A-LONG: An Open-Label, Multicenter Evaluation of the Safety, Pharmacokinetics, and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding in Previously Treated Subjects With Severe Hemophilia A
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 165
- 试验地点
- 1
- 主要终点
- Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay)
研究概览
简要总结
The primary objectives of this study are: to evaluate the safety and tolerability of rFVIIIFc administered as a prophylaxis (Arm 1), weekly (Arm 2), on-demand (Arm 3), and surgical treatment regimen; to evaluate the efficacy of the rFVIIIFc tailored prophylaxis regimen (Arm 1); to evaluate the efficacy of rFVIIIFc administered as an on-demand (Arm 3) and surgical treatment regimen. The secondary objectives of this study are: to characterize the PK profile of rFVIIIFc and compare the PK of rFVIIIFc with the currently marketed product, Advate®; to characterize the range of dose and schedules required to adequately prevent bleeding in a prophylaxis regimen, maintain hemostasis in a surgical setting, or to treat bleeding episodes in an on-demand, weekly treatment, or prophylaxis setting.
详细描述
Participants are assigned to one of three treatment regimens: 1) a tailored prophylaxis regimen, 2) a weekly dosing regimen, or 3) an on-demand regimen. Treatment continued for 28 (±2) to 52 (±2) weeks. PK assessments for all participants are conducted on varying schedules, according to participants' group assignments. Additionally, two subgroups are defined. One subgroup of participants undergo PK profiling with a single dose of the comparator Advate®. A second subgroup consists of participants from any of the treatment arms that required surgery during the study. Depending upon country location, participants might have the option of continuing treatment within study 8HA01EXT (NCT01454739).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Male, ≥12 years of age with weight at least 40 kg
- •Diagnosed with severe hemophilia A, defined as <1 IU/dL (<1%) endogenous Factor VIII)
- •History of at least 150 documented prior exposure days to any Factor VIII product
- •Platelet count ≥100,000 cells/μL
排除标准
- •History of Factor VIII inhibitors
- •Kidney and liver dysfunction
- •Diagnosed with other coagulation disorder(s) in addition to hemophilia A
- •Prior history of hypersensitivity or anaphylaxis associated with any FVIII or IV immunoglobulin administration
研究组 & 干预措施
Individualized (Tailored) Prophylaxis
On rFVIIIFc Day 0, all participants underwent pharmacokinetic (PK) analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of participants (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc.
After PK assessments, all participants started twice weekly treatment with 25 IU/kg of rFVIIIFc via intravenous (IV) injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days, as determined by rFVIIIFc PK analysis, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.
干预措施: Factor VIII (rFVIIIFc) (Drug)
Individualized (Tailored) Prophylaxis
On rFVIIIFc Day 0, all participants underwent pharmacokinetic (PK) analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of participants (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc.
After PK assessments, all participants started twice weekly treatment with 25 IU/kg of rFVIIIFc via intravenous (IV) injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days, as determined by rFVIIIFc PK analysis, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.
干预措施: Advate® (Drug)
Weekly Prophylaxis
65 IU/kg of rFVIIIFc via IV injection every 7 days
干预措施: Factor VIII (rFVIIIFc) (Drug)
Episodic (On-Demand) Dosing
10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
干预措施: Factor VIII (rFVIIIFc) (Drug)
结局指标
主要结局
Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay)
时间窗: See Measure Description for complete time frame.
Dose normalized area under the drug concentration-time curve. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
Incidence Rate of FVIII Inhibitor Development
时间窗: up to 52 weeks ± 2 weeks
An inhibitor test result ≥0.6 Bethesda units (BU)/mL, identified and confirmed by re-testing of a second sample obtained within 2 to 4 weeks, was considered positive. Both tests were to be performed using the Nijmegen-modified Bethesda Assay by the central laboratory. The incidence rates along with the 95% confidence interval (CI) were summarized for all titers for subjects with 50 or more exposure days (EDs) to rFVIIIFc and a valid inhibitor test after the 50th exposure. In addition, the incidence rates for all subjects regardless of their exposure days to rFVIIIFc were also summarized. The 95% CI was calculated using Clopper-Pearson exact method.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
时间窗: up to 52 weeks + 30 days ± 1 week
AE=any untoward medical occurrence that did not necessarily have a causal relationship with treatment, and could be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study product, whether related or not. TEAE=AE present prior to receiving the first injection of Advate or rFVIIIFc that subsequently worsened in severity or not present prior to receiving the first injection but subsequently appeared before the last visit on study. Serious AE (SAE)=AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital anomaly/birth defect, or any other medically important event. AEs emergent between the first Advate injection and first on-study rFVIIIFc injection (Sequential PK Subgroup) or during the surgical/rehabilitation period (Surgery Subgroup) are presented separately.
Annualized Bleeding Rate
时间窗: up to 52 weeks ± 2 weeks (efficacy period as defined in description)
Annualized bleeding episodes = (number of bleeding episodes during the efficacy period / number of days during the efficacy period)\*365.25. The efficacy period in Arms 1 and 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode.
Elimination Half Life (t1/2; One-stage Clotting Assay)
时间窗: See Measure Description for complete time frame.
Time required for the activity of the drug to reach half of its original value. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
Mean Residence Time (MRT; One-stage Clotting Assay)
时间窗: See Measure Description for complete time frame.
The average time that a drug molecule is present in the systemic circulation. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline
时间窗: up to 52 weeks ± 2 weeks
Clinical laboratory evaluations included hematology and blood chemistry. Table does not include laboratory tests evaluated during the surgical/rehabilitation period. ULN=upper limit of normal.
Number of Participants With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs
时间窗: up to 52 weeks ± 2 weeks
Number of participants with clinically relevant abnormalities or relevant changes from baseline in temperature, pulse (beats per minute \[bpm\]), systolic blood pressure (SBP), and diastolic blood pressure (DBP) are presented. Baseline (BL) is defined as the last non-missing evaluable assessment taken prior and closest to the first rFVIIIFc dose. ↑ signifies increase and ↓ signifies decrease.
Clearance (CL; One-stage Clotting Assay)
时间窗: See Measure Description for complete time frame.
Rate at which the body removes the drug, measured as the volume of the plasma cleared of drug per unit time per unit weight. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
Incremental Recovery (One-stage Clotting Assay)
时间窗: See Measure Description for complete time frame.
The rise in FVIII activity in IU/dL per unit dose administered in IU/kg. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3
时间窗: up to 52 weeks ± 2 weeks (efficacy period as defined in description)
Estimated using the negative binomial model with treatment arm as covariate, based on whole study duration for all participants. Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)\*365.25.The efficacy period in Arm 1 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered part of the same bleeding episode.
次要结局
- Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3(up to 52 weeks ± 2 weeks (efficacy period as defined in description))
- Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed(up to 52 weeks ± 2 weeks (efficacy period as defined in description))
- Participant Assessment of Response to Injections to Treat a Bleeding Episode(up to 52 weeks ± 2 weeks)
- Volume at Steady State (Vss; One-stage Clotting Assay)(See Measure Description for complete time frame.)
- Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay)(See Measure Description for complete time frame.)
- Annualized rFVIIIFc Consumption Per Participant(up to 52 weeks ± 2 weeks (efficacy period as defined in description))
- Investigator's Assessment of Participants' Bleeding Response to rFVIIIFc Injection(up to 52 weeks ± 2 weeks)
- Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)(up to 52 weeks ± 2 weeks (efficacy period as defined in description))
- Clearance (CL; Two-stage Chromogenic Assay)(See Measure Description for complete time frame.)
- Mean Residence Time (MRT; Two-stage Chromogenic Assay)(See Measure Description for complete time frame.)
- Estimated Total Blood Loss During Major Surgery(up to 52 weeks ± 2 weeks)
- Annualized Joint Bleeding Rate (Spontaneous and Traumatic)(up to 52 weeks ± 2 weeks (efficacy period as defined in description))
- Number of Injections Required for Resolution of a Bleeding Episode(up to 52 weeks ± 2 weeks (efficacy period as defined in description))
- Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed(up to 52 weeks ± 2 weeks (efficacy period as defined in description))
- Volume at Steady State (Vss; Two-stage Chromogenic Assay)(See Measure Description for complete time frame.)
- Time to 1% and 3% FVIII Activity (One-stage Clotting Assay)(See Measure Description for complete time frame.)
- Number of Days From Last Treatment Injection to a New Bleeding Episode(up to 52 weeks ± 2 weeks (efficacy period as defined in description))
- Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery(up to 52 weeks ± 2 weeks)
- Number of Transfusions Required Per Surgery(up to 52 weeks ± 2 weeks)
- Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay)(See Measure Description for complete time frame.)
- Time at Maximum Activity (Tmax; One-stage Clotting Assay)(See Measure Description for complete time frame.)
- Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)(See Measure Description for complete time frame.)
- Incremental Recovery (Two-stage Chromogenic Assay)(See Measure Description for complete time frame.)
- Investigators'/Surgeons' Assessment of Participants' Response to rFVIIIFc for Major Surgery(up to 52 weeks)
- Elimination Half Life (t1/2; Two-stage Chromogenic Assay)(See Measure Description for complete time frame.)
- Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28(Baseline, Week 28)
- Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 14 and Week 28 in Haemo-QoL III Total Score(Baseline, Week 14, Week 28)
- Number of Injections Required to Maintain Hemostasis During Major Surgery(up to 52 weeks)
- Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14(Baseline, Week 14)