Real-world long-term safety and effectiveness of turoctocog alfa in the treatment of haemophilia A in Japan: results from a multicentre, non-interventional, post-marketing study

ABSTRACT

Objectives

To assess the safety and effectiveness of turoctocog alfa in previously treated patients (PTPs) and previously untreated patients (PUPs) with haemophilia A in a real-world setting in Japan.

Methods

This multicentre, non-interventional, post-marketing study recruited patients with haemophilia A who initiated treatment with turoctocog alfa from 18 sites (08/2014-12/2018). The primary endpoint was adverse events (AEs) during the 2-year study period.

Results

The safety and effectiveness analysis set included 39 patients. In total, 13 (33.3%) patients reported ≥1 AE; incidence rate was 60.4 events/100 patient-years of exposure (PYE). Treatment was withdrawn in two cases: pruritus in a PTP and factor VIII inhibitor development in a PUP. Inhibitor development occurred in 2.6% of all patients, with an incidence rate of 3.8 events/100 PYE. The rate of inhibitor development was 0%, 25% and 20% in PTPs, PUPs and PUPs with severe type, respectively. The haemostatic success rate was 91.4% for 383 bleeding episodes and 85.7% for 14 surgeries. The negative binomial annualised bleeding rate for the prophylaxis regimen was 6.19 episodes/year (95% CI, 3.69–10.38). The mean (SD) total consumption of turoctocog alfa (n = 34; excluding FVIII inhibitors) was 5,382.6 (7,180.1) IU/kg/year/patient; consumption was 4,133.1 (1,452.4) IU/kg/year/patient for prophylaxis.

Discussion

The effectiveness and safety profiles were comparable to those observed in other turoctocog alfa trials; effectiveness analysis and consumption were not affected by treatment regimens.

Conclusion

Long-term use of turoctocog alfa therapy in clinical practice posed no newly identified safety issues and was effective for prophylaxis and treatment of bleeds in patients with haemophilia A in Japan.

KEYWORDS:

• Factor VIII
• Haemophilia A
• Japan
• inhibitors
• prophylaxis
• post-marketing product surveillance
• turoctocog alfa

1. Introduction

Haemophilia A is a congenital bleeding disorder caused by the deficiency of coagulation factor VIII (FVIII) [1]. As of 31 May 2021, an estimated 5,657 cases of haemophilia A were reported in Japan [2]. FVIII replacement therapy is currently the standard of care for prophylaxis or treatment of bleeding in individuals with haemophilia A, including management of surgery [1,3]. Turoctocog alfa (NovoEight®, Novo Nordisk A/S, Bagsværd, Denmark) is a B-domain-truncated recombinant FVIII protein approved for prophylaxis and treatment of bleeding episodes in haemophilia A [4,5]. Several clinical trials have established the safety and efficacy of turoctocog alfa in previously treated (PTPs) [6–10] and previously untreated (PUPs) [11] patients with haemophilia A. The multinational, non-interventional Guardian 5 study confirmed the real-world safety and effectiveness of turoctocog alfa in patients with haemophilia A from Europe and the United States (US) [12]. Real-world studies enable evaluation of the immunogenicity, safety and clinical effectiveness of turoctocog alfa in diverse and more representative patient populations than interventional clinical trials [12,13].

This study aimed to fulfil post-marketing surveillance (PMS) requirements [14] and evaluate the long-term safety and effectiveness of turoctocog alfa in a diverse and heterogeneous real-world patient population with haemophilia A in Japan.

2. Materials and methods

2.1. Study design

This was a multicentre, non-interventional, PMS study conducted in Japanese patients with haemophilia A (18 sites; August 2014-December 2018; NCT02207218). This study was required by Japan’s re-examination system (Article 14-4: Pharmaceutical Affairs Law) [14] and the Ministry of Health, Labour and Welfare (MHLW) ordinance on Good Post-marketing Study Practice (GPSP) [15]. All independent ethics committees, institutional review boards and other local bodies approved the study, which was conducted in accordance with the Declaration of Helsinki, MHLW ordinance on GPSP [15], Guidelines for Good Pharmacoepidemiology Practices [16] and applicable regulations. All patients/representatives provided written consent.

2.2. Patients

Male and female patients of any age with haemophilia A diagnosis, who themselves or their parents and physicians decided to initiate treatment with turoctocog alfa (including PTPs and PUPs), were eligible for participation. Exclusion criteria were previous participation in this study (rejoining after withdrawal); known/suspected allergy to turoctocog alfa or related products; mental incapacity, unwillingness or language barriers that preclude understanding or cooperation.

2.3. Treatment

Patients were treated with turoctocog alfa according to the Japanese package insert. For routine administration, doses were 20–40 IU FVIII per kg body weight every second day or 20–50 IU FVIII per kg body weight three times weekly. In patients aged ≤12 years, doses of 25–50 IU FVIII per kg body weight every second day or 25–60 IU FVIII per kg body weight three times weekly were administered [5]. The dose and frequency were based on the treating physician’s discretion. Turoctocog alfa treatment could be continued after FVIII inhibitor development.

2.4. Objectives, study endpoints and assessments

The primary objective was to assess the safety of turoctocog alfa in PTPs and PUPs with haemophilia A. The primary endpoint was the frequency of adverse events (AEs) during the 2-year study period. AEs were classified per Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and preferred term. Supportive secondary safety endpoints included frequency of adverse reactions (ARs), serious AEs (SAEs) and serious ARs (SARs). Medical event of special interest (MESI) was defined as follows: (i) medication errors concerning study products; (ii) inhibitor development: a positive result (Bethesda Unit [BU] ≥ 1.0/mL by Bethesda assay was used as a cutoff at the time of this study); and (iii) allergic reactions/hypersensitivity, including study product–related anaphylactic reaction. Rather than the globally used Nijmegen-Bethesda assay (with an FVIII inhibitor positivity cutoff of 0.6 BU/mL), the Bethesda assay cutoff value of 1.0 BU/mL has been frequently used in Japan [17,18]. Other post-marketing studies on FVIII products in Japan have also previously reported the use of the Bethesda assay with a cutoff value of 1.0 BU/mL.

The secondary objective was to assess the clinical effectiveness of turoctocog alfa for prophylaxis and on-demand treatment of bleeds and for prevention of bleeds during/after surgery in PTPs and PUPs with haemophilia A. Supportive secondary effectiveness endpoints included the haemostatic effect of turoctocog alfa in treating bleeds and during surgery, annualised bleeding rate (ABR) for patients on the prophylaxis regimen, total consumption of turoctocog alfa per patient (prophylaxis, treatment of bleeds and during surgery) per year, consumption of turoctocog alfa per bleed, consumption of turoctocog alfa per month with the prophylaxis regimen and consumption of turoctocog alfa during surgery. As this was a real-world treatment scenario, some of the same patients had periods of regular replacement and periods of on-demand treatment, hence making the separation into groups difficult. The ABR for the ‘treated including prophylaxis’ group has been calculated only for the period during which the patient was on regular replacement therapy.

2.5. Statistical methods

The safety analysis set (SAS) included patients who were administered ≥1 dose of turoctocog alfa during the study period (except cases of duplication, absence of doctor signature or seal on case report forms or informed consent and lost to follow-up). The effectiveness analysis set (EAS) included patients who were administered ≥1 dose of turoctocog alfa during the study period (except off-label use).

Data were mainly evaluated using descriptive statistics. The incidence rate of patients who developed FVIII inhibitors (≥1.0 BU/mL by Bethesda assay) was calculated as the number of patients who developed inhibitors divided by the number of patients exposed to turoctocog alfa during the study period.

All effectiveness endpoints were based only on data on the bleeds requiring treatment. Haemostatic responses for treatment of bleeds and during surgeries were evaluated using a 4-point scale (excellent/good [success]; moderate/none/missing [failure]) (Supplementary Table 1). ABR was calculated for each patient as the number of bleeding episodes requiring treatment divided by the time spent with prophylaxis in the study (years) and was summarised by median, 25th percentile, 75th percentile, minimum and maximum. In addition, ABR was estimated using a negative binomial model with a log-link function and the logarithm of the time spent with prophylaxis in the study as an offset, and corresponding 95% confidence interval (CI) values were presented. Sensitivity analysis was performed using a Poisson model, allowing for overdispersion with a log-link function and the logarithm of the time spent with prophylaxis in the trial as an offset. Missing values were not imputed. All analyses were performed using SAS version 9.4.

3. Results

3.1. Patients

Of the 40 patients enrolled, 39 patients were included in the SAS and EAS, with a mean (standard deviation [SD]) of 178.4 (156.9) exposure days to turoctocog alfa. In total, 25 patients (64.1%) completed the study (Figure 1; Table 1).

Figure 1. Patient disposition. CRF: clinical report form.

Table 1. Patient demographics and baseline clinical characteristics (SAS).

Baseline characteristics and demographics
All	n = 39
Median (IQR; Min, Max), age, years
All	39 (16.0–54.0; 0, 74)
PTP	42.0 (31.0–54.0; 5, 74)
PUP^a	0.0 (0.0–4.0; 0, 55)
Unknown/missing	15.0 (15.0–15.0; 15, 15)
Sex, male, n (%)	39 (100)
Body weight (kg)
n	37
Median (IQR; Min, Max)	64.4 (50.0–69.9; 6.5, 90.0)
Previous treatment with clotting factor, n (%)
PTP	33 (84.6)
PUP	5 (12.8)
Unknown/missing	1 (2.6)
Severity of haemophilia A, n (%)
Severe	27 (69.2)
Moderate	7 (17.9)
Mild	5 (12.8)
Unknown/missing	0 (0.0)
Severity of haemophilia A in PTPs, n (%)
Severe	22 (66.7)
Moderate	6 (18.2)
Mild	5 (15.2)
Unknown/missing	0 (0.0)
Severity of haemophilia A in PUPs, n (%)
Severe	4 (80.0)
Moderate	1 (20.0)
Mild	0 (0.0)
Unknown/missing	0 (0.0)
Lowest FVIII level, %
N	36
Median (IQR; Min, Max)	0.0 (0.0–1.0; 0.0, 10.0)
Presence of target joint, n (%)
Yes	14 (35.9%)
No	24 (61.5%)
Unknown/missing	1 (2.6%)
Number of bleeds in the 12 months prior to turoctocog alfa treatment
n	36
Median (IQR; Min, Max)	3.5 (1.0–11.0; 0.0, 60.0)
FVIII inhibitor at baseline, n (%)
Yes	4 (10.3)
No	33 (84.6)
Unknown/missing	2 (5.1)
Dose administered for prophylaxis regimen converted by BW, IU/kg per dose, during prophylaxis
N	24
Median (IQR; Min, Max)	29.8 (22.2–38.5; 16, 72)
Average number of bleeds per month for on-demand treatment (times)
N	13
Median (IQR; Min, Max)	1.0 (1.0–2.0; 0.0, 12.0)
Number of bleeds within the previous 12 months on prophylaxis therapy (times)
N	20
Median (IQR; Min, Max)	5.0 (1.0–13.5; 0.0, 60.0)

Severe: FVIII level <1%; moderate: FVIII level 1%-5%; mild: FVIII level >5% and <40% of normal.

^a Age of patients with no treatment history was 4 years (n = 1; severe), 0/<1 years (n = 3; severe) and 55 years (n = 1; moderate).

BW: body weight; FVIII: coagulation factor VIII; IQR: interquartile range; Min: minimum; Max: maximum; PTP: previously treated patient; PUP: previously untreated patient; SAS: safety analysis set.

In total, 33 (84.6%) patients were PTPs, 5 (12.8%) were PUPs and 1 patient’s previous treatment was unknown/missing. Four (10.3%) patients were FVIII inhibitor-positive at baseline, with highest history of inhibitor levels at 3.0, 15.0, 148.0 and 469.0 BU/mL, respectively (Table 1; Supplementary Table 2). Female patients were not receiving turoctocog alfa during this study period.

Patients were categorised into ‘prophylaxis only’ (5 [12.8%]), ‘on-demand only’ (3 [7.7%]), ‘others only’ (1 [2.6%]), ‘treated including prophylaxis’ (34 [87.2%]), ‘treated including on-demand’ (31 [79.5%]), ‘treated including others’ (14 [35.9%]) and ‘missing’ (0 [0.0%]) (Supplementary Table 3). Doctors could choose ‘prophylaxis’, ‘on-demand’ or ‘others’ (e.g. surgery) for patients’ treatment in the reporting form. Some doctors reported two or more types of treatments as these were real-world data. ‘Prophylaxis only’ means patients treated only prophylactically for the whole term of the study. On the other hand, ‘treated including prophylaxis’ means patients receiving any form of turoctocog alfa treatment in addition to prophylaxis, including prophylactic and on-demand treatment, for some period during the study period. Most patients received turoctocog alfa treatment regimens that included prophylaxis (87.2%) or included on-demand regimens (79.5%); only prophylaxis and on-demand regimens were reported by 12.8% and 7.7% of patients, respectively. All four patients who were FVIII inhibitor-positive at baseline received treatment regimens that included both prophylaxis and on-demand regimens (Supplementary Table 3), two of whom with high levels of inhibitor at baseline received immune tolerance induction. In both these PTPs who had inhibitors at baseline, the immune tolerance induction was not successful in eliminating the inhibitors.

3.2. Safety

Thirteen patients (33.3%) experienced 32 AEs, corresponding to an incidence rate of 60.4/100 patient-years of exposure (PYE). Of the 32 AEs, 17 were mild and 27 were unrelated to treatment (judged by the physician). Seven patients (17.9%) reported ≥1 SAE; the incidence rate was 30.2/100 PYE (Table 2; Supplementary Table 4). Two patients (5.1%) reported ≥1 AR (incidence: 7.6/100 PYE); one (2.6%) reported ≥1 SAR (incidence: 5.7/100 PYE) (Table 2). No death was reported in this study.

Table 2. Summary of AEs, ARs, SAEs and SARs (SAS).

	All N = 39
	n (%)	Event	Rate of occurrence, events per 100 PYE
AEs	13 (33.3)	32	60.4
ARs	2 (5.1)	4	7.6
SAEs	7 (17.9)	16	30.2
SARs	1 (2.6)	3	5.7
AEs that caused withdrawal	2 (5.1)	2	3.8
Severity of AEs
Severe	4 (10.3)	8	15.1
Moderate	2 (5.1)	6	11.3
Mild	6 (15.4)	17	32.1
Missing	1 (2.6)	1	1.9
Causality of AEs^a
Probable	2 (5.1)	3	5.7
Possible	1 (2.6)	2	3.8
Not related	10 (25.6)	27	51.0
Missing	0 (0.0)	0	0.0

Total exposed years: 52.9 years.

^a Causality judged by the physician.

AE: adverse event; AR: adverse reaction; n: number of patients; PYE: patient-years of exposure; SAE: serious adverse event; SAR: serious adverse reaction; SAS: safety analysis set.

MESI led to discontinuation of turoctocog alfa treatment in two patients. In a 30-year-old PTP with mild haemophilia A and without renal/liver impairment at baseline, allergic reaction/hypersensitivity (pruritus) led to withdrawal (2.6%; incidence: 1.9/100 PYE). The AE was deemed possibly related to turoctocog alfa use; the patient eventually recovered. The time from the last administration of turoctocog alfa to the onset of this AE was 720 hours (30 days). The total dose of turoctocog alfa until onset of this AE was 9000 IU.

The second case was an infant PUP with severe haemophilia A without renal/liver impairment at baseline who reported inhibitor development (2.6%; incidence: 3.8/100 PYE) that caused withdrawal. This patient first reported FVIII inhibitor development at 8 months of age, 25 days after turoctocog alfa initiation (12 exposure days [EDs]); the patient received prophylaxis with turoctocog alfa at 500 IU thrice per week; the inhibitor level was 39.4 BU/mL. Immune tolerance induction therapy was initiated, and the patient continued to receive turoctocog alfa (1,000 IU daily). At 2 years of age, the PUP reported increased inhibitor levels that resulted in study discontinuation after 534 EDs. The patient underwent two planned surgeries, central venous catheterization and central venous port placement during the study period. Recombinant FVIIa (rFVIIa) was used during central venous port placement, and no other drugs other than turoctocog alfa (with good haemostatic effect) were used during central venous catheterization. No medication errors were reported. The rate of inhibitor development was 0% (0/33), 20% (1/5) and 25% (1/4) in PTPs, PUPs and PUPs with severe type, respectively. Two out of 4 PTPs with inhibitors at baseline received immune tolerance induction, which was not successful in eliminating the inhibitors.

3.3. Effectiveness

3.3.1. Haemostatic effects

Turoctocog alfa was used to treat 383 bleeding episodes, of which treatment was considered successful for 350 (91.4%) bleeds. No apparent difference was observed in subgroup analyses by treatment regimen (Table 3). Turoctocog alfa was administered for 14 surgeries, of which the treatment was considered successful for 12 (85.7%) surgeries (Table 3). Subgroup analysis showed that treatment success rates for bleeding episodes and during surgery were 91.1% and 83.3% in PTPs and 100.0% and 87.5% in PUPs, respectively. The results of subgroup analysis of patients during surgical procedures and treatment of bleeding episodes by pre-treatment status, severity of haemophilia, and age and renal/liver impairment status are presented in Supplementary Tables 5 and 6.

Table 3. Haemostatic response to turoctocog alfa in the treatment of bleeding episodes and surgical bleeding by treatment regimen subgroup (EAS).

	All	Prophylaxis only (n = 5)	On-demand only (n = 3)	Treated including prophylaxis (n = 34)	Treated including on-demand (n = 31)
Treatment of bleeds
Total number of bleeding episodes^a, n	383	0	6	375	382
Two-point scale (including missing as failure)^b, n (%)
Success	350 (91.4)	0 (-)	6 (100.0)	342 (91.2)	349 (91.4)
Failure	33 (8.6)	0 (-)	0 (0.0)	33 (8.8)	33 (8.6)
Surgery management
Total number of surgical bleedings^a, n	14	1	0	13	10
Two-point scale (including missing as failure)^b, n (%)
Success	12 (85.7)	0 (0.0)	0 (-)	11 (84.6)	9 (90.0)
Failure	2 (14.3)	1 (100.0)	0 (-)	2 (15.4)	1 (10.0)

^a Only episodes of bleeding for which turoctocog alfa was administered were included.

^b Considered good/excellent as success, and moderate/none/missing as failure.

EAS: effectiveness analysis set; n: number of patients.

3.3.2. ABR for prophylaxis regimens

The median (interquartile range [IQR]) ABR (episodes/year) of patients receiving the prophylaxis regimen (treated including prophylaxis [n = 34] and prophylaxis only [5/34]) during the study period was 1.74 (0.00–10.99) and 0.00 (0.00–0.00), respectively. The median (IQR) ABR was 1.99 (0.00–13.20) in PTPs (n = 29) and 1.00 (0.23–2.36) in PUPs (n = 4) (Table 4). The estimated ABR (n = 34) was 6.19 (95% CI, 3.69–10.38). Poisson model sensitivity analysis estimated an ABR (n = 34) of 6.26 (95% CI, 3.95–9.94).

Table 4. ABR for prophylaxis regimen (EAS).

ABR, number of bleeding episodes/year
Treatment regimen	All (Treated including prophylaxis)	Prophylaxis only
N	34	5
Median	1.74	0.00
IQR	0.0–10.99	0.0–0.0
Minimum, maximum	0.0, 24.7	0.0, 0.0
Treatment history	PTP	PUP	Missing
N	29	4	1
Median	1.99	1.00	1.18
IQR	0.0–13.2	0.23–2.36	1.18–1.18
Minimum, maximum	0.0, 24.7	0.0, 3.2	1.2, 1.2
Estimated ABR of patients with prophylaxis regimen (negative binomial model; episodes/year)^a
Treatment regimen	All (Treated including prophylaxis)	Prophylaxis only
N	34	5
Estimate (95% CI)	6.19 (3.69–10.38)	-
Treatment history	PTP	PUP	Missing
N	29	4	1
Estimate (95% CI)	6.99 (4.11–11.90)	1.65 (0.34–8.15)	1.18 (0.06–23.44)

^a The number of bleeding episodes was analysed using a negative binomial model with a log-link function and the logarithm of the time spent with prophylaxis in the trial as an offset.

ABR: annualised bleeding rate; CI: confidence interval; EAS: effectiveness analysis set; IQR: interquartile range; n: number of patients; PTP: previously treated patient; PUP: previously untreated patient.

3.3.3. Consumption of turoctocog alfa excluding patients with factor VIII inhibitors

The consumption of turoctocog alfa for treatment of bleeds and management of surgery by treatment regimen, i.e., total consumption, prophylaxis regimen per month, per bleeding episode and per body weight at surgery, is presented in Table 5.

Table 5. Consumption of turoctocog alfa for treatment of bleeds and management of surgery by treatment regimen (EAS; excluding patients with FVIII inhibitors).

Consumption^a	All	Prophylaxis only	On-demand only	Treated including prophylaxis	Treated including on-demand
Total consumption per year, IU/kg/year/patient
n	34	5	3	29	26
Mean (SD)	5,382.6 (7,180.1)	4,133.1 (1,452.4)	5,274.8 (6,169.6)	5,760.4 (7,474.8)	6,118.7 (8,032.4)
Median	3,664.7	3,376.4	3,406.0	4,261.5	4,456.4
Minimum, maximum	63.6, 42,593.4	2,858.1, 5,990.7	255.7, 12,162.8	315.4, 42,593.4	69.3, 42,593.4
Consumption for prophylaxis regimen per month, IU/kg/month/patient
n	29	5	-	29	-
Mean (SD)	360.6 (193.2)	359.6 (140.0)	-	360.6 (193.2)	-
Median	354.5	281.5	-	354.5	-
Minimum, maximum	27.2, 788.2	239.2, 524.4	-	27.2, 788.2	-
Consumption per bleeding episode, IU/kg/episodes^b
n	357	1	6	349	355
Mean (SD)	75.2 (76.6)	0.0 (-)	32.7 (21.0)	76.3 (77.0)	75.6 (76.6)
Median	46.6	0.0	22.1	46.6	46.6
Minimum, maximum	0.0, 573.2	0.0, 0.0	22.1, 74.6	0.0, 573.2	0.0, 573.2
Consumption per body weight at surgery, IU/kg^c
N	6	0	0	5	4
Mean (SD)	339.9 (215.5)	-	-	395.5 (186.6)	430.2 (196.0)
Median	279.4	-	-	301.8	403.6
Minimum, maximum	61.6, 670.9	-	-	242.6, 670.9	242.6, 670.9

^a Episodes reported from patients without body weight data were excluded.

^b All bleeding cases requiring treatment were included, regardless of turoctocog alfa administration (non-administration was recorded as a dose of 0 IU).

^c Consumption of turoctocog alfa during surgery was defined as the dose from the day of surgery to the day of returning to the regimen before surgery (i.e. prophylaxis or on-demand regimen).

EAS: effectiveness analysis set; IU: international unit; n: number of patients/episodes; SD: standard deviation.

4. Discussion

This study confirmed the long-term safety and effectiveness of turoctocog alfa for the prophylaxis and treatment of bleeding in a diverse and heterogeneous Japanese patient population with haemophilia A, representative of the real-world setting in Japan. In this study, 84.6% of patients were PTPs and 12.8% were PUPs; 10.3% reported the presence of FVIII inhibitors at baseline. In total, 69.2% and 17.9% of patients were categorised as having severe and moderate haemophilia A, respectively. All patients were male. It is possible that the number of female patients receiving haemophilia treatment including turoctocog alfa was small, and there could be a lack of awareness in Japan. Twenty-five out of 40 patients completed the study as the remaining patients possibly switched to extended half-life coagulation factors (EHLs) or non-factor treatment, which were launched sequentially from 2015 onwards. The majority (≥80%) of patients received turoctocog alfa as both a prophylaxis and an on-demand regimen (prophylaxis only, 12.8%; on-demand only, 7.7%). In the real-world Guardian 5 study that only included PTPs treated with turoctocog alfa in Europe and the US, 85.3% and 13.2% of patients were categorised as having severe and moderately severe haemophilia A, respectively; 92.6% and 7.4% of patients were on prophylaxis and on-demand treatment, respectively, and no patient switched from on-demand to prophylaxis or vice versa during the study [12].

Overall, AEs were reported in 33.3% of patients, with 17.9% experiencing SAEs; the most frequently reported AEs/SAEs were infections and infestations. The safety profile was comparable to that observed in other turoctocog alfa trials [6–12]. One PTP experienced an allergic reaction/hypersensitivity of pruritus, which was not reported in Guardian 5 [12]. However, pruritus has already been identified as a risk of the products. PUPs and patients with severe disease are generally at an increased risk of developing inhibitors [11,19]. In this study, the rate of inhibitor development was 0% (0/33), 20% (1/5) and 25% (1/4) in PTPs, PUPs and PUPs with severe type, respectively. In Guardian 4 that included PUPs treated with turoctocog alfa, FVIII inhibition was reported in 43.1% (25/58) of patients [11]. In the current study, no inhibitor development was reported in PTPs (n = 33), consistent with the findings of Guardian 5 and other studies of turoctocog alfa in PTPs [6–10,12]. A systematic review reported that the overall incidence rate of inhibitor development in PTPs with severe or moderately severe haemophilia A was 2.06/1,000 PYE (Advate®, 0.99; Kogenate®/Helixate®, 5.86; Kogenate® FS/Helixate NexGen®, 1.35; ReFacto®, 12.05; ReFacto-AF®, 4.64) [20]. In this study, the haemostatic success rate was 91.4% for treating bleeds and 85.7% during major surgeries for all patients. In PTPs, the haemostatic success rates for treating bleeds and during surgery were 91.1% and 83.3%, respectively, comparable with those reported in other studies that included PTPs [6–10,12,21].

The median ABR (episodes/year) for patients receiving a prophylaxis regimen was 1.74 in this study, same as that reported in Guardian 5 [12]. However, the negative binomial estimates and Poisson estimates of ABR for patients receiving a prophylaxis regimen were 6.19 and 6.26, respectively, in this study, which are higher than those reported in Guardian 5 (3.65 and 3.32, respectively) [12] and other previous studies of turoctocog alfa [7,8,10]. A systematic review comparing three rFVIII products, Kovaltry®, Advate® and turoctocog alfa, concluded that these agents had comparable ABR [22].

In this study, the mean total consumption of turoctocog alfa per patient for all patients was ∼514.9 IU/kg/month (PTPs, ∼457.1 IU/kg/month; PUPs, ∼896.7 IU/kg/month). In Guardian 5, the mean total consumption per PTP was 309.0 IU/kg/month [12]. The mean consumption for the prophylaxis regimen (360.6 IU/kg/month; excluding FVIII inhibitor patients) was higher in this study than in Guardian 5 (302.9 IU/kg/month) [12] but lower than in Guardian 7 conducted in China (524.0 IU/kg/month) [10]. Considering the body weight of patients (mean, 57.95 kg), the maximum dose of 50 IU/kg (three times weekly) for prophylaxis was consistent with the product label [5]. The mean consumption per bleed was higher (75.3 IU/kg/episode) than that in Guardian 5 (23.8 IU/kg/episode) [12]. Turoctocog alfa was the first 3,000-unit vial FVIII product available, and it could be hypothesised that many patients with poor bleeding control received a 2,000-unit vial FVIII product switched to turoctocog alfa, regardless of body weight. Furthermore, 35.9% of patients had a target joint at baseline, which might have required an increase in dosing of turoctocog alfa. The mean consumption during surgery was 339.9 IU/kg. A previous study reported that turoctocog alfa consumption on the day of surgery ranged from 27 to 153 IU/kg [21]. The higher ABR and turoctocog alfa consumption in the current study might also be attributed to the fact that the majority of patients assessed in this study received both prophylactic and on-demand regimens.

Regarding study limitations, although the study design lacks the methodological rigour of a randomised controlled trial, it represents a real-world scenario of clinical practice with a heterogenous patient population. Unlike clinical trials, this study allowed administration of turoctocog alfa both as prophylaxis and on-demand treatment without differentiating between the two. The sample size based on data availability is likely to limit generalization; subgroup analyses of effectiveness outcomes were limited by small sample size and data variability.

5. Conclusion

The results of this multicentre, non-interventional, post-marketing study of turoctocog alfa in patients with haemophilia A in clinical practice in Japan demonstrated that long-term turoctocog alfa treatment posed no newly identified safety issues and demonstrated a haemostatic effect in prophylaxis and on-demand treatments of bleeding during a 2-year treatment period.

Acknowledgements

We would like to thank all the investigators and patients who participated in the study. Medical writing support was provided by Khi Khi Choo, PhD, of Cactus Life Sciences (part of Cactus Communications) and funded by Novo Nordisk Pharma Ltd., Japan. We would also like to acknowledge Masaki Endo (Novo Nordisk Pharma Ltd.) for his contribution.

Disclosure statement

Azusa Nagao received investigator-initiated grant funding from Takeda (Shire) and Bayer and honoraria from Sanofi, Takeda, Chugai, Bayer, Fujimoto, KMB, Pfizer, JB, Novo Nordisk and CSL, outside the submitted work. Ayumi Deguchi is an employee of Novo Nordisk Pharma Ltd. Keiji Nogami received grants from Takeda Co. Ltd., Sanofi S.A. and CSL Behring; research funding from Chugai Pharmaceutical Co., Ltd., F. Hoffmann-La Roche Ltd., Bayer A/G, Novo Nordisk A/S and KM Biologics; and honoraria from Takeda Co. Ltd. (Baxalta/Shire), Bayer A/G, Novo Nordisk A/S, Sanofi S.A. (Biogen/Bioverativ), CSL Behring, Chugai Pharmaceutical Co., Ltd., F. Hoffmann-La Roche Ltd., KM Biologics (Kaketsuken) and Fujimoto Seiyaku, outside the submitted work.

Data availability statement

Data sets from Novo Nordisk–sponsored clinical research completed after 2001 for product indications approved in both the EU and US will be shared with bona fide researchers submitting a research proposal requesting access to data. The access request proposal form and access criteria can be found at novonordisk-trials.com. Data will be available permanently after research completion and approval of product and product use in both the EU and US on a specialised statistical analysis system data platform. The analyses available for use will be those approved by an independent review board according to the IRB Charter (see novonordisk-trials.com). Individual participant data will be shared in data sets in a de-identified/anonymised format. In addition, the study protocol and redacted clinical study report will be available according to the Novo Nordisk data-sharing commitments.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This study and the editorial support for this article were funded by Novo Nordisk Pharma Ltd.