A Randomised, Double-Blind and Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SIR9900 after Oral Administrations in Healthy Elderly Volunteers. (Multiple Ascending Dose (MAD), Part 2 Cohort 5).

Exclusion Criteria22

• Clinically significant haematological findings at screening.
• Abnormal findings indicating hepatic impairment, such as aspartate transaminase (AST), alanine transaminase (ALT), or alkaline phosphatase greater than or equal to 1.5 times upper limit of normal (ULN), total bilirubin > ULN, albumin less than or equal to 3 g/dL, serum amylase or lipase greater than or equal to 1.5 times ULN at screening.
• Abnormal findings indicating renal impairment, such as creatinine greater than or equal to 1.5 times ULN, estimated glomerular filtration rate of 80 mL/minute or less calculated by the Cockcroft-Gault formula, at screening.
• Clinically significant ECG findings including QTcF value > 450 ms for male or > 470 ms for female at screening/pre-dose day 1.
• Participants with a mean systolic blood pressure (SBP) of three measurements >140 mmHg, or a mean diastolic blood pressure (DBP) of three measurements > 90 mmHg at screening. Blood pressure will be measured at sitting position at screening.
• Positive blood screen for human immunodeficiency virus (HIV), or hepatitis B surface antigen (HbsAg), or hepatitis C virus (HCV), or syphilis at screening or at any time during the screening period pre-dose.
• A history of seizure. However, a history of febrile seizure is allowed.
• Positive results of pregnancy test at screening or admission. Pregnant or breast feeding, or planning to become pregnant, breast feed or donate ova during the study and within 30 days after the study.
• A hospital admission or major surgery within 60 days prior to screening and/or planned surgery for the duration of the study and follow up period.
• Receipt of any other investigational drug product within 30 days or 5 half-lives of the other investigational drug (whichever is longer) prior to dosing.
• Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-V) substance use disorders and alcohol abuse within 12 months prior to screening and/or positive alcohol breath test at screening or admission.
• A positive result for drugs of abuse at screening or admission. One repeat test will be allowed if false positive is considered by the PI or designee.
• An unwillingness or inability to comply with food and beverage restrictions during study participation, including consumption of grapefruit (or pomelo or start fruit) or grapefruit juice, Seville oranges, Seville orange marmalade or other products containing grapefruit, pomelo, star fruit or Seville oranges within 7 days before dosing and until final discharge from the CRU.
• Donation or blood collection of more than 1 unit (approximately 450 mL) of blood (or blood products) or acute loss of blood during the 30 days prior to screening and/or planning to donate blood during the study and follow up period.
• Continued stable use within three months prior to screening of prescription and non-prescription medications, vitamins, and supplements that are not potential index substrates for CYP450 isoform 1A2, or inhibitor/inducers of isoforms 3A4 or 2C8 enzymes, and are used to manage and stabilise existing conditions or diseases are permitted at the discretion of the Investigator. The following is not permitted prior to dosing: use of prescription medicines or other products that are potential index substrates for CYP450 isoform 1A2, or inhibitor/inducers of isoforms 3A4 or 2C8 enzymes within 14 days, or within 5 half-lives (whichever is longer).
• A history of suicide attempt in the past 12 months and/or judged by the Investigator as having a significant history of risk of suicide or homicide.
• Participant has a known or suspected hypersensitivity to SIR9900 and any components of the SIR9900 (or placebo) tablets.
• Participant who has lactose intolerance history.
• Participant has any other condition which makes the participant unsuitable for study participation in the opinion of the Investigator.
• Identified as a site employee of the Investigator or study centre, with direct involvement in the proposed study or other studies under the direction of the Investigator or study centre, and/or is an immediate family member (i.e., spouse, de facto, child) of site employees or Investigator.
• If aged greater than or equal to 65 years, has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy that is not well managed and stable, as judged by the Investigator or designee.
• (Replacement for general exclusion criterion #3) If aged greater than or equal to 65 years, has an Estimated Glomerular Filtration Rate (calculated based on Cockcroft-Gault formula) < 60 mL/min.