A Dose Titration Study to Assess the Effects of SAR407899 in Patients With MVA and/or Persistent Stable Angina Despite Angiographically Successful PCI

Sanofi

Status and phase: Terminated; Phase 2

Conditions: Microvascular Coronary Artery Disease

Treatments: Drug: SAR407899; Drug: Regadenoson; Drug: Placebo; Drug: 13N-ammonia; Drug: 82Rubidium; Drug: Adenosine

Study type: Interventional

Funder types: Industry

Identifiers

NCT03236311

ACT14656

U1111-1182-1709 (Other Identifier)

2016-000629-38

Details and patient eligibility

About

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.

Full description

The total duration of study per participant was:

• up to 9 weeks for participants with previous coronary artery angiography or coronary computed tomography angiography (CCTA) within 24 months prior to screening with up to 4 weeks screening period, 3 weeks titration phase, 1 week maintenance period, and 1 week follow-up after the last investigational medicinal product administration.

or

• up to 11 weeks for participants with previous coronary artery angiography or CCTA between 24 months and 5 years prior to screening who need CCTA during screening period with up to 6 weeks screening period, 3 weeks titration phase, 1 week maintenance period, and 1 week follow-up after the last investigational medicinal product administration.

Enrollment: 10 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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10 participants in 2 patient groups, including a placebo group

Placebo

Placebo Comparator group

Description:

Matching placebo for 4 weeks.

Treatment:

Drug: 13N-ammonia

Drug: Adenosine

Drug: 82Rubidium

Drug: Regadenoson

Drug: Placebo

SAR407899

Experimental group

Description:

SAR407899 with dose titration over 4 weeks administration (3 week titration phase + 1 week maintenance phase).

Treatment:

Drug: 13N-ammonia

Drug: Adenosine

Drug: SAR407899

Drug: 82Rubidium

Drug: Regadenoson