Following amendment changes were made: The population of the study and its inclusion/exclusion criteria, modified to include both subjects with MVA and subjects with persistent stable angina despite angiographically successful elective PCI; the technique used to assess the primary endpoint, CFR: a non-invasive technique using PET scan replacing the invasive coronary angiogram; the statistical considerations including sample size calculation yielding more subjects to be randomised, stratification according to the sub-type of subject population and planned analyses, including those for the Data Monitoring Committee; the characterisation of female subjects pertaining to the potential for pregnancy that could be included in the study was further defined; biomarkers of endothelial dysfunction were deleted except the assessment of two biomarkers levels; the EQ-5D-5L questionnaire on quality of life was deleted as the study treatment duration was too short to allow detection of meaningful changes; change to the study title, inclusion/exclusion criteria, total expected number of subjects, study treatment, endpoints, statistical considerations, assessment of IMP, change to vital signs, and change to Appendix A.

Amendment changes: Clarified inclusion criterion 01C: symptomatic stable angina pectoris (typical or atypical symptoms) with at least once weekly episodes will be required to be an average of at least weekly episodes over the past month; deletion of inclusion criterion 01D (i.e. electrocardiogram[ECG]evidence of ischemia with ST-segment depression during a symptom limited exercise test or non-invasive evidence of ischemia [echo, single photon emission computed tomography, magnetic resonance imaging, PET] within previous 12 months); change to inclusion criterion 01E, whereby the time until previous imaging for evidence of non-obstructive coronary artery disease was changed from 12 to 24months.In subjects with stenting,minimum diameter stenosis of <10% was required.Coronary computed tomography angiography without regional abnormal perfusion defects within 12months in subjects without previous elective PCI). Use of instantaneous wave-free ratio as an alternative to fractional flow reserve was allowed; change to exclusion criterion 03 to allow calcium channel blockers (CCBs) during the study (any use of long-acting nitrates and/or CCBs and/or PDE-5 inhibitors within one week prior to baseline PET scan or anticipated to be used during the study); precisions of exclusion criterion 12 (i.e., regional local flow abnormal perfusion defects at baseline PET scan) were given; deletion of exclusion criterion13 (subjects with any ECG abnormalities preventing the interpretation of ischemia);change to exclusion criterion25 as systolic blood pressure <110 mmHg from <120 mmHg at baseline;addition of exclusion criterion for breast-feeding subjects; expansion of window period up to the Day1 visit for the baseline PET assessment from 3 to 7 days; changes to prohibited medications and authorized concomitant medications;assessment methods and activity parameters; clarified vital signs and ECG methodology; addition of NIMP; changed storage conditions and shelf life; deletion of Appendix A.

Following amendment changes were made: Opened the subject recruitment to subjects with MVA and stable symptoms who did not have recent coronary artery imaging with a special focus on those from large sites having access to existing registries of coronary microvascular dysfunction subjects; altered the study protocol so that it fits better with clinical practice at academic sites and previous guidelines on management of acute coronary syndrome; provided guidance on how to handle subjects who undergo premature study drug discontinuation; cancellation of “elective”; change to the inclusion/exclusion criteria; change to duration of study participation; change to safety endpoints; change to sample blood volume; change to pharmacokinetic endpoint; change to screening visit, assessment methods and activity parameters; change to baseline/randomisation/Day 1 visit, visits 2, 3, 4, and 6, change to definition of source data; and handling of subjects after permanent treatment discontinuation.