Clinical Trials Register

Summary
EudraCT Number:	2018-004393-10
Sponsor's Protocol Code Number:	GN18CA068
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-11-07
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

2018-004393-10

A.3

Full title of the trial

A randomised, double-blind, placebo-controlled, cross-over trial of zibotentan in microvascular angina

A.3.1

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

Precision medicine with zibotentan in microvascular angina (PRIZE)

A.3.2

Name or abbreviated title of the trial where available

Precision medicine with zibotentan in microvascular angina (PRIZE)

A.4.1

Sponsor's protocol code number

GN18CA068

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	NHS Greater Glasgow & Clyde
B.1.3.4	Country	United Kingdom
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	Medical Research Council
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	AstraZeneca UK Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	NHS Greater Glasgow & Clyde
B.5.2	Functional name of contact point	Dr Maureen Travers
B.5.3	Address:
B.5.3.1	Street Address	West Glasgow ACH, Dalnair Street
B.5.3.2	Town/ city	Glasgow
B.5.3.3	Post code	G3 8SW
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01412321813
B.5.6	E-mail	Maureen.Travers@ggc.scot.nhs.uk
B.Sponsor: 2
B.1.1	Name of Sponsor	University of Glasgow
B.1.3.4	Country	United Kingdom
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	Medical Research Council
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	AstraZeneca UK Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Zibotentan
D.3.2	Product code	ZD4054
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Zibotentan
D.3.9.1	CAS number	186497-07-4
D.3.9.2	Current sponsor code	Not applicable
D.3.9.3	Other descriptive name	Not applicable
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	Tablet
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

Microvascular Angina and impaired exercise intolerance.

E.1.1.1

Medical condition in easily understood language

Microvascular angina refers to disease in the small blood vessels, associated with both a reduced quality of life and often-repeated acute hospital admissions or long-term clinic attendance

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10065566
E.1.2	Term	Microvascular angina
E.1.2	System Organ Class	100000004849

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 is to assess the effect of add-on treatment with zibotentan on treadmill exercise time based on a Bruce protocol exercise test in patients with microvascular angina and impaired exercise intolerance.

E.2.2

Secondary objectives of the trial

To assess the effects of add-on treatment with zibotentan on other measures of exercise performance, anginal symptoms, and quality of life;

To assess whether the effects of add-on treatment with zibotentan on exercise test performance varies by genotype for the endothelin-1 gene SNP regulator;

To assess the safety of add-on treatment with zibotentan;

To assess the effects of add-on treatment with zibotentan on mechanistic biomarkers, and their association with treatment response/discontinuation

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

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

Full Title: A randomised, double-blind, placebo-controlled, cross-over trial of zibotentan in microvascular angina

An optional MRI sub-study is included in the protocol and is available to participants as part of the trial. MRI scanners will take detailed pictures of the heart and help evaluate whether treatment with zibotentan improves heart structure, function and blood flow. Software to be utilised for this sub-study has been funded and provided by Siemens Healthcare Ltd, and analysis of this data will take place in Glasgow.

E.3

Principal inclusion criteria

1. Age =>18 years.

2. Microvascular angina1.

3. Able to comply with study procedures.

4. Written informed consent.

FOR OPTIONAL MRI SUB-STUDY

1. Participation in the main study.

2. Able to comply with the sub-study procedures

3. Written informed consent.

E.4

Principal exclusion criteria

1. Exercise tolerance >540 seconds in men and >430 seconds in women (i.e. actual exercise duration (s) achieved on the Bruce protocol commensurate with predicted), or, lack of anginal symptoms and/or ST-segment depression (0.1 mV) limiting exercise.

2. Non-cardiovascular exercise-limiting problem e.g. morbid (or severe) obesity (BMI ≥40.0 kg/m2)

3. Endothelin genotype not available

4. Women who are pregnant, breast-feeding or of child-bearing potential (WoCBP) without a negative pregnancy test and who are unwilling or unable to follow the reproductive restrictions defined in section 8.10 (of the study protocol) and use highly effective contraception as defined in Appendix 3 for the duration of the study treatment and 30 days after last dose of study drug.

5. Men who are sexually active with a WoCBP who are unwilling to use condoms or other highly effective methods of contraception for the duration of study treatment and for 14 weeks after last dose of study drug.

6. Heart failure (New York Heart Association Grade ≥II i.e. mild symptoms and slight limitation during ordinary activity)

7. Recent (<3 months) myocardial infarction

8. A history of epilepsy, other CNS adverse events, neurologic symptoms or signs consistent with spinal cord compression or CNS metastases.

9. Moderate or more severe renal impairment (GFR < 45 mL/min)

10. Liver disease with a Child-Pugh score of A (5-6 points) or higher [41]

11. Participation in another intervention study involving a drug within the past 90 days or 5 half-lives whichever is longer (co-enrolment in observational studies is permitted).

FOR OPTIONAL MRI SUB-STUDY

1. Implantable cardiac device i.e. pacemaker, implantable defibrillator.

2. Contra-indication to intravenous adenosine, i.e. asthma; chronic obstructive lung disease; decompensated heart failure; long QT syndrome; second- or third-degree AV block and sick sinus syndrome; severe hypotension.

3. Contra-indication to contrast media

E.5 End points

E.5.1

Primary end point(s)

The primary outcome measure will be subject change in exercise duration(s) on the full Bruce protocol at visits 3 and 5

E.5.1.1

Timepoint(s) of evaluation of this end point

All of the analyses will be carried out according to a detailed Statistical Analysis Plan, to be written and approved prior to database lock and unblinding of treatment allocations, according to Glasgow Clinical Trials Unit (CTU) Standard Operating Procedures. An analysis by genotype will be prioritised.

The primary outcome will be analysed in the following sub-groups.

Categorical variables: - genotype, sex, history of vasospastic angina.

Continuously distributed variables (by thirds of the baseline distribution): age, eGFR, BMI, systolic blood pressure.

Results will be presented within each sub-group along with a test for treatment by sub-group interaction.

No interim analyses are planned.

E.5.2

Secondary end point(s)

EFFICACY AND MECHANISTIC

EXERCISE TEST
• Time (s) to 1 mm ST-depression,
• Maximum ST-segment deviation (mV),
• Time (s) to 75% of max age-related heart rate during exercise,
• Metabolic equivalent (METs) (O2/kg/min),
• The DUKE Score.

HEALTH STATUS
• Seattle Angina Questionnaire (SAQ) summary score
• SAQ component scores including physical limitation, angina stability & frequency
• Illness perception (Brief IPQ),
• Anxiety/depression (PHQ4),
• Treatment satisfaction (TSQM)

FEASIBILITY
Withdrawal rate

SAFETY
Serious adverse events (SAE).

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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

Yes

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

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

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