Clinical Trials Register

Summary
EudraCT Number:	2018-002088-25
Sponsor's Protocol Code Number:	N-003-CRD003
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-11-16
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

Spain - AEMPS

A.2

EudraCT number

2018-002088-25

A.3

Full title of the trial

A Phase II, Single-arm, Open-Label Study to Characterise the Effect on Portal Pressure, the Effect on Renal Function and the Pharmacokinetic Profile of N-003 in Patients with Decompensated Cirrhosis

Estudio de fase II, de un brazo, abierto para caracterizar el efecto en la presión portal, en la función renal y el perfil farmacocinético de N-003 en pacientes con cirrosis descompensada.

A.3.1

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

A Non-Placebo Clinical Trial in Patients with Chronic Liver Disease to Test the Safety and Effect of N-003 on Liver Blood Pressure and Renal Function, as well as N-003 Levels in Blood

Ensayo clínico no controlado con placebo en pacientes con enfermedad hepática grave para probar la seguridad y el efecto de N-003 en la presión sanguínea hepática y en la función renal así como los niveles de N-003 en sangre

A.4.1

Sponsor's protocol code number

N-003-CRD003

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 Gasse 15
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	4176 398 70 07
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 (ambrisentan) 5 mg/ml solution for oral or subcutaneous administration
D.3.2	Product code	N-003
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use Subcutaneous 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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

decompensated liver cirrhosis

cirrosis hepática descompensada

E.1.1.1

Medical condition in easily understood language

chronic liver disease with major complications:
- water in the belly (ascites)
- bleeding from stomach or oesophagus (variceal bleeding)
- disturbance of consciousness (hepatic encephalopathy)

enfermedad hepática crónica con complicaciones graves
-agua en el abdomen(ascitis)
-sangrado del estómago o del esófago(sangrado de varices)
-alteración de las consciencia(encefalopatía hepática)

E.1.1.2

Therapeutic area

Body processes [G] - Metabolic Phenomena [G03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10064704
E.1.2	Term	Decompensated cirrhosis
E.1.2	System Organ Class	100000004871

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 the study is to determine whether N-003 reduces portal pressure in patients with decompensated cirrhosis and a history of recurrent ascites.

El objetivo primario de este estudio es determinar si N-003 reduce la presión portal en pacientes con cirrosis hepática descompensada e historia recurrente de ascitis

E.2.2

Secondary objectives of the trial

• the effect of N-003 on renal function, as determined by 24-hour Urinary Sodium Volume (UNaV)
•the effect of N-003 on weight
•the effect of N-003 on abdominal girth
•the effect of N-003 on liver disease severity scores (MELD and Child-Pugh scores)
•the effect of N-003 on cardiac and pulmonary haemodynamics
•the pharmacokinetic profile of N-003 in patients with liver impairment
•the effect of N-003 on plasma endothelin
•to assess the safety and tolerability of N-003 in this population

•El efecto de N-003 en la función renal, determinada mediante el volumen de sodio en orina de 24-horas
•El efecto de N-003 en el peso
•El efecto de N-003 en el perímetro abdominal.
•El efecto de N-003 en los índices de severidad de enfermedad hepática (índices MELD y Child-Pugh).
•El efecto de N-003 en la hemodinamia cardiaca y pulmonar.
•El perfil farmacocinético de N-003 en pacientes con fallo hepático.
•El efecto de N-003 en la endotelina plasmática.
•Evaluar la seguridad y tolerabilidad de N-003 en esta población

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Signed informed consent including data protection declaration prior to study participation
2.Subjects with confirmed cirrhosis (by biopsy, ultrasound, and/or laboratory examinations)
3.Ascites Grade II or Grade III at screening
4.Currently treated with at least one diuretic or the subject is considered intolerant to diuretics in the investigator’s opinion

1.Firma del consentimiento informado, incluyendo una declaración de la protección de datos antes de la participación en el estudio.
2.Sujetos con cirrosis confirmada (mediante biopsia, ultrasonidos, y/o pruebas de laboratorio).
3.Ascitis de Grado II y Grado III en la selección.
4.Tratamiento actual con al menos un diurético o que el sujeto se considere intolerante a los diuréticos a juicio del investigador.

E.4

Principal exclusion criteria

1.Age <18 years of age
2.Any of the following laboratory findings at the time of screening
a.Serum creatinine level >1.5mg/dL (>132 µmol/L)
b.Serum Na+ < 125 meq/L
c.Serum K+ ≥ 5.5 meq/L
d.Serum bilirubin ≥ 5 mg/dL (85.5 µmol/L)
e.INR >3.0
3.Women of childbearing potential with no effective contraceptive method (women of childbearing potential [pre-menopausal, not surgically sterile for at least 3 months prior to the time of screening] must have a confirmed negative serum β-hCG pregnancy test prior to enrolment and at Baseline Visit. They must use an effective contraceptive method throughout the study, and agree to repeat serum β-hCG pregnancy tests at designated visits)
4.Pregnancy or lactation
5.Systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg
6.Sepsis and/or uncontrolled bacterial infection
7.Current or recent documented nephrotoxicity (within 4 weeks)
8.Hepatic Encephalopathy above grade 1
9.History of variceal bleeding in the last 2 months
10.Suspicion of active alcohol consumption in the last 3 months
11.History of liver or kidney transplantation
12.History of Transjugular Intrahepatic Portosystemic Shunt (TIPS)
13.Suspected occlusive portal vein or splenic vein thrombosis
14.Hepatocellular carcinoma (HCC) beyond the Milan criteria
15.Acute Liver Failure or superimposed acute liver injury due to drugs (e.g., acetaminophen), dietary supplements, herbal preparations, viral hepatitis, or toxins
16.Severe cardiovascular disease, including, but not limited to, unstable angina, pulmonary oedema, congestive heart failure
17.Current or recent (within 30 days) renal replacement therapy (RRT)
18.If on beta-blockers, a change in dose or drug within last 15 days prior to screening
19.Use of any other endothelin receptor antagonist, octreotide, midodrine, terlipressin in last 15 days prior to screening
20.Known hypersensitivity to contrast-media
21.Any clinically significant abnormality identified on physical examination, laboratory tests, ECG or vital signs at the time of screening that in the judgment of the investigator or any sub-investigator would preclude safe completion of the study or constrains the assessment of efficacy
22.Known sensitivity to ambrisentan or any of the excipients of the formulation
23.Participation in other clinical research involving investigational medicinal products within 30 days of enrolment
24.Subjects who have difficulties in understanding the language in which the study information is given
25.Subjects who do not agree to the transmission of their anonymous data within the liability of documentation and notification
26.Staff of the study centre, staff of the sponsor or CRO, the investigator himself or close relatives of the investigator.

Cardiac and Pulmonary Haemodynamic Study exclusion Criteria: Subjects fulfilling any of the exclusion criteria below may participate in the study, but will not undergo cardiac and pulmonary catheterisation:
1.Significant arrhythmias, which include any of the following: sustained ventricular tachycardia, bradycardia with sustained ventricular rate < 45 beats per minute or atrial fibrillation/flutter with sustained ventricular response of > 90 beats per minute at rest, or Long QT syndrome or QTc > 450 ms
2.Significant left ventricular outflow tract obstructions (e.g., severe valvular aortic stenosis, obstructive cardiomyopathy), severe mitral stenosis, restrictive amyloid myocardiopathy, acute myocarditis
3.Severe aortic insufficiency or severe mitral regurgitation for which surgical or percutaneous intervention is indicated
4.Major neurologic event including cerebrovascular events, within 30 days prior to screening
5.Clinical evidence of acute coronary syndrome currently or within 30 days prior to screening
6.Permanent pacemaker, cardiac resynchronisation device or implantable cardioverter-defibrillator in situ.

1.Edad <18 años.
2.Alguno de los siguientes hallazgos de laboratorio en el momento de la selección:
a.Nivel de creatinina sérica >1.5mg/dL (>132 µmol/L)
b.Na+ sérico< 125 meq/L
c.K+ sérico ≥ 5.5 meq/L
d.Bilirrubina sérica ≥ 5 mg/dL (85.5 µmol/L)
e.INR >3.0
3.Mujeres en edad fértil con un método anticonceptivo no eficaz (las mujeres en edad fértil [premenopáusicas, no esterilizadas quirúrgicamente al menos 3 meses antes de la Visita de Selección] deben confirmar que no están embarazadas mediante una prueba de β-hCG en suero antes de la inclusión en el estudio y en la visita basal. Deben usar un método anticonceptivo eficaz durante el estudio, y aceptar realizarse la prueba de embarazo de β-hCG en suero en las visitas designadas).
4. Embarazo o lactancia.
5.Tensión sistólica <90 mmHg o tensión diastólica <60 mmHg.
6.Sepsis y/o infección bacteriana no controlada.
7.Nefrotoxicidad documentada actual o reciente (en las 4 semanas anteriores).
8.Encefalopatía hepática mayor de grado 1.
9.Historia de sangrado de las varices en los dos últimos meses.
10.Sospecha de consumo de alcohol activo durante los últimos tres meses.
11.Historia de trasplante hepático o renal.
12.Historia de desvío portosistémico intrahepático transyugular (DPIT).
13.Sospecha de trombosis oclusiva de la vena porta o de la vena esplénica.
14.Carcinoma hepatocelular según el criterio Milan.
15.Fallo hepático agudo o daño hepático superpuesto inducido por fármacos (ej. paracetamol), suplementos dietéticos, preparaciones de hierbas, hepatitis vírica y/o toxinas.
16.Enfermedad cardiovascular severa, incluyendo, pero no únicamente, angina inestable, edema pulmonar y/o fallo cardíaco congestivo.
17.Terapia de reemplazo renal (RRT) actual o reciente (en los 30 días anteriores)
18.En caso de betabloqueantes, un cambio de dosis o de fármaco en los últimos 15 días antes de la selección.
19.Uso de algún otro antagonista de los receptores de endotelina, octreotido, midodrina, terlipresina en los últimos 15 días.
20.Hipersensibilidad conocida a los medios de contraste.
21.Anomalías clínicamente significativas en los resultados de la exploración física, de los análisis de laboratorio, en el ECG o en las constantes vitales en el momento de la selección que a juicio del investigador o del co-investigador puedan impedir la finalización del estudio de un modo seguro o puedan limitar la evaluación de la eficacia.
22.Alergia conocida a ambrisentan o a cualquier excipiente de la formulación.
23.Participación en cualquier ensayo clínico en los 30 días anteriores a la inclusión en el estudio.
24.Sujetos con dificultades para entender el lenguaje en el que se da la información al sujeto.
25.Sujetos que no accedan a la transmisión de sus datos anónimos en lo que respecta a las funciones de documentación y notificación.
26.Personal del centro de estudio, del promotor o de la CRO, el propio investigador o familiares de este.
Criterios de exclusión para el estudio de hemodinamia cardiaca y pulmonar: los sujetos que cumplan alguno de los siguientes criterios de exclusión pueden participar en el estudio, pero no se les realizará el cateterismo cardiaco y pulmonar:
1.Arritmias significativas, que incluyen: taquicardia ventricular sostenida, bradicardia con frecuencia ventricular sostenida de < 45 latidos por minuto o fibrilación/palpitación auricular con respuesta ventricular sostenida de > 90 latidos por minuto en descanso, o síndrome de QT largo o QTc > 450 ms.
2.Obstrucción significativa del tracto de salida del ventrículo izquierdo (ej., estenosis valvular aórtica severa, cardiomiopatía obstructiva), estenosis mitral severa, miocardiopatía amiloide restrictiva y/o miocarditis aguda.
3.Insuficiencia aortica severa o regurgitación mitral severa para las cuales está indicada la intervención quirúrgica o percutánea.
4.Eventos neurológicos graves incluyendo eventos cerebrovasculares, en los 30 días anteriores a la selección.
5.Evidencia clínica de síndrome agudo coronario en la actualidad o en los 30 días anteriores a la inclusión en el estudio.
6.Marcapasos permanente, dispositivo de resincronización cardiaca y/o desfibrilador cardioversor implantable in situ.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is defined as the mean change in Hepatic Vein Pressure Gradient (HVPG) from baseline to Day 14.

La primera variable de eficacia se define como el cambio medio en el Gradiente de Presión Venosa Hepático (GPVH) entre el valor basal y el Día 14.

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 1 - day 1 & visit 2 - day 14

Visita 1 - día 1 & visita 2 - día 14

E.5.2

Secondary end point(s)

Secondary efficacy endpoints include:
•change in 24-hour Urinary Sodium Volume (UNaV) from baseline to Visit 1 – Day 1
•change in weight from baseline to each study visit
•change in abdominal girth from baseline to each study visit
•change in MELD score from baseline to each study visit
•change in Child-Pugh score from baseline to each study visit
•change in cardiac and pulmonary haemodynamic variables from baseline to 90 minutes post-drug administration, Day 14 (trough) and 90 minutes after last dose (Day 14)

•Cambio en el volumen de sodio en orina de 24-horas entre el valor basal y en cada visita de estudio.
•Cambio del peso entre el valor basal y en cada visita de estudio.
•Cambio del perímetro abdominal entre el valor basal y en cada visita de estudio
•Cambio en la puntuación MELD entre el valor basal y en cada visita de estudio
•Cambio en la puntuación Child-Pugh entre el valor basal y en cada visita de estudio
•Cambio en las variables hemodinámicas cardíacas y pulmonares entre el valor basal y 90 minutos tras la administración el Día 1, Día 14 (medida valle) y 90 minutos tras la última dosis (Día 14).

E.5.2.1

Timepoint(s) of evaluation of this end point

at all visits starting from baseline

en todas las visitas desde la visita basal

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

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

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

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

última visita del último paciente

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 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:

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

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

F.4.2.2

In the whole clinical trial

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

Ninguno

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

2019-01-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-12-10

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2021-01-20

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