Clinical trial NCT03236311: A Dose Titration Study to Assess the Effects of SAR407899 in Patients With MVA and/or Persistent Stable Angina Despite Angiographically Successful PCI
Official title: A Randomized, Double-blind, Placebo-controlled Parallel Arm Dose Titration Study to Assess the Effects of SAR407899 in Patients With Microvascular Angina (MVA) and/or Persistent Stable Angina Despite Angiographically Successful Percutaneous Coronary Intervention (PCI)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Microvascular Coronary Artery Disease
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2017-08-01
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

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.

Primary outcomes:
measure: Change From Baseline in Uncorrected Global Coronary Flow Reserve (CFR) at Week 4
timeFrame: Baseline, Week 4
Secondary outcomes:
measure: Change From Baseline in Angina-induced Physical Limitation Assessed Using Seattle Angina Questionnaire Physical Limitation Scale (SAQ-PL) at Week 4
timeFrame: Baseline, Week 4
measure: Pharmacokinetic Parameter: SAR407899 Plasma Concentration
timeFrame: Day 1, 8, 15, 22, and Day 29
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Investigational Site Number 8400003
state: California
city: Jacksonville
country: United States
facility: Investigational Site Number 8400001
state: Florida
city: Wellington
country: United States
facility: Investigational Site Number 8400013
state: Florida
city: Baltimore
country: United States
facility: Investigational Site Number 8400008
state: Maryland
city: Boston
country: United States
facility: Investigational Site Number 8400006
state: Massachusetts
city: Philadelphia
country: United States
facility: Investigational Site Number 8400010
state: Pennsylvania
city: København Nv
country: Denmark
facility: Investigational Site Number 2080001
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 4100002
city: Nijmegen
country: Netherlands
facility: Investigational Site Number 5280001
city: Lund
country: Sweden
facility: Investigational Site Number 7520001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: