NCT03315455: HAVEN 5

Efficacy, Safety, and Pharmacokinetic Study of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Participants

Completed Phase 3 Results posted Last updated 1 April 2026

What this trial tests

Phase 3 trial testing Emicizumab in Hemophilia A in 85 participants. Completed in 29 August 2025.

Timeline

26 April 2018

Primary endpoint
3 August 2022

29 August 2025

Quick facts

Lead sponsor	Hoffmann-La Roche
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	85
Start date	26 April 2018
Primary completion	3 August 2022
Estimated completion	29 August 2025
Sites	13 locations across China, Hong Kong, Thailand, Malaysia

Drugs / interventions tested

• Emicizumab (EMICIZUMAB) — full drug profile →

Conditions studied

• Hemophilia A — all drugs for Hemophilia A →

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

Eligibility, any sex, with Hemophilia A. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Model-Based Annualized Bleeding Rate for All Bleeds Secondary · From Baseline to at least 24 weeks

The number of all bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the s

Group	Value	95% CI
Arm C (Control): No Prophylaxis	41.1	26.37 – 64.19
Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	1.9	1.23 – 2.97
Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	2.1	1.33 – 3.26
Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	3.8	2.21 – 6.69

Mean Calculated Annualized Bleeding Rate for All Bleeds Secondary · From Baseline to at least 24 weeks

The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleed

Group	Value	95% CI
Arm C (Control): No Prophylaxis	53.0	39.71 – 69.33
Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	2.7	0.51 – 8.37
Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	3.1	0.67 – 8.94
Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	3.8	1.01 – 10.01

Median Calculated Annualized Bleeding Rate for All Bleeds Secondary · From Baseline to at least 24 weeks

The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleed

Group	Value	95% CI
Arm C (Control): No Prophylaxis	56.7	26.09 – 70.81
Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	1.5	0.00 – 4.21
Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	1.9	0.00 – 5.62
Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	2.1	0.00 – 5.77

Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds Secondary · From Baseline to at least 24 weeks

The number of treated spontaneous bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 ho

Group	Value	95% CI
Arm C (Control): No Prophylaxis	23.6	9.28 – 60.03
Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	0.4	0.18 – 0.96
Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	0.5	0.20 – 1.12
Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	0.6	0.18 – 2.16

Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds Secondary · From Baseline to at least 24 weeks

The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical locat

Group	Value	95% CI
Arm C (Control): No Prophylaxis	30.9	20.95 – 43.85
Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	0.5	0.00 – 4.66
Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	0.6	0.00 – 4.88
Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	0.6	0.00 – 4.92

Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds Secondary · From Baseline to at least 24 weeks

The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical locat

Group	Value	95% CI
Arm C (Control): No Prophylaxis	21.8	6.48 – 52.18
Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	0.0	0.00 – 0.00
Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	0.0	0.00 – 0.96
Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	0.0	0.00 – 0.00

Model-Based Annualized Bleeding Rate for Treated Joint Bleeds Secondary · From Baseline to at least 24 weeks

The number of treated joint bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hou

Group	Value	95% CI
Arm C (Control): No Prophylaxis	17.7	8.33 – 37.57
Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	0.7	0.36 – 1.46
Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	0.6	0.28 – 1.22
Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	0.1	0.02 – 0.88

Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds Secondary · From Baseline to at least 24 weeks

The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a h

Group	Value	95% CI
Arm C (Control): No Prophylaxis	25.5	16.62 – 37.56
Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	1.0	0.02 – 5.57
Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	0.8	0.01 – 5.20
Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	0.1	0.00 – 3.93

Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds Secondary · From Baseline to at least 24 weeks

The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a h

Group	Value	95% CI
Arm C (Control): No Prophylaxis	10.9	8.70 – 50.00
Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	0.0	0.00 – 0.00
Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	0.0	0.00 – 1.40
Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	0.0	0.00 – 0.00

Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds Secondary · From Baseline to at least 24 weeks

The number of treated target joint bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be

Group	Value	95% CI
Arm C (Control): No Prophylaxis	8.6	3.15 – 23.42
Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	0.4	0.18 – 1.09
Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	0.3	0.12 – 0.85
Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	NA	NA – NA

Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds Secondary · From Baseline to at least 24 weeks

The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and th

Group	Value	95% CI
Arm C (Control): No Prophylaxis	15.6	8.83 – 25.47
Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	0.7	0.00 – 5.06
Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	0.5	0.00 – 4.76
Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	0.0	0.0 – 3.69

Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds Secondary · From Baseline to at least 24 weeks

The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and th

Group	Value	95% CI
Arm C (Control): No Prophylaxis	6.5	0.00 – 19.68
Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW	0.0	0.00 – 0.00
Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W	0.0	0.00 – 1.13
Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW	0.0	0.00 – 0.00

Adverse events — posted to ClinicalTrials.gov

Time frame: From the date of randomization or enrollment until the end of study (Arm C [Control] No Prophylaxis: up to 28 weeks; Arms A to C Emicizumab: up to 88 months; Arm D Emicizumab: up to 52.4 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Arm C (Control): No Prophylaxis

Serious: 0/14 (0%)

Deaths: 0/14

Arm A: 1.5 mg/kg Emicizumab Prophylaxis QW

Serious: 9/29 (31%)

Deaths: 1/29

Arm B: 6 mg/kg Emicizumab Prophylaxis Q4W

Serious: 6/27 (22%)

Deaths: 0/27

Arm C (Emi): 6 mg/kg Emicizumab Prophylaxis Q4W

Serious: 4/14 (29%)

Deaths: 0/14

Arm D: 1.5 mg/kg Emicizumab Prophylaxis QW

Serious: 2/15 (13%)

Deaths: 0/15

Serious adverse events (34 terms)

Reaction	System	Arm C (Control): No Prophy…	Arm A: 1.5 mg/kg Emicizuma…	Arm B: 6 mg/kg Emicizumab …	Arm C (Emi): 6 mg/kg Emici…	Arm D: 1.5 mg/kg Emicizuma…
Mass	General disorders	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—	—	—	—
Ileal ulcer	Gastrointestinal disorders	—	—	—	—	—
Intra-abdominal haemorrhage	Gastrointestinal disorders	—	—	—	—	—
Mallory-Weiss syndrome	Gastrointestinal disorders	—	—	—	—	—
Pancreatitis	Gastrointestinal disorders	—	—	—	—	—
Haemarthrosis	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Haemophilic arthropathy	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Haemorrhage	Vascular disorders	—	—	—	—	—
Shock haemorrhagic	Vascular disorders	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—
Cholelithiasis	Hepatobiliary disorders	—	—	—	—	—
Infective exacerbation of bronchiectasis	Infections and infestations	—	—	—	—	—
Limb fracture	Injury, poisoning and procedural complications	—	—	—	—	—
Adenocarcinoma of colon	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—
Ureteric dilatation	Renal and urinary disorders	—	—	—	—	—
Ureterolithiasis	Renal and urinary disorders	—	—	—	—	—
Bronchiectasis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Anal fistula	Gastrointestinal disorders	—	—	—	—	—
Haemorrhoidal haemorrhage	Gastrointestinal disorders	—	—	—	—	—
Large intestine polyp	Gastrointestinal disorders	—	—	—	—	—
Lower gastrointestinal haemorrhage	Gastrointestinal disorders	—	—	—	—	—
Mouth haemorrhage	Gastrointestinal disorders	—	—	—	—	—
Rectal ulcer	Gastrointestinal disorders	—	—	—	—	—

Other adverse events (108 terms — click to expand)

Reaction	System	Arm C (Control): No Prophy…	Arm A: 1.5 mg/kg Emicizuma…	Arm B: 6 mg/kg Emicizumab …	Arm C (Emi): 6 mg/kg Emici…	Arm D: 1.5 mg/kg Emicizuma…
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—
Hyperuricaemia	Metabolism and nutrition disorders	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—
COVID-19	Infections and infestations	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—
Injection site reaction	General disorders	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—
Blood uric acid increased	Investigations	—	—	—	—	—
Blood bilirubin increased	Investigations	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—
Hepatic steatosis	Hepatobiliary disorders	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—
Pharyngitis	Infections and infestations	—	—	—	—	—
Blood glucose increased	Investigations	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—
Dental caries	Gastrointestinal disorders	—	—	—	—	—
Toothache	Gastrointestinal disorders	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—
Suspected COVID-19	Infections and infestations	—	—	—	—	—
Bronchitis	Infections and infestations	—	—	—	—	—
Gingivitis	Infections and infestations	—	—	—	—	—
Tonsillitis	Infections and infestations	—	—	—	—	—
Rhinitis	Infections and infestations	—	—	—	—	—
Bilirubin conjugated increased	Investigations	—	—	—	—	—
Blood potassium decreased	Investigations	—	—	—	—	—
Weight decreased	Investigations	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—
Abdominal distension	Gastrointestinal disorders	—	—	—	—	—
Influenza like illness	General disorders	—	—	—	—	—
Contusion	Injury, poisoning and procedural complications	—	—	—	—	—
Ligament sprain	Injury, poisoning and procedural complications	—	—	—	—	—
Hepatic function abnormal	Hepatobiliary disorders	—	—	—	—	—
Gastritis	Gastrointestinal disorders	—	—	—	—	—
Gastrooesophageal reflux disease	Gastrointestinal disorders	—	—	—	—	—
Haemorrhoids	Gastrointestinal disorders	—	—	—	—	—

Most-reported serious reactions: Mass, Arthralgia, Gastrointestinal haemorrhage, Ileal ulcer, Intra-abdominal haemorrhage, Mallory-Weiss syndrome, Pancreatitis, Haemarthrosis.

Data from ClinicalTrials.gov NCT03315455 adverse events section.

Sponsor's own description

This multicenter, open-label, Phase 3 study with randomized and non-randomized arms is designed to investigate the efficacy, safety, and pharmacokinetics of emicizumab in participants with hemophilia A regardless of factor VIII (FVIII) inhibitor status. Participants greater than or equal to (≥)12 years old who received episodic therapy with FVIII or bypassing agents prior to study entry and experienced at least 5 bleeds over the prior 24 weeks will be randomized in a 2:2:1 ratio to the following regimens: Arm A: Emicizumab prophylaxis at 3 milligrams per kilogram (mg/kg) once every week (QW) subcutaneously (SC) for 4 weeks, followed by 1.5 mg/kg QW SC; Arm B: Emicizumab prophylaxis at 3 mg/kg QW SC for 4 weeks, followed by 6 mg/kg once every 4 weeks (Q4W) SC; and Arm C: No prophylaxis (control arm). In addition, pediatric participants less than (\<)12 years old with hemophilia A and FVIII inhibitors who received episodic therapy with bypassing agents prior to study entry will be enrolled to Arm D: Emicizumab prophylaxis at 3 mg/kg QW SC for 4 weeks, followed by 1.5 mg/kg QW SC.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Emicizumab state-of-the-art update.
   Mahlangu J, Iorio A, Kenet G. · · 2022 · cited 61× · PMID 35521723 · DOI 10.1111/hae.14524
2. Prophylactic emicizumab for hemophilia A in the Asia-Pacific region: A randomized study (HAVEN 5).
   Yang R, Wang S, Wang X, Sun J, et al · · 2022 · cited 52× · PMID 35284778 · DOI 10.1002/rth2.12670
3. The role of emicizumab, a bispecific factor IXa- and factor X-directed antibody, for the prevention of bleeding episodes in patients with hemophilia A.
   Knight T, Callaghan MU. · · 2018 · cited 31× · PMID 30344994 · DOI 10.1177/2040620718799997
4. Non-factor therapies for bleeding disorders: A primer for the general haematologist.
   Swan D, Mahlangu J, Thachil J. · · 2022 · cited 18× · PMID 36051064 · DOI 10.1002/jha2.442
5. Emicizumab dose up-titration in case of suboptimal bleeding control in people with haemophilia A.
   Schmitt C, Mancuso ME, Chang T, Podolak-Dawidziak M, et al · · 2023 · cited 13× · PMID 36271487 · DOI 10.1111/hae.14679
6. Clotting factor concentrates for preventing bleeding and bleeding-related complications in previously treated individuals with haemophilia A or B.
   Olasupo OO, Lowe MS, Krishan A, Collins P, et al · · 2021 · cited 8× · PMID 34407214 · DOI 10.1002/14651858.cd014201
7. Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks.
   Kiialainen A, Adamkewicz JI, Petry C, Oldenburg J, et al · · 2024 · cited 6× · PMID 38282901 · DOI 10.1016/j.rpth.2023.102306
8. Hemostats in the clinic.
   Joshi M, Zhao Z, Mitragotri S. · · 2024 · cited 4× · PMID 39545083 · DOI 10.1002/btm2.10673