NCT02795767: HAVEN 2

A Study of Emicizumab Administered Subcutaneously (SC) in Pediatric Participants With Hemophilia A and Factor VIII (FVIII) Inhibitors

Completed Phase 3 Results posted Last updated 2 June 2021

What this trial tests

Phase 3 trial testing Emicizumab in Hemophilia A in 88 participants. Completed in 11 November 2020.

Timeline

22 July 2016

Primary endpoint
30 April 2018

11 November 2020

Quick facts

Lead sponsor	Hoffmann-La Roche
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	88
Start date	22 July 2016
Primary completion	30 April 2018
Estimated completion	11 November 2020
Sites	28 locations across France, Italy, Costa Rica, Japan, South Africa, United Kingdom, Germany, United States

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

Under 17, 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.

Cohort A: Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Treated Participants <12 Years of Age Primary · From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

The number of treated bleeds over the efficacy period is presented here as a model-based ABR that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times. A bleed is considered a "treated bleed" if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a "treatment for bleed", irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if

Group	Value	95% CI
Cohort A: 1.5 mg/kg Emicizumab QW	0.3	0.17 – 0.50

Cohort A: Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Treated Participants <12 Years of Age Primary · From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

The number of all bleeds over the efficacy period is presented here as a model-based ABR that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in followup times (i.e., the time that each participant stays in the study). 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-trea

Group	Value	95% CI
Cohort A: 1.5 mg/kg Emicizumab QW	3.2	1.94 – 5.22

Cohort A: Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds in Treated Participants <12 Years of Age Primary · From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

The number of treated spontaneous bleeds over the efficacy period is presented here as a model-based ABR that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A "treated spontaneous bleed" is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds

Group	Value	95% CI
Cohort A: 1.5 mg/kg Emicizumab QW	0.0	0.0 – 0.1

Cohort A: Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds in Treated Participants <12 Years of Age Primary · From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

The number of treated joint bleeds over the efficacy period is presented here as a model-based ABR that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A "joint bleed" is defined as a bleed with type reported as "joint" and with 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. A "treated joint bl

Group	Value	95% CI
Cohort A: 1.5 mg/kg Emicizumab QW	0.2	0.08 – 0.29

Cohort A: Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds in Treated Participants <12 Years of Age Primary · From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

The number of treated target joint bleeds over the efficacy period is presented here as a model-based ABR that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A "target joint bleed" is 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. A "treated target joint bleed" is a target joint bleed that also fulfills the conditions of a treated bleed (see

Group	Value	95% CI
Cohort A: 1.5 mg/kg Emicizumab QW	NA	NA – NA

Cohort A: Mean Calculated Annualized Bleed Rate (ABR) for Treated Bleeds in Treated Participants <12 Years of Age Primary · From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

The number of treated bleeds over the efficacy period is presented here as a calculated 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 bleed is considered a "treated bleed" if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a "treatment for bleed", irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if

Group	Value	95% CI
Cohort A: 1.5 mg/kg Emicizumab QW	0.3	0.00 – 4.31

Cohort A: Mean Calculated Annualized Bleed Rate (ABR) for All Bleeds in Treated Participants <12 Years of Age Primary · From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

The number of all bleeds over the efficacy period is presented here as a calculated 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 bleeds, the 72-hour rule was imp

Group	Value	95% CI
Cohort A: 1.5 mg/kg Emicizumab QW	3.2	0.70 – 9.04

Cohort A: Mean Calculated Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds in Treated Participants <12 Years of Age Primary · From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated 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 bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A "treated spontaneous bleed" is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the ana

Group	Value	95% CI
Cohort A: 1.5 mg/kg Emicizumab QW	0.0	0.00 – 3.74

Cohort A: Mean Calculated Annualized Bleed Rate (ABR) for Treated Joint Bleeds in Treated Participants <12 Years of Age Primary · From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

The number of treated joint bleeds over the efficacy period is presented here as a calculated 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 "joint bleed" is defined as a bleed with type reported as "joint" and with 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. A "treated joint bleed" is a joint bleed that also fulfills the conditions o

Group	Value	95% CI
Cohort A: 1.5 mg/kg Emicizumab QW	0.2	0.00 – 4.01

Cohort A: Mean Calculated Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds in Treated Participants <12 Years of Age Primary · From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

The number of treated target joint bleeds over the efficacy period is presented here as a calculated 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 "target joint bleed" is 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. A "treated target joint bleed" is a target joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Bleeds due t

Group	Value	95% CI
Cohort A: 1.5 mg/kg Emicizumab QW	0.1	0.00 – 3.84

Cohort A: Median Calculated Annualized Bleed Rate (ABR) for Treated Bleeds in Treated Participants <12 Years of Age Primary · From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

The number of treated bleeds over the efficacy period is presented here as a calculated 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 bleed is considered a "treated bleed" if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a "treatment for bleed", irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if

Group	Value	95% CI
Cohort A: 1.5 mg/kg Emicizumab QW	0.0	0.00 – 0.00

Cohort A: Median Calculated Annualized Bleed Rate (ABR) for All Bleeds in Treated Participants <12 Years of Age Primary · From Baseline to 52 weeks; At the primary completion date, the median (min-max) duration of the efficacy period in Cohort A was 57.57 (17.9-92.6) weeks.

The number of all bleeds over the efficacy period is presented here as a calculated 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 bleeds, the 72-hour rule was imp

Group	Value	95% CI
Cohort A: 1.5 mg/kg Emicizumab QW	0.6	0.00 – 2.92

Adverse events — posted to ClinicalTrials.gov

Time frame: From Baseline up to 24 weeks after study drug discontinuation; the median (min-max) observation periods in Cohorts A, B, and C were 96.93 (36.1-188.1) weeks, 68.21 (56.7-129.4) weeks, and 69.43 (38.9-144.3) weeks, respectively.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cohort A: 1.5 mg/kg Emicizumab QW

Serious: 23/68 (34%)

Deaths: 0/68

Cohort B: 3 mg/kg Emicizumab Q2W

Serious: 1/10 (10%)

Deaths: 0/10

Cohort C: 6 mg/kg Emicizumab Q4W

Serious: 3/10 (30%)

Deaths: 0/10

Serious adverse events (24 terms)

Reaction	System	Cohort A: 1.5 mg/kg Emiciz…	Cohort B: 3 mg/kg Emicizum…	Cohort C: 6 mg/kg Emicizum…
Vascular device infection	Infections and infestations	—	—	—
Haematoma muscle	Musculoskeletal and connective tissue disorders	—	—	—
Haemorrhage	Vascular disorders	—	—	—
Haemarthrosis	Musculoskeletal and connective tissue disorders	—	—	—
Haematoma	Vascular disorders	—	—	—
Mouth haemorrhage	Gastrointestinal disorders	—	—	—
Appendicitis	Infections and infestations	—	—	—
Bronchiolitis	Infections and infestations	—	—	—
Epididymitis	Infections and infestations	—	—	—
Clavicle fracture	Injury, poisoning and procedural complications	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—
Head injury	Injury, poisoning and procedural complications	—	—	—
Ligament sprain	Injury, poisoning and procedural complications	—	—	—
Mouth injury	Injury, poisoning and procedural complications	—	—	—
Headache	Nervous system disorders	—	—	—
Asthma	Respiratory, thoracic and mediastinal disorders	—	—	—
Ketoacidosis	Metabolism and nutrition disorders	—	—	—
Neutralising antibodies positive	Investigations	—	—	—
Catheter site haematoma	General disorders	—	—	—
Acute sinusitis	Infections and infestations	—	—	—
Bronchitis	Infections and infestations	—	—	—
Peritonsillar abscess	Infections and infestations	—	—	—
Tonsillitis	Infections and infestations	—	—	—
Traumatic haematoma	Injury, poisoning and procedural complications	—	—	—

Other adverse events (63 terms — click to expand)

Reaction	System	Cohort A: 1.5 mg/kg Emiciz…	Cohort B: 3 mg/kg Emicizum…	Cohort C: 6 mg/kg Emicizum…
Nasopharyngitis	Infections and infestations	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—
Injection site reaction	General disorders	—	—	—
Pyrexia	General disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Contusion	Injury, poisoning and procedural complications	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—
Gastroenteritis	Infections and infestations	—	—	—
Influenza	Infections and infestations	—	—	—
Ligament sprain	Injury, poisoning and procedural complications	—	—	—
Skin abrasion	Injury, poisoning and procedural complications	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Bronchitis	Infections and infestations	—	—	—
Otitis media	Infections and infestations	—	—	—
Tonsilitis	Infections and infestations	—	—	—
Limb injury	Injury, poisoning and procedural complications	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—
Skin laceration	Injury, poisoning and procedural complications	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—
Dental caries	Gastrointestinal disorders	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Ear infection	Infections and infestations	—	—	—
Varicella	Infections and infestations	—	—	—
Urticaria	Skin and subcutaneous tissue disorders	—	—	—
Seasonal allergy	Immune system disorders	—	—	—
Gastrointestinal infection	Infections and infestations	—	—	—
Pharyngitis	Infections and infestations	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Conjunctivitis	Infections and infestations	—	—	—
Rhinitis	Infections and infestations	—	—	—
Head injury	Injury, poisoning and procedural complications	—	—	—
Joint injury	Injury, poisoning and procedural complications	—	—	—
Vaccination site erythema	General disorders	—	—	—

Most-reported serious reactions: Vascular device infection, Haematoma muscle, Haemorrhage, Haemarthrosis, Haematoma, Mouth haemorrhage, Appendicitis, Bronchiolitis.

Data from ClinicalTrials.gov NCT02795767 adverse events section.

Sponsor's own description

This non-randomized, multicenter, open-label, Phase III clinical study will evaluate the efficacy, safety, and pharmacokinetics of emicizumab administered subcutaneously initially once weekly (QW) in pediatric participants with hemophilia A with FVIII inhibitors. This study will open two additional non-randomized cohorts to investigate once every 2 weeks (Q2W) and once every 4 weeks (Q4W) regimens in pediatric participants.

Publications & conference data

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

1. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors.
   Young G, Liesner R, Chang T, Sidonio R, et al · · 2019 · cited 278× · PMID 31697801 · DOI 10.1182/blood.2019001869
2. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies.
   Callaghan MU, Negrier C, Paz-Priel I, Chang T, et al · · 2021 · cited 197× · PMID 33512413 · DOI 10.1182/blood.2020009217
3. Antibodies to watch in 2018.
   Kaplon H, Reichert JM. · · 2018 · cited 179× · PMID 29300693 · DOI 10.1080/19420862.2018.1415671
4. A comprehensive comparison between camelid nanobodies and single chain variable fragments.
   Asaadi Y, Jouneghani FF, Janani S, Rahbarizadeh F. · · 2021 · cited 123× · PMID 34863296 · DOI 10.1186/s40364-021-00332-6
5. Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies.
   Kruse-Jarres R, Peyvandi F, Oldenburg J, Chang T, et al · · 2022 · cited 35× · PMID 35939785 · DOI 10.1182/bloodadvances.2022007458
6. Population Pharmacokinetic Analysis and Exploratory Exposure-Bleeding Rate Relationship of Emicizumab in Adult and Pediatric Persons with Hemophilia A.
   Retout S, Schmitt C, Petry C, Mercier F, et al · · 2020 · cited 33× · PMID 32504271 · DOI 10.1007/s40262-020-00904-z
7. PROTECT VIII Kids: BAY 94-9027 (PEGylated Recombinant Factor VIII) safety and efficacy in previously treated children with severe haemophilia A.
   Santagostino E, Kenet G, Fischer K, Biss T, et al · · 2020 · cited 24× · PMID 32212300 · DOI 10.1111/hae.13963
8. Health-related quality of life and caregiver burden of emicizumab in children with haemophilia A and factor VIII inhibitors-Results from the HAVEN 2 study.
   Mancuso ME, Mahlangu J, Sidonio R, Trask P, et al · · 2020 · cited 23× · PMID 33084175 · DOI 10.1111/hae.14183