A Study Evaluating the Safety, Tolerability, and Effect on Microvascular Obstruction of Intravenous Temanogrel in Adult Participants Undergoing Percutaneous Coronary Intervention

Study Overview
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Brief Summary
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The purpose of this study is to determine whether intravenous temanogrel is a safe and effective treatment for microvascular obstruction (MVO) in adult participants undergoing percutaneous coronary intervention (PCI).

Detailed Description
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This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study to be conducted in 2 stages (Stage A and Stage B). Stage A is an ascending single-dose placebo-controlled study planned to consist of 2 cohorts. Stage B is a parallel-treatment group study planned to consist of a placebo group and 2 active treatment groups of temanogrel doses selected based on safety and tolerability data in Stage A.

Official Title
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A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, and Effect on Microvascular Obstruction of Temanogrel in Subjects Undergoing Percutaneous Coronary Intervention

Conditions
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Microvascular Obstruction

Intervention / Treatment
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* Drug: Temanogrel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stable angina participants suitable for elective PCI, or participants suitable for PCI for diagnosis of non-ST-elevation myocardial infarction or unstable angina (NSTEMI/UA) who are consistently hemodynamically stable until the time of PCI and have a thrombolysis in myocardial infarction (TIMI) Flow Grade 2 or 3 on the diagnostic angiography Target lesions for PCI must appear suitable for stenting as confirmed on the diagnostic angiography and must satisfy the study criteria regarding lesion size and vessel diameter/type. Females must not be of childbearing potential Males with pregnant or non-pregnant female partners of childbearing potential must agree to using a condom during treatment and for 90 days following treatment Exclusion Criteria: Planned or anticipated use of rotational atherectomy/ablation or shockwave therapies during the PCI procedure Any history of stroke, seizure, intracranial bleeding, or intracranial aneurysm Transient ischemic attack within the 6 months prior to Screening History of major trauma, major surgery, and/or clinically significant head injury or hemorrhage within the last 6 months of Screening Any ST-elevation myocardial infarction (STEMI) within 10 days of Screening or STEMI within the target vessel territory within the last 4 months of Screening

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage A (Dose Cohort 1) and Stage B (Dose Group 1)<br> | Drug: Temanogrel<br>* Participants will receive a single intravenous dose of temanogrel on Day 1 (Day 1 of PCI procedure)<br>|
| Experimental: Stage A (Dose Cohort 2) and Stage B (Dose Group 2)<br> | Drug: Temanogrel<br>* Participants will receive a single intravenous dose of temanogrel on Day 1 (Day 1 of PCI procedure)<br>|
| Placebo Comparator: Stage A (Dose Cohort 1 and Dose Cohort 2) and Stage B (Dose Group 1 and Dose Group 2)<br> | Drug: Placebo<br>* Participants will receive a single intravenous dose of temanogrel matching placebo on Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Index of Microcirculatory Resistance (IMR) From Baseline to Post Percutaneous Coronary Intervention (PCI) | IMR was defined as the mean distal pressure at maximum hyperemia multiplied by the mean hyperemic transit time. IMRcorr (IMR corrected for the influence from collateral supply) was calculated using the following equation, to account for the presence of significant epicardial stenosis without the need for balloon dilation to measure the coronary wedge pressure (Pw), IMRcorr = mean aortic pressure at maximum hyperemia (Pa)*mean transit time at maximal hyperemia (Tmn) * [1.34 * mean distal coronary pressure at maximum hyperemia (Pd)/Pa minus 0.32]. | From Baseline (prior to administration of study treatment) to 15 minutes post-PCI on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Post-PCI for Coronary Flow Reserve (CFR) | The coronary flow reserve (CFR) was calculated from the ratio of baseline (i.e., resting transit time) to hyperemic mean transit time. | From Baseline (prior to administration of study treatment) to 15 minutes post-PCI on Day 1 | 
| Change From Baseline to Post-PCI for Fractional Flow Reserve (FFR) | The FFR was calculated from the ratio of distal to proximal mean pressures at maximal hyperemia (FFR = [distal coronary pressure/aortic pressure at maximum hyperemia]). | From Baseline (prior to administration of study treatment) to 15 minutes post-PCI on Day 1 | 
| Change From Baseline to Post-PCI for Corrected Thrombolysis in Myocardial Infarction Frame Count (cTFC) | The cTFC is a quantitative index of coronary flow and was calculated based upon the number of cine-frames that the intracoronary dye required to reach distal coronary landmarks. | From Baseline (prior to administration of study treatment) to 15 minutes post-PCI on Day 1 | 
| Number of Participants According to Change From Baseline to Post-PCI for Thrombolysis in Myocardial Infarction (TIMI) Flow Grade (TFG) Post-PCI | The TFG is a measure of epicardial perfusion and was graded on a standard scale from 0 to 3, where Grade 0=no perfusion, grade 1=penetration without perfusion, grade 2=partial perfusion and grade 3= complete perfusion. | Baseline (prior to administration of study treatment) and anytime between 0 to 15 minutes post-PCI on Day 1 | 
| Number of Participants According to Change From Baseline to Post-PCI in Thrombolysis in Myocardial Infarction Myocardial Perfusion Grade (TMPG) Post-PCI | The TMPG (also known as myocardial blush grade [MBG]), is a measure of myocardial perfusion in the capillary bed at the tissues level following contrast injection into the coronary artery. TMPG was graded on a scale from 0 to 3, where grade 0 = failure of dye to enter the microvasculature; grade 1 = dye slowly enters but fails to exit the microvasculature; grade 2 = delayed entry and exit of dye from the microvasculature; grade 3= normal entry and exit of dye from the microvasculature. | Baseline (prior to administration of study treatment) and anytime between 0 to 15 minutes post-PCI on Day 1 | 
| Change From Baseline to Post-PCI for Creatine Kinase (CK) |  | Baseline (prior to administration of study treatment), anytime between 0 to 15 minutes, 6 hours post-PCI, and 24 hours post-PCI/discharge | 
| Change From Baseline to Post-PCI for Creatine Kinase-Myocardial Band (CK-MB) |  | Baseline (prior to administration of study treatment), anytime between 0 to 15 minutes, 6 hours post-PCI and 24 hours post-PCI/discharge | 
| Change From Baseline to Post-PCI for Cardiac Troponin I |  | Baseline (prior to administration of study treatment), anytime between 0 to 15 minutes, 6 hours post-PCI and 24 hours post-PCI/discharge | 
| Number of Participants With Procedural Myocardial Injury | Procedural myocardial injury was defined as elevation of cardiac troponin (cTn) values greater than (>) 99th percentile upper reference limit (URL) in participants with normal baseline values (<= 99th percentile URL) or elevation of cTn by > 20% of the baseline value in participants with elevated cTn levels (>99th percentile URL). | At 6 hours and 24 hours post-PCI/discharge on Day 1 | 
| Concentration of Temanogrel | Observed plasma concentration of temanogrel. Lower limit of quantification (LLOQ) of temanogrel was 0.500 nanograms/milliliter (ng/mL). | Pre-PCI, anytime between 0 to 15 minutes,1 hour, 3 hours, 6 hours post-PCI and 24 hours post PCI/discharge | 
| Concentration of AR295980 | Observed plasma concentration of AR295980. | Pre-PCI, anytime between 0 to 15 minutes,1 hour, 3 hours, 6 hours post-PCI and 24 hours post PCI/discharge | 
| Concentration of AR295981 | Observed plasma concentration of AR295981. | Pre-PCI, anytime between 0 to 15 minutes,1 hour, 3 hours, 6 hours post-PCI and 24 hours post PCI/discharge | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity | An adverse event (AE) was any untoward medical occurrence that did not necessarily have a causal relationship with study treatment. TEAE was an AE that occurred after initiation of study treatment that was not present at the time of treatment start or an AE that increased in severity after the initiation of medication, if the event was present at the time of treatment start emerges. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 as grade 1: mild; grade 2: moderate; grade 3: severe, grade 4: life threatening, grade 5: death related to AE. Number of participants with any TEAE and grade 3 or higher TEAE have been reported. | From start of study treatment on day 1 to up to maximum of 10 days | 
| Number of Participants With Serious Adverse Events (SAEs), Adverse Events Leading to Discontinuation of Study Treatment and Treatment-Related TEAEs | An AE was any untoward medical occurrence that did not necessarily have a causal relationship with study treatment. TEAE was an AE that occurred after initiation of study treatment that was not present at the time of treatment start or an AE that increased in severity after the initiation of medication, if the event was present at the time of treatment start emerges. SAE was an AE resulting in any of the following outcomes or considered medically significant: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or birth defect. Relatedness was based on investigator's assessment. | From start of study treatment on day 1 to up to maximum of 10 days | 
| Number of Participants With Treatment-Related TEAEs According to the Preferred Term | An adverse event was any untoward medical occurrence that did not necessarily have a causal relationship with study treatment. TEAE was an AE that occurred after initiation of study treatment that was not present at the time of treatment start or an AE that increased in severity after the initiation of medication, if the event was present at the time of treatment start emerges. Relatedness was based on investigator's assessment. | From start of study treatment on day 1 to up to maximum of 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Temanogrel, Microvascular obstruction, APD791, Percutaneous coronary intervention, MVO, PCI