Significant reduction in hemarthrosis in boys with severe hemophilia A: The China hemophilia individualized low‐dose secondary prophylaxis study

Research and Practice in Thrombosis and HaemostasisVolume 5, Issue 6 e12552 ORIGINAL ARTICLEOpen Access Significant reduction in hemarthrosis in boys with severe hemophilia A: The China hemophilia individualized low-dose secondary prophylaxis study Runhui Wu MD, PhD, Corresponding Author runhuiwu@hotmail.com orcid.org/0000-0003-4030-209X Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China Correspondence Dr. Runhui Wu, Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China Email: runhuiwu@hotmail.comSearch for more papers by this authorXiaojing Li MD, MSc, Hemophilia Diagnosis and Treatment Center, Department of Hematology and Oncology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China Hemophilia Treatment Center, Department of Pediatrics, New Century Women's and Children's Hospital, Chengdu, ChinaSearch for more papers by this authorWanru Yao MSc, Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, ChinaSearch for more papers by this authorQing Zhang MD, MSc, Hemophilia Diagnosis and Treatment Center, Department of Hematology and Oncology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, ChinaSearch for more papers by this authorMin Zhou MSc, Hemophilia Diagnosis and Treatment Center, Department of Hematology and Oncology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, ChinaSearch for more papers by this authorNingning Zhang MD, Hemophilia Comprehensive Care Center, Radiology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, ChinaSearch for more papers by this authorSheng Yang MD, MSc, Hemophilia and Diagnosis Treatment Center, Department of Ultrasound, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, ChinaSearch for more papers by this authorZhenping Chen MD, orcid.org/0000-0002-5273-145X Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, ChinaSearch for more papers by this authorYan Wang BSc, Hemophilia Comprehensive Care Center, Rehabilitation Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, ChinaSearch for more papers by this authorYangying Kuang MD, MSc, Hemophilia Diagnosis and Treatment Center, Department of Radiology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, ChinaSearch for more papers by this authorLing Tang MD, Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, ChinaSearch for more papers by this authorYingzi Zhen BSN, Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, ChinaSearch for more papers by this authorAudrey Abad BSc, audrey.abad@sickkids.ca orcid.org/0000-0001-8396-3168 Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, CanadaSearch for more papers by this authorAndrea S. Doria MD, PhD, MSc, MBA, Department of Diagnostic Imaging, Medical Imaging Department, The Hospital for Sick Children, University of Toronto, Toronto, Canada The Hospital for Sick Children, Research Institute, University of Toronto, Toronto, ON, CanadaSearch for more papers by this authorPamela Hilliard BSc.PT, pamela.hilliard@sickkids.ca orcid.org/0000-0002-3123-3400 Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, CanadaSearch for more papers by this authorDanial M. Ignas BEng, orcid.org/0000-0002-3036-9541 Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, CanadaSearch for more papers by this authorPrasad Mathew MD, Division of Pediatric Hematology/Oncology, Presbyterian Health Services Hospital, Albuquerque, NM, USASearch for more papers by this authorDerek Stephens MSc, The Hospital for Sick Children, Research Institute, University of Toronto, Toronto, ON, CanadaSearch for more papers by this authorVictor S. Blanchette MB, BChir(Cantab), FRCPC, victor.blanchette@sickkids.ca orcid.org/0000-0003-3341-5010 Division of Hematology/Oncology, The Hospital for Sick Children and Department of Pediatrics, University of Toronto, Toronto, ON, CanadaSearch for more papers by this authorKoon-Hung Luke MD, Department of Pediatrics, Laboratory Medicine and Pathology, Division of Hematology and Oncology, University of Ottawa, Children Hospital of Eastern Ontario, Ottawa, ON, CanadaSearch for more papers by this author Runhui Wu MD, PhD, Corresponding Author runhuiwu@hotmail.com orcid.org/0000-0003-4030-209X Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China Correspondence Dr. Runhui Wu, Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China Email: runhuiwu@hotmail.comSearch for more papers by this authorXiaojing Li MD, MSc, Hemophilia Diagnosis and Treatment Center, Department of Hematology and Oncology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China Hemophilia Treatment Center, Department of Pediatrics, New Century Women's and Children's Hospital, Chengdu, ChinaSearch for more papers by this authorWanru Yao MSc, Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, ChinaSearch for more papers by this authorQing Zhang MD, MSc, Hemophilia Diagnosis and Treatment Center, Department of Hematology and Oncology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, ChinaSearch for more papers by this authorMin Zhou MSc, Hemophilia Diagnosis and Treatment Center, Department of Hematology and Oncology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, ChinaSearch for more papers by this authorNingning Zhang MD, Hemophilia Comprehensive Care Center, Radiology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, ChinaSearch for more papers by this authorSheng Yang MD, MSc, Hemophilia and Diagnosis Treatment Center, Department of Ultrasound, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, ChinaSearch for more papers by this authorZhenping Chen MD, orcid.org/0000-0002-5273-145X Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, ChinaSearch for more papers by this authorYan Wang BSc, Hemophilia Comprehensive Care Center, Rehabilitation Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, ChinaSearch for more papers by this authorYangying Kuang MD, MSc, Hemophilia Diagnosis and Treatment Center, Department of Radiology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, ChinaSearch for more papers by this authorLing Tang MD, Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, ChinaSearch for more papers by this authorYingzi Zhen BSN, Hemophilia Comprehensive Care Center, Hematology Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, ChinaSearch for more papers by this authorAudrey Abad BSc, audrey.abad@sickkids.ca orcid.org/0000-0001-8396-3168 Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, CanadaSearch for more papers by this authorAndrea S. Doria MD, PhD, MSc, MBA, Department of Diagnostic Imaging, Medical Imaging Department, The Hospital for Sick Children, University of Toronto, Toronto, Canada The Hospital for Sick Children, Research Institute, University of Toronto, Toronto, ON, CanadaSearch for more papers by this authorPamela Hilliard BSc.PT, pamela.hilliard@sickkids.ca orcid.org/0000-0002-3123-3400 Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, CanadaSearch for more papers by this authorDanial M. Ignas BEng, orcid.org/0000-0002-3036-9541 Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, CanadaSearch for more papers by this authorPrasad Mathew MD, Division of Pediatric Hematology/Oncology, Presbyterian Health Services Hospital, Albuquerque, NM, USASearch for more papers by this authorDerek Stephens MSc, The Hospital for Sick Children, Research Institute, University of Toronto, Toronto, ON, CanadaSearch for more papers by this authorVictor S. Blanchette MB, BChir(Cantab), FRCPC, victor.blanchette@sickkids.ca orcid.org/0000-0003-3341-5010 Division of Hematology/Oncology, The Hospital for Sick Children and Department of Pediatrics, University of Toronto, Toronto, ON, CanadaSearch for more papers by this authorKoon-Hung Luke MD, Department of Pediatrics, Laboratory Medicine and Pathology, Division of Hematology and Oncology, University of Ottawa, Children Hospital of Eastern Ontario, Ottawa, ON, CanadaSearch for more papers by this author First published: 18 September 2021 https://doi.org/10.1002/rth2.12552 Handling Editor: Pantep Angchaisuksiri. Institutions where the work was carried out: (1) Beijing Children's Hospital, Capital Medical University, National Center for Children's Health. (2) Chengdu New Century Women and Children's Hospital. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract Introduction In countries with restricted access to clotting factor concentrates, early implementation of low-dose prophylaxis is recommended over episodic treatment. Objective The objective of this 1-year prospective secondary prophylaxis study was to evaluate the efficacy of a dose/frequency escalating protocol in young boys with hemophilia A in China. Methods Boys were started on a low-dose protocol (minimum 10–15 IU/kg of factor VIII [FVIII] twice weekly). Escalation was based on index joint bleeding, swelling/persistent joint swelling, and serial ultrasound (gray scale and color Doppler) examinations of index joints. Results Thirty-three boys, median age 4.8 years (interquartile range, 3.8-6.1) were enrolled in a 3-month observation period that preceded a 1-year prophylaxis phase. A significant reduction in total bleeding events (43.0%, P = .001), index joint bleeds (53.2%, P = .002), and target index joint bleeds (70.0%, P = 0.02) was observed during the prophylaxis phase. During the prophylaxis period, 40% of target joints resolved. The percentage of boys with zero index joint bleeds increased significantly (P = .004) from 51.5% during the observation phase to 81.8% in last quarter of the prophylaxis phase (months 10-12). There was no progression of arthropathy based on physical examination (Hemophilia Joint Health Score), X-ray, and ultrasound obtained at entry into the prophylaxis phase and at study exit. The median FVIII consumption over the prophylaxis phase was 1786 IU/kg/y. Conclusion A low-dose, individualized prophylaxis protocol, guided by individual bleeding profiles and serial assessment of joint status, enables escalation of treatment intensity in boys with severe hemophilia A, leading to a significant reduction in bleeding events and reduction in target joint bleeding. Essentials In resource-constrained countries, early low-dose. Significant reduction in total, index joint, and target joint bleeding was observed over 1 year. No progression of arthropathy based on physical examination, X-ray, and ultrasound was observed. Low-dose individualized secondary prophylaxis leads to reduced bleeding in boys with hemophilia A. 1 INTRODUCTION 1.1 Background The hallmark of moderate/severe hemophilia is recurrent bleeding into joints leading to painful, disabling arthropathy over time. The joints (index joints) most frequently affected are the ankles, knees, and elbows. In pursuit of optimizing long-term joint health in persons with hemophilia, preventive prophylaxis regimens have shifted from fixed, weight-based regimens1 to personalized regimens guided by individual clinical bleeding patterns2, 3 and/or pharmacokinetic profiles.4-6 Of note, evidence from recent prospective prophylaxis trials demonstrates a discrepancy between objectively determined joint damage and clinically evident index joint bleeding, suggesting that subclinical bleeding into index joints may contribute to arthropathy in persons with hemophilia.7, 8 Considering that the aim of long-term prophylaxis is to optimize joint health and quality of life (QoL) in persons with hemophilia, the use of outcome measures to assess the benefits of different prophylaxis regimens is becoming increasingly important. Included in the battery of available outcome measures are joint scores determined by physical examination using validated instruments such as the Hemophilia Health Joint Score (HJHS) and imaging studies that include some combination of plain radiographs (X-rays), magnetic resonance imaging, (MRI), and ultrasound.9-11 Until recently, care for boys with moderate/severe hemophilia in China was essentially episodic (on-demand) treatment leading to the development of clinically significant arthropathy in >90% of boys by ages 6 to 9 years with an associated impairment in their QoL.12 Following the introduction of weight-based, low-dose prophylaxis regimens demonstrating an impressive reduction in index joint bleeding rates, the need to introduce and evaluate personalized prophylaxis regimens for boys with moderate/severe hemophilia in China has become a high priority.13-15 The objective of this 1-year prospective study (the China Hemophilia Individualized Prophylaxis Study [CHIPS]) was to evaluate and report the efficacy of a dose/frequency escalating dose secondary prophylaxis protocol in young boys with hemophilia A. 2 MATERIALS AND METHODS This was an investigator-initiated, industry-sponsored (Bayer) 1-year prospective single-arm, interventional (secondary prophylaxis), clinical trial (ClinicalTrials.gov, NCT02999308). 2.1 Participating hemophilia treatment centers The sponsor site for the CHIPS study was Beijing Children's Hospital (BCH), in collaboration with the Chengdu New Century Women and Children's Hospital (CNCWCH). Initiation and ongoing support and oversight were provided throughout the study by invited experts from Canada (VSB, ASD, PH, and KHL). Subjects were enrolled from May 2016 until June 2017. 2.2 Research ethics approval The study was approved by the Research Ethics Boards at BCH and CNCWCH. Informed consent was obtained from parents of all enrolled boys. 2.3 Study design There were two periods within the study, a preprophylaxis observation period of 3 months followed by a 1-year prophylaxis period using a dose/frequency escalation protocol (Table 1 and Figure 1). Subjects were evaluated at the hemophilia treatment centers (HTCs) at BCH or CNCWCH every 3 months. These visits included a detailed review of all recorded bleeding events and factor VIII (FVIII) infusions by the local clinical/research staff, a physical examination of the index joints by an experienced physical therapist familiar with the use of the HJHS, and imaging studies as specified in the study protocol (Table 1). TABLE 1. Outline of CHIPS study protocol Outcome measures Prestudy observation period 1-year prophylaxis period (3 months) Q1 Q2 Q3 Q4 Review of bleeding events and FVIII infusions (IU/kg) X X X X X Physical examination of index joint scores (HJHS) X X X X X-ray (Pettersson) scores X X Ultrasound (gray-scale soft-tissue domain and color Doppler) scores X X X X Abbreviations: FVIII, factor VIII; HJHS, Hemophilia Joint Health Score; IU, International Units; Q, Quarter. FIGURE 1Open in figure viewerPowerPoint Dose and frequency escalation steps of the protocol 2.4 Study monitoring Teleconferences and in-person meetings between members of the local China study teams and the invited Canadian experts were held at regular intervals to review the progress of the study, bleeding events, and dose escalation of study participants (Table 2). Formal on-site study initiation and close-out visits by representatives of the expert team (ASD, PH, and KHL) occurred in 2017 and 2018. During these on-site visits, a comprehensive review of bleeding events and FVIII infusion logs, HJHS worksheets and scoresheets, imaging findings, and dose escalations were reviewed and cross-checked. TABLE 2. Dose escalation criteria Index joint assessment Frequency Description Score Bleeding Every 3 months ≥ 2 bleeds in any single index joint 2 1 index joint bleed 1 Ultrasound (gray-scale soft-tissue domain and color Doppler) Every 3 months Changes of gray-scale US score ≥3 2 Changes of gray-scale US score =1 AND changes of color Doppler perisynovial vascularity score ≥1; OR changes of gray-scale US score =2 1 Physical examination of index joints (HJHS) Every 3 months Change of swelling score on HJHS from 0 to 2 or 1 to 3 (not considered to be related to an acute bleed) 2 Persistent swelling that is mild (score 1) or moderate (score 2) 1 Total score required for dose escalation ≥2 Note Evaluation: <2 scores: "Sufficient", remain on current prophylaxis step (Figure 1). ≥2 scores: "Insufficient," escalate to the next prophylaxis step (Figure 1). Abbreviations: HJHS, Hemophilia Joint Health Score; US, ultrasound. 2.5 Study participants 2.5.1 Inclusion criteria Eligible participants were boys aged 1 to 7 years with moderate or severe hemophilia A and a baseline circulating FVIII level of <2 IU/dL16 who were receiving episodic (on-demand) treatment or low-dose prophylaxis (10–15 IU/ kg body weight twice per week) at the time of enrollment into the 3-month observation phase of the study (Table 1). A history of >50 exposure days to FVIII was an additional requirement to ensure that study participants were at low risk for developing neutralizing allo-antibodies (inhibitors) to FVIII during the period of the study. 2.5.2 Exclusion criteria Exclusion criteria included a current inhibitor to FVIII defined as an inhibitor level of >0.6 Bethesda Units (BU) using the Nijmegen modification of the Bethesda assay confirmed by two separate tests17 and presence of other bleeding or chronic disorders. Boys whose parents were deemed by the local study teams to be unable to comply with the study protocol were not eligible for study enrollment. 2.6 Observation and prophylaxis phases All participants started the 12-month prophylaxis phase of the study protocol (Table 1) on low-dose prophylaxis (Figure 1), including those boys who were on episodic treatment (n = 6) during the preprophylaxis observation phase. Intensification of prophylaxis (dose/frequency) occurred based on a priori escalation criteria that included frequency of index joint bleeding as recorded in participants' infusion logs; persistent or increased swelling (present from one 3-month assessment to the next) as assessed using the HJHS version 2.118; and ultrasound findings using gray-scale soft-tissue domain (effusion or hemarthrosis, synovial hypertrophy, and hemosiderin) 11 and color Doppler (Table 2).19 Treatment of breakthrough bleeding into index joints was at the discretion of the patients' local physicians. FVIII doses were rounded to the nearest vial to avoid waste. 2.7 Outcome variables 2.7.1 Target joints In this study, a target joint was defined as an index joint in which three or more spontaneous bleeds occurred within a consecutive 6-month period.16 Resolution of target joint bleeding was defined as ≤2 bleeds into an index joint within a consecutive 12-month period.16 2.8 Outcome measures Outcome measures included all bleeds, index joint bleeds, target index joint bleeds, index joint scores using the HJHS,18 Pettersson X-ray scores,10 gray-scale soft-tissue domain,11 and color Doppler ultrasound scores.19 2.9 FVIII consumption The annual FVIII consumption (IU/kg/y) was calculated for each participant based on information retrieved from infusion diaries and FVIII dispensation records provided by the Pharmacy Departments in each of the two participating HTCs. Dispensation records also included FVIII used for breakthrough bleeding episodes. 2.10 Data sources 2.10.1 Bleeding/infusion records Families were instructed to keep bleeding/infusion records in diaries that were reviewed at the 3-month study visits. As part of quality assurance for this study, parents of boys enrolled into this study received detailed training regarding the signs and symptoms of acute index joint bleeds based on the published ISTH definitions of an acute joint bleed.16 2.10.2 HJHS version 2.1 Musculoskeletal evaluation of each participant's index joints was performed by experienced physiotherapists trained in the use of the HJHS at each of the participating HTCs as per the approved study protocol (Table 1). Since the HJHS is validated only for boys with hemophilia aged ≥4 years, younger participants were not evaluated with this tool until they reached the age of 4 years. 2.11 Data acquisition of imaging studies 2.11.1 Plain radiographs Non–weight-bearing X-rays (anteroposterior and lateral) of the six index joints were obtained at entry into the prophylaxis phase and at study exit (month 12) as per the approved study protocol (Table 1). 2.11.2 Ultrasound Gray-scale and color Doppler ultrasound scans were performed at entry into the prophylaxis phase and at 3, 6, 9, and 12 months (study exit) by two experienced operators at BCH (NZ and AH) and one at CNCWCH (SY) using protocols for data acquisition of images as previously described.20-22 Ultrasound images were acquired using a 12–5-MHz linear-array transducer on an iU22 scanner (Philips Medical Systems, Bothell, WA, USA). The focus and depth of the ultrasound beam was adjusted to the patient's biotype. For color Doppler low filter, flow rate at the range of ±2.3 cm/s and color gain settings of 79% and pulse-repetition frequency of 402 Hz were set up, and the imaging parameters were held constant throughout the examination. The gray-scale/color Doppler scan time for each joint was ≈10 minutes. 2.12 Data interpretation of imaging studies At BCH, X-ray and ultrasound studies were scored independently by two radiologists (NZ and AH) with 12 and 6 years of experience. Differences in scores were adjudicated by consensus. At CNCWCH, X-ray studies were scored by YK, who at the time of evaluation had 3 years of experience. Ultrasound studies were scored by SY, who at the time of the evaluation had 10 years of experience. NZ, the senior study radiologist from BCH, acted as an independent reader for all X-ray and ultrasound studies from CNCWCH. Differences in scores were resolved by consensus. Study readers were not blinded to the identity of patients when interpreting findings from different imaging modalities; however, they were blinded to clinical information, and they were not involved with decisions regarding escalation of individual subjects. These decisions were the responsibility of the clinical teams at the two HTCs. 2.12.1 Plain radiographs Both BCH and CNCWCH used the Pettersson scale 10 for scoring X-ray images. 2.12.2 Ultrasound Gray-scale soft-tissue domain ultrasound Gray-scale ultrasound examinations were scored using a scale adjusted to the International Prophylaxis Study Group MRI scale.11 The subscores of this ultrasound scale were based on the worst finding for the distal tibia and fibula and proximal talus for ankles; the distal femur, proximal tibia, and patella for knees; and distal humerus and proximal radius and ulna for elbows. Cutoffs for normal (score = 0), mild (score = 1), moderate (score = 2), and severe (score = 3) soft-tissue domain scores (range, 0–9) of ankles and knees were based on a priori described criteria.11 Cutoffs for soft tissue scores of elbows were considered as similar to those of ankles given the similarity of size of the elbow and ankle joints. Color Doppler ultrasound The degree of synovial vascularity of study joints was measured on the plane that depicted the most marked vascularity according to a scoring system modified from a publication by Backhaus et al (Appendix A1–Table A1).19, 23 2.13 Sample size An a priori sample size calculation for this study was not possible given the lack of detailed bleed data in the medical records of potentially eligible subjects. An opportunity sample size of 46 subjects was used that yielded a total of 33 boys evaluable for analysis. 2.14 Statistical methods Descriptive statistics (median and interquartile range [IQR]) were used for data that was nonnormally distributed. McNemar's test was used for comparisons of all bleeds, index joint bleeds, target index joint bleeds, and subjects with zero bleeds. Wilcoxon signed-rank tests were used to compare the differences between HJHS, Pettersson, and ultrasound (gray-scale soft-tissue domain and color Doppler) scores obtained at entry into the prophylaxis phase and at study exit (month 12). Calculations and analyses were performed using SAS (version 9.4, SAS Institute, Cary, NC, USA). A two-tailed P value <0.05 was considered significant. 3 RESULTS 3.1 Characteristics of the study cohort Between May 2016 and June 2017, 46 boys were assessed for eligibility; 9 boys were excluded from enrollment into the 3-month observation phase for the following reasons: baseline FVIII level >2 dL (n = 1); age >7 years (n = 2); FVIII infusion dose >30 IU/kg (n = 1); presence of an inhibitor >0.6 BU (n = 1); and parents unwilling for their sons to comply with the burden of the study protocol (n = 4). The median age of boys at the start of the 3-month observation phase was 4.8 years (IQR, 3.8-6.1 years); 78.8% (26/33) of the study cohort had baseline FVIII levels of <1 IU/dL, and 21.2% (7/33) had FVIII baseline levels of 1–1.8 IU/dL. Nineteen boys (57.6%) had a lifetime history of target joints (n=20) before study enrollment based on reviews of available medical records at the two participating HTCs. The joints affected were ankles (n=10), knees (n = 4), and elbows (n = 6). One boy had a history of two target joints: an elbow and an ankle. The characteristics of the study cohort are detailed in Table 3. Four boys were withdrawn before the start of the prophylaxis phase: two because of inadequate insurance reimbursement for FVIII, and two because of poor compliance. TABLE 3. Characteristics of study cohort at enrollment into the observation and the 1-year prophylaxis phase Characteristics N Median Percentile 25th 75th Age at enrollment, y 33 4.8 3.8 6.1 Weight at enrollment, kg 33 18.5 16.0 20.5 BMI at enrollment 33 14.8 14.1 16.0 Physical examination of index joint scores (HJHS) 18 8.0 3.0 11.0 X-ray (Pettersson) scores 32 0.0 0.0 3.0 Ultrasound (gray-scale soft-tissue domain) scores 33 4.0 1.0 6.0 Ultrasound (color Doppler) scores 33 0.0 0.0 1.0 Note Reference ranges: The HJHS joint score ranges from 0 to 20 per index joint (total index joint score plus global gait, 0–124)18; the Pettersson joint score ranges from 0–13 per index joint (total index joint score, 0–78)10; the gray-scale ultrasound joint score ranges from 0 to 9 for soft tissues per index joint (total index joint score for soft tissues, 0–54)11; and the color Doppler ultrasound joint scores ranging from 0 to 2 per index joint (total index joint score, 0–12).19 For imaging scores, the higher the score the more diseased the joint. Abbreviations: BMI, body mass index; HJHS, Hemophilia Joint Health Score. Of the