Safety, Efficacy and PK of BIVV001 in Pediatric Patients With Hemophilia A
- Conditions
- Hemophilia A
- Interventions
- Drug: efanesoctocog alfa (BIVV001)
- Registration Number
- NCT04759131
- Lead Sponsor
- Bioverativ, a Sanofi company
- Brief Summary
Primary Objective:
- To evaluate the safety of BIVV001 in previously treated pediatric participants with hemophilia A.
Secondary Objectives:
* To evaluate the efficacy of BIVV001 as a prophylaxis treatment.
* To evaluate the efficacy of BIVV001 in the treatment of bleeding episodes.
* To evaluate BIVV001 consumption for prevention and treatment of bleeding episodes.
* To evaluate the effect of BIVV001 prophylaxis on joint health outcomes.
* To evaluate the effect of BIVV001 prophylaxis on Quality of Life (QoL) outcomes.
* To evaluate the efficacy of BIVV001 for perioperative management.
* To evaluate the safety and tolerability of BIVV001 treatment.
* To assess the pharmacokinetics (PK) of BIVV001.
- Detailed Description
Study duration per participants was approximately 60 weeks (maximum 8 weeks for screening and 52 weeks of treatment).
All participants completing or remaining at the end of study were offered participation in the planned extension trial.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 74
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description BIVV001: Participants aged <6 Years efanesoctocog alfa (BIVV001) Participants aged less than (\<) 6 years received BIVV001 at a dose of 50 international units per kilogram (IU/kg) intravenous (IV) injection once-weekly (QW) prophylaxis for 52 weeks. BIVV001: Participants aged 6 to <12 Years efanesoctocog alfa (BIVV001) Participants aged 6 to \<12 years received BIVV001 at a dose of 50 IU/kg IV injection QW prophylaxis for 52 weeks.
- Primary Outcome Measures
Name Time Method Number of Participants With Neutralising Antibodies (Development of Inhibitors) Directed Against Factor VIII Baseline up to Week 52 Inhibitor development was defined as an inhibitor result of greater than or equal to (\>=0.6) Bethesda units (BU/mL) that was confirmed by a second test result from a separate sample, drawn 2 to 4 weeks following the date when the original sample was drawn. Both tests must have been performed by the central laboratory using the Nijmegen modified Bethesda assay.
- Secondary Outcome Measures
Name Time Method Pharmacokinetics: Clearance (CL) Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1 CL is defined as the rate at which the drug is removed from the body.
Annualized Bleeding Rate (ABR): For Treated Bleeds Baseline up to Week 52 ABR: annualized number of treated bleeding episodes (BE) per participant per year. ABR=number of treated BE during efficacy period (EP)/total number of days during EP\*365.25. Treated BE:any occurrence of hemorrhage required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat BE, any subsequent bleeding at same location/injections administered less than or equal to (\<=) 72 hours apart from previous injection were considered same BE. Any injection after \>72 hours post preceding one=considered 1st injection to treat new BE in same location. Any bleed at different location:considered as separate BE, regardless of time from last injection. EP=sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. ABR:by negative binomial model with total number of treated BE during EP as response variable and log transformed EP duration (years) as offset variable.
Annualized Bleeding Rate for All Bleeding Episodes Baseline up to Week 52 ABR:annualized number of all BE (treated and untreated)/participant/year. ABR=number of all BE during EP/total number of days during EP\*365.25. BE:any occurrence of hemorrhage required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat BE, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same BE. Any injection after \>72 hours post preceding one=considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. EP:sum of all intervals of time during which participants treated with BIVV001 according to study arms \& treatment regimens. ABR:NB model with total number of treated BE during EP as response variable and log-transformed EP duration (years) as offset variable. Spontaneous:bleeding without contributing factor, Traumatic:bleeding with known reason.
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa) Baseline up to Week 52 ABR: annualized number of treated bleeding episodes per participant per year. ABR = number of all BE during EP/total number of days during EP\*365.25. Efficacy period reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. Treated bleeding episode: episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any injection \>72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: BE without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: BE with known/believed reason for bleed.
Sensitivity Analysis: Annualized Bleeding Rate for All Bleeding Episodes Baseline up to Week 52 ABR: annualized number of all BE (treated \& untreated)/participant/year. ABR=number of all BE during EP/total number of days during EP\*365.25. BE: any hemorrhage occurrence required administration of BIVV001. It started from 1st sign of bleed \& ended no more than 72 hours after last injection to treat BE, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same BE. Any bleed at different location: considered as separate BE, regardless of time from last injection. EP: sum of all intervals of time during which participants treated with BIVV001 according to study arms and treatment regimens. ABR: estimated by NB model with total number of treated BE during EP as response variable and log-transformed EP duration (years) as offset variable. Spontaneous: bleeding without contributing factor (definite trauma/antecedent strenuous activity). Traumatic: bleeding with known/believed reason.
Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type) Baseline up to Week 52 ABR: annualized number of treated bleeding episodes per participant per year. ABR = number of all BE during EP/total number of days during EP\*365.25. EP reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. Treated BE: episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken \>72 hours after preceding one was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: BE without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: BE with known/believed reason for bleed.
Sensitivity Analysis: Annualized Bleeding Rate: For Treated Bleeds Baseline up to Week 52 ABR: annualized number of treated BE per participant per year. ABR = number of treated BE during EP/total number of days during EP\*365.25. Treated BE: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat BE, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same BE. Any injection to treat bleed, taken \>72 hours after preceding one, was considered 1st injection to treat new bleeding episode in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. EP reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. ABR: using negative binomial (NB) model with total number of treated BE during EP as response variable and log-transformed EP duration (years) as offset variable.
Sensitivity Analysis: Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type) Baseline up to Week 52 ABR: annualized number of treated bleeding episodes per participant per year. ABR = number of all BE during EP/total number of days during EP\*365.25. EP reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. Treated BE: episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken \>72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: BE without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: BE with known/believed reason for bleed.
Sensitivity Analysis: Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa) Baseline up to Week 52 ABR: annualized number of treated bleeding episodes per participant per year. ABR = number of all BE during EP/total number of days during EP\*365.25. EP reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms \& treatment regimens. Treated BE: episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken \>72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: BE without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: BE with known/believed reason for bleed.
Percentage of Participants Achieving FVIII Activity Levels Above 1%, 3%, 5%, 10%, 15%, and 20% Baseline up to Week 52 FVIII activity level was measured using activated partial thromboplastin time (aPTT)-based one stage clotting assay. Percentage of participants who achieved steady-state trough FVIII activity levels above (\>) 1%, 3%, 5%, 10%, 15%, and 20% were reported in this outcome measure. Participants were counted in more than one category, as applicable.
Number of Injections of BIVV001 Required to Treat a Bleeding Episode Baseline up to Week 52 A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken \>72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection.
Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001 Baseline up to Week 52 A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken \>72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Percentage of bleeding episodes (of all bleeding episodes occurred) which were treated with single injection was reported in this outcome measure.
Sensitivity Analysis: Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001 Baseline up to Week 52 A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken \>72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Percentage of bleeding episodes (of all bleeding episodes occurred) which were treated with single injection was reported in this outcome measure.
Change From Baseline in Hemophilia Quality of Life Questionnaire (Haemo-QoL) Kids Short Version Total Score at Week 52 for Children Participants (Aged 4 to 7 and 8 to <12 Years) Baseline, Week 52 Haemo-QoL kids short version: used to measure physical and emotional impacts on quality of life in children \& adolescent with hemophilia. It was administered to children \& their caregivers. Short version for children containing 16 items (4 to 7 years) and 35 items (8 to \<12 years) were selected in this study. This version covers 9 dimensions relevant for children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia \& treatment). Items were rated along 5 response options: never, seldom, sometimes, often and always, higher scores=greater impairment. Raw score for each domain were transformed to scale ranged between 0 to 100, where lower score=better HRQoL. Haem- A-QoL total score=average of all domain scores and ranged from 0 to 100, where lower scores=better QoL.
Total Number of Target Joints Resolved in Participants at Week 52 Week 52 A target joint at Baseline was defined as a major joint with \>=3 spontaneous bleeding episodes in a consecutive 6 month period prior to entry to the study, captured at Baseline. A target joint resolved was defined as \<=2 spontaneous bleeds into that joint during 12 months of continuous exposure (defined as treatment regimen period \>=52 weeks). Total number of target joints resolved at Week 52 were reported.
Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery During the perioperative period (any time during Baseline up to Week 52) The perioperative period was the time lapse surrounding the surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). The number of blood component transfusions used during perioperative period were summarized categorically (0, 1, 2, 3 and \>3) for all major surgeries for the surgery subgroup. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or \>=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura).
Change From Baseline in Hemophilia Joint Health Score Domain Score at Week 52 Baseline, Week 52 HJHS is a validated 11-item scoring tool developed for the assessment of joint health in participants with hemophilia. Following domains were assessed for elbows, knee and ankle joints: swelling (score 0 = no swelling to 3=severe), duration of swelling (score 0 = no swelling and 1 = \>=6 months), muscle atrophy (score 0 = none to 2 = severe), crepitus on motion (score 0 = none to 2=severe), flexion loss (score 0 = \<5' to 3 = \>20'), extension loss (score 0 = \<5' to 3 = \>20'), joint pain (score 0 = no pain through active range of motion to 2 = pain through active range) and strength (score 0 = holds test position with maximum resistance to 4 = trace/no muscle contraction), for each item 0 = no damage and higher score = severe damage.
Change From Baseline in Hemophilia Quality of Life Questionnaire Parent Proxy Short Version Total Score at Week 52 for Children Participants (Aged 4 to 7 and 8 to <12 Years): Parent's Evaluation Baseline, Week 52 Haemo-QoL parent proxy short version: used to measure physical and emotional impacts on quality of life in children and adolescent with hemophilia. It was administered to children \& their caregivers. Short version for children's caregivers containing 16 items (participants 4 to 7 years) and 35 items (participants 8 to \<12 years) were selected in this study. This version covers 9 dimensions relevant for children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated along 5 response options: never, seldom, sometimes, often and always, higher scores=greater impairment. Raw score for each domain: transformed to scale ranged between 0 to 100, lower score=better HRQoL. Haem-A-QoL total score=average of all domain scores and ranged from 0 to 100, lower scores=better quality of life. Haemo-QoL Total Score as per parent's evaluation was reported in this outcome measure.
Change From Baseline in Hemophilia Quality of Life Questionnaire Kids Short Version Physical Health Domain Score at Week 52 for Children Participants (Aged 8 to <12 Years) Baseline, Week 52 Haemo-QoL kids short version: used to measure physical and emotional impacts on quality of life in children and adolescent with hemophilia. It was administered to children and their caregivers. Short version for children containing 35 items (8 to \<12 years) were selected in this study. This version covers 9 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). Items are rated along 5 response options: never, seldom, sometimes, often and always, higher scores=greater impairment. Raw score for physical health domain were transformed to scale ranged between 0 to 100, where lower score=better HRQoL. Change from baseline in physical Health domain score was reported in this outcome measure.
Total BIVV001 Consumption From Day -1 to 14 During Perioperative Period for Major Surgery Day -1 to Day 14 Perioperative period: time lapse surrounding surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). Total BIVV001 consumption were summarized from the loading dose (the day before surgery, i.e., on Day -1) up to 2 weeks following the surgery (i.e., Day 14) and were reported in this outcome measure.
Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery During the perioperative period (any time during Baseline up to Week 52) The perioperative period was the time lapse surrounding the surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). The type of blood component (Red blood cell, platelet, fresh frozen plasma, whole blood and other) transfusions used were summarized for all major surgeries. Post-operative referred to the day following the end of surgery to the date of hospital discharge. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or \>=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura).
Sensitivity Analysis: Number of Injections of BIVV001 Required to Treat a Bleeding Episode Baseline up to Week 52 A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken \>72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection.
Total Dose of BIVV001 Required to Treat a Bleeding Episode Baseline up to Week 52 A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken \>72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Total dose was expressed in unit: International units per kilogram (IU/kg).
Sensitivity Analysis: Total Dose of BIVV001 Required to Treat a Bleeding Episode Baseline up to Week 52 A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered \<=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken \>72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any injection after \>72 hours post preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Total dose was expressed in unit: IU/kg.
Participant's Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale Baseline up to Week 52 Participant's response to the 1st injection of BIVV001 treatment for treating a bleed was evaluated by ISTH 4-point response scale categorized as: Excellent (complete pain relief/complete resolution of signs of bleeding), Good (significant pain relief /improvement in signs of bleeding), Moderate (modest pain relief/improvement in signs of bleeding) and none (no or minimal improvement/condition worsened). Assessed approximately 72 hours after initial treatment for BE. Bleeding episode: an episode that started from 1st sign of bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location/injections \<=72 hours apart were considered same BE. Any injection after \>72 hours post preceding one=considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Participants were counted in more than one category, as applicable.
Physicians' Global Assessment (PGA) of Participant's Response to BIVV001 Treatment Based on a 4-point Response Scale Week 13 and Week 52/End of study (EOS)/Early termination (ET) Physicians assessed participant's response to BIVV001 treatment using 4-point response scale categorized as: Excellent= BE responded to fewer than/usual number of injections/less than/usual dose of FVIII/rate of breakthrough bleeding during prophylaxis was \<= that usually observed; Effective = most BE responded to same number of injections and dose, but some required more injections/higher doses/there was minor increase in rate of breakthrough bleeding; partially effective = BE most often required more injections and/or higher doses than expected/adequate breakthrough bleeding prevention during prophylaxis required more frequent injections and/or higher doses; Ineffective = routine failure to control hemostasis or hemostatic control required additional agents.
Total Annualized BIVV001 Consumption Per Participant Baseline up to Week 52 Total annualized BIVV001 consumption (in IU/kg) was calculated for each participant as: Total IU/kg of BIVV001 during EP divided by total number of days during EP\*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens.
Annualized Joint Bleeding Rate (AJBR) Baseline up to Week 52 AJBR: annualized number of joint bleeding/participant/year. ABR = number of treated joint BE during EP divided by total number of days during EP\*365.25. Joint BE: unusual sensation in joint ('aura') along with 1) increasing swelling/warmth over skin, joint; 2) increasing pain or 3) progressive loss of range of motion/difficulty in using limb compared to Baseline. BE: episode started from 1st sign of bleed \& ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location/injections \<=72 hours apart considered same BE. Any injection after \>72 hours post preceding one=1st injection to treat new BE in same location. Any bleed at different location=separate BE, regardless of time from last injection. EP: sum of all intervals of time during which participants treated with BIVV001 per study arms and treatment regimens. ABR:NB model with total number of treated BE during EP (response variable) \& log-transformed EP duration (offset variable).
Sensitivity Analysis: Annualized Joint Bleeding Rate (AJBR) Baseline up to Week 52 AJBR: annualized number of joint bleeding/participant/year. ABR = number of treated joint BE during EP divided by total number of days during EP\*365.25. Joint BE: unusual sensation in joint ('aura') along with 1) increasing swelling/warmth over skin, joint; 2) increasing pain or 3) progressive loss of range of motion/difficulty in using limb compared to Baseline. BE: episode started from 1st sign of bleed \& ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location/injections \<=72 hours apart considered same BE. Any injection after \>72 hours post preceding one=1st injection to treat new BE in same location. Any bleed at different location=separate BE, regardless of time from last injection. EP: sum of all intervals of time during which participants treated with BIVV001 per study arms and treatment regimens. ABR: NB model with total number of treated BE during EP (response variable) \& log-transformed EP duration (offset variable).
Change From Baseline in Hemophilia Joint Health Score (HJHS) Total Score at Week 52 Baseline, Week 52 HJHS is a validated 11-item scoring tool developed for the assessment of joint health in participants with hemophilia. It comprised an evaluation of the elbows, knee and ankle joints: swelling (0 to 3), duration of swelling (0 to 1), muscle atrophy (0 to 2), crepitus on motion (0 to 2), flexion loss (0 to 3), extension loss (0 to 3), joint pain (0 to 2) and strength (0 to 4), in each item 0 = none and higher score = severe damage and global gait (walking, stairs, running, hopping on 1 leg) scored on scale ranged from 0 to 4, where 0 = all skills in normal limit and 4 = no skills within normal limits). Total HJHS score = sum of joint totals (0 to 120) + general gait (1 to 4) and ranged from 0 (no joint damage) to 124 (severe joint damage), where higher score indicated severe joint damage.
Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough) Pre-dose at Baseline (Day 1) and Week 52 Ctrough is the pre-dose concentration of a drug. Ctrough was measured by apTT-Baseline-one-stage clotting assay.
Change From Baseline in Hemophilia Quality of Life Questionnaire Parent Proxy Short Version Physical Health Domain Score at Week 52 for Children Participants (Aged 8 to <12 Years): Parent's Evaluation Baseline, Week 52 Haemo-QoL parent proxy short version: used to measure physical \& emotional impacts on quality of life in children \& adolescent with hemophilia. It was administered to children \& their caregivers. Short version for children's caregivers containing 35 items (participants 8 to \<12 years) were selected in this study. This version covers 9 dimensions relevant for children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia \& treatment). Items are rated along 5 response options: never, seldom, sometimes, often and always, higher scores=greater impairment. Raw score for physical health domain were transformed to scale ranged between 0 and 100, where lower score=better HRQoL. Change from baseline in physical health domain score as per parent's evaluation was reported in this outcome measure.
Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery During the perioperative period (any time during Baseline up to Week 52) Perioperative period was time lapse surrounding the surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). The number of injections to maintain hemostasis (process to prevent and stop bleeding from blood vessel) per surgery included all injections from loading dose (i.e., the preoperative injection, administered either on the day of surgery or one day prior to the surgery), to end of surgery. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or \>=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura).
Pharmacokinetics: Volume of Distribution at Steady State (Vss) Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1 Volume of distribution (Vd) is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state.
Time Above Predefined (10% and 40%) FVIII Activity Levels Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1 Time above predefined (10% and 40%) FVIII activity levels mean time which BIVV001 maintains above 10 IU/dL and 40 IU/dL with single doses of 50 IU/kg.
Pharmacokinetics: Dose-normalized Area Under the Activity-time Curve (DNAUC0-tau) Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1 AUC0-tau was defined as the area under the activity-time curve over the dosing interval. AUC was normalized by dose.
Investigators' or Surgeons' Assessment of Participant's Hemostatic Response to BIVV001 Treatment Baseline up to Week 52 The Investigators/Surgeons who complete the surgical procedures assess the participant's response to surgery with BIVV001 treatment using a 4-point scale, where responses were categorized as: 1 = Excellent, 2 = Good, 3 = Fair, and 4 = Poor/none. Higher score indicated worst response. This assessment was performed 24 hours after the surgery. A surgery can be counted in more than one response category. As pre-specified, this outcome measure was planned to be analyzed combinedly for both the cohorts (participants \<6 years and participants 6 to \<12 years) and presented under a single reporting group.
Pharmacokinetics (PK): Maximum FVIII Activity (Cmax) Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1 Cmax was defined as the maximum observed plasma FVIII Activity.
Total Dose Required to Maintain Hemostasis From Day -1 to Day 0 During Perioperative Period for Major Surgery Day -1 to Day 0 (day of surgery) Perioperative period was time lapse surrounding surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during surgery) and post-operative (24-hour post-surgery). Total dose (IU/kg) was sum across all injections per major surgery (including loading dose) needed to maintain hemostasis (process to prevent and stop bleeding from blood vessel) during surgery. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on joint; removal of organ; dental extraction of any molar teeth or \>=3 non-molar teeth; operative alteration of normal anatomy; crossing of mesenchymal barrier (e.g., pleura, peritoneum, dura). Day 0=surgery day. Loading dose for given surgery was preoperative injection, administered either on day of surgery or one day prior to surgery (i.e., Day -1).
Estimated Blood Loss During Major Surgery Day 0 (i.e., day of surgery) The estimated total blood loss (in milliliters) during major surgeries were summarized. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or \>=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura).
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse (TESAEs) From Baseline (Day 1) up to 3 weeks post last dose of BIVV001 (i.e., up to Week 55) An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event. Treatment-emergent AEs were AEs that developed, worsened or became serious from Baseline (Day 1) up to 3 weeks post last dose.
Number of Participants With Occurrence of Embolic and Thrombotic Events Baseline up to Week 52 Embolic and thrombotic events were defined as arterial or venous thrombosis, confirmed by imaging.
Pharmacokinetics: Elimination Half-life (t1/2z) Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1 Plasma t1/2z was the time measured for the plasma concentration of drug to decrease by one half.
Pharmacokinetics: Mean Residence Time (MRT) Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1 MRT is the average total time a drug molecule spends in the body.
Pharmacokinetics: Area Under the Plasma FVIII Activity Versus Time Curve (AUC0-tau) Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1 AUC0-tau was defined as area under the plasma concentration-time profile from time zero (pre-dose) to dosing interval.
Pharmacokinetics: Total Clearance at Steady State (CLss) 0 hour - 168 hour at week 26, 39 or 52 CLss is defined as the rate at which the drug is removed from the body at steady state.
Pharmacokinetics: Incremental Recovery (IR) Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1 IR was calculated as (Peak activity \[in IU/dL\] - Trough activity \[in IU/dL\])/Actual Dose (in IU/kg), and peak activity at each visit was the highest activity level after the dosing, and trough activity at each visit was the activity level prior to the dosing.
Trial Locations
- Locations (40)
East Carolina University/Brody Medical Sciences Building-Site Number:8400015
🇺🇸Greenville, North Carolina, United States
Investigational Site Number :1240003
🇨🇦London, Ontario, Canada
Children's Healthcare of Atlanta-Site Number:8400019
🇺🇸Atlanta, Georgia, United States
Rush University Medical Center-Site Number:8400001
🇺🇸Chicago, Illinois, United States
Investigational Site Number :2500001
🇫🇷Kremlin Bicetre, France
Children's Hospital Los Angeles-Site Number:8400006
🇺🇸Los Angeles, California, United States
Investigational Site Number :2500004
🇫🇷Bron, France
University of Florida-Site Number:8400009
🇺🇸Gainesville, Florida, United States
Childrens Hospital Of Columbus-Site Number:8400012
🇺🇸Columbus, Ohio, United States
University of Iowa Hospitals and Clinics-Site Number:8400002
🇺🇸Iowa City, Iowa, United States
NY Presbyterian - Weill Cornell Medical Center-Site Number:8400020
🇺🇸New York, New York, United States
Investigational Site Number :0360001
🇦🇺Westmead, New South Wales, Australia
Investigational Site Number :0360002
🇦🇺South Brisbane, Queensland, Australia
Investigational Site Number :1240004
🇨🇦Hamilton, Ontario, Canada
Investigational Site Number :1240001
🇨🇦Toronto, Ontario, Canada
Investigational Site Number :1240002
🇨🇦Ottawa, Ontario, Canada
Investigational Site Number :2500003
🇫🇷Lille, France
Investigational Site Number :2760001
🇩🇪Frankfurt am Main, Germany
Investigational Site Number :2760002
🇩🇪München, Germany
Investigational Site Number :3480005
🇭🇺Pécs, Hungary
Investigational Site Number :3720001
🇮🇪Dublin, Ireland
Investigational Site Number :3800002
🇮🇹Napoli, Italy
Investigational Site Number :5280002
🇳🇱Amsterdam, Netherlands
Investigational Site Number :7240002
🇪🇸Esplugues de Llobregat, Catalunya [Cataluña], Spain
Investigational Site Number :5280001
🇳🇱Utrecht, Netherlands
Investigational Site Number :7240001
🇪🇸Madrid, Madrid, Comunidad De, Spain
Investigational Site Number :7520001
🇸🇪Malmö, Sweden
Investigational Site Number :7560001
🇨🇭Zürich, Switzerland
Investigational Site Number :1580001
🇨🇳Taichung, Taiwan
Investigational Site Number :1580003
🇨🇳Taichung, Taiwan
Investigational Site Number :1580002
🇨🇳Taipei, Taiwan
Investigational Site Number :1580004
🇨🇳Taipei, Taiwan
Investigational Site Number :7920004
🇹🇷Antalya, Turkey
Investigational Site Number :7920001
🇹🇷Istanbul, Turkey
Investigational Site Number :7920003
🇹🇷Izmir, Turkey
Investigational Site Number :8260003
🇬🇧Birmingham, United Kingdom
Investigational Site Number :8260001
🇬🇧London, United Kingdom
Investigational Site Number :3800001
🇮🇹Milano, Italy
Cincinnati Children's Hospital Medical Center-Site Number:8400008
🇺🇸Cincinnati, Ohio, United States
Children's Hospital Of Wisconsin-Site Number:8400005
🇺🇸Milwaukee, Wisconsin, United States