Precision Medicine With Zibotentan in Microvascular Angina

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Вход / Регистрация

Линкът е запазен в клипборда

СъстояниеНабиране

Спонсори

NHS Greater Glasgow and Clyde

Сътрудници

The University of Glasgow

King's College London

The University of Oxford

Oxford University Hospital NHS Foundation Trust

The University of Cambridge

Papworth Hospital NHS Foundation Trust

Blackpool Teaching Hospitals NHS Foundation Trust

Royal Free London NHS Foundation Trust

AstraZeneca UK Ltd

Siemens Healthcare Ltd

КЛИНИЧНО ИЗСЛЕДВАНЕ: NCT04097314

BioSeek: nct04097314

Ключови думи

синдром на дефицит на вниманието и хиперактивност

Резюме

Microvascular angina (MVA) is caused by abnormalities of the small vessels in the heart. Endothelin is a small chemical that circulates and accumulates in the blood vessel walls, causing them to narrow or go into spasm and thicken in the longer term especially as levels of endothelin increase. As a result, patients experience pain, psychological burden and an inability to carry out daily activities.

Originally developed by AstraZeneca for cancer treatment, prior research has confirmed that Zibotentan relaxes the small blood vessels of patients with MVA which lends support to the idea that Zibotentan may bring some benefits to patients with MVA. This trial therefore proposes to look into re-purposing zibotentan as a new treatment for patients with MVA. The primary objective is to assess the effect of add-on treatment with Zibotentan to treadmill exercise times in adult patients with MVA and impaired exercise intolerance. Zibotentan could provide a new treatment pathway for patients, as well as be made available to the NHS at substantially lower cost than the currently used medications.

The trial aims to initially invite approx. 356 participants for genetic testing. A minimum of 100 participants will go forward into the main study, receiving either 10mg zibotentan or a dummy matched tablet (placebo) daily over two 12 weeks periods of each, completing their final visit at week 34. The study assessments will involve a health check at each visit, including information on the patient's wellbeing, blood tests, some quality of life questionnaires, and an exercise test. Participants will also have the option to consent to additional sub-study cardiovascular MRI scanning. Finally, participants will be invited to provide consent for long-term follow-up (maximum 20 years) of their electronic medical records (no additional patient contact).

Дати

Последна проверка:	09/30/2019
Първо изпратено:	07/04/2019
Очаквано записване подадено:	09/18/2019
Първо публикувано:	09/19/2019
Изпратена последна актуализация:	10/21/2019
Последна актуализация публикувана:	10/22/2019
Действителна начална дата на проучването:	10/17/2019
Приблизителна дата на първично завършване:	04/29/2022
Очаквана дата на завършване на проучването:	11/29/2022

Състояние или заболяване

Microvascular Angina

Интервенция / лечение

Drug: Zibotentan

Drug: Placebo

Фаза

Фаза 2

Групи за ръце

Arm	Интервенция / лечение
Experimental: Zibotentan	Drug: Zibotentan 10mg OD Zibotentan
Placebo Comparator: Placebo	Drug: Placebo Placebo

Критерии за допустимост

Възрасти, отговарящи на условията за проучване	18 Years Да се 18 Years
Полове, допустими за проучване	All
Приема здрави доброволци	Да
Критерии	Inclusion Criteria: 1. Age >18 years. 2. Microvascular angina - as defined by COVADIS diagnostic criteria for microvascular angina. 3. Able to comply with study procedures. 4. Written informed consent. 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. 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 and use highly effective contraception as defined in Appendix 3 of the protocol 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 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).

Резултат

Първични изходни мерки

1. EFFICACY - Exercise Testing (treadmill exercise time, seconds) [34 weeks]

The primary outcome is the treadmill exercise time (TET) measured in seconds using the Full Bruce protocol, a measure of aerobic capacity that reflects disease severity. A within-subject improvement in exercise time (tested at week 10 (baseline), week 22 (crossover) and week 34 (final visit)) of 30 seconds is considered clinically relevant.

Вторични изходни мерки

1. EFFICACY - Health Status QLQ (Seattle Angina Questionnaire) [34 weeks]

Seattle Angina Questionnaire (SAQ) Summary Score and component scores (Angina Limitation, Angina Stability, Angina Frequency, Treatment Satisfaction and Quality of Life) will be recorded at all study visits.

2. EFFICACY - Health Status QLQ (Illness Perception - Brief IPQ) [34 weeks]

Brief Illness Perception Questionnaire (Brief IPQ), a nine-item scale designed to rapidly assess the cognitive and emotional representations of illness taken at all study visits.

3. EFFICACY - Health Status QLQ (Anxiety/depression - PHQ4) [34 weeks]

The Four-Item Patient Health Questionnaire (PHQ-4) for Anxiety and Depression is a validated tool for detecting both anxiety and depressive disorders and will administered at all study visits

4. EFFICACY - Health Status QLQ (Treatment satisfaction - TSQM) [34 weeks]

The 14-item Treatment Satisfaction Questionnaire for Medication (TSQM) is a reliable and valid instrument to assess patients' satisfaction with medication, providing scores on four scales - side effects, effectiveness, convenience and global satisfaction and will administered at all study visits

5. EFFICACY - Health Status QLQ (EQ5D-5L) [34 weeks]

The 5-item EuroQol Group EQ5D-5L is a validated questionnaire comprising mobility, self-care, usual activities, pain/discomfort and anxiety/depression to quantitatively assess patient's self-reported health status and will be administered at each study visit.

6. FEASIBILITY - Withdrawal Rate [34 weeks]

Participant withdrawal rate from study will be measured throughout.

7. SAFETY - SAEs [34 weeks]

Number of Participants With Treatment-Related Adverse Events as Assessed and reported by local study teams throughout trial.

8. EFFICACY - Exercise Testing (time,sec to 1mm ST-depression) [34 weeks]

Within-subject improvements in time (seconds) to 1 mm ST-depression during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit).

9. EFFICACY - Exercise Testing (maximum ST-segment deviation, mV) [34 weeks]

Within-subject improvements in maximum ST-segment deviation (mV) during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit).

10. EFFICACY - Exercise Testing (Time (s) to 75% of max age-related heart rate during exercise) [34 weeks]

Within-subject improvements in time (seconds) to 75% of max age-related heart rate during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit).

11. EFFICACY - Exercise Testing (Metabolic equivalent (METs) [34 weeks]

Within-subject improvements in metabolic equivalent (METs) during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit). The resting metabolic rate is defined as 3.5 ml O2/kg/min (METs).

12. EFFICACY - Exercise Testing (DUKE Score) [34 weeks]

Within-subject improvements in Duke treadmill score (DTS) during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit). Duke treadmill score is defined as maximum exercise time in minutes - (5 × the maximal net ST-segment deviation in mm during or after exercise) - (4 × the treadmill angina index (where 0 = no angina, 1 = non-limiting angina, 2 = exercise limiting angina).

Други изходни мерки

1. EFFICACY - Pharmacodynamics (Exploratory) [34 weeks]

Blood samples will be obtained at weeks 10, 22 and 34 to measure circulating concentrations of mechanistic biomarkers. These analyses are intended to provide insights into the mechanisms of treatment-related efficacy and safety responses.These measurements will be considered an exploratory endpoint.

2. EFFICACY - Pharmacokinetics (Exploratory) [34 weeks]

Blood samples will be obtained at weeks 10, 22 and 34 to measure steady-state plasma concentrations of zibotentan with a validated assay. These measurements will be considered an exploratory endpoint.

3. EFFICACY - Angina Diary (Exploratory) [34 weeks]

A novel, bespoke questionnaire for the diagnostic classification of patients with ischaemia with non-obstructive coronary artery disease (INOCA) and their treatment response will be assessed as an exploratory outcome. Patients are asked to complete this diary every time they suffer angina symptoms over the course of the trial.