Hemophilia B
Conditions
Keywords
Hemophilia B, on-demand, prophylaxis, nonacog alfa, BeneFIX, FIX
Brief summary
The purpose of this study will be to determine if a once-weekly prophylaxis regimen of BeneFIX in subjects with moderately severe to severe Hemophilia B is safe and effective.
Interventions
BIOLOGICALNonacog alfa
Period 1: During on-demand period, dosing at the discretion of investigator.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Documented history of moderately-severe to severe hemophilia B (FIX activity \</=2%). * Male subjects, aged 12 years to 65 years. * Subjects with at least 100 exposure days (EDs) to factor IX products. * Subjects with a minimum of 12 bleeding episodes, 6 of which must be joint bleeds, in the 12-month period before the Screening visit.
Exclusion criteria
* Subjects who have received FIX as a primary or secondary prophylaxis regimen within the last 12 months prior to the Screening visit. * Subjects who have had major surgery or an orthopedic surgical procedure within the past 3 months prior to Screening visit. * Subjects for which major surgery or orthopedic surgery is planned within the duration of study participation. * Subjects with a past history of, or current FIX inhibitor, defined as \>ULN (upper limit of normal) of the reporting laboratory. * Subjects with a known hypersensitivity to any FIX product or hamster protein.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Number of Bleeding Episodes. | 2 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Nonacog Alfa, Recombinant Factor IX (BeneFIX) Infusions Used to Treat Each Bleeding Episode. | 2 years | 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. |
| Number of Breakthrough (Spontaneous/Non-Traumatic) Bleeds Within 48 Hours of a Prophylaxis Dose of BeneFIX. | 2 years | 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. |
| Response to On-Demand Treatment for All Bleeding Episodes. | 2 years | 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. |
| Total Factor Consumption. | 2 years | 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. |
| Incidence of Less Than Expected Therapeutic Effect (LETE) | 2 years | 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. |
| Average Infusion Dose. | 2 years | The mean dose by per infusion by weight (IU/kg) was reported for both prophylaxis and on demand infusions |
Countries
Bulgaria, Canada, Croatia, Malaysia, Mexico, Poland, Singapore, South Korea, Turkey (Türkiye)
Participant flow
Recruitment details
Participation included 25 enrolled participants from 15 study centers and 9 countries.
Pre-assignment 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).
Participants by arm
| Arm | Count |
|---|---|
| All Participants The data for all the participants is presented. | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 31.3 Years STANDARD_DEVIATION 12.6 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 25 | 20 / 25 |
| serious Total, serious adverse events | 1 / 25 | 4 / 25 |
Outcome results
Primary
Annualized Number of Bleeding Episodes.
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.
Time frame: 2 years
Population: The efficacy analysis set (EAS) was used for the primary efficacy analyses with respect to ABR. It includes all participants who participated in at least one day of the routine prophylaxis period (ie, in the study through at least Visit 4).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| On-Demand Therapy | Annualized Number of Bleeding Episodes. | 32.9 Number of bleeds per year | Standard Deviation 17.4 |
| Prophylaxis Therapy | Annualized Number of Bleeding Episodes. | 3.6 Number of bleeds per year | Standard Deviation 4.6 |
p-value: <0.0001Paired t-test
Secondary
Average Infusion Dose.
The mean dose by per infusion by weight (IU/kg) was reported for both prophylaxis and on demand infusions
Time frame: 2 years
Population: The safety analysis set (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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| On-Demand Therapy | Average Infusion Dose. | 52 IU/Kg | Standard Deviation 16 |
| Prophylaxis Therapy | Average Infusion Dose. | 99 IU/Kg | Standard Deviation 2 |
Secondary
Incidence of Less Than Expected Therapeutic Effect (LETE)
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.
Time frame: 2 years
Population: The safety analysis set (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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| On-Demand Therapy | Incidence of Less Than Expected Therapeutic Effect (LETE) | LETE in On-Demand setting | 0 Percentage of occurence |
| On-Demand Therapy | Incidence of Less Than Expected Therapeutic Effect (LETE) | LETE in prophylaxis setting | 0 Percentage of occurence |
| On-Demand Therapy | Incidence of Less Than Expected Therapeutic Effect (LETE) | LETE (Low recovery) | 0 Percentage of occurence |
Secondary
Number of Breakthrough (Spontaneous/Non-Traumatic) Bleeds Within 48 Hours of a Prophylaxis Dose of BeneFIX.
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.
Time frame: 2 years
Population: The safety analysis set (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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| On-Demand Therapy | Number of Breakthrough (Spontaneous/Non-Traumatic) Bleeds Within 48 Hours of a Prophylaxis Dose of BeneFIX. | 1.0 Number of breakthrough bleeds | Standard Deviation 0 |
Secondary
Number of Nonacog Alfa, Recombinant Factor IX (BeneFIX) Infusions Used to Treat Each Bleeding Episode.
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.
Time frame: 2 years
Population: The safety analysis set (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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| On-Demand Therapy | Number of Nonacog Alfa, Recombinant Factor IX (BeneFIX) Infusions Used to Treat Each Bleeding Episode. | Number of Infusion: 1 | 416 Number of bleeds requiring infusion |
| On-Demand Therapy | Number of Nonacog Alfa, Recombinant Factor IX (BeneFIX) Infusions Used to Treat Each Bleeding Episode. | Number of Infusions: 2 | 69 Number of bleeds requiring infusion |
| On-Demand Therapy | Number of Nonacog Alfa, Recombinant Factor IX (BeneFIX) Infusions Used to Treat Each Bleeding Episode. | Number of Infusions: 3 | 9 Number of bleeds requiring infusion |
| On-Demand Therapy | Number of Nonacog Alfa, Recombinant Factor IX (BeneFIX) Infusions Used to Treat Each Bleeding Episode. | Number of Infusions: 4 | 3 Number of bleeds requiring infusion |
| On-Demand Therapy | Number of Nonacog Alfa, Recombinant Factor IX (BeneFIX) Infusions Used to Treat Each Bleeding Episode. | Number of Infusions: >4 | 10 Number of bleeds requiring infusion |
Secondary
Response to On-Demand Treatment for All Bleeding Episodes.
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.
Time frame: 2 years
Population: The safety analysis set (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. Follow-up infusion was only required for 18 participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| On-Demand Therapy | Response to On-Demand Treatment for All Bleeding Episodes. | Good | 177 Number of observations with response |
| On-Demand Therapy | Response to On-Demand Treatment for All Bleeding Episodes. | No response | 3 Number of observations with response |
| On-Demand Therapy | Response to On-Demand Treatment for All Bleeding Episodes. | Moderate | 55 Number of observations with response |
| On-Demand Therapy | Response to On-Demand Treatment for All Bleeding Episodes. | Data not recorded | 1 Number of observations with response |
| On-Demand Therapy | Response to On-Demand Treatment for All Bleeding Episodes. | Excellent | 271 Number of observations with response |
| Prophylaxis Therapy | Response to On-Demand Treatment for All Bleeding Episodes. | Data not recorded | 0 Number of observations with response |
| Prophylaxis Therapy | Response to On-Demand Treatment for All Bleeding Episodes. | Excellent | 39 Number of observations with response |
| Prophylaxis Therapy | Response to On-Demand Treatment for All Bleeding Episodes. | Good | 80 Number of observations with response |
| Prophylaxis Therapy | Response to On-Demand Treatment for All Bleeding Episodes. | Moderate | 33 Number of observations with response |
| Prophylaxis Therapy | Response to On-Demand Treatment for All Bleeding Episodes. | No response | 0 Number of observations with response |
Secondary
Total Factor Consumption.
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.
Time frame: 2 years
Population: The safety analysis set (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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| On-Demand Therapy | Total Factor Consumption. | 707 IU/Kg | Standard Deviation 519 |
| Prophylaxis Therapy | Total Factor Consumption. | 4985 IU/Kg | Standard Deviation 233 |