Abstract
Introduction
Patients with congenital afibrinogenaemia and hypofibrinogenaemia, experience frequent severe bleeding episodes starting at birth or early childhood. Bleeding may occur after a minor trauma or a small surgical intervention, into the skin, mucosa, muscles, gastrointestinal tract, or the brain. Therapeutic substitution with human fibrinogen concentrate can correct the haemostatic defect and arrest the bleeding in patients with these fibrinogen deficiencies. Octafibrin is a plasma derived, highly purified, lyophilized, fibrinogen concentrate, which has been double virus safeguarded using two dedicated virus inactivation/removal steps. In this study, the (PK) profile of this new concentrate is compared to a commercially available product.
Methods
This study was a prospective, randomized, open-label, multinational, crossover PK comparison of Octafibrin to an existing marketed product (Haemocomplettan¨ P/RiaSTAPTM) in adult and adolescent afibrinogenemic patients, including comparison of a surrogate efficacy endpoint Maximum Clot Firmness (MCF) measured by ROTEM¨. Patients were randomized to either product and received a single dose of 70mg/kg b.w. and blood samples were collected over 14 days followed by an observational period up to 45 days. Afibrinogenemia was confirmed by baseline fibrinogen activity plasma level of < 0.20. All fibrinogen and MCF testing was performed in a central lab using validated methods. Primary objective was to show bioequivalence between both products based on the Normalized Area Under the Curve (AUCnorm).
Results
Twenty two adult and adolescent patients were included in the final analysis. Mean AUCnorm) for Octafibrin was 1.62, and for the marketed concentrate 1.35 (hákgág/L/mg) and mean clearance 0.67 and 0.82 mL/h/kg, respectively. Both showed a statistically significant differences between the groups (see figure and table below). Other PK parameter were comparable between the products. Comparable haemostatic efficacy of the two products was demonstrated based on their ability to significantly increase MCF from baseline. There were no reports of adverse events (AE) related to the infusion of this novel concentrate.
Conclusions
In conclusion, this study showed a statistically significantly higher AUCnorm and lower clearance for Octafibrin compared to the comparator. Other PK parameters were in general comparable. Change in MCF compared to baseline as a surrogate efficacy parameter, was similar to that of the licensed comparator used in this study, and there was no related AE or SAE for Octafibrin after single-dose administration.
Ratios of Octafibrin Relative to Haemocomplettan¨ P/RiaSTAPTM for AUC and AUCnorm (PK Population, N=22)
| Fibrinogen activity | |||
|---|---|---|---|
| Parameter ratio | Mean | 90% CI of mean ratio | p-value |
| AUC | 1.34 | (1.23, 1.41) | <0.0001 |
| AUCnorm | 1.21 | (1.25, 1.44) | 0.0002 |
| Fibrinogen activity | |||
|---|---|---|---|
| Parameter ratio | Mean | 90% CI of mean ratio | p-value |
| AUC | 1.34 | (1.23, 1.41) | <0.0001 |
| AUCnorm | 1.21 | (1.25, 1.44) | 0.0002 |
Mean (± SD) Fibrinogen Levels (g/L) during PK Assessment after Octafibrin and Haemocomplettan¨ P/RiaSTAPTM Administration, Standardized to 70 mg/kg (PK Population, n=22)
Mean (± SD) Fibrinogen Levels (g/L) during PK Assessment after Octafibrin and Haemocomplettan¨ P/RiaSTAPTM Administration, Standardized to 70 mg/kg (PK Population, n=22)
Ross:Octapharma: Other: Investigator. Rangarajan:Octapharma: Other: Investigator. Karimi:Octapharma: Other: Investigator. Schwartz:Octapharma: Employment. Knaub:Octapharma: Employment. Peyvandi:LFB, Kedrion, Novonordisk, Bayer, Roche, CSL Behring.: Consultancy, Honoraria, Research Funding; Octapharma: Other: Investigator.
