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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03020160




Registration number
NCT03020160
Ethics application status
Date submitted
21/12/2016
Date registered
13/01/2017
Date last updated
17/05/2021

Titles & IDs
Public title
A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks in Participants With Hemophilia A
Scientific title
A Multicenter, Open-Label, Phase III Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks (Q4W) in Patients With Hemophilia A
Secondary ID [1] 0 0
2016-001094-33
Secondary ID [2] 0 0
BO39182
Universal Trial Number (UTN)
Trial acronym
HAVEN 4
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hemophilia A 0 0
Condition category
Condition code
Blood 0 0 0 0
Clotting disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Emicizumab

Experimental: Emicizumab: Expansion Part - Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.

Experimental: Emicizumab: PK Run-in Part - Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.


Treatment: Drugs: Emicizumab
Emicizumab will be administered according to dose and schedule described in respective arms. Upon implementation of protocol Version 5, treatment duration will be extended. During this study prolongation, participants will have the opportunity to switch to a preferred emicizumab dosing regimen (1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks) in order to provide them the same flexibility as with commercial product.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds - The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (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 multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.
Timepoint [1] 0 0
From Baseline to at least 24 weeks
Primary outcome [2] 0 0
Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds - The number of all bleeds over the efficacy period is presented as an annualized bleeding rate (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). 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 implemented exactly as defined for the "treated bleeds" outcome measure. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Timepoint [2] 0 0
From Baseline to at least 24 weeks
Primary outcome [3] 0 0
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds - The number of treated spontaneous bleeds over the efficacy period is presented as an annualized bleeding rate (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 that fulfilled the 72-hour rule were included in the analysis of spontaneous bleeds. Bleeds due to surgery/procedure are excluded.
Timepoint [3] 0 0
From Baseline to at least 24 weeks
Primary outcome [4] 0 0
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds - The number of treated joint bleeds over the efficacy period is presented as an annualized bleeding rate (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 bleed" is a joint 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 analysis of joint bleeds, excluding bleeds due to surgery/procedure.
Timepoint [4] 0 0
From Baseline to at least 24 weeks
Primary outcome [5] 0 0
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds - The number of treated target joint bleeds over the efficacy period is presented as an annualized bleeding rate (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 ABR for Treated Bleeds for the definition). Bleeds due to surgery/procedure are excluded.
Timepoint [5] 0 0
From Baseline to at least 24 weeks
Secondary outcome [1] 0 0
Expansion Part: Change From Baseline to Week 25 in the Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score for Adult Participants (=18 Years of Age) - The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a "not applicable" option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 7 points or more on the Total Score was defined as the threshold for a clinically meaningful improvement.
Timepoint [1] 0 0
Baseline, Week 25
Secondary outcome [2] 0 0
Expansion Part: Percentage of Adult Participants (=18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Total Score - The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a "not applicable" option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 7 points or more on the Total Score was defined as the threshold for a clinically meaningful improvement.
Timepoint [2] 0 0
Baseline, Week 25
Secondary outcome [3] 0 0
Expansion Part: Change From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Participants (=18 Years of Age) - The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a "not applicable" option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 10 points or more on the Physical Health Score was defined as the threshold for a clinically meaningful improvement.
Timepoint [3] 0 0
Baseline, Week 25
Secondary outcome [4] 0 0
Expansion Part: Percentage of Adult Participants (=18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score - The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a "not applicable" option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 10 points or more on the Physical Health Score was defined as the threshold for a clinically meaningful improvement.
Timepoint [4] 0 0
Baseline, Week 25
Secondary outcome [5] 0 0
Expansion Part: Change From Baseline to Week 25 in the Hemophilia-Quality of Life-Short Form (Haemo-QoL-SF) Questionnaire Total Score for Adolescent Participants (12-17 Years of Age) - The Haemo-QoL-SF was developed in a series of age-related questionnaires to measure health-related quality of life (HRQoL) in children and adolescents with hemophilia. The short version for older children containing 35 items was selected for adolescents in this study. Items are rated along five response options: never, rarely, sometimes, often, or all the time. This version covers nine dimensions considered relevant for the children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia, and treatment). Scale scores range from 0 to 100, with lower scores indicating better HRQoL. Given the small number of adolescent participants, the results of the Haemo-QoL-SF questionnaire should be interpreted with caution.
Timepoint [5] 0 0
Baseline, Week 25
Secondary outcome [6] 0 0
Expansion Part: Change From Baseline to Week 25 in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score - The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. An increase in the VAS score of 7 points or greater was defined as the threshold for a meaningful improvement.
Timepoint [6] 0 0
Baseline, Week 25
Secondary outcome [7] 0 0
Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score - The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. An increase in the VAS score of 7 points or greater was defined as the threshold for a meaningful improvement.
Timepoint [7] 0 0
Baseline, Week 25
Secondary outcome [8] 0 0
Expansion Part: Change From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score - The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Published weighting systems allow for creation of a single summary score for the Index Utility Score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction. An increase in the Index Utility Score of 0.07 points or greater was defined as the threshold for a meaningful improvement.
Timepoint [8] 0 0
Baseline, Week 25
Secondary outcome [9] 0 0
Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score - The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Published weighting systems allow for creation of a single summary score for the Index Utility Score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction. An increase in the Index Utility Score of 0.07 points or greater was defined as the threshold for a meaningful improvement.
Timepoint [9] 0 0
Baseline, Week 25
Secondary outcome [10] 0 0
Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks - Participants enrolled in the expansion part of the study reported at each time point the number of days away from work (i.e., days of work missed) and the expected number of days at work in the previous four weeks, which is reported here for each time point as the proportion of the number of days away from work to the expected number of days at work.
Timepoint [10] 0 0
Predose at Baseline, Weeks 13 and 25, and every 12 weeks thereafter up to study completion/early termination (up to approximately 4 years)
Secondary outcome [11] 0 0
Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks - Participants enrolled in the expansion part of the study reported at each time point the number of days away from school (i.e., days of school missed) and the expected number of days at school in the previous four weeks, which is reported here as the proportion of the number of days away from school to the expected number of days at school.
Timepoint [11] 0 0
Predose at Baseline, Weeks 13 and 25, and every 12 weeks thereafter up to study completion/early termination (up to approximately 4 years)
Secondary outcome [12] 0 0
Expansion Part: Number of Days Hospitalized - At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks); all participants had completed at least 24 weeks of treatment.
Timepoint [12] 0 0
From Baseline until at least 24 weeks of treatment through to study completion (up to approximately 4 years)
Secondary outcome [13] 0 0
Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey - The Emicizumab Preference Survey is a fit-for-purpose questionnaire developed by the sponsor to record the participant's preference for treatment with intravenous (IV) factor VIIII (FVIII) or subcutaneous (SC) emicizumab, or no preference.
Timepoint [13] 0 0
Predose at Week 17
Secondary outcome [14] 0 0
PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab
Timepoint [14] 0 0
Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)
Secondary outcome [15] 0 0
PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab
Timepoint [15] 0 0
Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)
Secondary outcome [16] 0 0
PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab
Timepoint [16] 0 0
Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)
Secondary outcome [17] 0 0
PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab
Timepoint [17] 0 0
Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)
Secondary outcome [18] 0 0
PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab
Timepoint [18] 0 0
Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)
Secondary outcome [19] 0 0
PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab - Only CL/F is reported after the first dose; the apparent clearance at steady state (CLss/F) is reported after the sixth dose instead. This is because t1/2 was not properly estimated after the first dose due to sampling time and dosing schedule, and dependent PK parameters, such as CL/F, could not be estimated.
Timepoint [19] 0 0
Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)
Secondary outcome [20] 0 0
Expansion Part: Minimum Observed Plasma Concentration (Cmin) of Emicizumab
Timepoint [20] 0 0
Predose at Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, and once every 12 weeks from Week 25 to study completion (up to approximately 4 years)
Secondary outcome [21] 0 0
Number of Participants With At Least One Adverse Event - The number of participants experiencing at least one adverse event, including all non-serious and serious adverse events, is reported here. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Timepoint [21] 0 0
From Baseline to study completion (up to approximately 4 years)
Secondary outcome [22] 0 0
Number of Participants With Grade =3 Adverse Events - The World Health Organization (WHO) toxicity grading scale will be used for assessing adverse event severity. For adverse events that are not specifically listed in the WHO toxicity grading scale, a grade 3 adverse event is defined as: severe, marked limitation in activity, some assistance usually required, medical intervention or therapy required, hospitalization possible; and a grade 4 adverse event is defined as: life-threatening, extreme limitation in activity, significant assistance required, significant medical intervention or therapy required, hospitalization or hospice care probable. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Timepoint [22] 0 0
From Baseline to study completion (up to approximately 4 years)
Secondary outcome [23] 0 0
Number of Participants With Adverse Events Leading to Withdrawal From Treatment - At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Timepoint [23] 0 0
From Baseline to study completion (up to approximately 4 years)
Secondary outcome [24] 0 0
Number of Participants With Adverse Events of Changes From Baseline in Vital Signs - The number of participants with adverse events of changes from baseline in vital signs is reported here. Vital signs measurements consisted of heart and respiratory rate, temperature, and systolic and diastolic blood pressures, with an abnormal vital sign value being outside of the normal range. An abnormal vital sign result is reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); results in a medical intervention or a change in concomitant therapy; or is clinically significant in the investigator's judgment. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Timepoint [24] 0 0
From Baseline to study completion (up to approximately 4 years)
Secondary outcome [25] 0 0
Number of Participants With Adverse Events of Changes From Baseline in Physical Examination Findings - Post-baseline physical examination abnormalities that were not present at baseline or worsened were reported as adverse events. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Timepoint [25] 0 0
From Baseline to study completion (up to approximately 4 years)
Secondary outcome [26] 0 0
Number of Participants With Adverse Events of Abnormal Laboratory Values - The number of participants with adverse events of abnormal laboratory values is reported here. An abnormal laboratory value is defined as a laboratory test result outside of the normal range for hematology or serum chemistries.
It is reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); results in a medical intervention or a change in concomitant therapy; or is clinically significant in the investigator's judgment. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Timepoint [26] 0 0
From Baseline to study completion (up to approximately 4 years)
Secondary outcome [27] 0 0
Number of Participants With Local Injection-Site Reactions - Local adverse events that occurred within 24 hours after study drug administration and, in the investigator's opinion, were judged to be related to study drug injection, were captured as an "injection-site reaction" on the Adverse Event electronic Case Report Form (eCRF). An injection-related reaction that was localized was marked as a "local injection-site reaction." At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Timepoint [27] 0 0
From Baseline to study completion (up to approximately 4 years)
Secondary outcome [28] 0 0
Number of Participants With Thromboembolic Events - At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Timepoint [28] 0 0
From Baseline to study completion (up to approximately 4 years)
Secondary outcome [29] 0 0
Number of Participants With Thrombotic Microangiopathy - At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Timepoint [29] 0 0
From Baseline to study completion (up to approximately 4 years)
Secondary outcome [30] 0 0
Number of Participants With Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions - At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Timepoint [30] 0 0
From Baseline to study completion (up to approximately 4 years)
Secondary outcome [31] 0 0
Number of Participants With Anti-Drug Antibodies to Emicizumab - A validated ELISA method was used to analyze the levels of anti-drug antibodies to emicizumab in blood plasma samples. A sample was considered positive for anti-drug antibodies if the test result reached or exceeded a pre-determined threshold. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Timepoint [31] 0 0
Baseline, Weeks 5, 9, 13, 17, 21, and 25, and every 12 weeks thereafter until study completion (up to approximately 4 years)
Secondary outcome [32] 0 0
Number of Participants With De Novo Development of Anti-Factor VIII (FVIII) Antibodies - The levels of anti-FVIII antibodies (inhibitors) were analyzed using a validated FVIII activity assay. A participant was considered to have developed de novo FVIII inhibitors if the inhibitor levels detected in a post-baseline sample reached or exceeded a pre-determined threshold. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
Timepoint [32] 0 0
Baseline, Weeks 9 and 17 (for non-inhibitor subjects only), Week 25, and every 12 weeks thereafter until study completion (up to approximately 4 years)

Eligibility
Key inclusion criteria
- Body weight greater than or equal to (>/=) 40 kilograms (kg) at screening

- Diagnosis of severe congenital hemophilia A or hemophilia A with FVIII inhibitors

- Participants using rFVIIa or willing to switch to recombinant activated factor VII
(rFVIIa) as primary bypassing agent for the treatment of breakthrough bleeds

- FVIII inhibitor test during screening with titer results available prior to first
administration of study drug

- Participants without FVIII inhibitors, that is with less than (<) 0.6 Bethesda unit
per milliliter [BU/mL];< 1.0 BU/mL only for laboratories with an historical
sensitivity cutoff for inhibitor detection of 1.0 BU/mL, who completed successful
immune tolerance induction (ITI) must have done so at least 5 years before screening
and must have no evidence of inhibitor recurrence (permanent or temporary) indicated
by detection of an inhibitor greater than (>) 0.6 BU/mL (> 1.0 BU/mL only for
laboratories with an historical sensitivity cutoff for inhibitor detection of 1.0
BU/mL) since ITI

- Adequate hematologic, hepatic, and renal function
Minimum age
12 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Inherited or acquired bleeding disorder other than hemophilia A

- Ongoing or planned ITI therapy; participants in whom ITI has failed will be eligible
with a 72-hour washout period prior to the first emicizumab administration

- History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the
investigator's judgment

- Participants who are at high risk for thrombotic microangiopathy (TMA) (for example,
have a previous medical or family history of TMA), in the investigator's judgment

- Previous (within the last 12 months) or current treatment for thromboembolic disease
(with the exception of previous catheter-associated thrombosis for which
anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease

- Other conditions (for example, certain autoimmune diseases) that may currently
increase the risk of bleeding or thrombosis

- History of clinically significant hypersensitivity associated with monoclonal antibody
therapies or components of the emicizumab injection

- Known HIV infection with cluster of differentiation (CD) 4 cells counts <200 cells per
microliter (cells/mcL)

- Use of systemic immunomodulators (for example, interferon) at enrollment or planned
use during the study, with the exception of anti-retroviral therapy

- Concomitant disease, condition, significant abnormality on screening evaluations or
laboratory tests, or treatment that could interfere with the conduct of the study, or
that would, in the opinion of the investigator, pose an additional unacceptable risk
in administering study drug to the participant

- Pregnancy or lactation or intention to become pregnant during the study

- Women with a positive serum pregnancy test result within 7 days prior to initiation of
study drug

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,SA
Recruitment hospital [1] 0 0
Royal Brisbane Hospital; Clinical Haematology - Brisbane
Recruitment hospital [2] 0 0
Royal Adelaide Hospital; Haematology Clinical Trials - Adelaide
Recruitment postcode(s) [1] 0 0
4029 - Brisbane
Recruitment postcode(s) [2] 0 0
5000 - Adelaide
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Indiana
Country [3] 0 0
United States of America
State/province [3] 0 0
Michigan
Country [4] 0 0
United States of America
State/province [4] 0 0
North Carolina
Country [5] 0 0
Belgium
State/province [5] 0 0
Bruxelles
Country [6] 0 0
Belgium
State/province [6] 0 0
Leuven
Country [7] 0 0
Japan
State/province [7] 0 0
Hokkaido
Country [8] 0 0
Japan
State/province [8] 0 0
Nara
Country [9] 0 0
Japan
State/province [9] 0 0
Tokyo
Country [10] 0 0
Poland
State/province [10] 0 0
Warsaw
Country [11] 0 0
Poland
State/province [11] 0 0
Wroclaw
Country [12] 0 0
Spain
State/province [12] 0 0
Madrid
Country [13] 0 0
Spain
State/province [13] 0 0
Sevilla
Country [14] 0 0
Spain
State/province [14] 0 0
Valencia

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Chugai Pharmaceutical
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This multicenter, open-label, non-randomized study will assess the efficacy, safety,
pharmacokinetics, and pharmacodynamics of emicizumab administered at a dose of 6 milligrams
per kilogram (mg/kg) every 4 weeks in participants with hemophilia A with or without
inhibitors against factor VIII (FVIII). The study consists of 2 parts: a pharmacokinetic (PK)
run-in part followed by an expansion part.
Trial website
https://clinicaltrials.gov/show/NCT03020160
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications