Non-severe Haemophilia Research Articles

Expert Opinion for Defining a Severe Bleeding Phenotype to Guide Prophylaxis in Patients with Nonsevere Hemophilia.

Prophylaxis is the standard of care for patients with severe hemophilia, patients with moderate hemophilia, or those with another congenital bleeding disorder that is associated with a severe bleeding phenotype and/or a high risk of spontaneous life-threatening bleeding. Patients with nonsevere hemophilia (factor VIII [FVIII] ≥ 1%) may also have a bleeding phenotype that requires prophylaxis. To date, however, there are no clear criteria as to when prophylaxis is indicated in these patients. Also, the term "severe bleeding phenotype (SBPT)" is neither included in the definitions of the International Society on Thrombosis and Haemostasis (ISTH) nor specified in the World Federation of Hemophilia (WFH) guidelines. Based on our personal experience and available evidence, we propose the criteria we use to define an SBPT and when we consider offering prophylaxis in patients with nonsevere hemophilia. Our proposals can be the basis for discussions in the community about the assessment of SBPT and the initiation of prophylaxis in patients with nonsevere hemophilia without inhibitors.

Bleeding phenotype according to factor level in 825 children with nonsevere hemophilia: data from the PedNet cohort

BackgroundInformation on bleeding phenotype in nonsevere hemophilia may be used to determine target factor levels for prophylaxis or gene therapy in severe hemophilia. ObjectivesTo assess the association between endogenous factor level and bleeding phenotype in children with nonsevere (factor [F]VIII/FIX activity 1%-25%) hemophilia A (HA) and B without prophylaxis. MethodsData on annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), and onset of bleeding were extracted from the international PedNet cohort including children born since 2000. Mean ABR and AJBR were modeled and compared according to FVIII/FIX endogenous activity (1%-2%, 3%-5%, 6%-10%, 11%-15%, 16%-20%, and 21%-25%) using negative binomial regression. Onset of bleeding was analyzed using Kaplan–Meier survival curves. ResultsEight hundred twenty-five children (40% with moderate hemophilia; 87% with HA) with median follow-up of 7.4 years/child were included. The median age at onset of bleeding and median bleeding rates changed with increasing endogenous activity. From endogenous FVIII 1% to 2% to 21% to 25%, the age at onset of bleeding changed from a median of 1.4 to 14.2 years, ABR from 1.6 to 0.1/y, and AJBR from 0.5 to 0.0/y. From endogenous FIX 1% to 2% to 16% to 25%, the onset of bleeding changed from a median of 1.7 to 6.1 years, ABR from 0.5 to 0.1/y, and AJBR from 0.1 to 0.0/y. The negative correlation between AJBR and factor level was most strongly pronounced up to a factor level of 6% in HA and hemophilia B. ConclusionEndogenous factor activity of >5% was identified as a threshold to significantly lower joint bleeding rate, while FVIII levels >15% and FIX levels >10% were sufficient to achieve the goal of 0 bleeds in this pediatric cohort.

Nonsevere Hemophilia: The Need for a Renewed Focus and Improved Outcomes.

People with nonsevere hemophilia (PWNSH) are phenotypically more diverse than those with severe hemophilia. Perceptions relating to a "nonsevere" phenotype have contributed to fewer research initiatives, fewer guidelines on optimal management, and a lack of standards for surveillance and clinical assessment for affected individuals. In many cases, episodes of abnormal bleeding could, if investigated, have led to earlier diagnosis. Furthermore, the major recent developments in therapy for hemophilia have largely focused on severe disease and, as a group, PWNSH have not been included in many key clinical trials. Benefiting people with severe disease, innovative replacement therapies have generally targeted factor levels that are above those present in a large proportion of PWNSH. Therapeutic advances can lead to improvement in phenotype for people with severe hemophilia over that currently experienced by many PWNSH. As a result, we are approaching a point where PWNSH may, in many countries, have a higher risk of bleeding and restriction in lifestyle than those with severe disease but with more limited therapeutic options. Given the multiple major advances in treatment for people with hemophilia, it is timely to review the aspects of nonsevere disease, to ensure equity in care and management for all individuals with this condition.

Mutational landscape, inhibitor development, and health-care burden in non-severe haemophilia A: A single-centre Australian experience.

To characterise non-severe haemophilia A (HA) patients enrolled on the Australian Bleeding Disorders Registry (ABDR) treated through a state-wide Haemophilia Treatment Centre (HTC) with respect to their mutational profile, inhibitor risk and health-care burden. We conducted a single-centre observational study of all non-severe HA patients treated at the Alfred Health HTC registered on the ABDR as of the 26thJuly 2023. Data were extracted from the ABDR and electronic medical record (EMR) regarding demographics, severity, genetic testing, treatment, inhibitors, bleeding events and procedures. Inhibitor risk was calculated as a function of exposure days (EDs) of FVIII replacement. There were 289 non-severe HA patients treated at the Alfred HTC registered on the ABDR as of July 2023, all of whom were adult patients aged>18 years old. Genotyping had been performed in 228/289 (78.9%). Of the inhibitor analysis population, 14/193 (7.3%) had an inhibitor. The cumulative incidence of inhibitor development at 75 EDs was 31% (95% CI 13%-46%). The median cost of bypassing agents per inhibitor patient was $57,087.50/year. These results demonstrate a relatively high inhibitor prevalence and incidence risk in non-severe HA compared to previously published work, although this may partly reflect a smaller population size. High rates of genotyping have allowed representative mutational characterisation. The burden of care imposed by non-severe HA in terms of bleeding events, procedures and bypassing agent cost is larger than expected, particularly within the inhibitor population.

Tachyphylaxis and reproducibility of desmopressin response in perioperative persons with nonsevere hemophilia A: implications for clinical practice

BackgroundDesmopressin is frequently used perioperatively in persons with nonsevere hemophilia A. However, increase in factor (F)VIII:C after desmopressin use is interindividually highly variable. Tachyphylaxis has only been reported in test setting for persons with hemophilia A, with a remaining response of approximately 70% after a second dose compared with that after a first dose. ObjectivesTo study tachyphylaxis of FVIII:C response after multiple administration(s) of desmopressin in perioperative persons with nonsevere hemophilia A. MethodsWe studied FVIII:C levels after desmopressin before (day 0 [D0]) and on days 1 (D1) and 2 (D2) after surgery in 26 patients of the DAVID and Little DAVID studies. We studied tachyphylaxis by comparing the responses at D1 and D2 with that at D0. We also assessed the reproducibility of the D0 response in comparison to an earlier performed desmopressin test. ResultsThe median absolute FVIII:C increase was 0.50 IU/mL (0.35-0.74; n = 23) at D0, 0.21 IU/mL (0.14-0.28; n = 17) at D1, and 0.23 IU/mL (0.16-0.30; n = 11) at D2. The median percentage of FVIII increase after the second administration (D1) compared with the first (D0) was 42.9% (29.2%-52.5%; n = 17) and that of the third (D2) compared with the first (D0) was 36.4% (23.7%-46.9%; n = 11). The FVIII:C desmopressin response at D0 was comparable with the desmopressin test response in 74% of the patients. ConclusionTachyphylaxis in the surgical setting was considerably more pronounced than previously reported, with FVIII:C at D1 and D2 of 36% to 43% of the initial response. Our results may have important implications for monitoring repeated desmopressin treatment when used perioperatively.

Peri-operative desmopressin combined with pharmacokinetic-guided factor VIII concentrate in non-severe haemophilia A patients.

Non-severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated. We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients. Non-severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri-operative combination treatment. In the single-arm DAVID study intravenous desmopressin (0.3μg/kg) once-a-day was, after sampling, immediately followed by PK-guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK-guided combination treatment (intervention arm) or PK-guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL. In total 32 patients (33 procedures) were included. In the DAVID study (n=21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n=12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C>1.00 IU/mL. Peri-operative combination treatment with desmopressin and PK-guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption.

Descriptive and Epidemiological Study of Joint Damage in Non-Severe Hemophilia: Update of the Damage Study of the Mediterranean Group

Introduction: There is growing evidence indicating joint damage (JD) in non-severe hemophilia (nSH) patients. Although age and baseline factor (F) VIII/FIX levels have been proposed as good predictors of JD in mild hemophilia (MiH), data are scarce and in moderate hemophilia (MoH) are lacking. Besides, global hemostatic capacity (GHC) in this population and its contribution to JD has not been assessed. Methods: We designed a cross-sectional, observational and multicenter study carried out in 12 Spanish hospitals (Mediterranean Group). We evaluated JD in nSH patients and its correlation with age, baseline FVIII/FIX and GHC. JD was defined as a HEAD-US score >0. Baseline FVIII (chromogenic assay), FIX (clotting assay) and GHC (assessed by thrombin generation test, TGT, Genesia ®, Stago) were evaluated in a central laboratory. Results were expressed as median (25 th-75 th percentiles). Categorical variables were expressed with percentage. A p value<0.05 was considered statistically significant. Results: A total of 98 nSH patients were included: 10 (10.2%) MoH (9 HA: age= 35.6 [21.7-45.0] years old (YO); FVIII = 4.0 [4.0-5.0] IU/dL; 1 HB: FIX= 2 IU/dL) and 88 MiH (84 HA: age= 38.6 [19.0-52.1 YO]; FVIII= 15.5 [11.0-24.0] IU/dL; 4 HB: FIX= 30.0 [16.8-35.4] IU/dL). Target joints were observed in patients with MiH (7/88: 8.6% of the MiH patients). HEAD-US score was obtained in 73 patients (74.5% of the total participating patients): nine MoH patients presented a HEAD-US= 1 (0-6) (age: 32.7 [21.7-42.9] YO) while 64 MiH patients presented a HEAD-US= 0 (0-3) (age: 37.9 [17.8-48.7] YO) (comparison between MoH and MiH patients: HEAD-US: p=0.427, age: p= 0.614). Only 55.5% (5/9) MoH patients and 45.3% (29/64) MiH patients, presented JD (p=0.725). Baseline FVIII/FIX was 13.0 (7.0-20.0) IU/dL and 16.0 (11.0-22.5) IU/dL in patients with or without JD respectively (p= 0.311). These mild difference of number of patients with JD and degree of JD between MiH and MoH were corroborated by not detecting correlation between baseline FVIII/FIX levels and JD (r= -0.095; p= 0.426) (Figure 1). JD increased with age (r= 0.380; p= 0.001) reinforcing previous findings. GHC correlated with baseline FVIII/FIX (Table 1) but not with the degree of JD, suggesting that thrombin generation, with the used conditions, might not be helpful to predict JD in this population. Conclusions: Around 50% of patients with nSH presented JD. This JD increased with age, supporting previous data. Although there was a correlation between baseline FVIII/FIX levels and thrombin generation, none of the TGT parameters were predictive of the degree of JD, enhancing that other variables might be influencing the development of JD in nSH patients. Of note, MiH individuals may develop severe JD due to presence of target joints. In summary, our results highlight the importance of evaluating JD in nSH in order to determine whether new protocols are required for the diagnosis, prevention, and treatment of JD in nSH patients.

Analysis of Perioperative Factor Replacement Therapy for Hemophilia

Background Hemophilia is a hereditary bleeding disorder, especially in severe hemophilia, that can lead to spontaneous bleeding. For hemophilia patients with inhibitors, even minor acute bleeding events or surgical procedures can have catastrophic consequences. Some hemophiliacs are forced to make surgical choices. There are many risks in perioperative period when hemophiliacs undergo major surgery. Seeking effective and safe perioperative clotting factor replacement therapy or bypass therapy is the basis of successful surgery. Aims To seek effective and safe perioperative coagulation factor replacement therapy or bypass therapy. Methods HA patients were treated with FVIII preparation during perioperative period. To calculate dosage, multiply the patient ' s weight in kilograms by the FVIII level in IU/dL desired, then multiply by 0.5. Example: 50 kg × 40 (IU/dL level desired) × 0.5 = 1000 IU of FVIII. HB patients were treated with PCC or FIX during perioperative period. To calculate dosage, multiply the patient ' s weight in kilograms by the FIX level in IU/dL desired. Example: 50 kg body weight × 40 (IU/dL level desired) = 2000 IU of plasma-derived FIX. For hemophilia patients with low titer inhibitors, estimate the amount of FVIII required as a neutralizing inhibitor loading dose as recommended by WFH. The following formula is used to estimate the amount of FVIII needed as a loading dose to neutralize the inhibitor: [body weight (kg) × 80 × [(1 − hematocrit) × antibody titer (BU)]. An additional 50 IU/kg above the calculated loading dose is added to achieve a measurable FVIII activity. Patients with hemophilia combined with high titer inhibitors were treated with rFVIIa combined with PCC SCBT regimen. Sequential use refers to alternating rFVIIa and aPCC every 3 hours. Results 69 patients with indications for surgery and/or desire for surgery who underwent different types of surgery with clotting factor replacement therapy or bypass therapy were evaluated (Table 1). There were 37 cases of severe hemophilia and 32 cases of non-severe hemophilia. There were 63 cases of HA, including 50 cases of negative inhibitor and 13 cases of positive inhibitor. After meeting the inclusion and exclusion criteria, 69 patients were evaluated for different types of surgery under clotting factor replacement therapy or bypass therapy during perioperative period. 59 cases underwent major operations, including: 49 cases underwent joint replacement, among which 34 cases underwent single joint replacement and 6 cases underwent double joint replacement and so on. 10 cases underwent minor operations. There were 14 cases of hemophilia with inhibitors, of which 13 were major operations with 175.38 (85.00-270.00) minutes of operation and 2 were minor operations with 45.00 minute of operation. In 12 patients with severe hemophilia and high titer inhibitors, the perioperative consumption of factor FVII was as follows: 447.62 (331.04-738.48)ug/kg on the day of surgery, and the total consumption was 2484.21 (1499.40-4500.00)ug/kg. The perioperative consumption of factor PCC was as follows: 126.10 (0-206.45)ug/kg on the day of surgery, and the total consumption was 1332.84 (529.20-1970.00)ug/kg. The mean preoperative FVIII:C level of the HA patients was 1.19 (0.00~6.00)%, the mean preoperative FIX:C level was 0.022 (0.01~0.07)% of the HB patients.The average intraoperative blood loss of the 69 patients was 537.98 (0-3000) ml. 20 patients received intraoperative transfusion of blood products (red blood cells or fresh frozen plasma) and 49 patients did not receive intraoperative transfusion of blood products. In 55 hemophiliacs without inhibitor, no inhibitor was found after surgery. Conclusion(s) It is safe and effective to adopt different schemes for perioperative alternative therapy for different hemophilia types.

PB0642 Determinants of the Bleeding Phenotype in Persons with Non-Severe Hemophilia

PB0642 Determinants of the Bleeding Phenotype in Persons with Non-Severe Hemophilia

PB1275 Multicenter and Cross-Sectional Study of Joint Damage of Patients with Non-Severe Hemophilia: A “Mediterranean Group” Study

PB1275 Multicenter and Cross-Sectional Study of Joint Damage of Patients with Non-Severe Hemophilia: A “Mediterranean Group” Study

PB0691 Inhibitor Eradication Strategies in Patients with Non-Severe Hemophilia A

PB0691 Inhibitor Eradication Strategies in Patients with Non-Severe Hemophilia A

PB0671 Poor Correlation between Biomarkers and MRI-Detected Joint Damage in a Cross-Sectional Study of Persons with Non-Severe Hemophilia A

PB0671 Poor Correlation between Biomarkers and MRI-Detected Joint Damage in a Cross-Sectional Study of Persons with Non-Severe Hemophilia A

PB0697 To Test or Not to Test: Do All Individuals with Non-Severe Hemophilia A Need DDAVP Response Testing?

PB0697 To Test or Not to Test: Do All Individuals with Non-Severe Hemophilia A Need DDAVP Response Testing?

OC 12.2 Decreased Quality of Life in Non-Severe Hemophilia Patients with an Increased Bleeding Phenotype

OC 12.2 Decreased Quality of Life in Non-Severe Hemophilia Patients with an Increased Bleeding Phenotype

Whole F8 gene sequencing combined with splicing functional analyses led to a substantial increase of the molecular diagnosis yield for non-severe haemophilia A.

Conventional genetic investigation fails to identify the F8 causal variant in 2.5%-10% of haemophilia A (HA) patients with non-severe phenotypes. In these cases, F8 deep intronic variants could be causal. To identify pathogenic F8 deep intronic variants in genetically unresolved families with non-severe HA analysed in the haematology laboratory of the Hospices Civils de Lyon. The whole F8 was analysed by next generation sequencing. The pathogenic impact of candidate variants identified was assessed using both in silico analysis (MaxEntScan and spliceAI) and functional analysis (RNA or minigene assay). Sequencing was performed in 49/55 families included for which a DNA sample from a male propositus was available. In total, 33 candidate variants from 43 propositi were identified. These variants corresponded to 31 single nucleotide substitutions, one 173-bp deletion, and an 869-bp tandem triplication. No candidate variant was found in six propositi. The most frequent variants found were the association of [c.2113+1154G>C and c.5374-304C>T], identified in five propositi, and the c.2114-6529C>G identified in nine propositi. Four variants had been previously described as HA-causing. Splicing functional assay found a deleterious impact for 11 substitutions (c.671-94G>A, c.788-312A>G, c.2113+1154G>C, c.2114-6529C>G, c.5999-820A>T, c.5999-786C>A, c.5999-669G>T, c.5999-669G>A, c.5999-669G>C, c.6900+4104A>C, and c.6901-2992A>G). The HA-causing variant was identified in 33/49 (67%) cases. In total, F8 deep intronic variants caused 8.8% of the non-severe HA among the 1643 families analysed in our laboratory. The results emphasise the value of whole F8 gene sequencing combined with splicing functional analyses to improve the diagnosis yield for non-severe HA.

Haemophilia joint health score (HJHS) usage, patterns and outcome data in patients with haemophilia A and haemophilia B in Australia: A descriptive study using the Australian Bleeding Disorders Registry (ABDR).

Assessment of joint health is an essential component of haemophilia management. A variety of clinical tools have been developed to standardise this assessment process. One such tool, the Haemophilia Joint Health Score (HJHS), is embedded for use within the Australian Bleeding Disorders Registry (ABDR). This provides a unique opportunity to analyse patterns of tool usage as well as associations between scores, demographics and clinical outcome factors. To characterise clinician practices regarding use of HJHS in routine clinical assessment of persons with haemophilia (PWH), to examine relationships between HJHS, and age, inhibitor status and body mass index (BMI), and to identify potential barriers to HJHS tool usage. A national, retrospective study was conducted using data extracted from the ABDR between 2014 and 2020, complemented by a qualitative questionnaire exploring haemophilia treatment centre (HTC) structure, resourcing and clinician perspectives about HJHS. 28.1% (622/2220) of PWH had at least one HJHS recorded in the ABDR during the defined study period (546 haemophilia A, 76 haemophilia B). HJHS were recorded more in children than adults and performed more in severe than non-severe haemophilia. Multivariate analysis demonstrated significant association of age, severity and inhibitor status with HJHS. No association was identified between BMI and HJHS. Qualitative surveys revealed significant variation in physiotherapy funding, availability and methods of tool use between HTCs. This study provides valuable insights into joint health assessment in Australia. It improved our understanding of factors influencing long-term joint outcomes. Practical limitations of HJHS tool were also discussed.

Desmopressin in nonsevere hemophilia A: patient perspectives on use and efficacy

BackgroundDesmopressin increases plasma factor VIII and von Willebrand factor levels in persons with nonsevere hemophilia A. Patients’ perspectives on desmopressin are relevant to increase and optimize its suboptimal use. However, patients’ views on desmopressin are not reported. ObjectivesTo evaluate the perspectives of persons with nonsevere hemophilia A on desmopressin use, barriers for its use, side effects, and their knowledge about desmopressin’s efficacy and side effects. MethodsPersons with nonsevere hemophilia A were included in a cross-sectional, national, multicenter study. Questionnaires were filled out by adult patients and children aged ≥12 years themselves. Caretakers filled out questionnaires for children aged <12 years. ResultsIn total, 706 persons with nonsevere hemophilia A were included (544 mild, 162 moderate, [age range, 0–88 years]). Of 508 patients, 234 (50%) patients reported previous desmopressin use. Desmopressin was considered as at least moderately effective in 171 of 187 (90%) patients. Intranasal administration was the modality of choice for 138 of 182 (76%) patients. Flushing was the most reported side effect in 54 of 206 (26%) adults and 7 of 22 (32%) children. The most frequently reported advantage and disadvantage were the convenience of intranasal, out-of-hospital administration by 56% (126/227) and side effects in 18% (41/227), respectively. Patients’ self-perceived knowledge was unsatisfactory or unknown in 28% (63/225). ConclusionOverall, desmopressin was most often used intranasally and considered effective, with flushing as the most common side effect. The most mentioned advantage was the convenience of intranasal administration and disadvantage was side effects. More information and education on desmopressin could answer unmet needs in patients with current or future desmopressin treatment.

Poor correlation between biomarkers and MRI-detected joint damage in a cross-sectional study of persons with nonsevere hemophilia A (DYNAMO study)

BackgroundPersons with nonsevere hemophilia A (NSHA) experience less frequent joint bleeding than persons with severe hemophilia A, but may still develop joint damage. Biomarkers of cartilage and synovial remodeling can reflect ongoing pathologic processes that may precede or coincide with damage on joint imaging. If so, biomarkers may be an important diagnostic tool for joint damage in NSHA. ObjectiveTo assess the correlation between biomarkers and MRI-detected joint damage in persons with NSHA. MethodsIn a cross-sectional study, men with NSHA (factor VIII [FVIII], 2-35 IU/dL) were included. Participants underwent magnetic resonance imaging of elbows, knees, and ankles and blood and urine sampling for biomarker analysis on a single visit. The following biomarker(s) were analyzed in urine: CTX-II or serum: cartilage oligomeric matrix protein, chondroitin sulfate 846, vascular cell adhesion molecule 1, osteopontin (OPN), neo-epitope of MMP -mediated degradation of type II collagen, N-terminal propeptide of type II collagen, collagen type IV M, and propetide of type IV collagen. Spearman’s rank correlations were calculated between these biomarkers and the total International Prophylaxis Study group (IPSG) score, soft-tissue subscore, and osteochondral subscore. ResultsIn total, 48 persons with NSHA were included. Median age was 43 years (range, 24-55 years) and median FVIII was 10 IU/dL (IQR, 4-16 IU/dL). The median IPSG score was 4 (IQR, 2-9). Median IPSG soft-tissue subscores were 3 (IQR, 2-4) and osteochondral subscores were 0 (IQR, 0-4). No strong correlations were found between the studied biomarkers, total IPSG score, subsequent soft-tissue, and osteochondral subscores. ConclusionsIn this study, selected biomarkers indicative of different aspects of hemophilic arthropathy showed no consistent correlation with IPSG scores. This suggests that systemically measured biomarkers are currently not suitable for identifying milder joint damage in NSHA, as observed on magnetic resonance imaging.

POSTER ABSTRACTS

POSTER ABSTRACTS

Emicizumab in people with moderate or mild haemophilia A (HAVEN 6): a multicentre, open-label, single-arm, phase 3 study

Clinical trial data are scarce for the use of prophylaxis in people with non-severe haemophilia A. The HAVEN 6 study aims to assess safety and efficacy of emicizumab prophylaxis in people with non-severe haemophilia A without factor VIII (FVIII) inhibitors. HAVEN 6 is a multicentre, open-label, single-arm, phase 3 study taking place in 22 specialty clinics and hospitals in Europe, North America, and South Africa. Eligible participants were people of all ages weighing at least 3 kg with a diagnosis of moderate (FVIII activity ≥1%-≤5%) or mild (FVIII >5%-<40%) haemophilia A without FVIII inhibitors requiring prophylaxis as assessed by the treating physician. Participants received subcutaneous emicizumab 3 mg/kg of bodyweight once weekly for 4 weeks, followed by the participant's choice of maintenance dose: 1·5 mg/kg once weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. Safety was the primary objective of the study. Safety endpoints included adverse events, serious adverse events, and adverse events of special interest including thromboembolic events and thrombotic microangiopathies. The primary efficacy endpoint was the annualised bleed rate for treated bleeds. Analyses were done for participants who received at least one dose of emicizumab. This study is registered with ClinicalTrials.gov, number NCT04158648, and is active but not recruiting. Between Feb 10, 2020, and Aug 31, 2021, we assigned 73 people to treatment. 72 participants received at least one dose of emicizumab (51 moderate [71%]; 21 mild [29%]; 69 male [96%]; three female [4%]; and 61 White [85%]). Median age was 23·5 years (IQR 12·0-36·0); median follow-up was 55·6 weeks (IQR 52·3-61·6) weeks. At baseline, 24 participants (33%) had target joints and 37 (51%) were receiving FVIII prophylaxis. 60 participants (83%) had at least one adverse event; the most common adverse events were headache (in 12 participants [17%]), injection-site reaction (12 [17%]), and arthralgia (11 [15%]). 15 (21%) had at least one emicizumab-related adverse event; no adverse events led to treatment withdrawal, modification, or interruption. Eight participants (11%) reported ten serious adverse events in total, none emicizumab-related. There were no deaths or thrombotic microangiopathies. One participant had grade 1 thrombosed haemorrhoids (classified as a thromboembolic event), unrelated to emicizumab. The annualised bleed rate was 0·9 (95% CI 0·55-1·52) for treated bleeds. 48 participants (67%) had no treated bleeds. All-bleed annualised bleed rates were 10·1 (95% CI 6·93-14·76) from 24 weeks pre-study and 2·3 (1·67-3·12) on-study after a median follow-up of 55·6 weeks. These data show efficacy and a favourable safety profile of emicizumab in people with non-severe haemophilia A without FVIII inhibitors who warrant prophylaxis, confirming emicizumab as a valuable treatment option in this population. F Hoffmann-La Roche.