Clinical ECG Study to Evaluate Electrophysiological Effects of Potential QT Prolonging Drugs With Novel ECG Biomarkers With Exposure-Response Analysis
Since 2005, FDA has required almost all new drugs be tested for their ability to prolong the QT interval through clinical studies. This requirement stems from the increased TdP risk QT interval prolongation can cause. However, the QT interval is an imperfect biomarker, as there are multiple drugs that can prolong the QT interval, without causing increased TdP occurrence. As such, numerous drugs labeled as causing QT prolongation, may in fact have no impact on TdP occurrence. To address this problem, FDA, in collaboration with multiple external partners, has led an initiative to combine novel preclinical in vitro experiments within silico modeling and simulation followed by pharmacodynamic electrocardiographic (ECG) biomarkers. The goal is to use these novel computational and analytical tools to better predict TdP risk (beyond just the QT interval) by focusing on understanding the underlying mechanisms and applying an integrated biological systems approach. This clinical study consists of 2 parts: a 3-arm, 22-subject crossover study (Part 1) and a 4-arm, 22-subject crossover study (Part 2). These parts are included in the same protocol and study due to the similarity of the inclusion and exclusion criteria, similar procedures, and similar primary goals.
• Subject has signed an IRB approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization) before any study related procedures are performed.
• Subject is a healthy non-smoker who weighs at least 50 kg (110 lbs) and has a body mass index of 18.5 to 33.0 kg/m2, inclusive, at Screening.
• Subject has normal medical history findings, clinical laboratory results, vital sign measurements, pulse oximetry, 12-lead ECG results, and physical examination findings at screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee).
• Subject must have a negative test result for alcohol and drugs of abuse at screening and check-in days.
• Subject must test negative for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) by a rapid antigen test at check-in for all study periods.
• Female subjects must be of non-childbearing potential (confirmed with follicle-stimulating hormone levels \> 40 mIU/mL) or, if they are of childbearing potential, they must: 1) have negative serum HCG at screening and check-in 2) have been strictly abstinent for 1 month before check-in (Day -1) and agree to remain strictly abstinent for the duration of the study and for at least 1month after the last application of study drug; OR 3) be practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from at least 1 month before check-in (Day -1) until at least 1 month after the end of the study.
• Male subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee) from at least 1 month before check-in (Day -1) until at least 3 months after the last dose of study drug.
• Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.