Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2020 Jan;26(1):64-72.
doi: 10.1111/hae.13883. Epub 2019 Dec 9.

Safety and efficacy of turoctocog alfa in the prevention and treatment of bleeds in previously untreated paediatric patients with severe haemophilia A: Results from the guardian 4 multinational clinical trial

Hassan Yaish  1 , Tadashi Matsushita  2 , Meriem Belhani  3 , Víctor Jiménez-Yuste  4 , Kaan Kavakli  5 , Lars Korsholm  6 , Irina Matytsina  6 , Claire Philipp  7 , Kirsten Reichwald  8 , Runhui Wu  9
Affiliations
Clinical Trial

Safety and efficacy of turoctocog alfa in the prevention and treatment of bleeds in previously untreated paediatric patients with severe haemophilia A: Results from the guardian 4 multinational clinical trial

Hassan Yaish et al. Haemophilia. 2020 Jan.

Abstract

Introduction: Turoctocog alfa is a recombinant, B domain-truncated factor VIII (FVIII) approved for patients with haemophilia A.

Aim: To evaluate the safety and efficacy of turoctocog alfa in previously untreated patients (PUPs) with severe haemophilia A.

Methods: Guardian 4 was a multicentre, multinational, non-randomized, open-label phase 3 trial comprising a main and extension phase. The former concluded once ≥ 50 patients had received treatment for ≥ 50 exposure days (EDs) or developed inhibitors. Patients received turoctocog alfa intravenously for prevention and treatment of bleeds. The primary endpoint was the incidence rate of FVIII inhibitors (≥0.6 Bethesda Units) reported during the first 50 EDs.

Results: Of the 58 patients who completed the main phase, 25 (43.1%) patients developed inhibitors (detected within 6-24 [mean: 14.2] EDs from treatment start). High-risk mutations were identified in 60% of patients who developed inhibitors in the main phase and were a significant predictor of inhibitor development (P = .003). Of the 21 patients who started immune tolerance induction therapy, 85.7% completed treatment with a negative inhibitor test (note that data on the last 3 patients completing ITI are based on information collated from sites prior to the final database lock). Haemostatic response (including missing values as failure) was rated as 'excellent' or 'good' for 86.1% of bleeds occurring during prophylaxis. The estimated mean annualized bleeding rate for patients on prophylaxis was 4.26 bleeds/patient/year (95% CI: 3.34 - 5.44).

Conclusions: Turoctocog alfa was effective at preventing and stopping bleeds and was well tolerated. Inhibitor development was within the expected range for this PUP population.

Keywords: Haemophilia A; annualized bleeding rate; immunogenicity; previously untreated patients; recombinant factor VIII; turoctocog alfa.

PubMed Disclaimer

Conflict of interest statement

HY has provided consultancy participating in advisory boards and received honoraria from Shire, Bayer, Novo Nordisk and Octapharma, and is on the speaker bureaus of Shire and Bayer; TM has participated in speaker bureaus and advisory boards for: Bayer, Shire, CSL Behring, Novo Nordisk, Chugai, Pfizer, Bioverativ, KM Biologistics and Nichiyaku; MFB has no competing interests; VJY has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Shire, Bayer, CSL Behring, Grifols, Novo Nordisk, Sobi, Roche, Octapharma and Pfizer; KK has received speaking fees, reimbursement for scientific congresses, funding as a study investigator and has advisory board membership with/from the sponsor (Novo Nordisk); LK is a former employee of Novo Nordisk A/S and held stocks in Novo Nordisk A/S at the time of writing; IM is an employee of Novo Nordisk A/S; CP has received research funding from Novo Nordisk, Bayer and Baxalta, has served as a consultant for Bayer, Novo Nordisk and Genentech, and serves on a Data Safety Monitoring Board for Spark; KR is an employee of Novo Nordisk A/S; RW has no competing interests.

Figures

Figure 1
Figure 1
Trial design. *Inhibitor testing was performed at visits 3, 4 and 5 (10‐15, 20‐25 and 50‐55 EDs, respectively) and could be done at any unscheduled visit at the investigators’ discretion. Patients receiving on‐demand treatment were allowed to postpone initiation of their prophylaxis regimen until they had experienced either a minimum of two treatment‐requiring bleeds or once they had reached 2 y of age (whichever came first). On‐demand treatment was initiated as soon as a bleed was identified. EDs, exposure days; EOT, end of end of trial; V, visit
Figure 2
Figure 2
Participant flow. *One patient restarted ITI treatment and one developed inhibitors during the extension phase: both patients rejoined the extension phase. ITI, immune tolerance induction
Figure 3
Figure 3
Time to development of confirmed inhibitor (during main phase). FVIII, factor VIII
See this image and copyright information in PMC

References

    1. Thim L, Vandahl B, Karlsson J, et al. Purification and characterization of a new recombinant factor VIII (N8). Haemophilia. 2010;16:349‐359. - PubMed
    1. Ahmadian H, Hansen EB, Faber JH, et al. Molecular design and downstream processing of turoctocog alfa (NovoEight), a B‐domain truncated factor VIII molecule. Blood Coagul Fibrinolysis. 2016;27:568‐575. - PMC - PubMed
    1. Lentz SR, Misgav M, Ozelo M, et al. Results from a large multinational clinical trial (guardian1) using prophylactic treatment with turoctocog alfa in adolescent and adult patients with severe haemophilia A: safety and efficacy. Haemophilia. 2013;19:691‐697. - PubMed
    1. Lentz SR, Janic D, Kavakli K, et al. Long‐term safety and efficacy of turoctocog alfa in prophylaxis and treatment of bleeding episodes in severe haemophilia A: Final results from the guardian 2 extension trial. Haemophilia. 2018;24:e391‐e394. - PubMed
    1. Kulkarni R, Karim FA, Glamocanin S, et al. Results from a large multinational clinical trial (guardian3) using prophylactic treatment with turoctocog alfa in paediatric patients with severe haemophilia A: safety, efficacy and pharmacokinetics. Haemophilia. 2013;19:698‐705. - PubMed

Publication types

Grants and funding

LinkOut - more resources