A Dose Titration Study to Assess the Effects of SAR407899 in Patients With MVA and/or Persistent Stable Angina Despite Angiographically Successful PCI
Condition: Microvascular Coronary Artery Disease
MeSH terms: Coronary Artery Disease; Angina, Stable
Intervention: SAR407899; Placebo; Adenosine; Regadenoson; 13N-ammonia; 82Rubidium
Intervention description: Pharmaceutical form: Capsule Route of administration: Oral; Pharmaceutical form: Capsule Route of administration: Oral; Pharmaceutical form: Solution for injection Route of administration: Intravenous; Pharmaceutical form: Solution for injection Route of administration: Intravenous; Pharmaceutical form: Solution for injection Route of administration: Intravenous; Pharmaceutical form: Solution for injection Route of administration: Intravenous
Intervention MeSH terms: Adenosine; Regadenoson
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Primary Objective:

      To assess the effects of SAR407899 on coronary vasomotor function using the coronary flow
      reserve (CFR) in participants with microvascular angina (MVA) and/or persistent stable angina
      despite angiographically successful percutaneous coronary intervention (PCI).

      Secondary Objectives:

        -  To assess the effects of SAR407899 on quality of life using Seattle Angina Questionnaire
           physical limitation scale (SAQ-PL) in participants with MVA and/or persistent stable
           angina despite angiographically successful PCI.

        -  To assess the safety of SAR407899 in participants 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 participants and/or persistent stable
           angina despite angiographically successful PCI.
    

Eligibility criteria:

        Inclusion criteria:

          -  Male or female participants not at childbearing potential >=18 year-old or legal age
             of majority.

          -  Female participant if she has undergone sterilization at least 3 months earlier or was
             post-menopausal.

          -  Post-menopausal status was defined by having no menses for 12 months without an
             alternative medical cause.

          -  In females not treated with hormonal replacement therapy (HRT), menopausal status was
             confirmed by a high follicle stimulating hormone (FSH) level greater than 40
             international units per litre (IU/L).

          -  In females on HRT and whose menopausal status was in doubt (i.e. in women aged less
             than 45 years), a highly effective contraception methods was required. Contraception
             was 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 bi-weekly episodes over the past month).

          -  Participants 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 participants 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 participants 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 participants 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
        13N-ammonia or 82Rubidium positron emission tomography (PET) scan <2.0.

        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.

          -  Participants 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.

          -  Participants with history of coronary artery bypass grafting (CABG).

          -  Recent (<=3 months) major surgery (i.e. 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 CCTA
             demonstrates non-obstructive coronary arteries or if the regional local flow abnormal
             perfusion defect on PET scan is consistent with previous studies then participant
             qualifies for the study.

          -  Participants with cardiac conduction abnormalities (second or third degree
             atrioventricular [AV] block, sick sinus syndrome, symptomatic bradycardia, sinus node
             disease) except in participants fitted with a functioning pacemaker.

          -  History or known carotid stenosis:

          -  Carotid stenosis (>50%) or

          -  History of carotid stenosis in participants 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.

          -  Participant unable to read, understand and fill a questionnaire without any help (eg,
             partially visually impaired or blind).

          -  Systolic blood pressure (SBP) <110 millimeter of mercury (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
             milliliter/minute/1.73 square meter (mL/min/1.73 m^2) at screening and baseline.

          -  Drug-induced liver injury related criteria:

          -  Underlying hepatobiliary disease.

          -  Alanine Aminotransferase (ALT) >3 times the upper limit of normal (ULN).

        The above information is not intended to contain all considerations relevant to a
        participant's potential participation in a clinical trial.