CSR section 11-style statistical text (synthetic study SIMBE01). Generated by study/06_csr/csr.R.

11.1 Data Sets Analyzed
Of the 40 participants randomized, all 40 received at least one dose and form the safety set. Participant SIMBE01-101-017 discontinued the study (withdrawal by participant). The PK concentration set includes 40 participants and the PK parameter set 40. Participant SIMBE01-101-029 vomited within 2 hours of a dose, so that period was excluded under the pre-specified rule. The bioequivalence set includes 38 participants (19 in each sequence), above the guideline minimum of 12 evaluable participants.

11.2 Demographic and Other Baseline Characteristics
Mean (SD) age in the safety set was 43.8 (7.5) years (range 32.0 to 59.0 years). Of the 40 participants, 21 were female (52.5%). Mean (SD) BMI was 25.2 (5.2) kg/m2. Table 14.1.2 gives the characteristics by sequence.

11.3 Measurements of Treatment Compliance
Each participant was scheduled to receive 2 single supervised oral doses. In total, 79 doses were given (40 Test and 39 Reference); the participant who withdrew did not receive the Period 2 dose.

11.4.1 Analysis of Pharmacokinetics and Bioequivalence
The adjusted geometric mean Cmax was 103.3 ng/mL for Test and 102.2 ng/mL for Reference. The ratio of geometric means (Test/Reference) was 101.07% with a 90% confidence interval of 98.89% to 103.30%. For AUC(0-t) the adjusted geometric means were 1204.9 and 1158.7 h*ng/mL, and the ratio was 103.99% (90% CI 98.52% to 109.75%). Both intervals lie within 80.00% to 125.00% (Table 14.4.3.1).
The within-participant CV was 5.6% for Cmax and 14.0% for AUC(0-t), below the 25% assumed for the sample size. The supportive AUC(0-inf) ratio was 104.62% (90% CI 98.63% to 110.97%) in the 37 participants whose AUC(0-inf) met the SAP rules in both periods. Median tmax was 1.05 hours for Test and 1.03 hours for Reference (Table 14.4.4.1).
In the ANOVA for ln(Cmax) the p-values were 0.8797 for sequence, 0.1657 for period and 0.4156 for formulation; for ln(AUC(0-t)) they were 0.5651, 0.6526 and 0.2295 (Table 14.4.3.2). As the SAP specifies, no test for carry-over was made; pre-dose concentrations were examined instead.

11.4.2 Statistical/Analytical Issues
Cmax occurred at the first post-dose sample (0.25 hours) in 2 of 78 evaluable profiles (participants SIMBE01-101-013 and SIMBE01-101-030), so the true Cmax may have come earlier. Without these participants (n = 36), the ratio was 100.57% (90% CI 98.40% to 102.80%) for Cmax and 103.35% (97.74% to 109.28%) for AUC(0-t); both intervals stay within 80.00% to 125.00%. With the excluded periods put back (n = 39), the Cmax ratio was 99.46% (96.03% to 103.00%) and the AUC(0-t) ratio 102.48% (96.67% to 108.63%).

11.4.2.2 Handling of Dropouts or Missing Data
No values were imputed. One 12-hour sample in Period 1 was not collected and the profile was analyzed without it. Concentrations below the LLOQ of 0.50 ng/mL were set to zero and left out of the terminal-phase fit. One 6-hour value in Period 2 was below the LLOQ between quantifiable samples; kept as zero, it gave an AUC(0-t) of 1312.1 h*ng/mL for that profile, against 1433.0 h*ng/mL with the PKNCA default, which drops such a value.
One Period 2 pre-dose concentration was 2.5% of that period's Cmax, below the 5% limit, so the period was kept. AUC(0-t) covered less than 80% of AUC(0-inf) in 2 of 78 profiles (2.6%), within the 20% allowed before the study's validity needs discussion. Under the SAP rules, AUC(0-inf) was not summarized for 2 profiles with more than 20% extrapolated, and no terminal fit had an adjusted R-squared below 0.90.

11.4.7 Conclusions
The 90% confidence intervals for the Test/Reference ratios of Cmax (98.89% to 103.30%) and AUC(0-t) (98.52% to 109.75%) both lie within 80.00% to 125.00%, so bioequivalence of the test and reference tablets is concluded for this synthetic study. The results were re-derived by a second method by the same author (40 of 40 QC checks passed); a second programmer did not re-derive them.