A First in Human, Randomized, Double-Blind, Placebo-Controlled, Ascending Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of TT20 Administered Intravenously as Single Dose Infusions and Continuous Infusions in Healthy Adult Volunteers

Exclusion Criteria41

• Known hypersensitivity or anaphylactic reaction to food (including egg, soybean, or peanut) or other allergies, or confirmed drug hypersensitivity reaction, including to any of the active ingredients or excipients of the investigational medicinal product (IMP).
• History of any significant chronic disease (in the opinion of the PI or delegate) including renal (glomerular filtration rate greater than 60 mL per min per 1.73m2 as estimated using the CKD-EPI equation), liver (including but not limited to, Metabolic Dysfunction-Associated Steatotic Liver Disease or Metabolic Dysfunction-Associated Steatohepatitis), endocrine (including but not limited to diabetes mellitus, Type 1 and 2), inflammatory, cardiovascular, gastrointestinal (including but not limited to Crohn’s disease, ulcerative colitis, celiac disease, pancreatic dysfunction, irritable bowel syndrome), neurological (including migraines), psychiatric, neoplastic, or other metabolic disease (including but not limited to familial or acquired lipid metabolism disorders).
• Note: Participants with resolved childhood asthma, Gilbert’s disease, or cholecystectomy may be considered for enrollment at the discretion of the PI.
• History of any acute systemic infection or significant localized infection that has not resolved fully by 1 week prior to admission (Day -1).
• History of malignancy (with the exception of adequately treated malignancies with an expected 5-year survival rate of greater than 90 percent at the time of diagnosis, e.g., squamous or basal cell carcinoma of the skin, carcinoma in-situ of the breast or cervix).
• History of loss of consciousness of unknown etiology, convulsions (with the exception of isolated childhood febrile convulsions), or traumatic head injury. Simple concussions occurring more than one year prior to screening are not exclusionary.
• Has any pre-infusion (i.e., screening, Day -1, or pre-infusion on Day 1) clinically significant ECG abnormalities in the opinion of the PI or delegate. This includes males with QTcF (Fridericia’s correction) greater than 450 msec or females with QTcF greater than 470 msec at any pre-infusion timepoint (i.e., screening, Day -1, or pre-infusion on Day 1).
• Known diagnosis of prolonged QT interval, history of arrhythmias (with the exception of sinus bradycardia or first-degree atrioventricular block considered to be not clinically significant by the PI or delegate) or previous episode of syncope thought to be of cardiac origin, or a first-degree family history of congenital long QT syndrome or unexplained death.
• Abnormal vital signs at any pre-infusion timepoint (i.e., screening, Day -1, or pre-infusion on Day 1) as follows:
• Systolic blood pressure (SBP) less than 90 or greater than 140 mmHg
• Diastolic blood pressure (DBP) greater than 90 mmHg
• Pulse rate (PR) less than 40 or greater than 100 bpm
• Body temperature (tympanic) equal to or greater than 37.7 degree Celcius.
• Vital signs assessment may be repeated once in evaluating this criterion if the PI or delegate believes that the values from the initial assessment were erroneous.
• If female, positive results on a pregnancy test at screening or Day -1, or breastfeeding or planning to breastfeed during the study.
• Recent (within the last 3 years) and or recurrent history of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.), and or symptomatic postural hypotension at screening (irrespective of the decrease in BP) or asymptomatic postural hypotension at screening (defined as a decrease in SBP equal to or greater than 20 mmHg 2 minutes after changing from a supine to standing position).
• Significant psychiatric history (including but not limited to, suicidal attempt within the previous 5 years, psychosis associated with a psychiatric diagnosis, or bipolar disorder). Participants with adequately treated depression or anxiety who have been stable off-treatment for at least 12 months prior to screening may be considered for enrollment at the discretion of the PI.
• Positive Hepatitis B surface antigen (HBsAg), Hepatitis B virus core antibody (HBcAb), Hepatitis C virus antibodies (HCVAb), or human immunodeficiency virus antibody (HIV Ab) at screening.
• Use of any prescription medications (with the exception of hormone replacement therapy (post-menopausal females only) or hormonal contraceptives (WOCBP only) within 14 days or 5 half-lives (whichever is longer) of dosing or use of over-the-counter medications (with the exception of paracetamol or acetaminophen, up to 2 g per day) or herbal supplements within 7 days or 5 half-lives (whichever is longer) of dosing, or an anticipated requirement for use of these during the course of the study. Use of antihistamines within 7 days of dosing is excluded. Nutritional supplements may be permitted but must be discussed with the Sponsor’s MM prior to subject enrollment.
• Use of chronic (more than 14 consecutive days) immunosuppressant or immunomodulatory drugs within the 6 months prior to IMP administration, or isolated (non-chronic) use within 30 days prior to IMP administration.
• Intake of any nutrients known to modulate cytochrome (CYP) enzyme activity (e.g., grapefruit or Seville orange containing products or quinine containing drinks [tonic water or bitter lemon) within 5 days before dosing and participant is unwilling to abstain from consumption of these products until the final PK sample is collected.
• History of receiving any vaccine within 14 days prior to randomization.
• Donation (or loss) of whole blood of 470 mL or more during 56 days prior to IMP administration and or plan to donate whole blood during the study or within 4 weeks after the last study-related blood draw.
• Donation of plasma or platelets during 14 days prior to IMP administration and or plan to donate plasma or platelets during the study or within 4 weeks after the last study-related blood draw.
• History of abuse of addictive substances (alcohol, illegal substances) in the 3 years prior to screening, or current use of more than 21 units (men) or 14 units (women) of alcohol per week, drug abuse, or use of illegal substances. Participant must not exhibit abusive behavior of sedatives, hypnotics, tranquilizers, or any other addictive agent including marijuana.
• Positive alcohol breath test, urine drug screen (for the following analytes: cocaine, phencyclidine, amphetamines, opiates or morphine, benzodiazepines, barbiturates, methadone, THC, methamphetamine, tricyclic antidepressants) at screening or Day -1.
• Participation in any other clinical interventional study (including screening, dosing, and follow-up) within 30 days or 5 half-lives prior to screening, whichever is longer. If clinical intervention was greater than 6 months prior to screening and the participant is in follow-up only, eligibility may be assessed on a case-by-case basis in consultation with the Sponsor’s MM.
• Previous participation in a study with an investigational drug or device involving a biological targeted therapy, where final administration of the investigational drug or utilization of the device occurred within 24 weeks prior to first dosing.
• Smoking more than 5 cigarettes per week (or equivalent, including other nicotine-based products) within 4 weeks prior to IMP administration and or unwillingness to abstain from the use of these during the study (including admission and follow-up).
• Habitual excessive xanthine consumption (equivalent to greater than 400 mg caffeine per day), and or inability or unwillingness to abstain from caffeine-containing foods and beverages from 7 days prior to dosing until the end of the admission period.
• Unwillingness to refrain from strenuous physical activity (e.g., heavy lifting, weight or fitness training) from 72 hours prior to admission until the EOS follow-up visit.
• Clinically significant laboratory abnormalities at screening or Day -1, as judged by the PI or delegate; minor deviations from the normal range may be accepted if judged by the PI or delegate and the Sponsor’s MM to have no clinical relevance, but the following absolute limits apply in addition to clinical judgement:
• a. Liver transaminases and or alkaline phosphatase must be equal to or less than 1.2 times Upper Limit of Normal (ULN) (elevated values may be repeated once on a separate day)
• b. Triglyceride levels must be equal to or less than 2.1 mmol per L (elevated values may be repeated once on a separate day)
• c. Total cholesterol levels must be equal to or less than 1.25 times ULN (elevated values may be repeated once on a separate day)
• d. Amylase and or lipase must be equal to or less than ULN (elevated values may be repeated once on a separate day)
• e. Platelet counts must be equal to or greater than Lower Limit of Normal (LLN) (values more than 0.9 times LLN may be repeated once on a separate day)
• f. International normalized ratio (INR) must be equal to or greater than 0.8 and equal to or less than 1.1, and activated partial thromboplastin time (aPTT) must be within normal limits (INR equal to or less than 1.2 and equal to or greater than 0.8, and an aPTT equal to or less than 1.1 times ULN or equal to or greater than 0.9 times LLN may be repeated once on a separate day).
• Major surgery within 4 weeks of screening that could interfere with, or for which the treatment might interfere with, the conduct of the study, or that would pose an unacceptable risk to the participant in the opinion of the PI (or qualified delegate).
• Participant is known to experience significant bruising or bleeding associated with blood draws.
• Any other condition which in the PI or delegate’s opinion may adversely affect the participant’s ability to complete the study, or which may pose significant risk to the participant.