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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

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ClinicalTrials.gov Identifier: NCT03236311
Recruitment Status : Terminated ((Recruitment was early terminated due to slow recruitment. Not linked to any safety concern.))
First Posted : August 1, 2017
Results First Posted : July 11, 2019
Last Update Posted : July 11, 2019
Sponsor:
Information provided by (Responsible Party):
Sanofi

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.

Condition or disease Intervention/treatment Phase
Microvascular Coronary Artery Disease Drug: SAR407899 Drug: Placebo Drug: Adenosine Drug: Regadenoson Drug: 13N-ammonia Drug: 82Rubidium Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)
Actual Study Start Date : October 12, 2017
Actual Primary Completion Date : July 23, 2018
Actual Study Completion Date : July 23, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Angina

Arm Intervention/treatment
Placebo Comparator: Placebo
Matching placebo for 4 weeks.
Drug: Placebo
Pharmaceutical form: Capsule Route of administration: Oral

Drug: Adenosine
Pharmaceutical form: Solution for injection Route of administration: Intravenous

Drug: Regadenoson
Pharmaceutical form: Solution for injection Route of administration: Intravenous

Drug: 13N-ammonia
Pharmaceutical form: Solution for injection Route of administration: Intravenous

Drug: 82Rubidium
Pharmaceutical form: Solution for injection Route of administration: Intravenous

Experimental: SAR407899
SAR407899 with dose titration over 4 weeks administration (3 week titration phase + 1 week maintenance phase).
Drug: SAR407899
Pharmaceutical form: Capsule Route of administration: Oral

Drug: Adenosine
Pharmaceutical form: Solution for injection Route of administration: Intravenous

Drug: Regadenoson
Pharmaceutical form: Solution for injection Route of administration: Intravenous

Drug: 13N-ammonia
Pharmaceutical form: Solution for injection Route of administration: Intravenous

Drug: 82Rubidium
Pharmaceutical form: Solution for injection Route of administration: Intravenous




Primary Outcome Measures :
  1. Change From Baseline in Uncorrected Global Coronary Flow Reserve (CFR) at Week 4 [ Time Frame: Baseline, 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 :
  1. Change From Baseline in Angina-induced Physical Limitation Assessed Using Seattle Angina Questionnaire Physical Limitation Scale (SAQ-PL) at Week 4 [ Time Frame: Baseline, 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.

  2. Pharmacokinetic Parameter: SAR407899 Plasma Concentration [ Time Frame: Day 1, 8, 15, 22, and Day 29 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03236311


Locations
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United States, California
Investigational Site Number 8400003
Los Angeles, California, United States, 90048
United States, Florida
Investigational Site Number 8400001
Jacksonville, Florida, United States, 32209
Investigational Site Number 8400013
Wellington, Florida, United States, 33449
United States, Maryland
Investigational Site Number 8400008
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Investigational Site Number 8400006
Boston, Massachusetts, United States, 02115
United States, Pennsylvania
Investigational Site Number 8400010
Philadelphia, Pennsylvania, United States, 19104
Denmark
Investigational Site Number 2080001
København Nv, Denmark, 2400
Korea, Republic of
Investigational Site Number 4100002
Seoul, Korea, Republic of, 03722
Netherlands
Investigational Site Number 5280001
Nijmegen, Netherlands, 6525 GA
Sweden
Investigational Site Number 7520001
Lund, Sweden, 221 85
Sponsors and Collaborators
Sanofi
Investigators
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Study Director: Clinical Sciences & Operations Sanofi
  Study Documents (Full-Text)

Documents provided by Sanofi:
Study Protocol  [PDF] April 18, 2018
Statistical Analysis Plan  [PDF] October 3, 2018


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Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT03236311     History of Changes
Other Study ID Numbers: ACT14656
2016-000629-38
U1111-1182-1709 ( Other Identifier: UTN )
First Posted: August 1, 2017    Key Record Dates
Results First Posted: July 11, 2019
Last Update Posted: July 11, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data (IPD) and supporting clinical documents are available for request at clinicalstudydatarequest.com. While making information available Sanofi continues to protect the privacy of the participants in clinical trials and to remove commercially confidential information (CCI). Details on Data Sharing criteria and process for requesting access can be found at this web address: clinicalstudydatarequest.com

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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
Additional relevant MeSH terms:
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Coronary Artery Disease
Angina, Stable
Coronary Disease
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Angina Pectoris
Chest Pain
Pain
Neurologic Manifestations
Signs and Symptoms
Adenosine
Regadenoson
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Vasodilator Agents
Purinergic P1 Receptor Agonists
Purinergic Agonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adenosine A2 Receptor Agonists