Clinical Trials Register

Summary
EudraCT Number:	2018-002448-10
Sponsor's Protocol Code Number:	BIA-51058-201
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2019-06-19
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

UK - MHRA

A.2

EudraCT number

2018-002448-10

A.3

Full title of the trial

An open-label, multicentre study to evaluate pharmacokinetics, safety and efficacy of zamicastat as adjunctive therapy in pulmonary arterial hypertension (PAH)

A.3.1

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

Multi centre study to assess the safety, effective and movement of Zamicastat within the body when given to a patient with pulmonary arterial hypertension as an additional medication.

A.3.2

Name or abbreviated title of the trial where available

Pharmcokinetics, safety and efficacy of BIA-5-1058 in PAH

A.4.1

Sponsor's protocol code number

BIA-51058-201

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	Bial - Portela & Ca, S.A
B.1.3.4	Country	Portugal
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bial - Portela & Ca, S.A
B.5.2	Functional name of contact point	Head of clinical operations
B.5.3	Address:
B.5.3.1	Street Address	À Av. da Siderurgia Nacional,
B.5.3.2	Town/ city	4745-457 Coronado (S. Romão e S. Mamede),
B.5.3.4	Country	Portugal
B.5.4	Telephone number	+351 229866100
B.5.5	Fax number	+351 229866192
B.5.6	E-mail	ana.santos@bial.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	Zamicastat
D.3.2	Product code	BIA 5-1058
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pulmonary arterial hypertension

E.1.1.1

Medical condition in easily understood language

High blood pressure

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

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	10064911
E.1.2	Term	Pulmonary arterial hypertension
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

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 assess what the body does to Zamicastat and where Zamicastat goes in the body in patients with Pulmonary Arterial Hypertension. This will test which is the 'best dose' for the patients.

E.2.2

Secondary objectives of the trial

1 - Further tests on where Zamicastat goes in the body and what the body does to Zamicastat; such as how long it takes for the body to get rid of all of Zamicastat and half of Zamicastat

2 - Check if zamicastat is safe for the patient and the highest amount of zamicastat a patient is able to take.

3 - How zamicastat affects chemicals in your body that make your heart beat

4 - How Zamicastat affect the levels of hormones in your urine

5 - How Zamicastat affects your heart rate and blood pressure

6 - Difference in the distance walked within 6 minutes

7 - How Zamicastat affects the biological indicators for Pulmonary Arterial Hypertension

8 - The changes in your heart by using an echocardiogram

9 - Changes in 'quality of life' through a questionnaire

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients aged 18 to 75 years inclusive.
2. Able to comprehend and willing to sign an informed consent form (ICF).
3. Diagnosis of PAH (pulmonary arterial hypertension WHO Group 1) documented by RHC with a mPAP ≥ 25 mmHg, a PAWP ≤ 15 mmHg and a PVR > 3 WU [7,8]:
e) Idiopathic, in non-vasoreactive patients
f) Heritable: Bone morphogenetic protein receptor type II (BMPR2) mutation and
other mutations, in non-vasoreactive patients
g) Drugs and toxin induced, in non-vasoreactive patients
h) Associated with connective tissue disease or with simple congenital defects (atrial septal defect and/or ventricular septal defect) if closed > 12 months before inclusion.
4. The patient’s last right heart catheterisation results, which were measured at the study site, must not be older than 90 days before V1 (will be considered as baseline value). Otherwise a right heart catheterisation has to be performed as part of the study at visit A1.
5. WHO functional class II or III as judged by the investigator.
6. Stable treatment with at least one of the following approved oral PAH therapies within 3 months before V1: Ambrisentan, Bosentan, Macitentan, Riociguat, Selexipag, Sildenafil or Tadalafil.
7. For women: Agree not to donate ova from the time of informed consent until 30 days after the last IMP intake.
For men: Agree not to donate sperm from the time of informed consent until 90 days after the last IMP intake.

E.4

Principal exclusion criteria

1. Contraindication to zamicastat, i.e. known hypersensitivity to ingredients of zamicastat formulation.
2. Persistent hypotension defined as SBP < 95 mmHg or DBP < 50 mmHg measured at V1.
3. Uncontrolled diabetes mellitus.
4. PAH WHO Group 1 due to portal hypertension, human immunodeficiency virus (HIV) infection and schistosomiasis.
5. Any disease known to cause pulmonary hypertension other than PAH WHO Group 1 e.g. obstructive lung diseases, parasitic disease affecting the pulmonary system, sickle cell anaemia, left heart disease.
6. History of moderate to severe hepatic impairment (Child-Pugh B and C), as demonstrated and documented by previous spirometry data which, in the opinion of the investigator, represent the clinical state of the patient at the time of the screening visit.
7. Restrictive lung disease: Total Lung Capacity (TLC) < 70% of predicted value, as demonstrated and documented by previous spirometry data which, in the opinion of the investigator, represent the clinical state of the patient at the time of the screening visit.
8. History of moderate to severe hepatic impairment (Child-Pugh B and C).
9. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (measured at V1).
10. se of the following prohibited medication or treatments during study participation: calcium channel blockers (CCBs) if used for the treatment of PAH in vasoreactive patients; drugs containing a catechol group that is metabolised by DβH e.g. rimiterole, isoprenaline, dopamine, dopexamine or dobutamide or α- and/or β-blockers.
11. Current or previous (within the past year) alcohol or substance abuse excluding caffeine or nicotine.
12. Presence of any other significant or progressive/unstable medical condition that, in the opinion of the investigator, would compromise evaluation of the study treatment or may jeopardise the patient’s safety, compliance or adherence to protocol requirements.
13. For women: Pregnancy or breast-feeding. Women of childbearing potential (as defined in Section 4.2) unable or unwilling to undergo pregnancy tests and practice highly effective contraceptive measures in combination with a barrier method e.g. condom (without spermicidal foam/gel/film/cream/suppository or fat- or oil-containing lubricants), occlusive cap (diaphragm or cervical/vault caps) with spermicidal gel/film/cream/suppository from the time of informed consent until 30 days after last IMP intake. Highly effective methods for women are surgical intervention (e.g. bilateral tubal occlusion), non-hormonal implantable intrauterine device, true sexual abstinence (i.e. when this is in line with the preferred and usual lifestyle of the patient) and vasectomised partner (provided that the partner is the sole sexual partner of the patient and the partner has received medical assessment of the surgical success).Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods), hormonal contraceptives and withdrawal are not acceptable methods of contraception.
For men: Male patients who are sexually active with a partner of childbearing potential must use, with their partner, a condom plus an approved acceptable contraceptive measure from the time of informed consent until 90 days after the last IMP intake. The following methods are acceptable methods of contraception: partner’s use of combined (oestrogen and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); partner’s use of progestogen-only hormonal contraception (oral, injectable/implantable, intrauterine hormone-releasing system); partner’s use of implantable intrauterine device; surgical sterilisation (for example, vasectomy or bilateral tubal occlusion).
14. Previous participation in any other drug investigational study within the past 30 days (or five half-lives of investigational medicinal product [IMP] whichever is longer) prior to V1.
15. Vulnerable patients according to Section 1.61 of the ICH guideline for Good Clinical Practice E6

E.5 End points

E.5.1

Primary end point(s)

To evaluate the pharmacokinetic (PK) profile of different zamicastat doses in PAH patients to find the most promising dosage window for the treatment of PAH patients.

E.5.1.1

Timepoint(s) of evaluation of this end point

PK parameters (24-hour profile) Zamicastat and its metabolites will be derived after single dose of 50mg.

E.5.2

Secondary end point(s)

1. To assess the safety and tolerability of different zamicastat doses
2. To investigate the effect of different zamicastat doses on DβH activity
3. To investigate the effect of different zamicastat doses on urinary catecholamine levels (norepinephrine and dopamine)
4. To investigate the change in pulmonary vascular resistance (PVR), assessed by right heart catheterisation
5. To investigate the change in the 6-minute walk test (6-MWT)
6. To investigate the change in pulmonary haemodynamics, including pulmonary arterial oxygen saturation
7. To investigate the change in biomarkers (NT-proBNP, BMPR2, St-2 and metalloproteases)
8. To investigate the change in cardiac structure and contractibility, assessed by echocardiography
9. To investigate the change in quality of life, assessed by SF-36

E.5.2.1

Timepoint(s) of evaluation of this end point

Last patient last visit.

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

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

E.8.1.1

Randomised

E.8.1.2

Open

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

Yes

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

Austria

Germany

Netherlands

Portugal

Spain

Ukraine

United Kingdom

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

LSLV Q4 2019

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