duration of hospitalisation.
• Whether ambrisentan can reduce the need for Intensive Care or High-Dependency Unit.
• The temporal characteristics of respiratory function in subjects treated with ambrisentan.
• Whether ambrisentan can improve respiratory function.
• Whether ambrisentan can reduce the incidence of thrombotic events.
• Whether ambrisentan can improve the overall clinical status of subjects.

Utvrditi:
• može li ambrisentan odgoditi napredovanje bolesti do respiratornog zatajenja ili smrti.
• može li ambrisentan smanjiti potrebu za nadomjesnom terapijom kisikom i mehaničkom ventilacijom.
• može li ambrisentan smanjiti trajanje hospitalizacije.
• može li ambrisentan smanjiti potrebu za liječenjem u jedinicama intenzivnog liječenja.
• karakteristike respiratorne funkcije tijekom vremena, u ispitanika
liječenih ambrisentanom.
• može li ambrisentan poboljšati respiratornu funkciju.
• može li ambrisentan smanjiti incidenciju trombotičkih događaja.
• može li ambrisentan poboljšati cjelokupni klinički status ispitanika.

E.2.3

Trial contains a sub-study

E.2.3.1

Full title, date and version of each sub-study and their related objectives

E.3

Principal inclusion criteria

• Subject (or legally authorized representative) provides informed consent (written or oral) prior to initiation of any study procedures.
• Male or non-pregnant, non-lactating female. Women of child-bearing potential must have a confirmed negative serum pregnancy test at the time of screening and must use a highly effective contraceptive method throughout the study (such as implants, injectables, hormonal contraceptives and condom, double barrier contraception [i.e., condom + diaphragm/spermicidal gel or foam]) and until one month after completing treatment with the study medication. In the case of hormonal contraception, women should have been on a stable regimen for a minimum of three months before study enrolment. Women not of child-bearing potential include post-menopausal females (defined as having a history of amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, bilateral oophorectomy, tubal ligation/salpingectomy). Men must use an effective contraception method (i.e., condom + diaphragm/spermicidal gel or foam, or vasectomy), and should not donate semen during the study. Men are considered to be fertile from the time of puberty, except for those men with permanent sterility secondary to bilateral orchiectomy.
• At least 18 years of age and not older than 85 years of age at time of enrolment
• Confirmed SARS-CoV-2 infection defined as:
- Positive RT-PCR result in sample collected in the 10 days prior to randomisation, OR
- Positive antigenic test result in sample collected in 10 days prior to randomisation.
• Radiological confirmation of pneumonia.
• Subject receiving low-flow oxygen supplementation of at least 3 L/min and not more than 15 L/min.
• Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
• Subject (or legally authorized representative) agrees to not participate in any other clinical trial, including clinical trials for the treatment or prevention of COVID-19 or SARS-CoV-2 through Day 30.

•Bolesnik (ili zakonski zastupnik) koji je dao informirani pristanak (pismeni ili usmeni) prije pokretanja bilo kakvog postupka u ispitivanju.
•Muškarac ili žena koja nije trudna, niti ne doji. Žene reproduktivne dobi moraju imati potvrđen negativan serumski test na trudnoću u vrijeme probira i moraju koristiti visoko učinkovitu metodu kontracepcije tijekom cijelog ispitivanja (kao što su implantati, injekcije, hormonski kontra-ceptivi i kondomi, kontracepcija s dvostrukom barijerom [tj. kondom + dijafragma/spermicidni gel ili pjena]) i do mjesec dana nakon završetka liječenja ispitivanim lijekom. U slučaju hormonske kontracepcije, žene trebaju biti na stabilnom režimu najmanje tri mjeseca prije uključivanja u ispitivanje. Žene u postmenopauzi (definirano kao da imaju amenoreju
u anamnezi najmanje godinu dana) ili uz dokumentirani status kirurške sterilizacije (histerektomija, bilateralna ooforektomija, podvezani jajovodi/salpingektomija). Muškarci moraju koristiti učinkovitu metodu kontracepcije (tj. kondom + dijafragma/sper-micidni gel ili pjena, ili vazektomija) i ne bi trebali donirati spermu tijekom ispitivanja. Smatra se da su muškarci plodni od puberteta, osim onih muškaraca s trajnim sterilitetom koji je posljedica bilateralne orhidektomije.
•Najmanje navršenih 18 godina i ne stariji od 85 godina u trenutku uključivanja
•Potvrđena SARS-CoV2 infekcija definirana kao:
- Pozitivan RT-PCR test na uzorku prikupljenom unutar 10 dana
prije randomizacije, ILI
- Pozitivan antigenski test na uzorku prikupljenom unutar
10 dana prije randomizacije.
•Radiološka potvrda upale pluća.
•Bolesnik koji prima nadomjesnu terapiju kisikom niskog protoka od najmanje 2 l/min i ne više od 15 l/min.
•Bolesnik (ili zakonski zastupnik) razumije i pristaje poštivati planirane postupke u ispitivanju.
•Bolesnik (ili zakonski zastupnik) pristaje ne sudjelovati u bilo kojem drugom kliničkom ispitivanju, uključujući klinička ispitivanja za liječenje ili prevenciju bolesti COVID-19 ili SARS-CoV-2 infekcije do 30. dana ispitivanja.

E.4

Principal exclusion criteria

• Subject at a high risk of death, according to investigator’s opinion, in the 3 months following enrolment from other causes than Acute Respiratory Distress Syndrome (e.g., severe neurological damage or cancer patients in terminal stages of the disease).
• Subject currently being treated with an endothelin receptor antagonist.
• Subject currently being treated with another pulmonary vasodilator.
• Anticipated need for high-flow oxygen supplementation, non-invasive mechanical ventilation, endotracheal intubation or tracheostomy at the time of screening..
• History of mechanical ventilation (invasive or non-invasive) in the last 7 days.
• Documented history of end-stage liver disease, cirrhosis or idiopathic pulmonary fibrosis (IPF) with or without pulmonary arterial hypertension.
• AST o ALT > 3-times the upper limit of normal (ULN)
• Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 96 hours.
• Participation in another interventional clinical trial in the 15 days prior to enrolment.
• Known hypersensitivity to ambrisentan or propylene glycol.

•Prema mišljenju ispitivača, kod bolesnika postoji visoki rizik od smrti, unutar 3 mjeseca nakon uključivanja, iz drugih uzroka osim akutnog respiratornog distres sindroma (npr. teška neurološka oštećenja ili pacijenti s rakom u terminalnoj fazi bolesti).
•Bolesnik koji se trenutno liječi antagonistom endotelinskog receptora.
•Bolesnik se trenutno liječi drugim plućnim vazodilatatorom.
•neinvazivnom mehaničkom ventilacijom, endotrahealnom intubacijom ili traheostomijom u vrijeme probira.
•Povijest mehaničke ventilacije (invazivne ili neinvazivne) u zad-njih 7 dana.
•Dokumentirana povijest bolesti jetre u završnoj fazi, ciroze ili idiopatske plućne fibroze (IPF) sa ili bez plućne arterijske hipertenzije.
•AST ili ALT > 3-puta iznad gornje granice normalne vrijednosti (ULN)
•Očekivani otpust iz bolnice ili premještaj u drugu bolnicu izvan mjesta ispitivanja unutar 96 sati.
• Sudjelovanje u drugom intervencijskom kliničkom ispitivanju
15 dana prije uključivanja
• Poznata preosjetljivost na ambrisentan ili propilen glikol. potreba za nadomjesnu terapiju kisikom visokog protoka

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is
• Proportion of subjects alive and not having developed respiratory failure from randomisation to Day 30

Primarna krajnja točka učinkovitosti je:
Udio ispitanika koji su ostali živi i kod kojih nije došlo do respiratornog zatajenja, od randomizacije do 30. dana.

E.5.1.1

Timepoint(s) of evaluation of this end point

Progression to respiratory failure, and the proportion of patients not developing respiratory failure in a 30-day observation period

Progresija do respiratornog zatajenja i udio bolesnika koji nisu razvili respiratorno zatajanje u 30-dnevnom periodu promatranja.

E.5.2

Secondary end point(s)

The secondary endpoints evaluated in this study will consist of:
• Proportion of subjects alive and free of respiratory failure at Day 14 and Day 30.
• Proportion of subjects alive and not requiring oxygen supplementation or higher respiratory support at Day 14 and Day 30.
• Time to hospital discharge (up to Day 30).
• Proportion of subjects admitted to the Intensive Care Unit or High-Dependency Unit (up to Day 30).
• Time until weaning from oxygen therapy (up to Day 30).
• Time until weaning from respiratory support other than low-flow oxygen supplementation for subjects having developed respiratory failure (up to Day 30).
• Change in SpO2/FiO2 from baseline to the time-weighted average obtained on Day 3.
• Change in SpO2/FiO2 from baseline to the time-weighted average obtained on Day 1 and Day 2.
• Proportion of subjects experiencing at least one event of venous thrombosis (specifically deep venous thrombosis or pulmonary embolism) (up to Day 30).
• Proportion of subjects by clinical status reported on a 11-point ordinal scale at Day 14 and Day 30.
• Time to death due to any cause (up to Day 30).
• All-cause mortality at Day 30.

Sekundarne krajnje točke učinkovitosti su:
• Udio živih ispitanika i bez respiratornog zatajenja 14. dan i 30. dan.
• Udio živih ispitanika koji ne zahtijevaju nadomjesnu terapiju kisikom ili veću respiratornu potporu 14. dan i 30. dan.
• Vrijeme do otpusta iz bolnice (do 30. dana).
• Udio ispitanika primljenih u jedinicu intenzivnog liječenja (do 30. dana).
• Vrijeme do odvikavanja od nadomjesne terapije kisikom (do 30. dana).
• Vrijeme do odvikavanja od respiratorne podrške, osim nadomjesne terapije kisikom niskog protoka za ispitanike koji su razvili respiratorno zatajenje (do 30. dana).
• Promjena SpO2/FiO2 od početne vrijednosti do vremenski ponderiranog prosjeka dobivenog 3. dana.
• Promjena SpO2/FiO2 od početne vrijednosti do vremenski ponderiranog prosjeka dobivenog 1. i 2. dana.
• Udio ispitanika koji su doživjeli barem jedan događaj venske tromboze (posebno duboke venske tromboze ili plućne embolije) do 30. dana.
• Udio ispitanika prema kliničkom statusu prijavljen na skali težine bolesti od 11 bodova, 14. dana i 30. dana.
• Vrijeme do smrti zbog bilo kojeg uzroka (do 30. dana).
• Smrtnost zbog bilo kojeg uzroka na 30. dan.

E.5.2.1

Timepoint(s) of evaluation of this end point

Timepoints for each secondary endpoint are indicated in secondary endpoint section E.5.2

Vremenske točke za svaku sekundarnu krajnju točku učinkovitosti navedene su u odjeljku E.5.2 sekundarne krajnje točke učinkovitosti

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

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

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

Romania

Spain

Czechia

Croatia

Georgia

Slovakia

E.8.7

Trial has a data monitoring committee

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

Last patient last visit

Posljednji posjet posljednjeg bolesnika

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

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:

180

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 patient is unable to signe the informed consent himself, his legal representative can do so on his behalf

Ako bolesnik nije u stanju sam potpisati informirani pristanak, umjesto njega to može učiniti njegov zakonski zastupnik

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

194

F.4.2.2

In the whole clinical trial

232

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

nije primjenjivo

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

2022-08-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-05-19

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

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