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

This study has been completed.
Sponsor:
Collaborator:
Swedish Orphan Biovitrum
Information provided by (Responsible Party):
Biogen Idec
ClinicalTrials.gov Identifier:
NCT01181128
First received: August 12, 2010
Last updated: August 18, 2014
Last verified: August 2014

August 12, 2010
August 18, 2014
November 2010
August 2012   (final data collection date for primary outcome measure)
  • Incidence Rate of FVIII Inhibitor Development [ Time Frame: up to 52 weeks ± 2 weeks ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: up to 52 weeks + 30 days ± 1 week ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ] [ Designated as safety issue: No ]
    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) [ Time Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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 Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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) [ Time Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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) [ Time Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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) [ Time Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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.
  • • Annualized number of bleeding episodes (spontaneous and traumatic) [ Time Frame: 156 weeks ] [ Designated as safety issue: Yes ]
  • • Clinically notable changes from baseline in physical examinations, vital signs, lab values, and incidence of AEs and inhibitor development [ Time Frame: 156 weeks ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01181128 on ClinicalTrials.gov Archive Site
  • Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3 [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks ] [ Designated as safety issue: No ]
    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) [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ] [ Designated as safety issue: No ]
    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) [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ] [ Designated as safety issue: No ]
    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) [ Time Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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 Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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.
  • Time to 1% and 3% FVIII Activity (One-stage Clotting Assay) [ Time Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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 Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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 at Maximum Activity (Tmax; One-stage Clotting Assay) [ Time Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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 Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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) [ Time Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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; Two-stage Chromogenic Assay) [ Time Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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; Two-stage Chromogenic Assay) [ Time Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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; Two-stage Chromogenic Assay) [ Time Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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 (Two-stage Chromogenic Assay) [ Time Frame: See Measure Description for complete time frame. ] [ Designated as safety issue: No ]
    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.
  • Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 [ Time Frame: Baseline, Week 14 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 28 ] [ Designated as safety issue: No ]
    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 Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 14 and Week 28 in Haemo-QoL III Total Score [ Time Frame: Baseline, Week 14, Week 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 52 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 52 weeks ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 52 weeks ± 2 weeks ] [ Designated as safety issue: No ]
  • Number of Transfusions Required Per Surgery [ Time Frame: up to 52 weeks ± 2 weeks ] [ Designated as safety issue: No ]
    Number of blood component transfusions during a single surgery.
  • • Total annualized rFVIIIFc consumption per subject [ Time Frame: 156 weeks ] [ Designated as safety issue: Yes ]
  • • Evaluation of PK parameter estimates of rFVIIIFc and rFVIII at baseline and at Week 12-28 [ Time Frame: 156 weeks ] [ Designated as safety issue: Yes ]
  • • Evaluation of subject's response to treatment [ Time Frame: 156 weeks ] [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Subjects With Severe Hemophilia A
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

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.

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).

Interventional
Phase 3
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Severe Hemophilia A
  • Drug: Factor VIII (rFVIIIFc)
    Other Name: Recombinant Factor VIII Fc Fusion Protein
  • Drug: Advate®
    Other Names:
    • octocog alfa
    • Antihemophilic Factor [Recombinant] Plasma/Albumin Free Method
  • Experimental: 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.

    Interventions:
    • Drug: Factor VIII (rFVIIIFc)
    • Drug: Advate®
  • Experimental: Weekly Prophylaxis
    65 IU/kg of rFVIIIFc via IV injection every 7 days
    Intervention: Drug: Factor VIII (rFVIIIFc)
  • Experimental: Episodic (On-Demand) Dosing
    10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
    Intervention: Drug: Factor VIII (rFVIIIFc)
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
165
August 2012
August 2012   (final data collection date for primary outcome measure)

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
Male
12 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Australia,   Austria,   Belgium,   Brazil,   Canada,   France,   Germany,   Hong Kong,   India,   Israel,   Italy,   Japan,   New Zealand,   South Africa,   Spain,   Sweden,   Switzerland,   United Kingdom
 
NCT01181128
997HA301
Yes
Biogen Idec
Biogen Idec
Swedish Orphan Biovitrum
Study Director: Medical Director Biogen Idec
Biogen Idec
August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP