Clinical Trial Results:
A MULTICENTER, OPEN LABEL STUDY TO COMPARE ON DEMAND TREATMENT TO A PROPHYLAXIS REGIMEN OF NONACOG ALFA (BENEFIX) IN SUBJECTS WITH MODERATELY SEVERE TO SEVERE HEMOPHILIA B (FIX:C ≤2%)
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Summary
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EudraCT number |
2011-000520-15 |
Trial protocol |
PL BG GR Outside EU/EEA |
Global end of trial date |
23 Apr 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
11 May 2016
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First version publication date |
08 Jul 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 |
B1821010
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01335061 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Pfizer, Inc.
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Sponsor organisation address |
235 E 42nd St,, New York,, United States,
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Public contact |
Clinical Trials.gov Call Center, Pfizer Inc., 011 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Scientific contact |
Clinical Trials.gov Call Center, Pfizer Inc., 011 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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 |
06 Oct 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
23 Apr 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Apr 2014
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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 is to demonstrate that a prophylaxis regimen of BeneFIX reduces the ABR compared to on-demand treatment in subjects with moderately-severe to severe hemophilia B.
The secondary objective is to describe the safety and efficacy of BeneFIX when administered for prophylaxis at a dose of 100 IU/kg once weekly.
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Protection of trial subjects |
The External Data Monitoring Committee met approximately every 6 months to review safety data. Per the DMC charter, safety data included line listings and summaries of all AEs, SAEs, discontinuations, demographic and other baseline characteristics, treatment information, and medically important events. Efficacy data could be reviewed if necessary for an accurate risk-benefit assessment.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
19 Sep 2011
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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 |
Poland: 4
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Country: Number of subjects enrolled |
Bulgaria: 1
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Country: Number of subjects enrolled |
Canada: 1
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Country: Number of subjects enrolled |
Croatia: 3
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Country: Number of subjects enrolled |
Korea, Republic of: 3
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Country: Number of subjects enrolled |
Malaysia: 4
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Country: Number of subjects enrolled |
Singapore: 2
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Country: Number of subjects enrolled |
Turkey: 5
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Country: Number of subjects enrolled |
Mexico: 2
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Worldwide total number of subjects |
25
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EEA total number of subjects |
8
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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) |
5
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Adults (18-64 years) |
20
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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 |
Participation included 25 enrolled participants from 15 study centers and 9 countries. | ||||||
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Pre-assignment
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Screening details |
The duration of participation was approximately 86 weeks, consisting of a Screening period (1 day to 4 weeks), Period 1 (on-demand treatment for 26 weeks), Period 2 (prophylaxis therapy for 52 weeks), and a follow-up safety period (4 weeks). | ||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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All participants | ||||||
Arm description |
Data for all the participants were analyzed. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
BeneFIX
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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 |
The first treatment period was 6 months (26 weeks) of on-demand treatment when BeneFIX was to be administered by participants according to the locally approved BeneFIX label or the BeneFIX Core Data Sheet to treat bleeding events at the discretion of the study physician. The participant began the second treatment period when the BeneFIX prophylaxis regimen of approximately 100 IU/kg was used once weekly for 12 months (52 weeks).
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Baseline characteristics reporting groups
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Reporting group title |
Overall Trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
All participants
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Reporting group description |
Data for all the participants were analyzed. | ||
Subject analysis set title |
On-Demand Therapy
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants were treated for the bleeding events at the discretion of the study physician according to BeneFIX label.
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Subject analysis set title |
Prophylaxis therapy
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The prophylaxis regimen of approximately 100 IU/kg once weekly was initiated at Visit 4.
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Subject analysis set title |
On-Demand therapy-First infusion
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants were treated for the bleeding events at the discretion of the study physician according to BeneFIX label.
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Subject analysis set title |
On-Demand therapy-Follow-up infusions
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants were treated for the bleeding events at the discretion of the study physician according to BeneFIX label.
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End point title |
Annualized number of bleeding episodes | ||||||||||||
End point description |
The annualized bleed rate (ABR) or the annualized number of bleeding episodes per year, will be derived for each participant for each treatment period by using the following formula: ABR = number of bleeds / (Days on treatment period / 365.25) The number of bleeds for the ABR calculation includes all bleeds requiring treatment with factor IX product during the time on treatment. The efficacy analysis set (EAS) was used for the primary efficacy analyses with respect to ABR.
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End point type |
Primary
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End point timeframe |
2 years
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Statistical analysis title |
Annualized number of bleeding episodes | ||||||||||||
Statistical analysis description |
This analysis compares within-subject difference in ABRs between 2 treatment periods (crossover design): On-Demand and Prophylaxis therapy. Both the groups (On-Demand and prophylaxis therapy) are not mutually exclusive, overall 25 participants data were analysed.
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Comparison groups |
On-Demand Therapy v Prophylaxis therapy
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Number of subjects included in analysis |
50
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Paired t-test | ||||||||||||
Confidence interval |
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End point title |
Response to On-Demand Treatment for all Bleeding Episodes | |||||||||||||||||||||||||||
End point description |
Assessment scores on a 4-point Response Scale for an on-demand bleeding episode, as assessed by participant/caregiver or investigator/qualified staff. The 4-point scale assessments are Excellent, Good, Moderate or No response. Responses to number of observations were noted. The safety analysis set (SAS) was used. The SAS was any participant who received at least one dose of BeneFIX, including the dose given during the enrollment visit (Visit 2) for the factor IX (FIX) recovery study. 507 bleeds were analysed in the On-Demand therapy-First infusion group and 152 bleeds were analysed in the On-Demand therapy-Follow-up infusion group.
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End point type |
Secondary
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End point timeframe |
2 years
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| Notes [1] - Follow-up infusion was only required for 18 participants. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Number of Nonacog Alfa, Recombinant Factor IX (BeneFIX) Infusions Used to Treat Each Bleeding Episode | ||||||||||||||||||
End point description |
The number of study drug infusions administered to treat a bleed will be calculated by adding the initial (on-demand) infusion to any subsequent (on-demand) infusions for the same bleed (same bleed start date/time). The number of infusions needed to treat a bleed will be classified into the following categories: 1, 2, 3, 4 and >4 infusions. If there were more than one bleed location (e.g., ankle and joint) with identical bleed start date and time, it was treated as one bleed occurrence. The SAS was any participant who received at least one dose of BeneFIX, including the dose given during the enrollment visit (Visit 2) for the factor IX (FIX) recovery study. 507 bleeds were analysed.
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End point type |
Secondary
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End point timeframe |
2 years
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of Breakthrough (Spontaneous/Non-Traumatic) Bleeds within 48 Hours of a Prophylaxis Dose of BeneFIX. | ||||||||
End point description |
The number of spontaneous, non-traumatic breakthrough bleeds within 48 hours following a prophylaxis dose of BeneFIX were summarized. If there was more than one bleed location (eg, ankle and joint) with identical bleed start date and time, it was treated as one bleed occurrence. The SAS was any participant who received at least one dose of BeneFIX, including the dose given during the enrollment visit (Visit 2) for the factor IX (FIX) recovery study. Three participants experienced 1 spontaneous bleeding episode each within 48 hours of a previous prophylaxis infusion.
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End point type |
Secondary
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End point timeframe |
2 years
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| No statistical analyses for this end point | |||||||||
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End point title |
Average Infusion Dose. | ||||||||||||
End point description |
The mean dose by per infusion by weight (IU/kg) was reported for both prophylaxis and on demand infusions. The SAS was any participant who received at least one dose of BeneFIX, including the dose given during the enrollment visit (Visit 2) for the factor IX (FIX) recovery study.
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End point type |
Secondary
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End point timeframe |
2 years
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Total Factor Consumption. | ||||||||||||
End point description |
The total amount (IU) infused for each infusion recorded were summed to calculate the total factor consumption for each participant. For each infusion, IU/kg was calculated, using the most recently recorded weight measurement and the total factor consumption, divided by number of infusions, and was summarized similarly to average infusion dose (IU). Annualized TFC by weight was reported. Annualized TFC by weight = (Total IU/kg / treatment interval duration)*365.25. The SAS was any participant who received at least one dose of BeneFIX, including the dose given during the enrollment visit (Visit 2) for the factor IX (FIX) recovery study.
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End point type |
Secondary
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End point timeframe |
2 years
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Incidence of Less than Expected Therapeutic Effect (LETE) | ||||||||||||||
End point description |
The following criteria are the definitions for LETE in this study: 1. LETE in the On-Demand Setting: LETE occurs in the on-demand setting if 2 successive “No Response” ratings are recorded after 2 successive BeneFIX drug infusions in the absence of confounding factors. 2. LETE in the Prophylaxis Setting: LETE occurs in the prophylaxis setting if there is a spontaneous bleed within 48 hours (≤ 48 hours) after a regularly scheduled prophylactic dose of BeneFIX in the absence of confounding factors. 3. LETE (Low Recovery): LETE can also be lower than expected recovery of FIX in the opinion of the investigator following infusion of BeneFIX in the absence of confounding factors. Each reported occurrence of low recovery LETE was listed. The SAS was any participant who received at least one dose of BeneFIX, including the dose given during the enrollment visit (Visit 2) for the factor IX (FIX) recovery study.
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End point type |
Secondary
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End point timeframe |
2 years
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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 |
Until follow-up 82 weeks +/- 4 days.
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Adverse event reporting additional description |
Five participants experienced six SAEs since one participant experienced the same event twice (nephrolithiasis).
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
On-Demand Therapy
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Reporting group description |
Participants were treated for the bleeding events at the discretion of the study physician according to BeneFIX label. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Prophylaxis therapy
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Reporting group description |
The prophylaxis regimen of approximately 100IU/kg once weekly was initiated at Visit 4. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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28 Sep 2011 |
Amendment 1 was due to addition of study procedures, as requested by the Food and Drug Administration (FDA) and changes to statistical methods section of protocol. |
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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 | |||
