Clinical trial NCT04158648: A Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Emicizumab in Participants With Mild or Moderate Hemophilia A Without FVIII Inhibitors
Official title: A Multicenter, Open-Label Study to Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Emicizumab in Patients With Mild or Moderate Hemophilia A Without FVIII Inhibitors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Mild Hereditary Factor VIII Deficiency Disease Without Inhibitor
Moderate Hereditary Factor VIII Deficiency Disease Without Inhibitor
Hemophilia A
Keywords: Mild Hemophilia A Without Factor VIII Inhibitors
Moderate Hemophilia A Without Factor VIII Inhibitors
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2019-11-12
Enrollment: 73
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a multicenter, open-label, single-arm study designed to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of emicizumab in participants with mild or moderate hemophilia A without inhibitors against factor VIII (FVIII).


Eligibility criteria: Inclusion Criteria:

* Diagnosis of mild (FVIII level between \>5% and \<40%) or moderate (FVIII level between ≥1% and ≤5%) congenital Hemophilia A without FVIII inhibitors
* Weight ≥3 kilograms (kg)
* Need for prophylaxis based on investigator assessment
* A negative test for inhibitor (i.e., \<0.6 Bethesda Units per milliliter \[BU/mL\]) within 8 weeks prior to enrollment
* No documented inhibitor (i.e., \<0.6 BU/mL), FVIII half-life \<6 hours, or FVIII recovery \<66% in the last 5 years
* Documentation of the details of prophylactic or episodic FVIII treatment and of number of bleeding episodes for at least the last 24 weeks prior to enrollment
* Adequate hematologic, hepatic, and renal function
* For women of childbearing potential: agreement to remain abstinent or use contraception (as defined in the protocol) during the treatment period and for at least 24 weeks after the final dose of study drug

Exclusion Criteria:

* Inherited or acquired bleeding disorder other than mild or moderate congenital hemophilia A
* History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the investigator's judgment
* Previous (within the last 12 months) or current treatment for thromboembolic disease or signs of thromboembolic disease
* Other conditions 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
* Planned surgery during the emicizumab loading dose phase (surgeries in participants on emicizumab from Week 5 onwards are allowed)
* Known HIV infection with CD4 counts \<200 cells per microlitre (/μL)
* Concomitant disease, condition, significant abnormality on screening evaluation 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
* Receipt of any of the following: An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration with the exception of prior emicizumab prophylaxis; A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, whichever is shorter; or Any other investigational drug currently being administered or planned to be administered
* Inability to comply with the study protocol in the opinion of the investigator
* Pregnant or breastfeeding, or intending to become pregnant during the study (women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study drug)

Primary outcomes:
measure: Model-Based Annualized Bleed Rate for Treated Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Mean Calculated Annualized Bleed Rate for Treated Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Median Calculated Annualized Bleed Rate for Treated Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Secondary outcomes:
measure: Model-Based Annualized Bleed Rate for All Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Mean Calculated Annualized Bleed Rate for All Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Median Calculated Annualized Bleed Rate for All Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Model-Based Annualized Bleed Rate for Treated Joint Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Mean Calculated Annualized Bleed Rate for Treated Joint Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Median Calculated Annualized Bleed Rate for Treated Joint Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Model-Based Annualized Bleed Rate for Treated Target Joint Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Mean Calculated Annualized Bleed Rate for Treated Target Joint Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Median Calculated Annualized Bleed Rate for Treated Target Joint Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Model-Based Annualized Bleed Rate for Treated Spontaneous Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Mean Calculated Annualized Bleed Rate for Treated Spontaneous Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: Median Calculated Annualized Bleed Rate for Treated Spontaneous Bleeds
timeFrame: From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
measure: CATCH Questionnaire for Adult Participants: Change From Baseline in the Daily Activity Risk Perception and Impact Domain Scores Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Adult Participants: Change From Baseline in the Social Activity Risk Perception and Impact Domain Scores Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Adult Participants: Change From Baseline in the Recreational Activity Risk Perception and Impact Domain Scores Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Adult Participants: Change From Baseline in the Work Impact Domain Score Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Adult Participants: Change From Baseline in the Preoccupation Domain Score Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Adult Participants: Change From Baseline in the Treatment Burden Domain Score Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain Associated With a Bleed Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain in Target Joints Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain at Its Worst Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain at Its Least Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain on Average Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Daily Activity Risk Perception and Impact Domain Score Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Social Activity Risk Perception and Impact Domain Score Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Recreational Activity Risk Perception and Impact Domain Score Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Pediatric Participants: Change From Baseline in the School Impact Domain Score Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Preoccupation Domain Score Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Treatment Burden Domain Score Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Pediatric Participants: Number of Participants by Responses to Their Level of Pain Associated With a Bleed Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Pediatric Participants: Number of Participants by Responses to Their Level of Pain at Its Worst Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Caregivers: Change From Baseline in the Preoccupation Domain Score Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: CATCH Questionnaire for Caregivers: Change From Baseline in the Treatment Burden Domain Score Over Time
timeFrame: Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Percentage of Participants Who Prefer Emicizumab SC Treatment, Their Previous Hemophilia IV Treatment, or Have No Preference, as Assessed Through Use of the Emicizumab Preference Survey at Week 17
timeFrame: Week 17
measure: Percentage of Caregivers Who Prefer Emicizumab SC Treatment, Their Child's Previous Hemophilia IV Treatment, or Have No Preference, as Assessed Through Use of the Emicizumab Preference Survey at Week 17
timeFrame: Week 17
measure: Hemophilia Joint Health Scores Over Time
timeFrame: Days -7 to -1, Weeks 25, 49, and every 24 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Change From Baseline in Mean Daily Peak Activity Duration Over Time
timeFrame: Baseline (Weeks 1-2) and Weeks 13 (Weeks 12-13 period), 25 (Weeks 24-25 period), 37 (Weeks 36-37 period), and 49 (Weeks 48-49 period)
measure: Change From Baseline in Mean Daily Step Count Over Time
timeFrame: Baseline (Weeks 1-2) and Weeks 13 (Weeks 12-13), 25 (Weeks 24-25), 37 (Weeks 36-37), and 49 (Weeks 48-49)
measure: Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the MBQ Total Score Over Time
timeFrame: Baseline (Week 1), Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and every 4 weeks thereafter until Study Completion (up to approximately 48 months)
measure: Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Heaviness Subscale Score Over Time
timeFrame: Baseline (Week 1), Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and every 4 weeks thereafter until Study Completion (up to approximately 48 months)
measure: Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Quality of Life Subscale Score Over Time
timeFrame: Baseline (Week 1), Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and every 4 weeks thereafter until Study Completion (up to approximately 48 months)
measure: Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Irregularity Subscale Score Over Time
timeFrame: Baseline (Week 1), Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and every 4 weeks thereafter until Study Completion (up to approximately 48 months)
measure: Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Pain Subscale Score Over Time
timeFrame: Baseline (Week 1), Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and every 4 weeks thereafter until Study Completion (up to approximately 48 months)
measure: Menstruation Diary With the Pictorial Blood Assessment Chart (PBAC) for Female Participants of Childbearing Potential: PBAC Scores Over Time
timeFrame: Baseline (Day 1) and monthly (on days of menstruation) until Study Completion (up to approximately 48 months)
measure: Number of Participants With at Least One Adverse Event by Severity, According to the World Health Organization (WHO) Toxicity Grading Scale
timeFrame: From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Number of Participants With Adverse Events Leading to Study Drug Discontinuation
timeFrame: From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Number of Participants With at Least One Thromboembolic Event
timeFrame: From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Number of Participants With at Least One Event of Thrombotic Microangiopathy
timeFrame: From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Number of Participants With at Least One Injection-Site Reaction by Severity, According to the WHO Toxicity Grading Scale
timeFrame: From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Number of Participants With at Least One Severe Hypersensitivity, Anaphylaxis, and Anaphylactoid Event
timeFrame: From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Number of Participants With at Least One Laboratory Abnormality
timeFrame: From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Change From Baseline in Respiratory Rate Over Time
timeFrame: Baseline, Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Change From Baseline in Pulse Rate Over Time
timeFrame: Baseline, Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Change From Baseline in Body Temperature Over Time
timeFrame: Baseline, Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Change From Baseline in Systolic Blood Pressure Over Time
timeFrame: Baseline, Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Change From Baseline in Diastolic Blood Pressure Over Time
timeFrame: Baseline, Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Change From Baseline in Electrocardiogram (ECG) Parameters Over Time: QT, QTcB, QTcF, RR, PR, and QRS Intervals
timeFrame: Baseline, Weeks 5, 25, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Change From Baseline in Heart Rate Over Time, as Measured by Electrocardiogram (ECG)
timeFrame: Baseline, Weeks 5, 25, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
measure: Plasma Trough Concentration (Ctrough) of Emicizumab Over Time
timeFrame: Pre-dose at Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and every 12 weeks thereafter until study completion/discontinuation (up to approximately 48 months)
measure: Number of Participants With Anti-Drug Antibodies Against Emicizumab at Baseline and Post-Baseline
timeFrame: Pre-dose at Baseline (Week 1) and Weeks 5, 13, 25, 33, 41, and 49, and every 12 weeks thereafter until study completion/discontinuation (up to approximately 48 months)
measure: Number of Participants Who Develop Anti-FVIII Inhibitors Over Time
timeFrame: Screening (Day -28 to -1) and Weeks 1, 13, 25, 37, and 49, and every 12 weeks thereafter until study completion/discontinuation (up to approximately 48 months)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Childrens Hospital LA
state: California
city: Atlanta
country: United States
facility: Hemophilia of Georgia Center for Bleeding & Clotting Disorders
state: Georgia
city: Indianapolis
country: United States
facility: Indiana Hemophilia & Thrombosis center
state: Indiana
city: Ann Arbor
country: United States
facility: University of Michigan, C.S. Mott Children's Hospital
state: Michigan
city: Seattle
country: United States
facility: Washington Institute for Coagulation
state: Washington
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Edmonton
country: Canada
facility: Kaye Edmonton Clinic
state: Alberta
city: St. John's
country: Canada
facility: Eastern Health - General Hospital
state: Newfoundland and Labrador
city: Bron
country: France
facility: Hopital Cardio-vasculaire Louis Pradel
city: Le Kremlin Bicetre
country: France
facility: CH de Bicetre
city: Paris
country: France
facility: Groupe Hospitalier Necker Enfants Malades
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: München
country: Germany
facility: Klinikum der Universität München, Campus Innenstadt
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC Location AMC
city: Warsaw
country: Poland
facility: Instytut Hematologii i Transfuzjologii
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Johannesburg Hospital
city: Madrid
country: Spain
facility: Hospital Universitario la Paz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Cardiff
country: United Kingdom
facility: Cardiff and Vale NHS Trust
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: Great Ormond street Hospital for Children NHS Foundation Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: