A Study of Flurpiridaz (18F) Injection for PET Imaging for Assessment of MPI Quality Using HPLC and SPE Manufacturing Processes

Study Overview
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Brief Summary
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This was a Phase 2 prospective, randomized, crossover study of Flurpiridaz (18F) Injection for PET-MPI in participants referred for evaluation of known coronary artery disease (CAD) or for suspected CAD with intermediate to high pre-test probability (PTP). The objective is to assess the difference and variability between 2 sets of rest images synthesized by the same or 2 different manufacturing processes. Twenty-eight evaluable [participants were enrolled in this study and underwent 2 Flurpiridaz (18F) Injection PET-MPI at rest. Each participant attended a Screening Visit at least 2 days and up to 14 days prior to the first Flurpiridaz (18F) Injection PET-MPI. The participants were randomized 1:1:1:1 to 4 possible sequences of receiving 2 doses of Flurpiridaz (18F) Injection: 2 groups of 7 participants received 2 Flurpiridaz (18F) Injection doses synthesized by the same manufacturing processes (either HPLC or SPE) and 2 groups of 7 subjects will receive 2 Flurpiridaz (18F) Injection doses synthesized by different manufacturing processes (1 dose by HPLC followed by 1 dose by SPE or 1 dose by SPE followed by 1 dose by HPLC). All participants were followed up by telephone for adverse events (AEs) and serious AEs (SAEs) at 24 (+8) hours following each Flurpiridaz (18F) Injection administration.

Official Title
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A Descriptive, Comparative, Randomized, Crossover Study of Flurpiridaz (18F) Injection for Positron Emission Tomography (PET) Imaging for Assessment of Myocardial Perfusion Imaging Quality Using High Performance Liquid Chromatography (HPLC) and Solid Phase Extraction (SPE) Manufacturing Processes

Conditions
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Coronary Artery Disease (CAD), Ischemic Heart Disease

Intervention / Treatment
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* Drug: Flurpiridaz (18F) Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: * The participant was a man or woman ≥18 years of age The participant was undergoing evaluation of known CAD or for suspected CAD with an intermediate to high PTP. The participant had read, signed, and dated an informed consent form (ICF) prior to any study procedures being performed, and was willing to allow the study investigator to make the participant's medical records available to GE Healthcare. The participant was male or was a nonpregnant, nonlactating female who was either surgically sterile (had a documented bilateral tubal ligation and oophorectomy and/or documented hysterectomy [bilateral tubal ligation alone was insufficient]) or was post-menopausal (cessation of menses for more than 1 year); enrollment in the study without a pregnancy test at Screening was allowed for these categories of female participants. For women of childbearing potential, the results of either a urine or serum human chorionic gonadotropin pregnancy test (with the result known on the day of each radiopharmaceutical administration) must be negative. These participants must have been practicing appropriate birth control from the time of the screening to 30 days after the second radiopharmaceutical administration. Such methods included: hormonal contraception including oral contraceptives; intrauterine device; intrauterine hormone releasing system; bilateral tubal occlusion; vasectomized partner; sexual abstinence; adequate barrier method with spermicide (e.g., diaphragm, condom). The participant was able and willing to comply with all study procedures as described in the protocol. Exclusion Criteria: * Participants who were pregnant, may possibly be pregnant, or wish (including their partners) to become pregnant during the study period, or were lactating Participants who were unable to undergo all of the imaging procedures Participant with unstable cardiovascular condition, including but not limited to: Transient ischemic attack/stroke within 3 months of enrollment; Significant congenital heart disease; Uncontrolled hypertension; Uncontrolled tachyarrhythmia led to symptoms or hemodynamic compromise. Participants required cardiac intervention (i.e., percutaneous coronary intervention or coronary artery bypass graft) before completing the study. Primary hemodynamically significant uncorrected valvular heart disease, obstructive or regurgitant. Participants with screening laboratory findings as follows: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) was greater than 3 times the upper limit of normal; Total bilirubin ≥2.0 mg/dL (34.2 μmol/L); Serum creatinine ≥3.0 mg/dL (265.2 μmol/L). Participants who presented with any clinically active, serious, life-threatening disease, medical or psychiatric condition, and/or who have a life expectancy of <6 months, or for whom study participation may compromise their management; and participants whom the investigator judges to be unsuitable for participation in the study for any reason. Participants undergone evaluation for heart transplantation or with a history of heart transplantation. Participants enrolled in another clinical study within the 30 days before enrollment in this study. Participants previously enrolled in this study or any Flurpiridaz (18F) Injection study.

Ages Eligible for Study
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Minimum Age: 18 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: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence: SPE-SPE<br>Participants received 2 intravenous (IV) boluses of Flurpiridaz (18F) Injection manufactured by SPE process at Visit 1 and 2. The targeted dose to the body of Flurpiridaz (18F) Injection was to be in the range of 1.7 to 2.5 millicurie (mCi) (63 to 93 megabecquerel [MBq]) for each administration and not exceed a total of 6 mCi (222 MBq) for an individual participant. | Drug: Flurpiridaz (18F) Injection<br>* All participants received 2 IV boluses of Flurpiridaz (18F) Injection in a large peripheral vein at rest.<br>|
| Experimental: Treatment Sequence: HPLC-HPLC<br>Participants received 2 IV boluses of Flurpiridaz (18F) Injection manufactured by HPLC process at Visit 1 and 2. The targeted dose to the body of Flurpiridaz (18F) Injection was to be in the range of 1.7 to 2.5 mCi (63 to 93 MBq) for each administration and not exceed a total of 6 mCi (222 MBq) for an individual participant. | Drug: Flurpiridaz (18F) Injection<br>* All participants received 2 IV boluses of Flurpiridaz (18F) Injection in a large peripheral vein at rest.<br>|
| Experimental: Treatment Sequence: SPE-HPLC<br>Participants received 2 IV boluses of Flurpiridaz (18F) Injection manufactured by 2 different processes (1 dose manufactured by SPE followed by 1 dose manufactured by HPLC) at Visit 1 and 2. The targeted dose to the body of Flurpiridaz (18F) Injection was to be in the range of 1.7 to 2.5 mCi (63 to 93 MBq) for each administration and not exceed a total of 6 mCi (222 MBq) for an individual participant. | Drug: Flurpiridaz (18F) Injection<br>* All participants received 2 IV boluses of Flurpiridaz (18F) Injection in a large peripheral vein at rest.<br>|
| Experimental: Treatment Sequence: HPLC-SPE<br>Participants received 2 IV boluses of Flurpiridaz (18F) Injection manufactured by 2 different processes (1 dose manufactured by HPLC followed by 1 dose manufactured by SPE) at Visit 1 and 2. The targeted dose to the body of Flurpiridaz (18F) Injection was to be in the range of 1.7 to 2.5 mCi (63 to 93 MBq) for each administration and not exceed a total of 6 mCi (222 MBq) for an individual participant. | Drug: Flurpiridaz (18F) Injection<br>* All participants received 2 IV boluses of Flurpiridaz (18F) Injection in a large peripheral vein at rest.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intra-reader Difference of Summed Rest Score (SRS) for Positron Emission Tomography (PET) Myocardial Perfusion Imaging (MPI) | 3 qualified readers (independent from the study) performed independent reads of all MPI images, inclusive of standard 17-segment polar-maps of perfusion defects. Each reader scored the perfusion pattern in each segment (17 segments) using a 5-point scale score range from 0 to 4: Normal 0, Minimal, mild impairment of perfusion = 1, Moderate impairment of perfusion = 2, Significant impairment of perfusion = 3, No perfusion = 4. Higher score indicated = impairment of perfusion. SRS was calculated by summing individual scores from each of 17 segments to give an overall score between 0 and 68; a score of 0 indicates normal outcome and scores more than 0 indicate increasingly worse outcomes as the score increases. The summed score of the 17 segments SRS was used for analysis. Intra-reader difference of SRS for PET MPI was reported. | Up to 2 weeks | 
| Intra-reader Difference of Summed Rest Percent (SR%) for PET MPI | 3 qualified readers (independent from the study) performed independent reads of all MPI images, inclusive of standard 17-segment polar-maps of perfusion defects. Each reader scored the perfusion pattern in each segment (17 segments) using a 5-point scale score range from 0 to 4: Normal 0, Minimal, mild impairment of perfusion = 1, Moderate impairment of perfusion = 2, Significant impairment of perfusion = 3, No perfusion = 4. Higher score indicated = impairment of perfusion. SRS was calculated by summing individual scores from each of 17 segments to give an overall score between 0 and 68; a score of 0 indicates normal outcome and scores more than 0 indicate increasingly worse outcomes as the score increases. Summed score of the 17 segments SRS was used for analysis. SR% is calculated by dividing the SRS by a number corresponding to the SRS value indicating a deficit of 4 in every segment and then multiplying the result by 100. Intra-reader difference of SR% for PET MPI was reported. | Up to 2 weeks | 
| Intra-reader Correlation of SRS for PET MPI: Pearson's Correlation | 3 qualified readers (independent from the study) performed independent reads of all MPI images, inclusive of standard 17-segment polar-maps of perfusion defects. Each reader scored the perfusion pattern in each segment (17 segments) using a 5-point scale score range from 0 to 4: Normal 0, Minimal, mild impairment of perfusion = 1, Moderate impairment of perfusion = 2, Significant impairment of perfusion = 3, No perfusion = 4. Higher score indicated = impairment of perfusion. SRS was calculated by summing individual scores from each of 17 segments to give an overall score between 0 and 68; a score of 0 indicates normal outcome and scores more than 0 indicate increasingly worse outcomes as the score increases. The summed score of the 17 segments SRS was used for analysis. Intra-reader correlation of SRS for PET MPI assessed using Pearson's correlation was reported. | Up to 2 weeks | 
| Intra-reader Correlation of SRS for PET MPI: Kendall's Tau-b | 3 qualified readers (independent from the study) performed independent reads of all MPI images, inclusive of standard 17-segment polar-maps of perfusion defects. Each reader scored the perfusion pattern in each segment (17 segments) using a 5-point scale score range from 0 to 4: Normal 0, Minimal, mild impairment of perfusion = 1, Moderate impairment of perfusion = 2, Significant impairment of perfusion = 3, No perfusion = 4. Higher score indicated = impairment of perfusion. SRS was calculated by summing individual scores from each of 17 segments to give an overall score between 0 and 68; a score of 0 indicates normal outcome and scores more than 0 indicate increasingly worse outcomes as the score increases. The summed score of the 17 segments SRS was used for analysis. Intra-reader correlation of SRS for PET MPI assessed using Kendall's tau-b was reported. | Up to 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variability of the SRS After MPI Sessions Using 2 Flurpiridaz (18F) Injection Doses by the Same Process | Variability of SRS was estimated by using the SD of the paired difference divided by square root of 2. SRS was used for myocardial perfusion defects examination. The independent reads of all MPI images were based on standard 17-segment polar-maps of perfusion defects. Each reader scored the perfusion pattern in each segment (17 segments) using a 5-point scale score range from 0 to 4: Normal 0, Minimal, mild impairment of perfusion = 1, Moderate impairment of perfusion = 2, Significant impairment of perfusion = 3, No perfusion = 4. Higher score indicated = impairment of perfusion. SRS was calculated by summing individual scores from each of 17 segments to give an overall score between 0 and 68; a score of 0 indicates normal outcome and scores more than 0 indicate increasingly worse outcomes as the score increases. Variability of the SRS after MPI sessions using 2 Flurpiridaz (18F) injection doses by the same process was reported. | Up to 2 weeks | 
| Percentage of Participants With Intra-Reader Agreement of the Detection of Ischemic Defect on PET-MPI at Rest Between 2 MPI Acquisitions Using 2 Flurpiridaz (18F) Injection Doses | Percentage of participants with intra-reader agreement of the detected ischemic defect on PET-MPI was reported. | Up to 2 weeks | 
| Difference Between the Perfusion Rest Scores for Each of the 17 Segments and Each Reader for 2 Flurpiridaz (18F) Injection Doses From Same and Different Manufacturing Process | Perfusion rest score was used for myocardial perfusion defects examination. The independent reads of all MPI images were based on standard 17-segment polar-maps of perfusion defects. Each reader scored the perfusion pattern in each segment (17 segments) using a 5-point scale score range from 0 to 4: Normal: 0; Minimal, mild impairment of perfusion, ambiguous image: 1; Moderate impairment of perfusion: 2; Significant impairment of perfusion: 3, No perfusion: 4. Higher score indicates impairment. Mean of the paired difference between the perfusion rest scores from 2 manufacturing processes for each of the 17 segments and each reader for 2 Flurpiridaz (18F) injection doses from same and different manufacturing process was reported. | Up to 2 weeks | 
| Difference in Standard Uptake Value (SUV) of Time-activity Curves (TACs) by Region After MPI Sessions Using 2 Flurpiridaz (18F) Injection Doses Synthesized by Same and 2 Different Manufacturing Processes | Difference was calculated by (Mean SUV from the second injection - Mean SUV from the first injection). SUV was calculated as Decay Corrected Uptake (kBq/cc) / (Injected Dose [MBq] / Weight (kilogram [kg]). Difference in SUV of TACs by region after MPI sessions using 2 Flurpiridaz (18F) injection doses synthesized by same and 2 different manufacturing processes was reported. | Up to 2 weeks | 
| Relative Difference in SUV (5- to 15-minute Perfusion Image) of TACs by Region After MPI Sessions Using 2 Flurpiridaz (18F) Injection Doses Synthesized by Same and 2 Different Manufacturing Processes | Relative difference was calculated as 100 (SUV1-SUV2) / (0.5*[SUV1 + SUV2]) and SUV was calculated as Decay Corrected Uptake (kBq/cc) / (Injected Dose [MBq] / Weight [kg]). Relative difference in SUV of TACs by region after MPI sessions using 2 Flurpiridaz (18F) injection doses synthesized by same and 2 different manufacturing processes was reported. | Up to 2 weeks | 
| Number of Participants Categorized Based on Intra-Reader Agreement of the Image Quality Score Between the 2 Sets of PET Images for 2 Flurpiridaz (18F) Injection Doses From Different Manufacturing Processes | Image quality scoring was performed as following: SPE image was worse than HPLC image when the difference (SPE - HPLC) score was less than or equal (<=)-3. SPE image was slightly worse than HPTC image when the difference score was <=-1 and greater than (>)-3. SPE and HPLC images were the same when the difference score was >-1 and less than (<) 1. SPE image was slightly better when the difference score >=1 and <3. SPE image was better when the difference was >=3. Higher score indicates better outcomes. Number of participants categorized based on intra-reader agreement of the image quality score between the 2 Sets of PET images for 2 Flurpiridaz (18F) injection doses from different manufacturing processes was reported. | Up to 2 weeks | 
| Number of Participants Categorized Based on Intra-Reader Agreement of the Image Quality Score Between the 2 Sets of PET Images for 2 Flurpiridaz (18F) Injection Doses From Same Manufacturing Processes | Image quality scoring was performed as following: 2 images were the same when the absolute difference score was >=0 and <1. 2 images were slightly different when the absolute difference score >=1 and <3. 2 images were different when the absolute difference score >=3. Higher score indicates better outcomes. Number of participants categorized based on intra-reader agreement of the image quality score between the 2 sets of PET Images for 2 Flurpiridaz (18F) injection doses from same manufacturing processes was reported. | Up to 2 weeks | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | A TEAE was defined as an adverse events (AE) that occurred from the time of investigational medicinal product (IMP) administration through the end of the follow-up period for the corresponding dose. Any medication error, clinically significant vital signs, electrocardiograms (ECGs), hematology, clinical chemistry laboratory tests, and urinalysis values determined by investigator were reported as TEAEs. Number of participants with TEAEs and serious TEAEs were reported. | From screening up to end of follow up (up to 30 days) |