Safety and tolerability of increasing doses of ZY-19489 compared to placebo in healthy volunteers.

Exclusion Criteria49

• Haematology, clinical chemistry or urinalysis results at screening or on admission prior to IMP administration that are outside of Sponsor-approved clinically acceptable laboratory ranges and are considered clinically significant by the Investigator.
• Participation in any investigational product study within the 12 weeks preceding IMP administration.
• Symptomatic postural hypotension at screening irrespective of the decrease in blood pressure, or asymptomatic postural hypotension defined as a decrease in systolic blood pressure greater than or equal to 20 mmHg within 2-3 minutes when changing from supine to standing position.
• History or presence of diagnosed (by an allergist/immunologist) or treated (by a physician) food or known drug allergies, or history of anaphylaxis or other severe allergic reactions. Subjects with seasonal allergies/hay fever or allergy to animals
• or house dust mite that are untreated and asymptomatic at the time of dosing can be enrolled in the study.
• History of convulsion (including intravenous drug or vaccine-induced episodes).A medical history of a single febrile convulsion during childhood is not an exclusion criterion.
• Presence of current or suspected serious chronic diseases such as cardiac or autoimmune disease (HIV or other immuno-deficiencies), insulin-dependent and non-insulin dependent diabetes, progressive neurological disease, severe malnutrition, acute or progressive hepatic disease, acute or progressive renal disease, porphyria, psoriasis, rheumatoid arthritis, asthma (excluding childhood asthma, or mild asthma with preventative asthma medication required less than monthly), epilepsy, or obsessive-compulsive disorder.
• History of malignancy of any organ system (other than localised basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within 5 years of screening, regardless of whether there is evidence of local recurrence or metastases.
• Subjects with history of schizophrenia, bi-polar disease, psychoses, disorders requiring lithium, attempted or planned suicide, or any other severe (disabling) chronic psychiatric diagnosis.
• Subjects who have received psychiatric medications within 1 year prior to enrolment, or who have been hospitalised within 5 years prior to enrolment for either a psychiatric illness or due to danger to self or others.
• History of more than one previous episode of major depression, any previous single episode of major depression lasting for or requiring treatment for more than 6 months, or any episode of major depression during the 5 years preceding screening.
• The Beck Depression Inventory will be used as an objective tool for the assessment of depression at screening. In addition to the conditions listed above, subjects with a score of 20 or more on the Beck Depression Inventory and/or a response of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation) will not be eligible for participation. These subjects will be referred to a general practitioner or medical specialist as appropriate.
• Subjects with a Beck score of 17 to 19 may be enrolled at the discretion of the Investigator if they do not have a history of the psychiatric conditions mentioned in this criterion and their mental state is not considered to pose additional risk to the health of the subject or to the execution of the study and interpretation of the data gathered.
• History of recurrent headache (e.g. tension-type, cluster or migraine) with a frequency of greater than or equal to 2 episodes per month on average and/or severe enough to require medical therapy, during the 5 years preceding screening.
• Presence of clinically significant infectious disease or fever (e.g. sublingual temperature greater than or equal to 38.5°C) within the 5 days prior to IMP administration.
• Evidence of acute illness within the 4 weeks prior to screening that the Investigator deems may compromise subject safety.
• Significant inter-current disease of any type, in particular liver, renal, cardiac, pulmonary, neurologic, rheumatologic, or autoimmune disease by history, physical examination, and/or laboratory studies including urinalysis.
• Subject has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion (e.g. gastrectomy, diarrhoea).
• Blood donation of any volume within 1 month before IMP administration, or participation in any research study involving blood sampling (more than 450 mL/unit of blood), or blood donation to Australian Red Cross Blood Service (Blood Service) or other blood bank during the 8 weeks prior to IMP administration.
• Medical requirement for intravenous immunoglobulin or blood transfusions.
• History or presence of alcohol abuse (alcohol consumption more than 40 g/4 units/4 standard drinks per day), or drug habituation, or any prior intravenous usage of an illicit substance.
• Tobacco use of more than 5 cigarettes or equivalent per day, and unable to stop smoking for the duration of the clinical unit confinement.
• Female subject who is breastfeeding
• Any vaccination within the last 28 days.
• Any corticosteroids, anti-inflammatory drugs (excluding ibuprofen, acetylsalicylic acid, diclofenac), immunomodulators or anticoagulants within the past 3 months. Any subject currently receiving or having previously received immunosuppressive therapy (including systemic steroids, adrenocorticotrophic hormone or inhaled steroids) at a dose or duration potentially associated with hypothalamic-pituitary-adrenal axis suppression within the past year.
• Ingestion of any poppy seeds within the 24 hours prior to screening (subjects will be advised by phone not to consume any poppy seeds in this time period).
• Excessive consumption of beverages or food containing xanthine bases including Red Bull, chocolate, coffee etc. (more than 400 mg caffeine per day, equivalent to more than 4 cups of coffee per day).
• Unwillingness to abstain from consumption of grapefruit or Seville oranges from 5 days prior to IMP dose until the EOS.
• Use of prescription drugs (excluding oral contraceptives) or non-prescription drugs or herbal supplements (such as St John’s Wort), within 14 days or 5 half-lives (whichever is longer) prior to IMP dosing.
• Limited use of other non-prescription medications or dietary supplements, not believed to affect subject safety or the overall results of the study, may be permitted on a case-by case basis following approval by the Sponsor in consultation with the Investigator.
• Subjects are requested to refrain from taking non-approved concomitant medications from recruitment until the conclusion of the study.
• Any subject who, in the judgment of the Investigator, is likely to be non-compliant during the study, or is unable to cooperate because of a language problem or poor mental
• development.
• Any subject in the exclusion period of a previous study according to applicable regulations.
• Any subject who is the Principal Investigator or any sub-Investigator, research assistant, pharmacist, study coordinator, or other staff thereof, directly involved in conducting the study.
• Any subject without a good peripheral venous access.
• Positive result on any of the following tests: hepatitis B surface antigen (HBs Ag), antihepatitis
• B core antibodies (anti-HBc Ab), anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab).
• Positive urine drug test. Any drug in the urine drug screen unless there is an explanation acceptable to the Investigator (e.g., the subject has stated in advance that they consumed a prescription or over-the-counter product which contained the detected drug) and/or the subject has a negative urine drug screen on retest by the pathology laboratory. Any subject testing positive for acetaminophen (paracetamol) at screening and/or inoculation day may still be eligible for study participation, at the
• Investigator’s discretion.
• Positive alcohol breath test.
• Cardiac/QT risk:
• Family history of sudden death or of congenital prolongation of the QTc interval or known congenital prolongation of the QTc interval or any clinical condition known to prolong the QTc interval.
• History of symptomatic cardiac arrhythmias or with clinically relevant
• bradycardia.
• Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia, or
• hypomagnesaemia.
• ECG abnormalities in the standard 12-lead ECG (at screening, prior to IMP
• dosing,) which in the opinion of the Investigator is clinically relevant or will interfere with the ECG analyses.