A Novel Modified-Vista Technique With Connective Tissue Graft in the Treatment of Gingival Recession: A Case Report.

INTRODUCTION: The increasing esthetic demands from patients have required that clinicians sharpen their skills and adopt newer and more novel techniques to satisfy these demands. In periodontal therapy, periodontal plastic surgery poses a substantial challenge to the clinician, both because it is technique sensitive and also because it includes a wide array of procedures and their variations. Conventional plastic procedures have provided satisfactory results in the treatment of gingival recession but there is, presently, a greater need for more advanced procedures that cause less surgical morbidity as also provide improved results. Minimally invasive surgery has been harnessed in periodontics for this purpose and has been extensively used in multiple indications, including root coverage. Modified-Vestibular Incision Supra-periosteal Tunnel Access (M-VISTA) applies the principles of minimally invasive surgery to provide satisfactory results in root coverage. CASE PRESENTATION: A 28-year-old male patient presented with multiple Miller Class I/II buccal recession defects and associated high labial frenum on right maxillary anterior teeth. M-VISTA technique allowed coronal repositioning of gingival margin, which was then stabilized by orthodontics bracket assisted suturing technique. The V-shaped incision in the region of the frenal attachment allowed for conducting both the M-VISTA and frenectomy techniques simultaneously. Connective tissue graft was inserted in the supra-periosteal tunnel and vertical incision was sutured. Complete root coverage was achieved and maintained at 9 months with excellent esthetic outcomes. CONCLUSIONS: The use of connective tissue graft along with M-VISTA technique allows the clinician to successfully treat multiple recession defects.

How does a lifetime of painful experiences influence sensations and beliefs about pain in adults with severe haemophilia? A qualitative study.

PURPOSE: To explore the life experiences of pain in people with severe haemophilia and understand how such experiences influence beliefs and sensation of pain in adulthood. METHODS: A qualitative inquiry approach using focus groups and semi-structured individual interviews was used. Participants included people with severe haemophilia living with chronic pain. Data were analysed using reflexive thematic analysis. RESULTS: Fourteen men with a median age of 47 (range 23-73) agreed to take part. Eleven participated in two focus groups and three were interviewed over telephone. Two themes were conceptualised from the data: (i) haemophilia and pain - an evolving life biography (the personal narrative, historical, social, and medical context, continuous adaptation of activity choices, surveillance of pain and its meaning); (ii) "My normal isn't normal" - identity and self-agency (pain as a feature of life and identify with severe haemophilia, loss of enjoyable activities balanced against staying active, barriers to participation). CONCLUSIONS: Pain is a constantly evolving, lifetime feature for many adults with haemophilia and it is viewed as part of their identity with their condition. Healthcare professionals working in haemophilia should try to better understand the influence of an individuals lived experience with their haemophilia on beliefs and behaviours of pain.Implications for rehabilitationSevere haemophilia is a rare bleeding disorder that results in musculoskeletal joint disease.Adults with severe haemophilia have experienced multiple episodes of bleeding related musculoskeletal pain since childhood.Pain beliefs and behaviours in adulthood appear to be influenced by a lifetime of painful experiences associated with haemophilia.In order to better support people with haemophilia and chronic pain, healthcare professionals in haemophilia need to better understand how an individuals lived experience of pain helps inform their beliefs about it.

The experiences and beliefs of people with severe haemophilia and healthcare professionals on pain management, and their views of using exercise as an aspect of intervention: a qualitative study.

PURPOSE: To explore the experiences, views and beliefs of people with severe haemophilia and healthcare professionals (HCPs) on approaches for pain management, as well as their views on exercise being used as an aspect of management. METHODS: Taking a qualitative inquiry approach using focus groups and semi-structured interviews, participants included people with severe haemophilia living with chronic pain and haemophilia HCPs. Data were analysed using reflexive thematic analysis. RESULTS: Fourteen men with haemophilia with a median age of 47 (range 23-73) and six haemophilia HCPs agreed to participate. Of the people with haemophilia, 11 attended two focus groups and three were interviewed over telephone. Healthcare professionals were interviewed face-to-face. Two themes were conceptualised from the data: (i) haemophilia management and pain management is discordant (imbalance between good haemophilia care but poor pain management, historical medico-social influences on pain management, the need for trust); (ii) uncertain about exercise but clear on what matters (conflicting views on exercise, the need for proof of safety, personalised care). CONCLUSIONS: Options for effective pain management remain limited and what is used is heavily influenced by beliefs and experience. Exercise as a treatment option in pain management is conceptually acceptable for people with haemophilia. Effective pain management requires understanding of individual beliefs and fears, and a personalised approach supported by knowledgeable, trusted clinicians.Implications for rehabilitationMusculoskeletal joint pain and its relationship with bleeding in people with haemophilia continues to be a management challenge.Current pain management strategies are of limited effectiveness with little evidence of an approach that reflects the multi-modal pain experience.Whilst exercise and rehabilitation approaches are conceptually possible for people with severe haemophilia, barriers remain regarding perception of overall safety and effectiveness.People with severe haemophilia may consider exercise as part of a pain management strategy if it is individualised, and they are supported to do it by clinicians who understand them and their haemophilia.

A study of unprotected left main intervention in the ACS population 2013-2018.

OBJECTIVES: Our objectives were to evaluate the outcomes of left main percutaneous coronary interventions in Acute Coronary Syndrome population. METHODS: This is a retrospective& observational study. Primary endpoint is a composite of death, stent thrombosis/MI, target lesion revascularization. Secondary endpoints include individual components of the primary events analyzed separately. RESULTS: Seventy five patients, two year follow - up data was analyzed. The primary event analysis showed that the Elective Double Stent (EDS) group had a higher primary events (36% vs. 14%, p value - 0.008, Hazard ratio - 0.76 (0.51-1.15, 95% CI), in secondary event analysis stent thrombosis (ST)/Myocardial infarction (MI) rates were higher in EDS group (8% Vs 36%, p Value - 0.008, Hazard ratio- 0.63(0.35-1.14, 95%CI), there is no difference in target lesion revascularization (TLR)and death rates in both the groups. CONCLUSIONS: The provisional strategy is better than EDS in treatment of left main bifurcation lesions in the ACS population.

Population pharmacokinetics of factor IX in hemophilia B patients undergoing surgery.

Essentials Factor IX (FIX) dosing using body weight frequently results in under and overdosing during surgery. We aimed to establish a population pharmacokinetic (PK) model describing the perioperative FIX levels. Population PK parameter values for clearance and V1 were 284 mL h-170 kg-1 and 5450 mL70 kg-1. Perioperative PK parameters differ from those during non-surgical prophylactic treatment. SUMMARY: Background Hemophilia B is a bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). In the perioperative setting, patients receive FIX concentrates to ensure hemostasis. Although FIX is usually dosed according to bodyweight, under- and overdosing occurs frequently during surgery. Aim The objective was to quantify and explain the interpatient variability of perioperatively administered plasma-derived (pd) and recombinant (r) FIX concentrates. Methods Data were collected from 118 patients (median age, 40 years [range, 0.2-90]; weight, 79 kg [range, 5.3-132]) with moderate (28%) or severe hemophilia B (72%), undergoing 255 surgical procedures. Population pharmacokinetic (PK) parameters were estimated using nonlinear mixed-effect modeling in NONMEM. Results Measured perioperative FIX level vs. time profiles were adequately described using a three-compartment PK model. For a typical 34-year-old patient receiving rFIX, clearance (CL), intercompartmental clearance (Q2, Q3), distribution volume of the central compartment (V1) and peripheral compartments (V2, V3) plus interpatient variability (%CV) were: CL, 284 mL h-170 kg-1 (18%); V1, 5450 mL70 kg-1 (19%); Q2, 110 mL h-170 kg-1; V2, 4800 mL70 kg-1; Q3, 1610 mL h-170 kg-1; V3, 2040 mL70 kg-1. From 0.2 years, CL and V1 decreased 0.89% and 1.15% per year, respectively, until the age of 34 years. Patients receiving pdFIX exhibited a lower CL (11%) and V1 (17%) than patients receiving rFIX. Interpatient variability was successfully quantified and explained. Conclusions The estimated perioperative PK parameters of both pdFIX and rFIX are different from those reported for prophylactic treatment. The developed model may be used to apply PK-guided dosing of FIX concentrates during surgery.

Treatment of bleeding episodes in haemophilia A complicated by a factor VIII inhibitor in patients receiving Emicizumab. Interim guidance from UKHCDO Inhibitor Working Party and Executive Committee.

Emicizumab is a bispecific antibody that activates FX to FXa in the absence of FVIII. It has been shown to reduce bleeding episodes in people with haemophilia A complicated by a FVIII inhibitor. Despite the protection against bleeds, some breakthrough bleeds are inevitable and these may require additional haemostatic treatment. Emicizumab has been associated with severe adverse events when co-administered with activated prothrombin complex concentrate. To minimize the risk of adverse events, the UK Haemophilia Centre Doctors' Organisation issues the following updated interim guidance to its Inhibitor Guidelines for managing patients receiving Emicizumab based on the limit published information available in February 2018.

A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A.

Essentials explorer™3 was a double-blinded, multiple-dose escalation trial of subcutaneous concizumab. A pharmacodynamic relationship for unbound TFPI and thrombin generation was confirmed. No serious adverse events and no anti-drug antibodies were observed. explorer™3 data support further clinical development of concizumab in people with hemophilia. SUMMARY: Background Concizumab is a humanized mAb targeting tissue factor pathway inhibitor (TFPI), leading to enhanced thrombin generation (TG) potential. explorer™3 (NCT02490787) was a phase 1b, double-blind, multiple-dose escalation trial of subcutaneous concizumab in people with severe hemophilia A without inhibitors. Objectives The primary objective was to evaluate safety. Assessments of pharmacokinetics, pharmacodynamics and subcutaneous concizumab immunogenicity were secondary objectives. Patients/Methods Adverse events (AEs), clinical assessments and bleeding episodes were recorded. Plasma concizumab levels and unbound TFPI levels were measured with ELISAs; residual TFPI activity was measured with a chromogenic assay. Standardized assays were used to assess TG, D-dimer and prothrombin fragment 1 + 2 (F1 + 2 ) levels. explorer™3 was completed after investigation of three dose cohorts (0.25, 0.5 and 0.8 mg kg-1 , once every 4 days) had been completed. Twenty-four patients received 12 doses of concizumab or placebo in a 3 : 1 randomization over a 42-day period. Results No serious AEs and no anti-drug antibodies were observed. Fifty-four mild and two moderate AEs were observed in 19 patients. Concizumab exposure increased with dose in a non-linear manner, confirming target-mediated drug disposition. D-dimer and F1 + 2 levels were increased mostly in the highest dose cohort, in line with previous observations. The level of unbound TFPI decreased in a dose-dependent manner, and was accompanied by a residual TFPI activity decrease and an increase in peak TG. Although the trial was not powered to evaluate efficacy, a trend towards lower bleeding rates was observed in patients in the highest dose cohort. Conclusion explorer™3 data support further clinical development of concizumab for use in people with hemophilia, with or without inhibitors.

Phase 1, single-dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia.

Essentials Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII. A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia. MarzAA was safe and tolerated at intravenous doses up to 30 µg kg-1 Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX. SUMMARY: Background Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia. Objectives To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non-bleeding patients with congenital hemophilia A or B with or without inhibitors. Methods This international, phase 1, open-label study (NCT01439971) enrolled males aged 18-64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single-dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 µg kg-1 ). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD. Results Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose-limiting toxicity. No treatment-emergent severe or serious adverse events occurred. MarzAA showed linear dose-response PK across the 4.5-30 µg kg-1 dose range, with a terminal half-life of ⁓ 3.5 h. Dose-dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses. Conclusions MarzAA was tolerated at doses up to 30 µg kg-1 . The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.

Perioperative replacement therapy in haemophilia B: An appeal to "B" more precise.

INTRODUCTION: Haemophilia B is caused by a deficiency of coagulation factor IX (FIX) and characterized by bleeding in muscles and joints. In the perioperative setting, patients are treated with FIX replacement therapy to secure haemostasis. Targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of therapy. AIM: To evaluate perioperative management in haemophilia B, including monitoring of FIX infusions and observed FIX levels, whereby predictors of low and high FIX levels were assessed. METHODS: In this international multicentre study, haemophilia B patients with FIX < 0.05 IU mL-1 undergoing elective, minor or major surgical procedures between 2000 and 2015 were included. Data were collected on patient, surgical and treatment characteristics. Observed FIX levels were compared to target levels as recommended by guidelines. RESULTS: A total of 255 surgical procedures were performed in 118 patients (median age 40 years, median body weight 79 kg). Sixty percent of FIX levels within 24 hours of surgery were below target with a median difference of 0.22 IU mL-1 [IQR 0.12-0.36]; while >6 days after surgery, 59% of FIX levels were above target with a median difference of 0.19 IU mL-1 [IQR 0.10-0.39]. Clinically relevant bleeding complications (necessity of a second surgical intervention or red blood cell transfusion) occurred in 7 procedures (2.7%). CONCLUSION: This study demonstrates that targeting of FIX levels in the perioperative setting is complex and suboptimal, but although this bleeding is minimal. Alternative dosing strategies taking patient and surgical characteristics as well as pharmacokinetic principles into account may help to optimize and individualize treatment.

Ligneous cervicitis and endometritis: A gynaecological presentation of congenital plasminogen deficiency.

BACKGROUND: Congenital plasminogen deficiency is a rare autosomal recessive condition. Plasminogen deficiency is thought to result in an inability of fibrin breakdown and therefore accumulation of fibrin and formation of ligneous changes. Ligneous lesions can form on a number of mucosal membranes including the cervix and endometrium. METHODS: We report the case of a 25-year-old woman with type 1 plasminogen deficiency with ligneous cervicitis and endometritis and her treatment and clinical course over the last few years. We then review the current literature of ligneous cases of the female genital tract and discuss available treatment options. KEY RESULTS: We found 30 reported cases of ligneous lesions affecting the female genital tract, with the cervix being the most affected part. A number of treatment options have been tried by our patient and other cases in the literature. These include use of the combined oral contraceptive pill, fresh frozen plasma infusion, topical plasmin and plasminogen and trial use of plasminogen concentrate. CONCLUSIONS: This is a chronic condition requiring a multidisciplinary approach. There is currently no definitive treatment for the condition, current trials with plasminogen concentrate replacement therapy may provide a promising option for these patients in the future.

Pharmacokinetics, safety and efficacy of a recombinant factor IX product, trenonacog alfa in previously treated haemophilia B patients.

INTRODUCTION: Trenonacog alfa (IB1001) is a recombinant factor IX (rFIX) manufactured in Chinese hamster ovary (CHO) cells. IB1001 was evaluated in a multicentre clinical trial with haemophilia B patients. AIM: The aim was to establish IB1001 pharmacokinetic non-inferiority to comparator rFIX, safety and efficacy in previously treated patients (PTPs) with haemophilia B. METHODS: Subjects were severe or moderately severe haemophilia B adult and adolescent PTPs with no history of FIX inhibitors. RESULTS: IB1001 PK non-inferiority to comparator rFIX was demonstrated through ratio of AUC0-∞ in 32 subjects. IB1001 was well tolerated in all 76 treated subjects; the most common adverse drug reaction was headache (2.6% of subjects) and there were no reports of FIX inhibitors. Transient non-inhibitory binding FIX antibodies and anti-CHO cell protein antibodies developed in 21% and 29% of subjects respectively; no safety concerns were associated with development of these antibodies. Prophylaxis (mean duration ± SD: 17.9 ± 9.6 months, mean dose: 55.5 ± 12.9 IU/kg, median 1.0 infusion per week) was effective in preventing bleeds (median annual bleed rate: 1.52, interquartile range: 0.0-3.46). One or two IB1001 infusions resolved 84% of the bleeds, while for 84% of treatments haemostatic efficacy of IB1001 was rated excellent or good. IB1001 haemostatic efficacy for all 19 major surgeries was rated adequate or better than adequate. CONCLUSIONS: IB1001 is safe and efficacious for treatment of bleeds, routine prophylaxis and perioperative management in haemophilia B patients.

First report on the safety and efficacy of an extended half-life glycoPEGylated recombinant FVIII for major surgery in severe haemophilia A.

BACKGROUND: N8-GP (turoctocog alfa pegol) is an extended half-life glycoPEGylated recombinant factor VIII (FVIII) product developed for the prevention and treatment of bleeds in haemophilia A patients. AIM: This is a planned interim analysis of pathfinder™3, an international, open-label, Phase 3 trial evaluating the efficacy and safety (including immunogenicity) of N8-GP administered before, during and after major surgery in severe haemophilia A patients aged ≥12 years. METHODS: Sixteen patients who underwent 18 major surgical procedures (including synovectomy, joint replacement and ankle arthrodesis) were included here. Postoperative assessments were conducted daily for days 1-6, and once for days 7-14. Primary endpoint was N8-GP haemostatic efficacy, assessed after completion of surgery using a four-point scale ('excellent', 'good', 'moderate', 'none'). RESULTS: Haemostasis was successful (rated 'excellent' or 'good') on completion of surgery in 17 (94.4%) procedures and rated as 'moderate' (5.6%) for one surgery in a patient with multiple comorbidities who needed an intraoperative N8-GP dose (20.7 IU kg-1 ). In the postoperative period, three bleeds occurred (one during days 1-6; two during days 7-14); all were successfully treated with N8-GP. Mean N8-GP consumption on day of surgery was 80.0 IU kg-1 ; patients received a mean of 1.7 doses (median: 2, range: 1-3). No safety concerns were identified. CONCLUSION: The data showed that N8-GP was effective and well tolerated for the prevention and treatment of bleeds during major surgery; such FVIII products with extended half-lives may modify current treatment schedules, enabling fewer infusions and earlier patient discharge.

Treatment of bleeding episodes with recombinant factor VIII Fc fusion protein in A-LONG study subjects with severe haemophilia A.

INTRODUCTION: The Phase 3 A-LONG study demonstrated the safety and efficacy of rFVIIIFc for the control and prevention of bleeding episodes in severe haemophilia A. AIM: To describe the treatment of bleeding episodes with rFVIIIFc in the A-LONG study. METHODS: A-LONG subjects (<1 IU dL-1 endogenous FVIII) were treated with individualized prophylaxis (Arm 1), weekly prophylaxis (Arm 2) or episodic treatment (Arm 3). Information recorded for each bleeding episode included type, location and dose to treat the episode. RESULTS: During A-LONG, 757 bleeding episodes occurred during the efficacy period; the majority [456 (60%)] occurred in Arm 3 (episodic treatment). Of 93 subjects in the prophylaxis arms who entered the study with target joints, 43 (60%) in Arm 1 and 11 (52%) in Arm 2 did not experience a target joint bleed. Overall, 98% of bleeding episodes (and 98% of bleeds involving a target joint) resolved with one or two infusions; the median dose per infusion to treat a bleed was 27 IU kg-1 (27 IU kg-1 for target joints). Using population pharmacokinetic simulations, FVIII activity levels were predicted to be below the upper limit of normal (150 IU dL-1 ) in most patients in the event that rFVIIIFc is used to treat a bleeding episode in close proximity to a prophylactic dose. CONCLUSIONS: These findings demonstrate the efficacy of rFVIIIFc for the treatment of acute bleeding episodes in subjects with severe haemophilia A, regardless of treatment regimen.

Risk-based management of dental procedures in patients with inherited bleeding disorders: Development of a Dental Bleeding Risk Assessment and Treatment Tool (DeBRATT).

INTRODUCTION: Successful outcomes in dental management for patients with inherited bleeding disorders require close collaboration between haematology teams and dentists. AIM: To review outcomes of an interdisciplinary pathway for dental procedures by assessing adequacy and appropriateness of haemostatic management. METHODS: Two hundred dental procedures in 30 patients with inherited bleeding disorders were included. A Dental Bleeding Risk Assessment and Treatment Tool (DeBRATT) was developed to identify four categories of bleeding risk (no risk, low, moderate and high risk of bleeding) in relation to the severity of the bleeding disorder and the invasiveness of dental procedure. The adequacy and appropriateness of haemostatic therapy provided in relation to the bleeding risk was assessed with reference to the published literature. Treatment was classified as appropriate, over or under-treatment. Bleeding complication was the primary outcome. RESULTS: A high level of dental disease was noted, with 83% of patients having at least one decayed tooth and 46.7% having chronic gum disease. A total of 59.1% of the dental procedures in patients with mild bleeding disorders were over-treated (n = 65/110) and 8.9% in patients with severe disorders had an extended duration of treatment (n = 7/79). One bleeding complication was observed in a patient with Von Willebrand's disease and severe thrombocytopenia. All other procedures (99.5%) were uneventful. CONCLUSION: DeBRATT enables a risk-based approach for the management of dental procedures in patients with inherited bleeding disorders. The tool facilitates a comprehensive evaluation of bleeding risk with the potential to minimize unnecessary treatment and aid interdisciplinary communication among different clinical teams.

Low-factor consumption for major surgery in haemophilia B with long-acting recombinant glycoPEGylated factor IX.

INTRODUCTION: Surgery in patients with haemophilia B carries a high risk of excessive bleeding and requires adequate haemostatic control until wound healing. Nonacog beta pegol, a long-acting recombinant glycoPEGylated factor IX (FIX), was used in the perioperative management of patients undergoing major surgery. AIM: To evaluate the efficacy and safety of nonacog beta pegol in patients with haemophilia B who undergo major surgery. METHODS: This was an open-label, multicentre, non-controlled surgery trial aimed at assessing peri- and postoperative efficacy and safety of nonacog beta pegol in 13 previously treated patients with haemophilia B. All patients received a preoperative nonacog beta pegol bolus injection of 80 IU kg-1 . Postoperatively, the patients received fixed nonacog beta pegol doses of 40 IU kg-1 , repeated at the investigator's discretion. Safety assessments included monitoring of immunogenicity and adverse events. RESULTS: Intraoperative haemostatic effect was rated 'excellent' or 'good' in all 13 cases. Apart from the preoperative injection, none of the patients needed additional doses of nonacog beta pegol on the day of surgery. The median number of postoperative doses of nonacog beta pegol was 2.0 from days 1 to 6 and 1.5 from days 7 to 13. No unexpected intra- or postoperative complications were observed including deaths or thromboembolic events. No patients developed inhibitors. CONCLUSIONS: These results indicated that nonacog beta pegol was safe and effective in the perioperative setting, allowing major surgical interventions in patients with haemophilia B with minimal peri- and postoperative concentrate consumption and infrequent injections as reported with standard FIX products.

The use of enhanced half-life coagulation factor concentrates in routine clinical practice: guidance from UKHCDO.

Enhanced half-life factor VIII and IX products are being introduced into routine clinical practice. Published data report on clinical trials and there are limited data available on how to use these products in routine clinical practice. Many patients, for example, those with a past history of an inhibitor, have been excluded from clinical trials and there are limited data published on children. This guidance document is a consensus statement from the UK Haemophilia Centres Doctors' Organisation and aims to give pragmatic advice on the use of these products in routine practice.

Improvement in health-related quality of life in patients with haemophilia B treated with nonacog beta pegol, a new extended half-life recombinant FIX product.

INTRODUCTION: Health-related quality of life (HRQoL) of individuals with haemophilia has greatly improved with the use of factor replacement and routine prophylaxis. AIM: To explore the HRQoL of individuals with haemophilia B treated with nonacog beta pegol, an extended half-life recombinant factor IX, in a single-blind, randomized multinational phase III pivotal trial (paradigm(™) 2) and its open-label extension (paradigm(™) 4). METHODS: In the pivotal trial, adolescents and adults with haemophilia B were allocated to 28-week on-demand treatment or randomized to 52 weeks of prophylaxis with 10 or 40 IU kg(-1) nonacog beta pegol administered every seven days. In the extension trial, patients could continue on the same treatment or switch to the alternate dosing regimen at any time. HRQoL was assessed with the HAEMO-QOL/HAEM-A-QOL age-specific questionnaires and the EQ-5D. RESULTS: In the pivotal trial, adults receiving 40 IU kg(-1) prophylaxis reported significant improvements in the 'HAEM-A-QOL Total' score (-6.4 ± 8.5, P = 0.017) and in 'Sport' (-15.3 ± 8.5, P = 0.020), 'Feeling' (-15.2 ± 18.3, P = 0.010) and 'Partnership' (-9.6 ± 15.5, P = 0.046) domain scores; no significant improvements were seen in the other arms. At the pivotal trial end, fewer patients reported problems in the EQ-5D 'Mobility' and 'Pain/Discomfort' dimensions, in particular those receiving prophylaxis. In the extension trial, adult patients switching from 10 to 40 IU kg(-1) prophylaxis showed significant improvements in 'HAEM-A-QOL Total' score (-12.5 ± 8.7, P = 0.016) and 'Physical health' domain (-23.1 ± 14.4, P = 0.016). CONCLUSION: Prophylactic treatment with nonacog beta pegol 40 IU kg(-1) once weekly leads to HRQoL benefits in individuals with haemophilia B; this might be related to fewer bleeding episodes and higher FIX activity levels.