4 Oliceridine respiratory effects Materials and Methods Ethics and Registration The study was performed at a single site after approval of the protocol by the medical ethics committee of the Leiden University Medical Center, METC Leiden-Den Haag-Delft (under identifier P21.025) and the Central Committee on Research Involving Human Subjects (competent authority) in The Hague, The Netherlands (identifier NL75790.058.21). The study was performed from June 29, 2021, to January 4, 2022 in the Anesthesia & Pain Research Unit of the Department of Anesthesiology at Leiden University Medical Center. The study was registered in the trial register of the Dutch trial registry, currently available at the World Health Organization International Clinical Trials Registry Platform, under identifier NL9524 on June 2, 2021. The principal investigator of the study was Albert Dahan M.D. Ph.D. The study was conducted in accordance with current Good Clinical Practice Guidelines and adhered to the principles of the Declaration of Helsinki. Before enrollment, all subjects gave oral and written informed consent. Thereafter, their medical history was obtained and a physical examination was performed. The whole project was monitored by an independent data input monitor and a data safety monitoring committee. Participants Healthy volunteers of either sex were recruited to participate in the study. Inclusion criteria were age 55 yr or older; body mass index in the range 19 to 35 kg/m2 (inclusive); absence of any significant medical, neurologic, or psychiatric illness as determined by the investigators; and willing and able to sign a written informed consent. The inclusion process was aimed to include an equal number of men and women, include half of the participants with an age of 65 yr or older, and a third of subjects with a body mass index range of 30 to 35 kg/m2, to represent an average elective surgical population. The main exclusion criteria were intolerance, hypersensitivity, or recent (less than 1 month) exposure to opioids; a positive drug test or breath alcohol test on screening or subsequent study visits; inability to perform the study procedures as tested during screening; cognitive impairment as determined by the short version of the Mini Mental Status Examination (score less than 24); any clinically significant laboratory abnormality; abnormalities on the electrocardiogram including a corrected QT interval greater than 450 ms; alcohol intake of more than 4 units per day; participation in a drug trial in the 30 days before screening; or any other condition that in the opinion of the investigator would complicate or compromise the study or the well-being of the subject. 67
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