2.2. Study design

A total of 96 subjects (80 evaluable subjects plus 16 subjects accounting for possible drop‐outs) were allocated to receive Pelmeg (T) or Neulasta (R) in a two‐treatment, two‐sequence, and three‐period cross‐over design. The main purpose of the design and size of the study was to investigate potential major differences in immunogenicity between Pelmeg and Neulasta. Forty evaluable subjects per sequence were considered to provide an appropriate precision of estimates for the proportions of ADA‐positive subjects.

The given sample size also supported the assessment of biosimilarity for the PD endpoint, AUEC_0‐last for ANC. Assuming an expected true test/reference ratio of 0.95‐1/0.95 and equivalence limits of 80.00%‐125.00% for the 95% CIs, 80 evaluable subjects provided 90% power to lie within the acceptance ranges, as long as the intraindividual coefficient of variation (CV) did not exceed 40%.

The study design is shown in Figure ​Figure11.

Study design {"type":"entrez-nucleotide","attrs":{"text":"B12019","term_id":"2093139","term_text":"B12019"}}B12019‐102

Subjects were screened within 28 and 2 days prior to administration of study drug. Eligible subjects were admitted to the study site and remained hospitalized until Day 5, while ambulatory visits were performed after Day 5 until Day 43 of each period. Each subject participated in three study periods. Subjects were randomized in a 1:1 ratio to sequentially receive T‐T‐R or R‐R‐T. Dosing was separated by a wash‐out period of at least 6 weeks (maximum 8 weeks), corresponding to approximately 15 half‐lives. Study drugs were administered as subcutaneous (s.c.) injections into the abdomen, at a dose of 3 mg (Pelmeg: 3 mg/0.3 mL, batch number 9201516002, Cinfa Biotech SL, Spain, Neulasta: 3 mg/0.3 mL, batch number 1061466C, Amgen Europe BV, The Netherlands).