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OBJECTIVEIndividualization of therapy choices requires the prediction of likely response. Predictor and explanatory factors of change in HbA 1c were studied using data from a large observational study of starting insulin analog therapy (the A 1 chieve study). RESEARCH DESIGN AND METHODSUnivariate analyses were performed for insulin-naive people and prior insulin users in the A 1 chieve study. Statistically significant factors were carried forward to baseline factor-only multivariate analyses ("predictor" analysis), and separately using all significant factors ("explanatory" analysis). Power was considered in terms of the variance explained. RESULTSGeographical region, baseline HbA 1c level, lipid levels, and baseline insulin dose were the most powerful predictors of HbA 1c change (mean change 22.1% [223 mmol/mol]) observed in the univariate analysis (r 2 > 0.010, P < 0.001). However, although the predictor and explanatory multivariate models explained 62-82% of the variance in HbA 1c change, this was mainly associated with baseline HbA 1c (r 2 = 0.544-0.701) and region (r 2 = 0.014-0.037). Other factors were statistically significant but had low predictive power (r 2 < 0.010); in the explanatory analysis, this included end-of-study hypoglycemia (insulin-naive group), insulin dose, and health-related quality of life (r 2 < 0.001-0.006, P £ 0.007). CONCLUSIONSMany factors can guide clinicians in predicting the response to starting therapy with insulin analogs, but many are interdependent and thus of poor utility. The factor explaining most of the variance in HbA 1c change is baseline HbA 1c level, with each increase of 1.0%-units (11 mmol/mol) providing a 0.7-0.8%-units (8-9 mmol/mol) greater fall. Other factors do not explain much of the remaining variance, even when including all end-of-trial measures.

Background N8‐GP (turoctocog alfa pegol; Esperoct®, Novo Nordisk A/S, Bagsvaerd, Denmark) is a glycoPEGylated, extended half‐life human recombinant factor VIII (FVIII). Objective Here, we report end‐of‐trial safety and efficacy results from the completed N8‐GP pathfinder5 trial. Methods pathfinder5 (NCT01731600) was a multi‐national, open‐label, single‐arm, non‐randomized, non‐controlled trial in previously treated male patients aged <12 years old with severe hemophilia A that comprised a main and an extension phase. During the main phase, patients received twice‐weekly N8‐GP 60 IU/kg for 50 exposure days (~26 weeks). During the extension phase, patients received the same regimen until the end of trial (first patient in main phase, 20 February 2013; trial end, 28 September 2018). Results Sixty‐eight patients were exposed to N8‐GP for a median time of ~4.9 years on regimen. Of the 63 patients who started in the extension phase, 62 completed the trial. No FVIII inhibitors (≥0.6 BU) or other safety concerns were detected. The overall estimated annualized bleeding rate was 1.08 (median 0.81), and nearly 20% of patients had no bleeds during the entire trial. The proportion of patients with no annual bleeds increased with time, with 56% of patients experiencing no bleeds and 86% experiencing no spontaneous bleeds during the fourth year of exposure. All baseline target joints of patients who participated in both phases of this trial were resolved in slightly over 2 years. Conclusion Overall, data from the completed pathfinder5 trial show that long‐term (median 4.9 years) N8‐GP treatment was efficacious and well tolerated in previously treated pediatric patients with severe hemophilia A.

Introduction:Turoctocog alfa pegol is a glycoPEGylated recombinant factor VIII (FVIII) with an extended half-life developed for prophylaxis, treatment of bleeds and perioperative management in patients with haemophilia A.Aim: Evaluate the efficacy and safety of turoctocog alfa pegol treatment for major and minor surgeries in the pathfinder 3 and 5 phase III trials.Methods: Adults/adolescents aged ≥12 years with severe haemophilia A (FVIII <1%) received perioperative turoctocog alfa pegol treatment planned to achieve FVIII activity levels >80% during major surgery (pathfinder 3). The primary end point was haemostatic efficacy during surgery; secondary end points were blood loss, haemostatic effect postsurgery, consumption, transfusions, safety and health economics. Children (0-11 years) undergoing minor surgeries received 20-75 IU/kg turoctocog alfa pegol at Investigator's discretion (pathfinder 5). Results: pathfinder 3 included 35 patients undergoing 49 major surgeries. Haemostasis was successful in 47/49 (95.9%) surgeries; two had moderate haemostatic responses.Median (mean) blood loss during major surgery was 75 (322.6) mL. Four bleeds were reported postsurgery; three were successfully treated with turoctocog alfa pegol (one was not evaluated). On the day of surgery, overall mean (median) dose was 75.5 (74.5) IU/kg and mean (median) number of doses was 1.7 (2.0). Five procedures required 11 transfusions on the day of surgery or days 1-6. No safety concerns or inhibitors were identified.Forty-five minor surgeries in 23 children were performed without complications.Conclusion: Turoctocog alfa pegol was effective for perioperative haemostatic management of major and minor surgeries in patients across age groups with severe haemophilia A. K E Y W O R D Sextended half-life, factor VIII, haemophilia A, haemostasis, surgery, turoctocog alfa pegol This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Background N8‐GP is an extended half‐life recombinant factor VIII developed for prophylaxis and treatment of bleeds in patients with hemophilia A. Objective To assess pharmacokinetic (PK) characteristics of N8‐GP in previously treated patients with severe hemophilia A, model the time spent at hemophilia thresholds of ≥1 and ≤5 IU/dL (moderate) or >5 IU/dL (mild) FVIII levels during N8‐GP prophylaxis, and investigate the relationship between N8‐GP half‐life and von Willebrand factor (vWF). Methods PK assessments were obtained from patients with severe hemophilia A (FVIII < 1 IU/dL) participating in 4 clinical trials: pathfinder 1 (20‐60 years); pathfinder 2 (12‐17 and ≥18 years); pathfinder 5 (0‐11 years), and pathfinder 7 (25‐71 years). All PK profiles were assessed after washout and considered single‐dose PK profiles. Pre‐ and postdose FVIII activity at steady state was measured at all visits. Results From 69 patients, 108 PK profiles of N8‐GP 50 IU/kg were assessed. Adults/adolescents received 50 IU/kg every 4 days, achieving mean trough levels of 3.0 IU/dL (95% confidence interval, 2.6‐3.5, adults) and 2.7 IU/dL (1.8‐4.0, adolescents). Children received 60 IU/kg twice weekly, leading to mean trough levels of 1.2 IU/dL (0.8‐1.6, 0‐ to 5‐year‐olds) and 2.0 IU/dL (1.5‐2.7, 6‐ to 11‐year‐olds). PK modeling predicted children dosed every 3 days and adults/adolescents dosed every 3 to 4 days would maintain FVIII levels >5 and >1 IU/dL for >80% and 100% of the time, respectively. N8‐GP half‐life correlated linearly with von Willebrand factor levels in adults/adolescents, less in children. Conclusions Prophylaxis with fixed intervals (Q4D/twice weekly) and fixed weight‐based dosing (50/60 IU/kg) ensured >1 IU/dL FVIII trough levels in both adults and children.