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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

Tracking Information
First Submitted Date  ICMJE July 24, 2017
First Posted Date  ICMJE August 1, 2017
Results First Submitted Date  ICMJE June 17, 2019
Results First Posted Date  ICMJE July 11, 2019
Last Update Posted Date July 11, 2019
Actual Study Start Date  ICMJE October 12, 2017
Actual Primary Completion Date July 23, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 17, 2019)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 31, 2017)
Change in uncorrected global coronary flow reserve (CFR) [ Time Frame: From baseline to Week 4 ]
Absolute change from baseline to Week 4 in uncorrected global CFR assessed by 13N-ammonia or 82rubidium PET scan
Change History Complete list of historical versions of study NCT03236311 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 17, 2019)
  • 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.
  • Pharmacokinetic Parameter: SAR407899 Plasma Concentration [ Time Frame: Day 1, 8, 15, 22, and Day 29 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: July 31, 2017)
  • Change in angina-induced physical limitation [ Time Frame: From baseline to Week 4 ]
    Absolute change from baseline to Week 4 on angina-induced physical limitation using SAQ-PL (disease-specific health-related quality of life)
  • Safety: Adverse events (AEs) / treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 9 weeks ]
    Percentage of patients with TEAEs, treatment emergent serious adverse events, TEAEs leading to treatment discontinuation, and treatment emergent adverse events of specific interest (AESIs)
  • Safety: Blood pressure (BP) and orthostatic blood pressure [ Time Frame: From Day 1 to Week 5 ]
    Description of BP and orthostatic BP during the course of the study, and percentage of patients with hypotension, orthostatic hypotension
  • Pharmacokinetics: SAR407899 plasma concentration level [ Time Frame: From Day 1 to Week 4 ]
    SAR407899 concentrations at specific time points
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Microvascular Coronary Artery Disease
Intervention  ICMJE
  • Drug: SAR407899
    Pharmaceutical form: Capsule Route of administration: Oral
  • 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
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Matching placebo for 4 weeks.
    Interventions:
    • Drug: Placebo
    • Drug: Adenosine
    • Drug: Regadenoson
    • Drug: 13N-ammonia
    • Drug: 82Rubidium
  • Experimental: SAR407899
    SAR407899 with dose titration over 4 weeks administration (3 week titration phase + 1 week maintenance phase).
    Interventions:
    • Drug: SAR407899
    • Drug: Adenosine
    • Drug: Regadenoson
    • Drug: 13N-ammonia
    • Drug: 82Rubidium
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: August 17, 2018)
10
Original Estimated Enrollment  ICMJE
 (submitted: July 31, 2017)
78
Actual Study Completion Date  ICMJE July 23, 2018
Actual Primary Completion Date July 23, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Denmark,   Korea, Republic of,   Netherlands,   Sweden,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03236311
Other Study ID Numbers  ICMJE ACT14656
2016-000629-38
U1111-1182-1709 ( Other Identifier: UTN )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
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
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP