A single dose phase 1 study to evaluate safety and Pharmacokinetics of three tocilizumab products in normal healthy volunteers

Exclusion Criteria27

• Positive test result for Quantiferon-TB Gold test, syphilis, hepatitis B, hepatitis C, or HIV-1 or 2.
• Any prior exposure to tocilizumab or to any other agent directly acting on interleukin-6 or on its receptors including investigational products (e.g. siltuximab, sarilumab etc.).
• Live virus vaccination within 3 months prior to screening or intention to receive live virus vaccination during the trial or up to 3 months after the administration of the study drug.
• Administration of immunoglobulins for anti-tetanus and antirabies post-exposure prophylaxis within 3 weeks prior to administration of study drug.
• History of immunodeficiency or other clinically significant immunological disorders, or auto-immune disorders, ongoing or frequent/ recurring infection defined as more than 3 per year requiring treatment or prior herpes zoster not fully healed (including the post-herpetic neuralgia period if occurring) within one year prior to randomization or history of systemic fungal infection at any time.
• Allergy, or hypersensitivity to any recombinant human, or humanized antibodies, other therapeutic proteins, or any excipients in the study formulations.
• Current manifestation of clinically significant (in the opinion of the Investigator) atopic allergy (e.g., asthma including childhood asthma currently showing clinical manifestations, urticaria, angioedema, eczematous dermatitis), hypersensitivity, or allergic reactions.
• Non-suitable skin for dosing or post-dosing evaluations of upper arm (same arm to be used as the injection site in the both periods) for any reasons (including presence of tattoos, skin pigmentation disorders, scarring etc., which may obscure the injection site).
• Blood donation, participation in any study requiring repeated blood sampling or haemorrhage requiring treatment or any transfusion in the past 3 months.
• Screening blood pressure higher than 140 mm Hg (systolic) or higher than 90 mm Hg (diastolic) or volunteers currently on anti-hypertensive drugs. Up to two repeats on different days are allowed and, in this case, the mean of the measurements will be used to decide on eligibility. Screening blood pressure is to be measured in the sitting position after 5 minutes rest.
• History of relevant orthostatic hypotension, fainting spells, or blackouts deemed in the opinion of the Investigator to pose clinical risk to the subjects.
• QTc (Fridericia correction) longer than 450 milliseconds or other clinically relevant ECG abnormalities such as atrial fibrillation, atrial flutter, Wolf-Parkinson-White syndrome, or presence of a cardiac pacemaker.
• History or presence of any clinically relevant nervous system disease including, but not restricted to any stroke/TIA (Transient Ischemic Attack), or of seizures other than febrile seizures before the age of 5 years.
• History of and/or current gastrointestinal, renal endocrine, pulmonary, hepatic, cardiovascular (including history of or presence of angina, exertional dyspnoea, orthopnoea, congestive heart failure or myocardial infarction and thrombotic or embolic episode requiring treatment), hematological (including pancytopenia, aplastic anemia or blood dyscrasia and coagulopathies, or an INR higher than 1.5), metabolic (including known diabetes mellitus) considered as significant by the Investigator. This criterion includes any disorder or condition that, in the Investigator’s opinion, may interfere with the safety of the subject, the study evaluations or the subject compliance to the study procedures and limitations.
• ALT or AST higher than 1.25 times the ULN at screening.
• Neutrophil count below 2 x 109/liter (2,000 per mm3) or platelet count below 100 x 109/liter (100,000 per mm3) at screening.
• Clinically relevant hyperlipidemia (fasting serum LDL-cholesterol higher than 190 mg/dL or fasting serum triglycerides higher than 200 mg/dL or subject currently on antihyperlipidemic drugs).
• Any active infection, even if minor, ongoing at the time of screening or dosing.
• Presence of any non-healed wound or bone fracture of a clinically relevant size (in the Investigator’s opinion).
• Participation in an interventional or Phase I study in the last three months, or on, or participation in more than 3 studies of experimental drug products in the past 12 months, or intake of an investigational drug in another trial within 3 months or 5 half-lives (whichever is longer) prior to intake of study drug in this trial or planned intake of an investigational drug (any drug administered in a clinical trial setting is considered an investigational drug) or follow up visit scheduled from any study during the course of this trial or intake for any reason in the last 6 months of some specific long body residence drugs such as any immunoglobulin or antibody drug (except for post-exposure prophylaxis of tetanus or rabies given more than 3 weeks before the date of the first study drug dose) pirimethamine, teicoplanin, systemic retinoids, mefloquine and hydroxychloroquine.
• History of any cancer, including carcinoma in situ, lymphoma or leukemia.
• History of, or current intestinal ulceration or diverticulitis.
• Major surgery within the past 12 months, major surgery planned within 12 months of study enrolment or any surgery including dental interventions planned within 3 months of study enrolment.
• Intake of any medication including herbal products within 3 weeks prior to dosing other than for the exceptions detailed in Section 10.2-Prior and Concomitant Medications.
• Current smokers or those who gave up smoking less than 3 months prior to screening, (thus 3 months cessation required at screening time), including alternative tobacco products such as chewing tobacco and vaping, or positive urine cotinine test at screening.
• Positive test for alcohol in breath or drugs of abuse (including benzodiazepines, amphetamines, barbiturates, cocaine, methadone, phencyclidine 3,4-methylenedioxymethamphetamine [MDMA/ecstasy], tetrahydrocannabinol, and opiates) in urine.
• Any history of difficulty in blood sampling or any vasovagal attack during blood sampling which in the opinion of the Investigator may relevantly interfere with the study sampling.