Clinical Trial Results:
An Open-Label, Single-Arm, Post-Authorization Pragmatic Clinical Trial on the Safety and Efficacy of BeneFIX (Nonacog-Alfa, Recombinant Factor IX) in Subjects With Hemophilia B in Usual Care Settings in China
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Summary
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EudraCT number |
2016-000765-22 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
22 Aug 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Feb 2017
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First version publication date |
02 Feb 2017
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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 |
B1821052
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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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 Street, New York, United States, NY 10017
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Public contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Scientific contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 Sep 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 Jul 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Aug 2016
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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 evaluate the occurrence and severity of product medically important events (Factor IX inhibitor development, allergic reactions, thrombotic events) of BeneFIX in subjects with hemophilia B in usual care settings in China.
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Protection of trial subjects |
This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
23 Jan 2015
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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 |
China: 70
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Worldwide total number of subjects |
70
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EEA total number of subjects |
0
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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) |
8
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Children (2-11 years) |
52
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Adolescents (12-17 years) |
4
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Adults (18-64 years) |
6
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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 |
This study enrolled 70 subjects. | ||||||||||||||||
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Pre-assignment
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Screening details |
A total of 77 potential subjects were screened, 70 of them met the inclusion criteria and were enrolled into this study. | ||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall 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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Arm title
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BeneFIX | ||||||||||||||||
Arm description |
Subjects received treatment with BeneFIX according to usual care in China and in accord with the China BeneFIX Package Insert. The treatment duration was 6 months (±7 days) or 50 Exposure Days (EDs) (±5 EDs) whichever occurred first. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
BeneFIX kit
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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 in pre-filled syringe
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Routes of administration |
Intravenous use
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Dosage and administration details |
Dosage was determined according to usual care in China and in accord with China BeneFIX Package Insert. BeneFIX was administered via intravenous injection.
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Baseline characteristics reporting groups
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Reporting group title |
BeneFIX
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Reporting group description |
Subjects received treatment with BeneFIX according to usual care in China and in accord with the China BeneFIX Package Insert. The treatment duration was 6 months (±7 days) or 50 Exposure Days (EDs) (±5 EDs) whichever occurred first. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
BeneFIX
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Reporting group description |
Subjects received treatment with BeneFIX according to usual care in China and in accord with the China BeneFIX Package Insert. The treatment duration was 6 months (±7 days) or 50 Exposure Days (EDs) (±5 EDs) whichever occurred first. | ||
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End point title |
Proportion of subjects who developed Factor IX inhibitor [1] | ||||||||||||
End point description |
Factor IX (FIX) inhibitor development was defined as Bethesda inhibitor titer >=0.6 Bethesda Unit (BU)/mL. Proportion of subjects who developed FIX inhibitor during on-demand period and prophylaxis period is presented. All subjects who received at least 1 dose of BeneFIX during the study were included. Here, n refers to the total number of subjects in each category, and 24 subjects were included in both on-demand and prophylaxis category, therefore the total number was less than 37 + 57.
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End point type |
Primary
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End point timeframe |
7 months
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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. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of subjects with allergic reactions [2] | ||||||||||
End point description |
Number of subjects with allergic reactions is presented for on-demand and prophylaxis analysis set. All subjects who received at least 1 dose of BeneFIX during the study were included. Here, n refers to the total number of subjects in each category, and 24 subjects were included in both on-demand and prophylaxis category, therefore the total number was less than 37 + 57.
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End point type |
Primary
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End point timeframe |
7 months
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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. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of subjects with thrombotic events [3] | ||||||||||
End point description |
Number of subjects with thrombotic events is presented for on-demand and prophylaxis analysis set. All subjects who received at least 1 dose of BeneFIX during the study were included. Here, n refers to the total number of subjects in each category, and 24 subjects were included in both on-demand and prophylaxis category, therefore the total number was less than 37 + 57.
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End point type |
Primary
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End point timeframe |
7 months
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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. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of subjects with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) | ||||||||||||||
End point description |
An adverse event (AE) was any untoward medical occurrence in a clinical investigation subject, regardless of the causality with study treatment. A serious adverse event (SAE) was any untoward occurrence that resulted in death; was life threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both serious and non-serious AEs. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study drug. Number of subjects with treatment-emergent AEs and SAEs is presented for on-demand and prophylaxis analysis set. All subjects who received at least 1 dose of BeneFIX were included. Here, n refers to the total number of subjects in each category, and 24 subjects were included in both on-demand and prophylaxis category, therefore the total number was less than 37 + 57.
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End point type |
Secondary
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End point timeframe |
7 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Annualized bleeding rates (ABRs) in subjects receiving prophylaxis treatment with BeneFIX during their prophylaxis period | ||||||||
End point description |
For prophylaxis treatment period, annualized bleeding rate (ABR) was derived for each subject by the following formula: ABR = number of bleeds in prophylaxis period / (number of days in prophylaxis period/365.25). In this formula, number of days in prophylaxis period was the sum of time from all prophylaxis treatment periods for the subject. The number of bleeds for the ABR calculation included all bleeds during all the prophylaxis periods. Time on a single treatment period was defined as first day of the treatment period through the day before the start of the next treatment period. For a prophylaxis regimen to be qualified to have ABR calculated, the sum of its periods needs to be equal to or more than 14 days. All subjects who participated in at least one day of a prophylaxis period (ie, had at least one prophylaxis dose) were included.
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End point type |
Secondary
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End point timeframe |
Up to 6 months or 50 exposure days whichever occurred first
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of spontaneous/non-traumatic breakthrough 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 was summarized. The prophylaxis infusion time, bleed start time and bleed type (etiology) were used to determine the number of spontaneous, non-traumatic breakthrough bleeds that occurred <=48 hours after a prophylaxis infusion. If there was more than 1 bleed location (eg, ankle and joint) with identical bleed start date and time, it was treated as 1 bleed occurrence. All subjects who participated in at least one day of a prophylaxis period (ie, had at least one prophylaxis dose) were included. A total of 2032 prophylaxis infusions were administered during the study. In the prophylaxis analysis set, 23 breakthrough bleeds occurred in 11 subjects.
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End point type |
Secondary
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End point timeframe |
Up to 6 months or 50 exposure days whichever occurred first
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| No statistical analyses for this end point | |||||||||
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End point title |
Annualized bleeding rates (ABRs) in subjects receiving on-demand treatment with BeneFIX during their on-demand period | ||||||||
End point description |
For on-demand treatment period, the annualized bleeding rate (ABR) was derived for each subject by the following formula: ABR = number of bleeds in on-demand period / (number of days in on-demand period/365.25). In this formula, number of days in on-demand period was the sum of time from all on-demand treatment periods for the subject. The number of bleeds for the ABR calculation included all bleeds during all the on-demand periods. Time on a single treatment period was defined as first day of the treatment period through the day before the start of the next treatment period. For an on-demand regimen to be qualified to have ABR calculated, the sum of its periods needs to be equal to or more than 14 days. All subjects who participated in at least one day of on-demand period were included in this analysis. Number of subjects analyzed represents the number of subjects who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Up to 6 months or 50 exposure days whichever occurred first
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of infusions resulted in the following response to on-demand treatment of bleeds: excellent, good, moderate, no response | ||||||||||||||
End point description |
Response was assessed using 4-point On-Demand Hemostasis Efficacy Rating Scale, based on a) definite pain relief and b) improvement in signs of bleeding. Excellent: a) and/or b) within 8 hours after an infusion, with no additional infusion administered; good: a) and/or b) within 8 hours after an infusion, with at least 1 additional infusion administered for complete resolution of bleeding, or a) and/or b) after 8 hours following an infusion, with no additional infusion administered; moderate: probable or slight improvement after 8 hours following an infusion, with at least 1 additional infusion administered for complete resolution of bleeding; no response: no improvement between infusions or during the 24 hour interval following an infusion, or condition worsens. Number of subjects analyzed represents the number of subjects who received at least one on-demand infusion of BeneFIX during the study. A total of 520 on-demand infusions were given during the study.
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End point type |
Secondary
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End point timeframe |
Up to 6 months or 50 exposure days whichever occurred first
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Average infusion dose and total Factor IX consumption in prophylaxis, on-demand and recovery settings | ||||||||||||||||||||
End point description |
The total amount (international units [IU]) infused for each BeneFIX infusion was summed to calculate the total factor IX consumption for each subject. The average infusion dose for each subject was calculated as his total factor IX consumption (in IU) divided by the number of infusions administered. All subjects who received at lease one dose of BeneFIX were included in this analysis. Here, n refers to the total number of subjects who were evaluable for this endpoint in each category, and subjects in each category were not mutually exclusive.
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End point type |
Secondary
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End point timeframe |
Up to 6 months or 50 exposure days whichever occurred first
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Number of BeneFIX infusions to treat each new bleed | ||||||||
End point description |
The number of BeneFIX infusions administered to treat each new bleed was calculated by adding the on-demand initial treatment and any on-demand follow-up treatments for the same bleed. 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. All subjects who received at least one on-demand infusion of BeneFIX to treat new bleed were included. A total of 353 new bleeds occurred during the study.
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End point type |
Secondary
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End point timeframe |
Up to 6 months or 50 exposure days whichever occurred first
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| No statistical analyses for this end point | |||||||||
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End point title |
Incidence rate of less than expected therapeutic effects (LETEs) in on-demand, prophylaxis, and low recovery settings | ||||||||||||||
End point description |
Less than expected therapeutic effect (LETE) in the on-demand setting was defined as 2 successive “no response” ratings recorded after 2 successive BeneFIX drug infusions, respectively. LETE in the prophylaxis setting was defined as occurrence of any spontaneous bleed within 48 hours after a regularly scheduled prophylactic dose of BeneFIX (which was not used to treat a bleed). LETE could also be lower than expected recovery of FIX in the opinion of the investigator following infusion of BeneFIX, which didn't occur in this study. All subjects who received at least one dose of BeneFIX were included in this analysis. Here, n refers to the total number of infusions in each category.
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End point type |
Secondary
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End point timeframe |
Up to 6 months or 50 exposure days whichever occurred first
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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 |
Baseline up to 28 calendar days after the last administration of the investigational product
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Adverse event reporting additional description |
The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another subject, or one subject may have experienced both a serious and non-serious event during the study.
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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 |
19.0
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Reporting groups
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Reporting group title |
BeneFIX
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Reporting group description |
Subjects received treatment with BeneFIX according to usual care in China and in accord with the China BeneFIX Package Insert. The treatment duration was 6 months (±7 days) or 50 Exposure Days (EDs) (±5 EDs) whichever occurred first. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
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 | |||
