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

Primary Purpose

Microvascular Coronary Artery Disease

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
SAR407899
Placebo
Adenosine
Regadenoson
13N-ammonia
82Rubidium
Sponsored by
Sanofi
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Microvascular Coronary Artery Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • Investigational Site Number 8400003
  • Investigational Site Number 8400001
  • Investigational Site Number 8400013
  • Investigational Site Number 8400008
  • Investigational Site Number 8400006
  • Investigational Site Number 8400010
  • Investigational Site Number 2080001
  • Investigational Site Number 4100002
  • Investigational Site Number 5280001
  • Investigational Site Number 7520001

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

SAR407899

Arm Description

Matching placebo for 4 weeks.

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

Outcomes

Primary Outcome Measures

Change From Baseline in Uncorrected Global Coronary Flow Reserve (CFR) at Week 4
Absolute change from baseline to Week 4 in uncorrected global CFR, as assessed by the central core laboratory. The global CFR is the ratio of absolute myocardial blood flow (MBF) at stress over that at rest. The MBF was assessed by 13N-ammonia or 82Rubidium positron emission tomography (PET) scan.

Secondary Outcome Measures

Change From Baseline in Angina-induced Physical Limitation Assessed Using Seattle Angina Questionnaire Physical Limitation Scale (SAQ-PL) at Week 4
The SAQ-PL measures how common daily activities representing low, medium, and high exertional requirements were limited by angina (9 items). It was scored by assigning each response an ordinal value, beginning with 1 for the response that implied the 'lowest level of functioning' to 5 for 'not at all limited', and summing across the 9 items. The score of 9 items was then transformed to 0-100 range by subtracting the lowest possible scale score, dividing by the range of the scale and multiplying by 100. The range of scores was 0 to 100, with higher scores indicates better functioning. A change of 10 points was considered to be clinically important.
Pharmacokinetic Parameter: SAR407899 Plasma Concentration

Full Information

First Posted
July 24, 2017
Last Updated
March 15, 2022
Sponsor
Sanofi
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1. Study Identification

Unique Protocol Identification Number
NCT03236311
Brief Title
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

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Terminated
Why Stopped
(Recruitment was early terminated due to slow recruitment. Not linked to any safety concern.)
Study Start Date
October 12, 2017 (Actual)
Primary Completion Date
July 23, 2018 (Actual)
Study Completion Date
July 23, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sanofi

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Microvascular Coronary Artery Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Matching placebo for 4 weeks.
Arm Title
SAR407899
Arm Type
Experimental
Arm Description
SAR407899 with dose titration over 4 weeks administration (3 week titration phase + 1 week maintenance phase).
Intervention Type
Drug
Intervention Name(s)
SAR407899
Intervention Description
Pharmaceutical form: Capsule Route of administration: Oral
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Pharmaceutical form: Capsule Route of administration: Oral
Intervention Type
Drug
Intervention Name(s)
Adenosine
Intervention Description
Pharmaceutical form: Solution for injection Route of administration: Intravenous
Intervention Type
Drug
Intervention Name(s)
Regadenoson
Intervention Description
Pharmaceutical form: Solution for injection Route of administration: Intravenous
Intervention Type
Drug
Intervention Name(s)
13N-ammonia
Intervention Description
Pharmaceutical form: Solution for injection Route of administration: Intravenous
Intervention Type
Drug
Intervention Name(s)
82Rubidium
Intervention Description
Pharmaceutical form: Solution for injection Route of administration: Intravenous
Primary Outcome Measure Information:
Title
Change From Baseline in Uncorrected Global Coronary Flow Reserve (CFR) at Week 4
Description
Absolute change from baseline to Week 4 in uncorrected global CFR, as assessed by the central core laboratory. The global CFR is the ratio of absolute myocardial blood flow (MBF) at stress over that at rest. The MBF was assessed by 13N-ammonia or 82Rubidium positron emission tomography (PET) scan.
Time Frame
Baseline, Week 4
Secondary Outcome Measure Information:
Title
Change From Baseline in Angina-induced Physical Limitation Assessed Using Seattle Angina Questionnaire Physical Limitation Scale (SAQ-PL) at Week 4
Description
The SAQ-PL measures how common daily activities representing low, medium, and high exertional requirements were limited by angina (9 items). It was scored by assigning each response an ordinal value, beginning with 1 for the response that implied the 'lowest level of functioning' to 5 for 'not at all limited', and summing across the 9 items. The score of 9 items was then transformed to 0-100 range by subtracting the lowest possible scale score, dividing by the range of the scale and multiplying by 100. The range of scores was 0 to 100, with higher scores indicates better functioning. A change of 10 points was considered to be clinically important.
Time Frame
Baseline, Week 4
Title
Pharmacokinetic Parameter: SAR407899 Plasma Concentration
Time Frame
Day 1, 8, 15, 22, and Day 29

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Sciences & Operations
Organizational Affiliation
Sanofi
Official's Role
Study Director
Facility Information:
Facility Name
Investigational Site Number 8400003
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Facility Name
Investigational Site Number 8400001
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32209
Country
United States
Facility Name
Investigational Site Number 8400013
City
Wellington
State/Province
Florida
ZIP/Postal Code
33449
Country
United States
Facility Name
Investigational Site Number 8400008
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Investigational Site Number 8400006
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Investigational Site Number 8400010
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Investigational Site Number 2080001
City
København Nv
ZIP/Postal Code
2400
Country
Denmark
Facility Name
Investigational Site Number 4100002
City
Seoul
ZIP/Postal Code
03722
Country
Korea, Republic of
Facility Name
Investigational Site Number 5280001
City
Nijmegen
ZIP/Postal Code
6525 GA
Country
Netherlands
Facility Name
Investigational Site Number 7520001
City
Lund
ZIP/Postal Code
221 85
Country
Sweden

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Learn more about this trial

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

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