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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

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
Results First Received: June 9, 2014  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Severe Hemophilia A
Interventions: Drug: Factor VIII (rFVIIIFc)
Drug: Advate®

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups
  Description
Arm 1: 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.

Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days
Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode

Participant Flow:   Overall Study
    Arm 1: Individualized (Tailored) Prophylaxis     Arm 2: Weekly Prophylaxis     Arm 3: Episodic (On-Demand) Dosing  
STARTED     118     24     23  
Pharmacokinetic (PK) Subgroup     30     0     0  
Perioperative Management Subgroup     8 [1]   1 [1]   0 [1]
COMPLETED     112     19     22  
NOT COMPLETED     6     5     1  
Withdrawal by Subject                 2                 2                 0  
Death                 1                 0                 0  
Physician Decision                 2                 0                 0  
Adverse Event                 0                 2                 0  
Not Specified                 1                 1                 1  
[1] Participants who underwent major surgery.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Arm 1: 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.

Arm 2: Weekly Prophylaxis 65 IU/kg of rFVIIIFc via IV injection every 7 days
Arm 3: Episodic (On-Demand) Dosing 10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
Total Total of all reporting groups

Baseline Measures
    Arm 1: Individualized (Tailored) Prophylaxis     Arm 2: Weekly Prophylaxis     Arm 3: Episodic (On-Demand) Dosing     Total  
Number of Participants  
[units: participants]
  118     24     23     165  
Age  
[units: years]
Median ( Full Range )
  29.0  
  ( 12 to 65 )  
  31.5  
  ( 18 to 59 )  
  34.0  
  ( 13 to 62 )  
  30.0  
  ( 12 to 65 )  
Gender  
[units: participants]
       
Female     0     0     0     0  
Male     118     24     23     165  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Incidence Rate of FVIII Inhibitor Development   [ Time Frame: up to 52 weeks ± 2 weeks ]

2.  Primary:   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 ]

3.  Primary:   Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline   [ Time Frame: up to 52 weeks ± 2 weeks ]

4.  Primary:   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 ]

5.  Primary:   Annualized Bleeding Rate   [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ]

6.  Primary:   Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3   [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ]

7.  Primary:   Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay)   [ Time Frame: See Measure Description for complete time frame. ]

8.  Primary:   Elimination Half Life (t1/2; One-stage Clotting Assay)   [ Time Frame: See Measure Description for complete time frame. ]

9.  Primary:   Clearance (CL; One-stage Clotting Assay)   [ Time Frame: See Measure Description for complete time frame. ]

10.  Primary:   Mean Residence Time (MRT; One-stage Clotting Assay)   [ Time Frame: See Measure Description for complete time frame. ]

11.  Primary:   Incremental Recovery (One-stage Clotting Assay)   [ Time Frame: See Measure Description for complete time frame. ]

12.  Secondary:   Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3   [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ]

13.  Secondary:   Annualized rFVIIIFc Consumption Per Participant   [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ]

14.  Secondary:   Participant Assessment of Response to Injections to Treat a Bleeding Episode   [ Time Frame: up to 52 weeks ± 2 weeks ]

15.  Secondary:   Investigator’s Assessment of Participants’ Bleeding Response to rFVIIIFc Injection   [ Time Frame: up to 52 weeks ± 2 weeks ]

16.  Secondary:   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) ]

17.  Secondary:   Annualized Joint Bleeding Rate (Spontaneous and Traumatic)   [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ]

18.  Secondary:   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) ]

19.  Secondary:   Number of Injections Required for Resolution of a Bleeding Episode   [ Time Frame: up to 52 weeks ± 2 weeks (efficacy period as defined in description) ]

20.  Secondary:   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) ]

21.  Secondary:   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) ]

22.  Secondary:   Volume at Steady State (Vss; One-stage Clotting Assay)   [ Time Frame: See Measure Description for complete time frame. ]

23.  Secondary:   Volume at Steady State (Vss; Two-stage Chromogenic Assay)   [ Time Frame: See Measure Description for complete time frame. ]

24.  Secondary:   Time to 1% and 3% FVIII Activity (One-stage Clotting Assay)   [ Time Frame: See Measure Description for complete time frame. ]

25.  Secondary:   Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay)   [ Time Frame: See Measure Description for complete time frame. ]

26.  Secondary:   Time at Maximum Activity (Tmax; One-stage Clotting Assay)   [ Time Frame: See Measure Description for complete time frame. ]

27.  Secondary:   Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)   [ Time Frame: See Measure Description for complete time frame. ]

28.  Secondary:   Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay)   [ Time Frame: See Measure Description for complete time frame. ]

29.  Secondary:   Elimination Half Life (t1/2; Two-stage Chromogenic Assay)   [ Time Frame: See Measure Description for complete time frame. ]

30.  Secondary:   Clearance (CL; Two-stage Chromogenic Assay)   [ Time Frame: See Measure Description for complete time frame. ]

31.  Secondary:   Mean Residence Time (MRT; Two-stage Chromogenic Assay)   [ Time Frame: See Measure Description for complete time frame. ]

32.  Secondary:   Incremental Recovery (Two-stage Chromogenic Assay)   [ Time Frame: See Measure Description for complete time frame. ]

33.  Secondary:   Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14   [ Time Frame: Baseline, Week 14 ]

34.  Secondary:   Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28   [ Time Frame: Baseline, Week 28 ]

35.  Secondary:   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 ]

36.  Secondary:   Investigators’/Surgeons’ Assessment of Participants’ Response to rFVIIIFc for Major Surgery   [ Time Frame: up to 52 weeks ]

37.  Secondary:   Number of Injections Required to Maintain Hemostasis During Major Surgery   [ Time Frame: up to 52 weeks ]

38.  Secondary:   Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery   [ Time Frame: up to 52 weeks ± 2 weeks ]

39.  Secondary:   Estimated Total Blood Loss During Major Surgery   [ Time Frame: up to 52 weeks ± 2 weeks ]

40.  Secondary:   Number of Transfusions Required Per Surgery   [ Time Frame: up to 52 weeks ± 2 weeks ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Biogen Idec Study Medical Director
Organization: Biogen Idec
e-mail: clinicaltrials@biogenidec.com


Publications of Results:

Responsible Party: Biogen Idec
ClinicalTrials.gov Identifier: NCT01181128     History of Changes
Other Study ID Numbers: 997HA301
Study First Received: August 12, 2010
Results First Received: June 9, 2014
Last Updated: August 18, 2014
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
Austria: Federal Office for Safety in Health Care
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Brazil: National Health Surveillance Agency
Canada: Health Canada
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Paul-Ehrlich-Institut
Hong Kong: Department of Health
India: Drugs Controller General of India
Israel: Ministry of Health
Italy: The Italian Medicines Agency
Japan: Pharmaceuticals and Medical Devices Agency
New Zealand: Medsafe
South Africa: Medicines Control Council
Spain: Spanish Agency of Medicines
Sweden: Medical Products Agency
Switzerland: Swissmedic
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration