Comparison of the Safety and PK of SYN060 to Humira® in Healthy Adult Subjects

Study Overview
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Brief Summary
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This is a single site, parallel randomized, double blinded comparison of the safety, pharmacokinetics, and immunogenicity of a single 0.57 mg/kg dose of SYN060 to a single 0.57 mg/kg dose of adalimumab (Humira®) reference product from North American and European sources. The study is open to healthy individuals on no medications that might confound the results of this safety study.

Detailed Description
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This is a single site, parallel randomized, double blinded comparison of the safety, pharmacokinetics, and immunogenicity of a single 0.57 mg/kg dose of SYN060 to a single 0.57 mg/kg dose of adalimumab (Humira®) reference product from North American and European sources. The study is open to healthy individuals on no medications that might confound the results of this safety study. A total of 90 subjects will be randomized in a 1:1:1 ratio to from a centrally generated randomization schedule to SYN060 or adalimumab of American or European sources resulting in 30 subjects in each group.

Official Title
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A Phase 1 Randomized Blinded Single Dose Comparison of the Safety and Pharmacokinetics of SYN060 Compared to Adalimumab (Humira®) From North American and European Sources in Healthy Adult Subjects

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Biological: SYN060
* Biological: Adalimumab North American source
* Biological: Adalimumab European source


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects between 18 and 50 years of age, inclusive Body mass index between 18 and 30 kg/m², inclusive Female subjects physically capable of pregnancy (i.e., not sterilized and still menstruating or within 1 year of the last menses if menopausal) must: Agree to avoid pregnancy from the Study Day screening visit through six months after receipt of Study Drug. If in a sexual relationship with a man, use an acceptable method of avoiding pregnancy during this period, still menstruating or within 1 year of the last menses if menopausal) in sexual relationships with men must use an acceptable method of avoiding pregnancy during this period. Acceptable methods of avoiding pregnancy include a sterile sexual partner, sexual abstinence (not engaging in sexual intercourse), hormonal contraceptives (oral, injection, transdermal patch, or implant), vaginal ring or intrauterine device (IUD). Women of childbearing potential must have a negative serum pregnancy test within 24 hours preceding receipt of the dose. Can understand and sign the informed consent document, can communicate with the investigator and provide updated contact information as needed for the duration of the study, has no current plans to move from the study area for the duration of the study, and can understand and comply with the requirements of the protocol. Exclusion Criteria: Acute illness on Study Day 1 Oral temperature ≥37.5°C on Study Day 1 Inability to discontinue daily medications other than oral contraceptives or other hormonal therapy. Receipt of an immunoglobulin or blood product within 90 days prior to Study Day 1 Any receipt of adalimumab, or other licensed monoclonal antibody Any receipt of another investigational product within 4 weeks or 4 half-lives whichever is longer prior to Study Day 1 Abnormal laboratory values per local laboratory parameters from blood collected at screening prior to Study Day 1 randomization as follows: Severe anemia, defined as haemoglobin <100 g/L or hematocrit <0.3 L/L absolute neutrophil count, below lower limit of normal (LLN) white blood cell count above upper limit of normal (ULN) or below LLN (i.e., must be within normal limits) ALT, AST, alkaline phosphatase (ALP) above ULN with exception that a one of the three values may be permitted up to 10% above ULN. Creatinine above upper limit of normal , INR, or activated partial thromboplastin time (APTT) above ULN Abnormal screening urinalysis result that is, per the investigator, clinically significant, or a screening urine dipstick result of ≥2+ protein Positive screening urine test for illicit drugs (amphetamines, methamphetamines, barbiturates, benzodiazepine, cocaine, opiates, PCP, MDMA, methadone) History of systemic allergic reactions, to more than one medication. History or evidence of malignancy. Receipt of immunosuppressive medications other than inhaled or topical immunosuppressant drugs such as corticosteroids within 45 days prior to Study Day 1 Hepatitis B surface antigen positive, HIV positive, hepatitis C antibody positive Uncontrolled Type 2 Diabetes or Type I diabetes History systemic fungal infection. Shared a residence within the last year with an individual on anti-tuberculosis treatment or with culture or smear positive tuberculosis Previous medical history that may compromise the safety of the subject in the study, including but not limited to: severe impairment of pulmonary function or other pulmonary disease; chronic illness with signs of cardiac or renal failure; suspected progressive neurological disease or poorly controlled epilepsy History or evidence on physical examination of any systemic disease or any acute or chronic illness that, in the opinion of the investigator, may interfere with the evaluation of the safety of the Study Drug History or evidence of tuberculosis infection Positive Quantiferon test Chest X ray with evidence of malignancy or chronic infection (such as tuberculosis or other) Any current medical, psychiatric, occupational, or substance abuse problem such as alcoholism that, in the opinion of the investigator, will make it unlikely that the subject will comply with the protocol. Elective surgery that would interfere with participation. Live virus vaccination within 60 days and during the study. Blood donation less than 30 days prior to Study Day 1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SYN060<br>a single 0.57 mg/kg dose of SYN060 | Biological: SYN060<br>* a single subcutaneous 0.57 mg/kg dose of SYN060<br>|
| Active Comparator: Adalimumab North American source<br>a single 0.57 mg/kg dose of adalimumab from North American source | Biological: Adalimumab North American source<br>* a single subcutaneous 0.57 mg/kg dose of adalimumab (Humira®) reference product from North American source<br>|
| Active Comparator: Adalimumab European source<br>a single 0.57 mg/kg dose of adalimumab from European source | Biological: Adalimumab European source<br>* a single subcutaneous 0.57 mg/kg dose of adalimumab (Humira®) reference product from European source<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-last (area under the concentration-time curve from time zero to the last non-zero concentration) and AUC0-inf (area under the concentration-time curve from time zero to infinity) | AUC0-last and AUC0-inf will be estimated using non-compartmental analysis fpr SYN060 to adalimumab (Humira®) from North American and European sources. | 85 days | 
| Cmax (maximum observed concentration) | Cmax will be estimated using non-compartmental analysis for SYN060 and adalimumab (Humira®) from North American and European sources | 85 days | 
| Residual area (%AUCextrap) [percent extrapolated area under the curve to infinity calculated as 100*(1- AUC0-last / AUC0-inf)] | Residual area (%AUCextrap) will be estimated using non-compartmental analysis for SYN060 and adalimumab (Humira®) from North American and European sources | 85 days | 
| Tmax (time of observed Cmax) | Tmax will be estimated using non-compartmental analysis for SYN060 and adalimumab (Humira®) from North American and European sources | 85 days | 
| t½ (elimination half-life) | t½ will be estimated using non-compartmental analysis for SYN060 and adalimumab (Humira®) from North American and European sources | 85 days | 
| λz (elimination rate constant) | λz will be estimated using non-compartmental analysis for SYN060 and adalimumab (Humira®) from North American and European sources | 85 days | 
| CL/F (apparent body clearance, calculated as Dose/AUC0-inf) | CL/F will be estimated using non-compartmental analysis for SYN060 and adalimumab (Humira®) from North American and European sources | 85 days | 
| Vz/F [apparent volume of distribution, calculated as Dose/ (λz x AUC0-inf)] | Vz/F will be estimated using non-compartmental analysis for SYN060 and adalimumab (Humira®) from North American and European sources | 85 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse event incidence of SYN060 compared to adalimumab (Humira®) from North American and European sources | Safety monitoring will include vital signs (blood pressure, temperature, pulse, oximetry and respiration rates), physical examination, electrocardiogram (ECG) and clinical laboratory tests (serum chemistry, hematology, troponins, creatinine phosphokinase [CPK], human anti-SYN060 antibodies, human anti-adalimumab antibodies and urinalysis). Adverse events will be recorded throughout the study and will be coded using the most current version of MedDRA (Medical Dictionary for Regulatory Activities) at the time of study commencement. | 85 days | 
| anti-SYN060 antibodies | The development of anti-SYN060 antibodieswill be determined on Study Days 0, and 7 through 85, or the last blood specimen available for subjects who leave the study prior to Day 85. The development of anti-SYN060 antibodies will be analyzed as a continuous measure across categorical groups and compared to anti-adalimumab antibodies with descriptive statistics. | 85 days | 
| anti-adalimumab antibodies | The development of anti-adalimumab antibodies will be determined on Study Days 0, and 7 through 85, or the last blood specimen available for subjects who leave the study prior to Day 85. The development of anti-adalimumab antibodies will be analyzed as a continuous measure across categorical groups and compared to anti-SYN060 antibodies with descriptive statistics. | 85 days |