Clinical Trial Results:
An Open-label, Multicenter, Dose-escalation Safety and Pharmacokinetic Study of a Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in subjects with Hemophilia B
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Summary
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EudraCT number |
2010-018477-38 |
Trial protocol |
DE AT ES GB IT FR |
Global end of trial date |
18 Jul 2011
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Jul 2016
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First version publication date |
06 Aug 2015
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CSL654_2001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01233440 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
CSL Behring GmbH
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Sponsor organisation address |
Emil-von-Behring-Str. 76, Marburg, Germany, 35041
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Public contact |
Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
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Scientific contact |
Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001107-PIP01-10 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Aug 2011
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Jul 2011
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of the study was to assess the safety of intravenous (IV) administration of rIX-FP. Safety was evaluated by adverse events and laboratory changes over time.
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Protection of trial subjects |
This study was carried out in accordance with the International Conference on Harmonisation (ICH)
Good Clinical Practice guidelines, and standard operating procedures for clinical research and
development at CSL Behring (CSLB).
The study protocol and all amendments were approved by the Independent Ethics Committee(s) (IECs) /
Institutional Review Board(s) (IRBs) of the participating centers.
Before undergoing screening procedures for possible enrollment into the study, subjects were informed,
in an understandable form, about the nature, scope, and possible consequences of the study. The
investigator was responsible for obtaining a subject’s written informed consent to participate in the
study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
21 Oct 2010
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
Austria: 3
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Country: Number of subjects enrolled |
France: 6
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Country: Number of subjects enrolled |
Germany: 5
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Country: Number of subjects enrolled |
Italy: 5
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Country: Number of subjects enrolled |
Israel: 3
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Worldwide total number of subjects |
25
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EEA total number of subjects |
22
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
24
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
In the dose-escalation safety part of the study 4 subjects per cohort were tested sequentially at 25, 50, and 75 IU/kg of rIX-FP. For the PK evaluation at least 13 subjects were to be tested at 50 IU/kg and up to 8 subjects each in the 25 and/or 75 IU/kg rIX-FP dosing groups. The initial 12 subjects could be dosed a second time for PK testing. | ||||||||||||
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Pre-assignment
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Screening details |
Males with severe hemophilia B (Factor IX [FIX] activity ≤ 2%), 12-65 years old, who had received FIX products for > 150 exposure days were screened. Seven subjects received 2 doses of rIX-FP; 3 subjects received 25 and 50 IU/kg rIX-FP, 1 subject received 25 and 75 IU/kg rIX-FP, and 3 subjects received 50 and 75 IU/kg rIX-FP. | ||||||||||||
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Period 1
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Period 1 title |
rIX-FP Safety and PK Period
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Are arms mutually exclusive |
No
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Arm title
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25 IU/kg rIX-FP | ||||||||||||
Arm description |
Subjects received a single dose of 25 IU/kg rIX-FP by bolus intravenous injection. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP)
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Investigational medicinal product code |
CSL654
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Other name |
rIX-FP
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Pharmaceutical forms |
Powder for concentrate for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects were administered the dose as a bolus IV injection at a rate of approximately 250 IU per minute or complete the infusion in approximately 10 to 15 minutes. Subjects were to receive rIX-FP at least 2 weeks after a non life-threatening bleeding episode, at least 3 months after a life-threatening bleeding episode, at least 4 days after receiving their previous FIX product dose and were not actively bleeding.
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Arm title
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50 IU/kg rIX-FP | ||||||||||||
Arm description |
Subjects received a single dose of 50 IU/kg rIX-FP by bolus intravenous injection. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP)
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Investigational medicinal product code |
CSL654
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Other name |
rIX-FP
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Pharmaceutical forms |
Powder for concentrate for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects were administered the dose as a bolus IV injection at a rate of approximately 250 IU per minute or complete the infusion in approximately 10 to 15 minutes. Subjects were to receive rIX-FP at least 2 weeks after a non life-threatening bleeding episode, at least 3 months after a life-threatening bleeding episode, at least 4 days after receiving their previous FIX product dose and were not actively bleeding.
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Arm title
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75 IU/kg rIX-FP | ||||||||||||
Arm description |
Subjects received a single dose of 75 IU/kg rIX-FP by bolus intravenous injection. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP)
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Investigational medicinal product code |
CSL654
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Other name |
rIX-FP
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Pharmaceutical forms |
Powder for concentrate for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects were administered the dose as a bolus IV injection at a rate of approximately 250 IU per minute or complete the infusion in approximately 10 to 15 minutes. Subjects were to receive rIX-FP at least 2 weeks after a non life-threatening bleeding episode, at least 3 months after a life-threatening bleeding episode, at least 4 days after receiving their previous FIX product dose and were not actively bleeding.
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Period 2
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Period 2 title |
FIX PK Period
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Is this the baseline period? |
No | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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50 IU/kg FIX | ||||||||||||
Arm description |
Participants received a single dose of 50 IU/kg of their previous Factor IX (FIX) product. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Factor IX (recombinant or plasma derived)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
50 IU/kg by IV infusion, at least 4 days following the previous FIX treatment or at least 14 days following the rIX-FP dose.
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Baseline characteristics reporting groups
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Reporting group title |
rIX-FP Safety and PK Period
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
25 IU/kg rIX-FP
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Reporting group description |
Subjects received a single dose of 25 IU/kg rIX-FP by bolus intravenous injection. | ||
Reporting group title |
50 IU/kg rIX-FP
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Reporting group description |
Subjects received a single dose of 50 IU/kg rIX-FP by bolus intravenous injection. | ||
Reporting group title |
75 IU/kg rIX-FP
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Reporting group description |
Subjects received a single dose of 75 IU/kg rIX-FP by bolus intravenous injection. | ||
Reporting group title |
50 IU/kg FIX
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Reporting group description |
Participants received a single dose of 50 IU/kg of their previous Factor IX (FIX) product. | ||
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End point title |
Number of subjects with adverse events and serious adverse events after administration of rIX-FP [1] | ||||||||||||||||||||
End point description |
An adverse event (AE) was defined as any untoward medical occurrence in a subject administered an Investigational Medicinal Product (IMP) (whether it was the study or any reference product[s]). An AE could have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the IMP, whether or not causally related to the IMP.
A serious adverse event was defined as any untoward medical occurrence that at any dose
• resulted in death,
• was life-threatening,
• required in-patient hospitalization or prolongation of existing hospitalization,
• resulted in persistent or significant disability/incapacity,
• was a congenital anomaly/birth defect,
• or was considered according to the investigator’s judgment to be a medically significant event.
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End point type |
Primary
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End point timeframe |
From the first dose of rIX-FP until 28 days after the last dose.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analyses were conducted for this end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Number of subjects developing inhibitors against FIX [2] | ||||||||||||
End point description |
Assessing the neutralizing capacity of antibodies was achieved via a FIX potency assay. For this assay, the respective subject sample was mixed and pre-incubated with the same volume of FIX containing plasma. Subsequently, the remaining FIX activity was assessed by a one-stage clotting assay.
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End point type |
Primary
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End point timeframe |
From the first dose of IMP until 28 days after the last dose.
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analyses were conducted for this end point. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of subjects developing antibodies against rIX-FP [3] | ||||||||||||
End point description |
Antibodies against rIX-FP were detected using a direct binding enzyme-linked immunosorbent assay (ELISA).
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End point type |
Primary
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End point timeframe |
From the first dose of IMP until 28 days after the last dose.
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analyses were conducted for this end point. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Incremental recovery following a single intravenous dose of 50 IU/kg rIX-FP [4] | ||||||||
End point description |
Incremental recovery (IU/mL/IU/kg) is defined as FIX activity (IU/mL) obtained 30 minutes following infusion, per dose of (IU/kg) infusion.
FIX activity was measured at a central laboratory using validated one-stage clotting method.
Recovery values were baseline-corrected for pre-infusion plasma FIX activity.
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End point type |
Secondary
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End point timeframe |
Pre-dose and at 30 minutes after infusion
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| Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Per the protocol, secondary endpoints included pharmacokinetic analyses following a single intravenous dose of 50 IU/kg rIX-FP. |
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| Notes [5] - Pharmacokinetic (PK) population |
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| No statistical analyses for this end point | |||||||||
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End point title |
Half Life of FIX activity following a single intravenous dose of 50 IU/kg rIX-FP [6] | ||||||||
End point description |
FIX activity was measured at a central laboratory using validated one-stage clotting method. FIX levels
were baseline adjusted by subtracting the pre-dose values.
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End point type |
Secondary
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End point timeframe |
Pre-dose and 30 minutes, 3, 6 24, 48, 72, 120, 168, 240 and 336 hours after the end of infusion.
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| Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Per the protocol, secondary endpoints included pharmacokinetic analyses following a single intravenous dose of 50 IU/kg rIX-FP. |
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| Notes [7] - PK population |
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| No statistical analyses for this end point | |||||||||
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End point title |
Area under the curve extrapolated to infinity (AUC0-inf) following a single intravenous dose of 50 IU/kg rIX-FP [8] | ||||||||
End point description |
FIX activity was measured at a central laboratory using validated one-stage clotting method. FIX levels
were baseline adjusted by subtracting the pre-dose values.
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End point type |
Secondary
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End point timeframe |
Pre-dose and 30 minutes, 3, 6 24, 48, 72, 120, 168, 240 and 336 hours after the end of infusion.
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| Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Per the protocol, secondary endpoints included pharmacokinetic analyses following a single intravenous dose of 50 IU/kg rIX-FP. |
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| Notes [9] - PK population |
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| No statistical analyses for this end point | |||||||||
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End point title |
Clearance for FIX activity following a single intravenous dose of 50 IU/kg rIX-FP [10] | ||||||||
End point description |
FIX activity was measured at a central laboratory using validated one-stage clotting method. FIX levels
were baseline adjusted by subtracting the pre-dose values.
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End point type |
Secondary
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End point timeframe |
Pre-dose and 30 minutes, 3, 6 24, 48, 72, 120, 168, 240 and 336 hours after the end of infusion.
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| Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Per the protocol, secondary endpoints included pharmacokinetic analyses following a single intravenous dose of 50 IU/kg rIX-FP. |
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| Notes [11] - PK population |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From the first dose of IMP until 28 days after the last dose.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
13.1
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Reporting groups
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Reporting group title |
25 IU/kg rIX-FP
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Reporting group description |
Subjects received a single dose of 25 IU/kg rIX-FP by bolus intravenous injection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
50 IU/kg rIX-FP
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Reporting group description |
Subjects received a single dose of 50 IU/kg rIX-FP by bolus intravenous injection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
75 IU/kg rIX-FP
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Reporting group description |
Subjects received a single dose of 75 IU/kg rIX-FP by bolus intravenous injection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
50 IU/kg FIX
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Reporting group description |
Participants received a single dose of 50 IU/kg of their previous Factor IX (FIX) product. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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29 Jun 2010 |
Protocol Amendment 1 was issued before the enrolment of the first subject. Main changes to the protocol included:
- Adding central laboratory tests for FIX inhibitor, albumin and FIX activity at the Screening visit.
- Adding a test for rIX-FP antigen level following rIX-FP administration as a study endpoint.
- Adding 2 additional rIX-FP PK blood sample collection time points.
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17 Aug 2010 |
Protocol Amendment 2 was issued before the enrollment of the first subject. Main changes to the protocol included the addition of information related to the testing for antibody against albumin: a sample to be collected prior to rIX-FP infusion and tested together with the Day 28 post-infusion blood sample; a tiered approach to immunogenicity testing for rIX-FP was to be employed; and a finding of non-inhibitory antibody against albumin was not to be considered an exclusion criterion. |
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20 Dec 2010 |
Protocol Amendment 3 included the following main changes:
• Pharmacokinetics (PK) of 75 IU/kg rIX-FP was to be tested in the 3rd safety cohort study subjects, and up to 4 more subjects per each dose of 25 and 75 IU/kg of rIX-FP could be included for PK assessment.
• Change to the PK sampling time points after rIX-FP infusion: 2 time points were omitted and 1 optional time point was added.
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21 Dec 2010 |
Protocol Amendment 4 included a change in the age requirement from 12 – 65 years to 18 – 65 years for sites in France, Germany and UK. For sites in Germany and the UK aged 12 – 17 years could be enrolled after the safety data from the first 2 safety cohorts have been reviewed with no safety concerns identified by Data Review Committee. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
