E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Microvascular coronary artery disease |
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E.1.1.1 | Medical condition in easily understood language |
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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 | PT |
E.1.2 | Classification code | 10072685 |
E.1.2 | Term | Microvascular coronary artery disease |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the effects of SAR407899 on coronary vasomotor function using the coronary flow reserve (CFR) in patients with microvascular angina (MVA) and/or persistent stable angina despite angiographically successful percutaneous coronary intervention (PCI). |
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E.2.2 | Secondary objectives of the trial |
-To assess the effects of SAR407899 on quality of life using Seattle Angina Questionnaire physical limitation domain (SAQ-PL) in patients with MVA and/or persistent stable angina despite angiographically successful PCI.
-To assess the safety of SAR407899 in patients with MVA and/or persistent stable angina despite angiographically successful PCI with a focus on identified risks such as hypotension and orthostatic hypotension.
-To assess SAR407899 plasma concentrations in MVA patients and/or persistent stable angina despite angiographically successful PCI.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female patient not at childbearing potential ≥18 year-old or legal age of majority.
- Female patient if she has undergone sterilization at least 3 months earlier or is postmenopausal.
- Post-menopausal status is defined by having no menses for 12 months without an alternative medical cause.
- In females not treated with hormonal replacement therapy (HRT), menopausal status is confirmed by a high follicle stimulating hormone (FSH) level greater than 40 IU/L.
- In females on HRT and whose menopausal status is in doubt (ie, in women aged less than 45 years), a highly effective contraception methods will be required. Contraception should be used during the whole study and for at least seven days corresponding to time needed to eliminate study treatment.
- Symptomatic stable angina pectoris (typical or atypical symptoms with an average of at least biweekly episodes over the past month).
- Patients with non-obstructive (<50% stenosis) coronary arteries or intermediate stenosis (between 50 and 70%) should have fractional flow reserve (FFR) >0.80 or instantaneous wave-free ratio (iFR) >0.89 on angiogram, documented within the previous 24 months*. In patients with stenting, a minimum diameter stenosis of <10% is required.
or
Coronary computed tomography angiography (CCTA) with finding of non-obstructive coronary arteries within the past 24 months* in patients without previous percutaneous coronary intervention (PCI).
*Note: in cases of clinically suspected progression of atherosclerosis as per the Investigator, a more contemporary (i.e., 6 months) evidence should be provided.
or
CCTA performed during screening period, with finding of non-obstructive coronary arteries, in patients diagnosed with microvascular angina (MVA) and stable angina without previous PCI who did not have a coronary angiogram or CCTA in the previous 24 months but between 24 months to 5 years.
- Baseline global coronary flow reserve (CFR) (measured during the study) assessed by 13Nammonia or 82Rubidium positron emission tomography (PET) scan <2.0. |
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E.4 | Principal exclusion criteria |
- Any use of nitrates (except short-acting nitrates) and/or dipyridamole and/or phosphodiesterase type 5 (PDE 5) inhibitors within one week prior to baseline PET scan or anticipated to be used during the study.
- Esophageal dysmotility or esophagitis.
- Patients with acute coronary syndrome (ACS) (myocardial infarction [MI] and/or unstable angina) in previous 3 months.
- Unsuccessful or incomplete coronary revascularization with residual obstructive stenosis or coronary artery disease (CAD) progression in native vessels as documented on invasive coronary angiography (≥50% stenosis) within 24 months of enrollment.
- Percutaneous coronary intervention performed at the time of an ACS (MI or unstable angina) in the previous 12 months.
- Recent PCI within the past 3 months.
- Patients with history of coronary artery bypass grafting (CABG).
- Recent (≤3 months) major surgery (ie, valvular surgery, surgery for congenital heart disease), stroke, transient ischemic attack [TIA], sustained ventricular arrhythmia, clinically significant structural heart disease (moderate-severe valvular disease, hypertrophic cardiomyopathy, congenital heart disease, pulmonary hypertension).
- Regional local flow abnormal perfusion defects at baseline PET scan*.
*Note: if contemporary evidence with invasive coronary angiography or coronary computed tomography angiography (CCTA) demonstrates non-obstructive coronary arteries or if the regional local flow abnormal perfusion defect on PET scan is consistent with previous studies then patient qualifies for the study.
- Patients with cardiac conduction abnormalities (second or third degree atrioventricular [AV] block, sick sinus syndrome, symptomatic bradycardia, sinus node disease) except in patients fitted with a functioning pacemaker.
- History or known carotid stenosis:
- Carotid stenosis (>50%)
or
- History of carotid stenosis in patients with previous symptoms.
- Contraindication or known hypersensitivity to adenosine or regadenoson.
- Contraindication to aminophylline.
- Contraindication to vasodilator stress PET scan and/or CCTA if CCTA needed during screening.
- Inability to discontinue treatment with methylxanthines treatment within 24 hours prior to PET scan.
- Patient unable to read, understand and fill a questionnaire without any help (eg, partially visually impaired or blind).
- Systolic blood pressure (SBP) <110 mmHg at baseline.
- Presence at baseline of symptomatic orthostatic hypotension (SBP decrease of 20 mmHg or more at Minute 3 or Minute 5 between seated and standing position), or asymptomatic orthostatic hypotension with a decrease in SBP equal or greater than 30 mmHg at Minute 3 or Minute 5 when changing from the seated to the standing position.
- Renal impairment with estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 at screening and baseline.
- Drug-induced liver injury related criteria:
- Underlying hepatobiliary disease.
- Alanine Aminotransferase (ALT) >3 times the upper limit of normal (ULN). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in uncorrected global coronary flow reserve (CFR): Absolute change from baseline to Week 4 in uncorrected global CFR assessed by 13N-ammonia or 82Rubidium positron emission tomography (PET) scan. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Change in angina-induced physical limitation: Absolute change from baseline to Week 4 on angina-induced physical limitation using Seattle Angina Questionnaire physical limitation (SAQ-PL) scale (disease-specific health-related quality of life).
2. Safety: Adverse events (AEs) / treatment-emergent adverse events (TEAEs): Percentage of patients with TEAEs, treatment emergent serious adverse events, TEAEs leading to treatment discontinuation, and treatment emergent adverse events of specific interest (AESIs).
3. Safety: Blood pressure (BP) and orthostatic blood pressure: Description of BP and orthostatic BP during the course of the study, and percentage of patients with hypotension, orthostatic hypotension.
4. Pharmacokinetics: SAR407899 plasma concentration level SAR407899 concentrations at specific time points. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From baseline to Week 4
2. Up to 9 weeks
3. From Day 1 to Week 5
4. From Day 1 to Week 4 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
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 | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 | No |
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 |
Denmark |
Korea, Republic of |
Netherlands |
Spain |
Sweden |
United States |
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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
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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 | 13 |
E.8.9.1 | In the Member State concerned days | 4 |
E.8.9.2 | In all countries concerned by the trial months | 13 |
E.8.9.2 | In all countries concerned by the trial days | 4 |