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Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Subjects With Severe Hemophilia A

Primary Purpose

Severe Hemophilia A

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Factor VIII (rFVIIIFc)

Advate®

About this trial

This is an interventional treatment trial for Severe Hemophilia A

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Individualized (Tailored) Prophylaxis

Weekly Prophylaxis

Episodic (On-Demand) Dosing

Arm Description

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.

65 IU/kg of rFVIIIFc via IV injection every 7 days

10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode

Outcomes

Primary Outcome Measures

Incidence Rate of FVIII Inhibitor Development

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)

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.

Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline

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

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.

Annualized Bleeding Rate

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.

Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3

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.

Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay)

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.

Elimination Half Life (t1/2; One-stage Clotting Assay)

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.

Clearance (CL; One-stage Clotting Assay)

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.

Mean Residence Time (MRT; One-stage Clotting Assay)

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.

Incremental Recovery (One-stage Clotting Assay)

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.

Secondary Outcome Measures

Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3

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 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.

Annualized rFVIIIFc Consumption Per Participant

Consumption is calculated for the efficacy period. 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. Overall units (IU/kg) of annualized rFVIIIFc consumption = [Total rFVIIIFc IU/kg received during the efficacy period / number of days in efficacy period] x 365.25.

Participant Assessment of Response to Injections to Treat a Bleeding Episode

Participant's assessment of the response to the first rFVIIIFc injection for each bleeding episode. Percentages were based on the number of bleeding episodes for which a response was provided for the first injection, using the following 4-point scale: excellent=abrupt pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial injection; good=definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after an injection, but possibly requiring more than one injection after 24 to 48 hours for complete resolution; moderate=probable or slight beneficial effect within 8 hours after the initial injection and requiring more than one injection; no response=no improvement, or condition worsened, within approximately 8 hours after the initial injection.

Investigator's Assessment of Participants' Bleeding Response to rFVIIIFc Injection

The investigator was given the opportunity to record an assessment of a participant's response to treatment, if the participant was treated in the hospital for a major bleed, using the following 4-point scale: excellent=abrupt pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial injection; good=definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after an injection, but possibly requiring more than one injection after 24 to 48 hours for complete resolution; moderate=probable or slight beneficial effect within 8 hours after the initial injection and requiring more than one injection; no response=no improvement, or condition worsened, within approximately 8 hours after the initial injection.

Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)

Annualized bleeding episodes = (Number of bleeding episodes at the specified location / number of days in efficacy period) x 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 were 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. Any bleeding at a different location was a separate bleeding episode regardless of time from the last injection.

Annualized Joint Bleeding Rate (Spontaneous and Traumatic)

Annualized bleeding episodes = (Number of bleeding episodes of the specified type / number of days in efficacy period) x 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 were 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.

Number of Days From Last Treatment Injection to a New Bleeding Episode

Number of days from the last injection to treat a bleeding episode to a new bleeding episode, analyzed for per evaluable bleeding episode and per participant. For "per participant" values, number of days from last injection to treat a bleed to a new bleeding episode is averaged across all evaluable bleeding episodes for each participant first, and then descriptive statistics were calculated across participants. A follow-up injection administered >72 hours after the most recent injection given to treat a bleed was considered a new bleed at the same location and was classified as type=Unknown (not evaluable). 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 were not included in the efficacy period.

Number of Injections Required for Resolution of a Bleeding Episode

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. All injections given from the initial sign of a bleed until the last date/time within the bleed window are counted. The resolution of a bleed is defined as no sign of bleeding following injection for the bleed. 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.

Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed

Please see Outcome Measure 20 for a definition of 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. All injections given from the initial sign of a bleed until the last date/time within the bleed window were counted. The resolution of a bleed was defined as no sign of bleeding following injection for the bleed. Bleeding episodes that presented in multiple locations are included as a single event in the overall summary for the number of injections to resolve that bleeding episode but are included in summaries for each location.

Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed

For each bleeding episode at one location, the total dose is the sum of the doses (IU/kg) administered across all injections given to treat that bleeding episode. Please see Outcome Measure 20 for a definition of 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. Bleeding episodes that presented in multiple locations are included as a single event in the overall summary for dose administered to resolve that bleeding episode but are included in the individual summaries for each location.

Volume at Steady State (Vss; One-stage Clotting Assay)

Volume of distribution at steady state. 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.

Volume at Steady State (Vss; Two-stage Chromogenic Assay)

Time to 1% and 3% FVIII Activity (One-stage Clotting Assay)

Estimated time after dose (in days) when FVIII activity has declined to approximately 1 or 3 IU/dL (1% or 3%) above baseline, respectively. 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.

Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay)

Time at Maximum Activity (Tmax; One-stage Clotting Assay)

Time at which maximum activity (Cmax) is observed. 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.

Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)

Time at which the maximum activity (Cmax) is observed. 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.

Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay)

Elimination Half Life (t1/2; Two-stage Chromogenic Assay)

Clearance (CL; Two-stage Chromogenic Assay)

Mean Residence Time (MRT; Two-stage Chromogenic Assay)

Incremental Recovery (Two-stage Chromogenic Assay)

Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14

The Haem-A-QoL consists of items pertaining to 10 domains specific to living with hemophilia and was administered to adult participants (17 years and older). The 10 domains are: physical health, feeling, view of yourself, sports/leisure, school/work, dealing with hemophilia, and treatment (time frame for all 7 domains, during the last month) and future, family planning, and outlook for the future (time frame for all 3 domains, recently). Lower scores represent better QoL; therefore, a negative change from baseline represents improvement during the course of the study. Scores on a scale range between 0 and 100. Participants in Arm 1 were stratified by their prestudy regimen (either prophylaxis or on-demand).

Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to 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

The Haemo-QoL III, a quality of life assessment instrument for adolescents with hemophilia, was administered to participants from 13 to 16 years old. This instrument assesses domains specific to living with hemophilia and consists of 12 domains: physical health, feeling, view of yourself, family, friends, others, sports and school, treatment, perceived support, dealing with hemophilia, future, and relationships. Total HAEMO-QoL score is the sum of all raw scores for all subscales for participants for whom at least the minimum number of required questions have been answered. Total scores are presented as the Transformed Scale Score (TSS) from 0-100%, with lower scores indicating a better quality of life. A negative change indicates improvement.

Investigators'/Surgeons' Assessment of Participants' Response to rFVIIIFc for Major Surgery

Based on the first assessment of hemostasis by the surgeon/investigator 24 hours or later post-surgery. Scaled responses: Excellent = 1, Good = 2, Fair = 3, Poor/none = 4.

Number of Injections Required to Maintain Hemostasis During Major Surgery

The number of injections to maintain hemostasis during surgery includes all injections for surgery purposes, including from the loading dose to the end date/time of surgery.

Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery

Mean dose per injection is the average dose for all injections (including loading dose) needed to maintain hemostasis during surgery. Total dose is the sum across all injections (including loading dose) needed to maintain hemostasis during surgery.

Estimated Total Blood Loss During Major Surgery

Number of Transfusions Required Per Surgery

Number of blood component transfusions during a single surgery.

Full Information

NCT ID

NCT01181128

First Posted

August 12, 2010

Last Updated

December 16, 2020

Sponsor

Bioverativ Therapeutics Inc.

Collaborators

Swedish Orphan Biovitrum

1. Study Identification

Unique Protocol Identification Number

NCT01181128

Brief Title

Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Subjects With Severe Hemophilia A

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2017

Overall Recruitment Status

Completed

Study Start Date

November 2010 (undefined)

Primary Completion Date

August 2012 (Actual)

Study Completion Date

August 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Bioverativ Therapeutics Inc.

Collaborators

Swedish Orphan Biovitrum

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Severe Hemophilia A

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

165 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Individualized (Tailored) Prophylaxis

Arm Type

Experimental

Arm Description

Arm Title

Weekly Prophylaxis

Arm Type

Experimental

Arm Description

65 IU/kg of rFVIIIFc via IV injection every 7 days

Arm Title

Episodic (On-Demand) Dosing

Arm Type

Experimental

Arm Description

10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode

Intervention Type

Drug

Intervention Name(s)

Factor VIII (rFVIIIFc)

Other Intervention Name(s)

Recombinant Factor VIII Fc Fusion Protein

Intervention Type

Drug

Intervention Name(s)

Advate®

Other Intervention Name(s)

octocog alfa, Antihemophilic Factor [Recombinant] Plasma/Albumin Free Method

Primary Outcome Measure Information:

Title

Incidence Rate of FVIII Inhibitor Development

Description

Time Frame

up to 52 weeks ± 2 weeks

Title

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Description

Time Frame

up to 52 weeks + 30 days ± 1 week

Title

Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline

Description

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.

Time Frame

up to 52 weeks ± 2 weeks

Title

Number of Participants With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs

Description

Time Frame

up to 52 weeks ± 2 weeks

Title

Annualized Bleeding Rate

Description

Time Frame

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Title

Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3

Description

Time Frame

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Title

Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Elimination Half Life (t1/2; One-stage Clotting Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Clearance (CL; One-stage Clotting Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Mean Residence Time (MRT; One-stage Clotting Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Incremental Recovery (One-stage Clotting Assay)

Description

Time Frame

See Measure Description for complete time frame.

Secondary Outcome Measure Information:

Title

Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3

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 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.

Time Frame

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Title

Annualized rFVIIIFc Consumption Per Participant

Description

Time Frame

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Title

Participant Assessment of Response to Injections to Treat a Bleeding Episode

Description

Time Frame

up to 52 weeks ± 2 weeks

Title

Investigator's Assessment of Participants' Bleeding Response to rFVIIIFc Injection

Description

Time Frame

up to 52 weeks ± 2 weeks

Title

Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)

Description

Time Frame

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Title

Annualized Joint Bleeding Rate (Spontaneous and Traumatic)

Description

Time Frame

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Title

Number of Days From Last Treatment Injection to a New Bleeding Episode

Description

Time Frame

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Title

Number of Injections Required for Resolution of a Bleeding Episode

Description

Time Frame

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Title

Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed

Description

Time Frame

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Title

Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed

Description

Time Frame

up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Title

Volume at Steady State (Vss; One-stage Clotting Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Volume at Steady State (Vss; Two-stage Chromogenic Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Time to 1% and 3% FVIII Activity (One-stage Clotting Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Time at Maximum Activity (Tmax; One-stage Clotting Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Elimination Half Life (t1/2; Two-stage Chromogenic Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Clearance (CL; Two-stage Chromogenic Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Mean Residence Time (MRT; Two-stage Chromogenic Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Incremental Recovery (Two-stage Chromogenic Assay)

Description

Time Frame

See Measure Description for complete time frame.

Title

Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14

Description

Time Frame

Baseline, Week 14

Title

Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28

Description

Time Frame

Baseline, Week 28

Title

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

Description

Time Frame

Baseline, Week 14, Week 28

Title

Investigators'/Surgeons' Assessment of Participants' Response to rFVIIIFc for Major Surgery

Description

Based on the first assessment of hemostasis by the surgeon/investigator 24 hours or later post-surgery. Scaled responses: Excellent = 1, Good = 2, Fair = 3, Poor/none = 4.

Time Frame

up to 52 weeks

Title

Number of Injections Required to Maintain Hemostasis During Major Surgery

Description

The number of injections to maintain hemostasis during surgery includes all injections for surgery purposes, including from the loading dose to the end date/time of surgery.

Time Frame

up to 52 weeks

Title

Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery

Description

Time Frame

up to 52 weeks ± 2 weeks

Title

Estimated Total Blood Loss During Major Surgery

Time Frame

up to 52 weeks ± 2 weeks

Title

Number of Transfusions Required Per Surgery

Description

Number of blood component transfusions during a single surgery.

Time Frame

up to 52 weeks ± 2 weeks

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

12 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Exclusion Criteria: 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Bioverativ Therapeutics Inc.

Official's Role

Study Director

Facility Information:

Facility Name

Research Site

City

Little Rock

State/Province

Arkansas

Country

United States

Facility Name

Research Site

City

Los Angeles

State/Province

California

Country

United States

Facility Name

Research Site

City

Orange

State/Province

California

Country

United States

Facility Name

Research Site

City

Sacramento

State/Province

California

Country

United States

Facility Name

Research Site

City

San Diego

State/Province

California

Country

United States

Facility Name

Research Site

City

Washington

State/Province

District of Columbia

Country

United States

Facility Name

Research Site

City

Indianapolis

State/Province

Indiana

Country

United States

Facility Name

Research Site

City

Iowa City

State/Province

Iowa

Country

United States

Facility Name

Research Site

City

Louisville

State/Province

Kentucky

Country

United States

Facility Name

Research Site

City

New Orleans

State/Province

Louisiana

Country

United States

Facility Name

Research Site

City

Boston

State/Province

Massachusetts

Country

United States

Facility Name

Research Site

City

East Lansing

State/Province

Michigan

Country

United States

Facility Name

Research Site

City

Las Vegas

State/Province

Nevada

Country

United States

Facility Name

Research Site

City

New York

State/Province

New York

Country

United States

Facility Name

Research Site

City

Chapel Hill

State/Province

North Carolina

Country

United States

Facility Name

Research Site

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Facility Name

Research Site

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19107

Country

United States

Facility Name

Research Site

City

Pittsburgh

State/Province

Pennsylvania

Country

United States

Facility Name

Research Site

City

Houston

State/Province

Texas

Country

United States

Facility Name

Research Site

City

Salt Lake City

State/Province

Utah

Country

United States

Facility Name

Research Site

City

Seattle

State/Province

Washington

Country

United States

Facility Name

Research Site

City

Camperdown

State/Province

New South Wales

Country

Australia

Facility Name

Research Site

City

Adelaide

State/Province

South Australia

Country

Australia

Facility Name

Research Site

City

Perth

State/Province

Western Australia

Country

Australia

Facility Name

Research Site

City

Wien

ZIP/Postal Code

1090

Country

Austria

Facility Name

Research Site

City

Bruxelles

ZIP/Postal Code

1200

Country

Belgium

Facility Name

Research Site

City

Campinas

Country

Brazil

Facility Name

Research Site

City

Calgary

ZIP/Postal Code

T2N 2T9

Country

Canada

Facility Name

Research Site

City

Toronto

Country

Canada

Facility Name

Research Site

City

Vancouver

ZIP/Postal Code

V6Z 1Y6

Country

Canada

Facility Name

Research Site

City

Lyon Cedex 3

ZIP/Postal Code

69437

Country

France

Facility Name

Research Site

City

Berlin

State/Province

Country

Germany

Facility Name

Research Site

City

Bonn

State/Province

Northwest

Country

Germany

Facility Name

Research Site

City

Hong Kong

Country

Hong Kong

Facility Name

Research Site

City

New Delhi

State/Province

Delhi

Country

India

Facility Name

Research Site

City

Bangalore

State/Province

Karna

Country

India

Facility Name

Research Site

City

Pune

State/Province

Mahara

Country

India

Facility Name

Research Site

City

Ludhiana

State/Province

Punjab

Country

India

Facility Name

Research Site

City

Vellore

State/Province

Tamilnadu

Country

India

Facility Name

Research Site

City

Ramat Gan

ZIP/Postal Code

52621

Country

Israel

Facility Name

Research Site

City

Firenze

State/Province

Country

Italy

Facility Name

Research Site

City

Milano

State/Province

Country

Italy

Facility Name

Research Site

City

Vicenza

State/Province

Country

Italy

Facility Name

Research Site

City

Kashihara-shi

Country

Japan

Facility Name

Research Site

City

Kawasaki-shi

Country

Japan

Facility Name

Research Site

City

Kitakyushu-shi

Country

Japan

Facility Name

Research Site

City

Nagoya-shi

Country

Japan

Facility Name

Research Site

City

Shinjuku-ku

Country

Japan

Facility Name

Research Site

City

Suginami-ku

Country

Japan

Facility Name

Research Site

City

Auckland

ZIP/Postal Code

1023

Country

New Zealand

Facility Name

Research Site

City

Christchurch

ZIP/Postal Code

8001

Country

New Zealand

Facility Name

Research Site

City

Palmerston North

ZIP/Postal Code

4442

Country

New Zealand

Facility Name

Research Site

City

Johannesburg Parktown

State/Province

Gauteng

Country

South Africa

Facility Name

Research Site

City

Cape Town

State/Province

W Cape

Country

South Africa

Facility Name

Research Site

City

Barcelona

Country

Spain

Facility Name

Research Site

City

Madrid

Country

Spain

Facility Name

Research Site

City

Göteborg

ZIP/Postal Code

41345

Country

Sweden

Facility Name

Research Site

City

Zurich

Country

Switzerland

Facility Name

Research Site

City

Basingstoke

ZIP/Postal Code

RG24 9NA

Country

United Kingdom

Facility Name

Research Site

City

Cambridge

ZIP/Postal Code

CB2 2QQ

Country

United Kingdom

Facility Name

Research Site

City

Glasgow

ZIP/Postal Code

G4 0SF

Country

United Kingdom

Facility Name

Research Site

City

London

ZIP/Postal Code

E1 1BB

Country

United Kingdom

Facility Name

Research Site

City

London

ZIP/Postal Code

NW3 2QG

Country

United Kingdom

Facility Name

Research Site

City

London

ZIP/Postal Code

SE1 7EH

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

24227821

Citation

Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, Hanabusa H, Gupta N, Kulkarni R, Fogarty P, Perry D, Shapiro A, Pasi KJ, Apte S, Nestorov I, Jiang H, Li S, Neelakantan S, Cristiano LM, Goyal J, Sommer JM, Dumont JA, Dodd N, Nugent K, Vigliani G, Luk A, Brennan A, Pierce GF; A-LONG Investigators. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014 Jan 16;123(3):317-25. doi: 10.1182/blood-2013-10-529974. Epub 2013 Nov 13.

Results Reference

result

PubMed Identifier

25196897

Citation

Shapiro AD, Ragni MV, Kulkarni R, Oldenberg J, Srivastava A, Quon DV, Pasi KJ, Hanabusa H, Pabinger I, Mahlangu J, Fogarty P, Lillicrap D, Kulke S, Potts J, Neelakantan S, Nestorov I, Li S, Dumont JA, Jiang H, Brennan A, Pierce GF. Recombinant factor VIII Fc fusion protein: extended-interval dosing maintains low bleeding rates and correlates with von Willebrand factor levels. J Thromb Haemost. 2014 Nov;12(11):1788-800. doi: 10.1111/jth.12723. Epub 2014 Oct 10.

Results Reference

result

PubMed Identifier

33719084

Citation

Katragadda S, Neelakantan S, Diao L, Wong N. Population Pharmacokinetic Analysis of Recombinant Factor VIII Fc Fusion Protein in Subjects With Severe Hemophilia A: Expanded to Include Pediatric Subjects. J Clin Pharmacol. 2021 Jul;61(7):889-900. doi: 10.1002/jcph.1854. Epub 2021 Apr 14.

Results Reference

derived

Learn more about this trial

Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Subjects With Severe Hemophilia A

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Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Subjects With Severe Hemophilia A

Severe Hemophilia A

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial