A Study to Evaluate the Bioequivalence of Tocilizumab Following Subcutaneous Administration Via an Autoinjector (AI 1000-G2) Versus a Pre-Filled Syringe in Healthy Volunteers

Study Overview
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Brief Summary
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The study consists of an eligibility screening period, two study periods involving single doses of tocilizumab (TCZ) according to an open-label, randomized, two-period crossover design with an interval of 6 weeks between periods, and a 6 week follow-up period. Healthy participants will receive a single subcutaneous (SC) injection of TCZ via a pre-filled syringe-needle safety device (PFS-NSD) and a single injection via an autoinjector (AI). The total duration of the study is up to 16 weeks from screening to follow-up. After screening, eligible participants will be randomly assigned to one of the two possible treatment sequences (Sequence 1: AI-1000 G2 followed by PFS-NSD or Sequence 2: PFS-NSD followed by AI-1000 G2) and assigned to one of three injection sites (1: abdomen, 2: thigh, or 3: upper arm). All participant groups will receive a total of two TCZ administrations each.

Conditions
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Healthy Volunteer

Intervention / Treatment
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* Device: AI-1000 G2
* Device: PFS-NSD
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male participants and their partners of child-bearing potential must be willing to use two effective contraceptive methods Female participants must be either postmenopausal or surgically sterile Intact normal skin in the area for intended injection Body weight less than (<) 150 kilograms (kg) Have no contraindications from the following: a detailed medical and surgical history, a complete physical examination, including vital signs, 12-lead electro cardio gram (ECG), hematology, blood chemistry, serology, and urinalysis Exclusion Criteria: Participants with any known active current or history of recurrent Infectious disease Positive result on hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus-1 (HIV-1) and HIV-2 at screening A history of clinically significant gastrointestinal, renal, hepatic, cardiovascular, or allergic disease Evidence of malignant disease, or malignancies diagnosed within the previous 5 years Use of or being dependent within the last 12 months on any substances of abuse, including a relevant past history of alcohol abuse Participants with a history of, or currently active primary or secondary immunodeficiency Participants who smoke more than 10 cigarettes per day or equivalent in tobacco Clinically relevant deviation from normal in the physical examination, including vital signs Clinically relevant ECG abnormalities on screening Evidence of atrial fibrillation, atrial flutter, right or left bundle branch block, Wolf-Parkinson-White syndrome, or cardiac pacemaker or any other significant cardiac abnormalities Known allergy to TCZ or any other ingredient in the subcutaneous (SC) formulation History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies Known coagulopathy Clinically significant abnormalities in laboratory test results Immunization with a live or attenuated vaccine is prohibited within 4 weeks prior to study drug administration

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A1: Tocilizumab AI followed by PFS-NSD in abdomen<br>Participants will receive two single doses of 162 milligrams (mg) tocilizumab SC, first dose via AI on Day 1 (Period 1) followed by a washout period of 6 weeks, thereafter second dose via PFS-NSD on Day 43 (Period 2), in abdomen. | Device: AI-1000 G2<br>* The device will contain TCZ (180 milligrams per milliliter [mg/mL]) SC formulation single dose of 0.9 mL that corresponds to 162 mg TCZ administered via PFS and assembled in the AI (AI-1000 G2).<br>Device: PFS-NSD<br>* The device will contain TCZ (180 mg/mL) SC formulation single dose of 0.9 mL that corresponds to 162 mg TCZ administered via PFS-NSD.<br>Drug: Tocilizumab<br>* Participants will receive two single doses of 162 mg tocilizumab SC on Day 1 (Period 1) and Day 43 (Period 2), with a washout period of 6 weeks between the periods.<br>* Other names: RO4877533; Actemra/RoActemra;|
| Experimental: A2: Tocilizumab AI followed by PFS-NSD in thigh<br>Participants will receive two single doses of 162 mg tocilizumab SC, first dose via AI on Day 1 (Period 1) followed by a washout period of 6 weeks, thereafter second dose via PFS-NSD on Day 43 (Period 2) in thigh. | Device: AI-1000 G2<br>* The device will contain TCZ (180 milligrams per milliliter [mg/mL]) SC formulation single dose of 0.9 mL that corresponds to 162 mg TCZ administered via PFS and assembled in the AI (AI-1000 G2).<br>Device: PFS-NSD<br>* The device will contain TCZ (180 mg/mL) SC formulation single dose of 0.9 mL that corresponds to 162 mg TCZ administered via PFS-NSD.<br>Drug: Tocilizumab<br>* Participants will receive two single doses of 162 mg tocilizumab SC on Day 1 (Period 1) and Day 43 (Period 2), with a washout period of 6 weeks between the periods.<br>* Other names: RO4877533; Actemra/RoActemra;|
| Experimental: A3: Tocilizumab AI followed by PFS-NSD in upper arm<br>Participants will receive two single doses of 162 mg tocilizumab SC, first dose via AI on Day 1 (Period 1) followed by a washout period of 6 weeks, thereafter second dose via PFS-NSD on Day 43 (Period 2), in upper arm. | Device: AI-1000 G2<br>* The device will contain TCZ (180 milligrams per milliliter [mg/mL]) SC formulation single dose of 0.9 mL that corresponds to 162 mg TCZ administered via PFS and assembled in the AI (AI-1000 G2).<br>Device: PFS-NSD<br>* The device will contain TCZ (180 mg/mL) SC formulation single dose of 0.9 mL that corresponds to 162 mg TCZ administered via PFS-NSD.<br>Drug: Tocilizumab<br>* Participants will receive two single doses of 162 mg tocilizumab SC on Day 1 (Period 1) and Day 43 (Period 2), with a washout period of 6 weeks between the periods.<br>* Other names: RO4877533; Actemra/RoActemra;|
| Experimental: B1: Tocilizumab PFS-NSD followed by AI in abdomen<br>Participants will receive two single doses of 162 mg tocilizumab SC, first dose via PFS-NSD on Day 1 (Period 1) followed by a washout period of 6 weeks, thereafter second dose via AI on Day 43 (Period 2), in abdomen. | Device: AI-1000 G2<br>* The device will contain TCZ (180 milligrams per milliliter [mg/mL]) SC formulation single dose of 0.9 mL that corresponds to 162 mg TCZ administered via PFS and assembled in the AI (AI-1000 G2).<br>Device: PFS-NSD<br>* The device will contain TCZ (180 mg/mL) SC formulation single dose of 0.9 mL that corresponds to 162 mg TCZ administered via PFS-NSD.<br>Drug: Tocilizumab<br>* Participants will receive two single doses of 162 mg tocilizumab SC on Day 1 (Period 1) and Day 43 (Period 2), with a washout period of 6 weeks between the periods.<br>* Other names: RO4877533; Actemra/RoActemra;|
| Experimental: B2: Tocilizumab PFS-NSD followed by AI in thigh<br>Participants will receive two single doses of 162 mg tocilizumab SC, first dose via PFS-NSD on Day 1 (Period 1) followed by a washout period of 6 weeks, thereafter second dose via AI on Day 43 (Period 2), in thigh. | Device: AI-1000 G2<br>* The device will contain TCZ (180 milligrams per milliliter [mg/mL]) SC formulation single dose of 0.9 mL that corresponds to 162 mg TCZ administered via PFS and assembled in the AI (AI-1000 G2).<br>Device: PFS-NSD<br>* The device will contain TCZ (180 mg/mL) SC formulation single dose of 0.9 mL that corresponds to 162 mg TCZ administered via PFS-NSD.<br>Drug: Tocilizumab<br>* Participants will receive two single doses of 162 mg tocilizumab SC on Day 1 (Period 1) and Day 43 (Period 2), with a washout period of 6 weeks between the periods.<br>* Other names: RO4877533; Actemra/RoActemra;|
| Experimental: B3: Tocilizumab PFS-NSD followed by AI in upper arm<br>Participants will receive two single doses of 162 mg tocilizumab SC, first dose via PFS-NSD on Day 1 (Period 1) followed by a washout period of 6 weeks, thereafter second dose via AI on Day 43 (Period 2), in thigh. | Device: AI-1000 G2<br>* The device will contain TCZ (180 milligrams per milliliter [mg/mL]) SC formulation single dose of 0.9 mL that corresponds to 162 mg TCZ administered via PFS and assembled in the AI (AI-1000 G2).<br>Device: PFS-NSD<br>* The device will contain TCZ (180 mg/mL) SC formulation single dose of 0.9 mL that corresponds to 162 mg TCZ administered via PFS-NSD.<br>Drug: Tocilizumab<br>* Participants will receive two single doses of 162 mg tocilizumab SC on Day 1 (Period 1) and Day 43 (Period 2), with a washout period of 6 weeks between the periods.<br>* Other names: RO4877533; Actemra/RoActemra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed serum concentration (Cmax) of TCZ |  | Pre-dose and 8 hours post-dose on Day 1, and pre-dose on Days 2, 3, 4, 5, 6, 8, 10, 13, 16, 19, 22, 29, 36, pre-dose and 8 hours post-dose on Day 43, and pre-dose on Days 44, 45, 46, 47, 48, 50, 52, 55, 58, 61, 64, 71, 78 and 85 | 
| Area under the serum concentration-time curve from time zero to last quantifiable concentration (AUClast) of TCZ |  | Pre-dose and 8 hours post-dose on Day 1, and pre-dose on Days 2, 3, 4, 5, 6, 8, 10, 13, 16, 19, 22, 29, 36, pre-dose and 8 hours post-dose on Day 43, and pre-dose on Days 44, 45, 46, 47, 48, 50, 52, 55, 58, 61, 64, 71, 78 and 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the serum concentration-time curve from time zero to extrapolated infinite time [AUC (0-inf)] of TCZ |  | Pre-dose and 8 hours post-dose on Day 1, and pre-dose on Days 2, 3, 4, 5, 6, 8, 10, 13, 16, 19, 22, 29, 36, pre-dose and 8 hours post-dose on Day 43, and pre-dose on Days 44, 45, 46, 47, 48, 50, 52, 55, 58, 61, 64, 71, 78 and 85 | 
| Time to reach maximum observed serum concentration (Tmax) of TCZ |  | Pre-dose and 8 hours post-dose on Day 1, and pre-dose on Days 2, 3, 4, 5, 6, 8, 10, 13, 16, 19, 22, 29, 36, pre-dose and 8 hours post-dose on Day 43, and pre-dose on Days 44, 45, 46, 47, 48, 50, 52, 55, 58, 61, 64, 71, 78 and 85 | 
| Apparent elimination rate constant (Kel) of TCZ |  | Pre-dose and 8 hours post-dose on Day 1, and pre-dose on Days 2, 3, 4, 5, 6, 8, 10, 13, 16, 19, 22, 29, 36, pre-dose and 8 hours post-dose on Day 43, and pre-dose on Days 44, 45, 46, 47, 48, 50, 52, 55, 58, 61, 64, 71, 78 and 85 | 
| Number of participants with adverse events |  | Baseline up to 8 weeks after the last dose of study drug (approximately 7 months) | 
| Number of participants with anti-drug antibody (ADA) response |  | Pre-dose on Days 1 and 43, and Day 85 |