Clinical Trials Register

Summary
EudraCT Number:	2019-001078-27
Sponsor's Protocol Code Number:	BAY1097761/19999
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-10-21
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2019-001078-27

A.3

Full title of the trial

Safety and efficacy of inhaled pegylated adrenomedullin (PEG-ADM) in patients suffering from Acute Respiratory Distress Syndrome (ARDS): a double-blind, randomized, placebo-controlled, multicenter Phase 2a/b clinical trial

Sicurezza ed efficacia dell’adrenomedullina PEGilata (PEG-ADM) per inalazione in pazienti affetti da Sindrome da Distress Respiratorio Acuto (ARDS): studio clinico in doppio cieco, randomizzato, controllato verso placebo, multicentrico di fase 2a/b.

A.3.1

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

This study collects information on the safety of inhaled pegylated adrenomedullin (PEG-ADM), how the drug is tolerated and how it effects patients suffering from a type of lung failure that cause fluid to build up in the lungs making breathing difficult (ARDS)

Sicurezza ed efficacia di PEG-ADM per inalazione nell’ARDS: studio clinico in doppio cieco, randomizzato, controllato verso placebo, multicentrico di fase 2a/b.

A.3.2

Name or abbreviated title of the trial where available

SEAL Trial

Studio SEAL

A.4.1

Sponsor's protocol code number

BAY1097761/19999

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	BAYER AG
B.1.3.4	Country	Germany
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	BAYER AG
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	Bayer AG
B.5.2	Functional name of contact point	Bayer Clinical Trials Contact
B.5.3	Address:
B.5.3.1	Street Address	na
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13342
B.5.3.4	Country	Germany
B.5.4	Telephone number	004930300139003
B.5.5	Fax number	004930300139003
B.5.6	E-mail	clinical-trials-contact@bayer.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	BAY 1097761 liofilizzato per inalazione
D.3.2	Product code	[BAY 1097761]
D.3.4	Pharmaceutical form	Powder for nebuliser solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	1432735-93-7
D.3.9.2	Current sponsor code	BAY 1097761
D.3.9.4	EV Substance Code	PEG-ADM
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	960
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder for nebuliser solution
D.8.4	Route of administration of the placebo	Inhalation use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute respiratory distress syndrome (ARDS)

Sindrome da Distress Respiratorio Acuto (ARDS)

E.1.1.1

Medical condition in easily understood language

A type of lung failure that cause fluid to build up in the lungs making breathing difficult

Condizione infiammatoria dei polmoni che porta a gravi difficoltà respiratorie

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10001052
E.1.2	Term	Acute respiratory distress syndrome
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate safety and efficacy of inhaled PEG-ADM in ARDS

Valutare la sicurezza e l’efficacia di PEG-ADM per inalazione nell’ARDS

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. =18 years of age at the time of inclusion into study.
2. Invasively mechanically ventilated ARDS patients (diagnosed
according to Berlin definition of ARDS, including PEEP of =5 cm H²O, Xray
(or CT scan) indicative of ARDS: bilateral opacities not fully
explained by cardiac failure, fluid overload, lobar/lung collapse,
effusions or nodules).
3. Initial diagnosis of mild, moderate or severe ARDS prior to study
inclusion, with acute onset of ARDS within 1 week after suspected
trigger factor of
a. Pneumonia
b. Aspiration
c. Sepsis
d. Pancreatitis
4. Prior to randomization, hypoxemia with PaO²:FiO² =300 mmHg
continuously observed for a period of =4 hours (with values of =2
arterial blood gas [ABG] analyses during that time, with the last value
obtained timely (generally =3 hours) prior to randomization), under
ventilation with minimum PEEP =8 cm H²O.
5. Time from first meeting the last diagnostic ARDS criterion (Berlin
criteria) to randomization must be =48 hours.
6. For Study Part A: ARDS patients for whom measurements of extravascular
lung water are regarded as medically indicated by the treating
physician, and these measurements are planned as part of their clinical care, from Study Day 1 up to Study Day 7 (if then still intubated).
7. Male and non-pregnant female
8. Informed consent of capable patient or, in case of patient being
incapable of giving informed consent, consent for study inclusion will be
sought according to applicable laws and regulations.

I partecipanti sono ritenuti eleggibili per lo studio soltanto se si applicano tutti i seguenti criteri:
Età
1. Età = 18 anni alla data dell’inclusione nello studio.
Tipologia di partecipante e caratteristiche della malattia
2. Pazienti con ARDS sottoposti a ventilazione meccanica invasiva (diagnosi formulata secondo la definizione di ARDS di Berlino, compreso un valore di PEEP =5 cm H2O, riscontro radiografico (o TAC) di ARDS: opacità bilaterali non completamente spiegate da insufficienza cardiaca, sovraccarico di fluidi, collasso lobare/polmonare, versamenti o noduli).
3. Diagnosi iniziale di ARDS lieve, moderata o grave prima dell’inclusione nello studio con manifestazione acuta di ARDS entro 1 settimana dal sospetto fattore scatenante di:
a. Polmonite
b. Aspirazione
c. Sepsi
d. Pancreatite
4. Prima della randomizzazione, ipossiemia con PaO2:FiO2 =300 mmHg osservata per un periodo continuativo =4 ore (con =2 valori di emogasanalisi arteriosa [ABG] durante questo intervallo, con l’ultimo valore ottenuto tempestivamente (in generale =3 ore) prima della randomizzazione), in ventilazione con PEEP minima =8 cm H2O (e considerando la strategia di ventilazione raccomandata durante questo periodo, come descritto nel paragrafo 8.11).
5. Il tempo tra il riscontro iniziale dell’ultimo criterio diagnostico di ARDS (criteri di Berlino) e la randomizzazione deve essere =48 ore.
6. Per la Parte A dello studio: pazienti con ARDS per i quali il medico curante ritiene indicata a livello clinico la misurazione del volume di acqua extravascolare polmonare e per i quali tali misurazioni sono previste nell’ambito dell’assistenza clinica tra il giorno 1 e il giorno 7 dello studio (se ancora intubati).
Sesso
7. Soggetti di sesso maschile e femminile non in gravidanza
Poiché la popolazione reclutata è gravemente malata, ventilata meccanicamente in modo invasivo e pertanto considerata in astinenza da rapporti sessuali durante il periodo di trattamento, la necessità di consulenza in materia di contraccezione durante tale periodo è ritenuta molto improbabile. A discrezione dello sperimentatore, la consulenza per l’uso di adeguati metodi contraccettivi sarà fornita ai partecipanti che abbiano ripreso conoscenza e che possono essere sessualmente attivi entro i 30 giorni precedenti il termine del trattamento.
Consenso informato
8. Il consenso informato del paziente capace o, in caso di paziente incapace di fornire il consenso informato, il consenso per l’inclusione nello studio dovrà essere ottenuto nel rispetto delle leggi e normative applicabili.

E.4

Principal exclusion criteria

1. Any value of a PaO²:FiO² ratio >300 mmHg within a time interval of 4
hours before randomization
2. Rescue therapy (e.g. inhalation of nitric oxide gas and/or inhalation of
prostacyclin analogues, or ECMO/ECCO2R) already initiated at screening
and/or Study Day 1 (prior to first dose of the study intervention)
3. Moribund participants not expected to survive 24 hours (clinical
decision)
4. Expected duration of invasive mechanical ventilation less than 48
hours (clinical decision)
5. History of co-morbidities requiring long-term/home oxygen use (e.g.
severe chronic obstructive pulmonary disease [COPD], pulmonary
fibrosis) or non-invasive ventilation (except for sleep apnea
management), or making weaning per se improbable (e.g. ALS, muscular
dystrophy)
6. Smoke inhalation injury, extensive burns or trauma/head injury as
concomitant condition
7. History of pneumectomy, lung lobectomy or lung transplant
8. Diffuse alveolar hemorrhage from vasculitis
9. Current lung malignancy (incl. lung metastasis), or other malignancy
requiring chemotherapy or radiation within the last month
10. Chronic kidney disease with a history of renal replacement therapy
(e.g. dialysis)
11. Chronic liver disease Child-Pugh Class C
12. Chronic heart failure NYHA IV
13. Known hypersensitivity to polyethylenglycol (PEG, Macrogol)
14. Participation in other interventional studies involving
pharmacological interventions, or biological or cell therapy
interventions.

I partecipanti sono esclusi dallo studio qualora si applichi uno qualsiasi dei seguenti criteri:

Condizioni mediche
1. Qualunque valore del rapporto PaO2:FiO2 >300 mmHg entro un intervallo di tempo di 4 ore precedenti la randomizzazione
2. Terapia di salvataggio (ad esempio inalazione di ossido nitrico e/o inalazione di analoghi delle prostacicline, o ECMO/ECCO2R[rimozione extracorporea di CO2]) già avviata in sede di screening e/o il giorno 1 dello studio (prima della prima dose del trattamento in studio)
3. Partecipanti moribondi per cui non si preveda una sopravvivenza superiore alle 24 ore (decisione clinica)
4. Durata prevista della ventilazione meccanica invasiva inferiore a 48 ore (decisione clinica)
5. Anamnesi di co-morbilità che richiedono l’impiego di ossigeno a lungo termine/a domicilio (per esempio, broncopneumopatia cronica ostruttiva [BPCO], fibrosi polmonare) o ventilazione non invasiva (se non per la gestione dell’apnea del sonno) o che rendono lo svezzamento di per sé improbabile (per esempio SLA o distrofia muscolare)
6. Danno da inalazione di fumi, ustioni estese o lesioni da trauma/craniche come condizioni concomitanti
7. Anamnesi di pneumectomia, lobectomia polmonare o trapianto di polmone
8. Emorragia alveolare diffusa dovuta a vasculite
9. Cancro polmonare presente (compresa metastasi del polmone) o altra malignità che abbia richiesto trattamento con chemioterapia o radioterapia nel corso dell’ultimo mese
10. Malattia renale cronica con anamnesi di terapia renale sostitutiva (per esempio, dialisi)
11. Malattia epatica cronica (Classe C Child-Pugh)
12. Insufficienza cardiaca cronica (Classe IV NYHA)
13. Ipersensibilità nota al polietilenglicole (PEG, macrogol)
Esperienza in studio clinico precedente/concomitante
14. Intenzione di partecipare o partecipazione precedente (nei 30 giorni precedenti il giorno 1 dello studio) ad altri studi interventistici comprendenti interventi farmacologici o interventi con terapia biologica o cellulare. La partecipazione ad altri studi interventistici, che studiano le modifiche dei regimi terapeutici di supporto o obiettivi simili, è possibile se l’intervento in questione viene considerato non pregiudizievole per la valutazione dei risultati o delle raccomandazioni terapeutiche di supporto descritte in questo protocollo. Lo sperimentatore e il promotore valuteranno le implicazioni di tale studio; in assenza di accordo reciproco, il paziente deve essere escluso.

E.5 End points

E.5.1

Primary end point(s)

Part B only: Ventilator-free survival (VFS, proportion of participants alive and off invasive mechanical ventilation) at study day 28

Parte B: sopravvivenza (VFS) senza ventilatore al giorno 28

E.5.1.1

Timepoint(s) of evaluation of this end point

day 28

giorno 28

E.5.2

Secondary end point(s)

Part A only:
1. Clinical Utility Index (CUI) based on data from the first week of treatment (change vs. baseline), CUI is derived from
o Extravascular lung water index (EVLWi)
o Oxygenation index (OI)
o Non-pulmonary Sequential Organ Failure Assessment (npSOFA) score
2.Ventilator-free survival (VFS, proportion of participants alive and off invasive mechanical ventilation) at study day 28
Part A and Part B:
3. All-cause mortality at study day 28, study day 60 and study day 90
4. Proportion of participants who still require invasive mechanical ventilation support at study day 28 and study day 60
5. Ventilator-free days (VFDs) within study day 28 and study day 60
6. Ventilator-free survival at study day 60
7. Integrated analysis on Ventilator-free survival at study day 28 and study day 60, involving all participants from Part A and Part B

Solo Parte A
· Indice di utilità clinica (CUI) basato sui dati della prima settimana di trattamento (variazione rispetto al basale). Il CUI è ottenuto da:
o Acqua ExtraVascolare Polmonare indicizzata (EVLWi)
o Indice di ossigenazione (OI)
o punteggio di Valutazione dell'Insufficienza d'Organo Sequenziale non polmonare (npSOFA)
· Sopravvivenza senza ventilatore (VFS, percentuale di partecipanti in vita e senza ventilazione meccanica invasiva) al giorno 28 dello studio
Parte A e Parte B
· Mortalità per tutte le cause al giorno 28, al giorno 60 e al giorno 90 dello studio
· Percentuale di partecipanti che necessitano ancora del supporto della ventilazione meccanica invasiva al giorno 28 e al giorno 60 dello studio
· Giorni liberi dal ventilatore (VFD) entro il giorno 28 e il giorno 60 dello studio
· Sopravvivenza senza ventilatore al giorno 60 dello studio
· Analisi integrata sulla sopravvivenza senza ventilatore al giorno 28 e 60 dello studio estesa a tutti i partecipanti della Parte A e della Parte B.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. during the first week of the study
2. at study day 28
3. at study day 28, study day 60 and study day 90
4 at study day 28 and study day 60
5. within study day 28 and study day 60
6. at study day 60
7. at study day 28 and study day 60

1. prima settimana di studio
2. giorno 28
3. giorno 28, giorno 60, giorno 90
4 giorno 28, giorno 60
5. entro giorno 28 e giorno 60
6. giorno 60
7. giorno 28, giorno 60

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

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

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

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

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

Information not present in EudraCT

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

Austria

Belgium

Canada

Czech Republic

Denmark

Finland

France

Germany

Greece

Hungary

Israel

Italy

Japan

Netherlands

Portugal

Romania

Russian Federation

Slovakia

Switzerland

United Kingdom

United States

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

166

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Eligible patients for this study suffer from ARDS and are invasively mechanically ventilated, hence many will also be sedated. Patients will be in severe distress due to dyspnea; hypotonia in case concomitant sepsis with limited cognitive functioning

I pazienti eleggibili in questo studio soffrono di ARDS e sono invasivamente ventilati in modo meccanico e spesso sedati. I pazienti saranno in grave difficoltà a causa di dispnea; ipotonia in caso di sepsi con limitate funzioni cognitive

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

280

F.4.2.2

In the whole clinical trial

466

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)

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

2020-07-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-03-01

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