Bioequivalence of two hydroxyurea test formulations demonstrated in a partly replicate design trial

Introduction: Hydroxyurea is approved for the indication of chronic myeloid leukaemia in the chronic or accelerated phase of the disease and essential thrombocythaemia or polycythaemia vera with a high risk for thromboembolic complications. Hydroxyurea is available as capsule formulations for oral use. This trial investigated the bioequivalence (BE) of standard (T1) and halal‐compliant (T2) products of Hydroxyurea medac 500 mg capsule as compared to the reference product Litalir® 500 mg capsule (R). Method: The trial was a randomised, open‐label, 4‐period, 3‐treatment, partly replicate, crossover, single‐centre, single‐dose Phase 1 trial in healthy male and female subjects under fasting conditions. The key endpoints were Cmax, AUC0‐t, and AUC∞. The statistical analysis was performed as two separate pairwise comparisons (T1‐R and T2‐R), with a sensitivity analysis using data of all three formulations simultaneously. The reference treatment was replicated‐this was statistically efficient and reduced the sample size to 24 subjects with complete data, which was derived based on a gCV of 21% to achieve 90% total power. An alternative would have been to perform two separate 2x2 crossover trials, which would have required a total of 2 × 28 = 56 subjects. Results: In total, 31 subjects were randomised and received at least one trial treatment. Twenty‐eight subjects completed the trial, while three subjects discontinued prematurely after one or two periods. Subjects' age ranged from 18 to 59 years, with a mean (SD) of 49.6 (9.8) years. The majority of subjects (24 [77%]) were male. The PK profiles of hydroxyurea following administration of any of the trial treatments were comparable, and the 90% CIs for the ratios (T1/R and T2/R) of the adjusted mean for Cmax, AUC0‐t, and AUC∞ were within the regulatory 80.00% to 125.00% acceptance range. Table 1 shows the results using the FDA analysis; the results were similar for the EMA analysis. Overall, 17 Adverse events were reported in 6 of 31 (19%) subjects in the trial; the majority were headache (7) and nasopharyngitis (4), which were balanced across the treatments. Conclusion: The analyses demonstrate that both T1 and T2 are bioequivalent with the reference product according to both the FDA and EMA BE criteria. The trial design with replicated reference treatment was statistically efficient because it reduced the overall samples size for the two comparisons while maintaining a power of 90%, hence reduced costs and time compared to the more traditional performance of two separate BE trials. (Table Presented) .