Hemophilia B
Conditions
Brief summary
Phase 3/4, single arm, open-label study to evaluate PK, safety, and efficacy of APVO101 prophylaxis in severe or moderately severe hemophilia B subjects \< 12 years of age.
Detailed description
Study APVO101-903 is a Phase 3/4, single arm, open-label clinical trial. The purpose of the study is to evaluate pharmacokinetics (PK), safety, and efficacy of APVO101 prophylaxis in severe or moderately severe hemophilia B subjects \< 12 years of age. The study is designed to gather information in two age groups of previously treated (with a minimum of 50 previous ED to factor IX replacement therapy) pediatric patients, specifically those \< 6 years of age and 6 to \<12 years of age. Study APVO101-903 consists of three distinct phases: * PK Phase - PK evaluation will consist of administration of a single 75 ± 5 IU/kg dose, followed by factor IX activity and safety assessments up to 50 hours post-infusion. * Treatment Phase - subjects will receive APVO101 prophylaxis (starting prophylaxis dose to be determined based on APVO101 recovery; ideally within the recommended dose range: 35 - 75 IU/kg; twice weekly) for 50 ED (approximately 6 months). * Continuation Phase - subjects may continue to receive APVO101 prophylaxis (recommended dose range: 35 - 75 IU/kg; twice weekly) for an additional ≥ 50 ED.
Interventions
DRUGAPVO101
Subjects will receive a single IV dose of APVO101 twice weekly or at a frequency of infusions as determined appropriate by the investigator for the particular study subject for a total of 50 ED. The starting prophylaxis dose will be based on APVO101 recovery from PK Phase assessments (only pre-infusion and 15-30 minute post-infusion samples).
Sponsors
Medexus Pharma, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 3/4, single arm, open-label study with three defined phases: * PK Phase: Initial PK evaluation - single dose of APVO101 * Treatment Phase: APVO101 prophylaxis treatment for 50 ED * Continuation Phase: After completion of the Treatment Phase, subjects may continue APVO101 prophylaxis treatment (for an additional ≥ 50 ED)
Eligibility
Sex/Gender
ALL
Age
No minimum to 11 Years
Healthy volunteers
No
Inclusion criteria
1. Age: \< 11.5 years of age at the time of the first dose and \< 12 years throughout the Treatment Phase of the study (for at least 50 ED). 2. Informed consent: subject's parent or legal guardian written Institutional Review Board (IRB)/Ethics Committee (EC)-approved informed consent. An assent form (IRB/EC-approved) will be obtained, when required by local regulations/guidelines. 3. Willingness and ability to make the required study visits, and follow instructions while enrolled in the study (for at least 50 ED; approximately 6 months). 4. Documented severe or moderately severe hemophilia B diagnosis (factor IX activity ≤ 2 IU/dL); in addition, severity may be indicated by the occurrence of one or more joint bleeding episode(s) at any point in the child's medical history requiring infusion(s) to replace factor IX. 5. Subjects must be on prophylaxis or switch to a prophylaxis regimen for the duration of the study. 6. Previously treated patients with a minimum of 50 ED (as documented and determined by the investigator) to a preparation/blood components containing factor IX. 7. Willingness to adhere to the 4-day washout period of any factor IX replacement therapy prior to PK evaluation. In case of previous exposure to a factor IX product with a prolonged half-life, a washout period of 3 half-lives is required in order to achieve steady state factor IX level prior to exposure to APVO101. 8. Immunocompetent (CD4 count \> 400/mm3) and not receiving immune modulating or chemotherapeutic agents. 9. Platelet count at least 150,000/mm3. 10. Liver function: alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2 times the upper limit of the normal range. 11. Total bilirubin ≤ 1.5 times the upper limit of the normal range. 12. Renal function: serum creatinine ≤ 1.25 times the upper limit of the normal range. 13. Hemoglobin ≥ 7 g/dL.
Exclusion criteria
1. History of factor IX inhibitor ≥ 0.6 Bethesda Units (BU); confirmed by the screening result. 2. Existence of another coagulation disorder. 3. Evidence of thrombotic disease, fibrinolysis, or disseminated intravascular coagulation (DIC). 4. Use of an investigational drug within 30 days prior to study entry. 5. Previous use of APVO101. 6. Use of medications that could impact hemostasis, such as aspirin. 7. Known hypersensitivity to the active substance or to any of the excipients in the investigational products. 8. Known allergic reaction to hamster proteins. 9. History of poor compliance, geographic isolation, unreliable transportation, a serious medical or social condition, or any other circumstance that, in the opinion of the investigator, would interfere with participation or compliance with the study protocol. 10. History of adverse reaction to either plasma-derived factor IX or recombinant factor IX that interfered with the subject's ability to treat bleeding episodes with a factor IX product. 11. History of any medical condition that would impact the efficacy evaluation and/or safety evaluation of the study product.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Bleeding Rate (ABR) | Exposure Day 1 up to 50 exposure days (approximately 6 months) | The primary efficacy variable was the ABR while on prophylaxis to prevent bleeding episodes. The ABR was defined as the number of bleeding episodes per year. |
| Annualized Bleeding Rate (ABR) Overall | Exposure Day 1 through study completion (up to 2.5 years) | The primary efficacy variable was the ABR while on prophylaxis to prevent bleeding episodes. The ABR was defined as the number of bleeding episodes per year. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal Half-Life (t 1/2) | Pre-infusion to 50 hours post-infusion | Terminal half-life is the length of time required for the concentration of drug to decrease by one half of its starting dose in the body. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours. |
| Volume of Distribution at Steady-State (Vdss) | Pre-infusion to 50 hours post-infusion | Volume of distribution is defined as the theoretical volume in which the total amount of FIX would need to be uniformly distributed to produce the observed plasma concentration of FIX. Steady state volume of distribution (Vdss) is the apparent volume of distribution at steady-state. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours. |
| Incremental Recovery (IR) | Pre-infusion to 50 hours post-infusion | Incremental recovery was the increase in circulating FIX activity for every international unit (IU) of APVO101 administered per kilogram of body weight of participant. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours. |
| Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Treatment Phase) | Exposure Day 1 up to 50 exposure days (approximately 6 months) | Subjects rated APVO101 efficacy for each bleeding episode based on a four-point scale: 1. Excellent: a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size 2. Good: pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution; 3. Fair: probable or slight beneficial response usually requiring one of more additional infusions for resolution; 4. Poor: no improvement or condition worsens. |
| Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Overall) | Exposure Day 1 through study completion (up to 2.5 years) | Subjects rated APVO101 efficacy for each bleeding episode based on a four-point scale: 1. Excellent: a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size 2. Good: pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution; 3. Fair: probable or slight beneficial response usually requiring one of more additional infusions for resolution; 4. Poor: no improvement or condition worsens. |
| Investigator Rating of APVO101 Prophylaxis Efficacy (Treatment Phase) | Exposure Day 1 up to 50 exposure days (approximately 6 months) | The investigator will indicate the overall assessment of APVO101 prophylaxis efficacy, considering the absence of bleeding episodes, site, severity and types of bleeding episodes treated, and other factors that might influence the therapeutic response. The investigator's efficacy assessment categories for prophylaxis will include: 'effective', 'partially effective' and 'not effective'. |
| Investigator Rating of APVO101 Prophylaxis Efficacy (Overall) | Exposure Day 1 through study completion (up to 2.5 years) | The investigator will indicate the overall assessment of APVO101 prophylaxis efficacy, considering the absence of bleeding episodes, site, severity and types of bleeding episodes treated, and other factors that might influence the therapeutic response. The investigator's efficacy assessment categories for prophylaxis will include: 'effective', 'partially effective' and 'not effective'. |
| Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Treatment Phase) | Exposure Day 1 up to 50 exposure days (approximately 6 months) | Of the bleeding episodes requiring treatment, the investigator considered the site, severity and type of the bleeding episode while evaluating efficacy for control and management of the bleeding episode. The investigator's efficacy assessment categories control of bleeding episodes included: 'effective', 'partially effective' and 'not effective'. |
| Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Overall) | Exposure Day 1 through study completion (up to 2.5 years) | Of the bleeding episodes requiring treatment, the investigator considered the site, severity and type of the bleeding episode while evaluating efficacy for control and management of the bleeding episode. The investigator's efficacy assessment categories control of bleeding episodes included: 'effective', 'partially effective' and 'not effective'. |
| Concentration (Cmax) | Pre-infusion to 50 hours post-infusion | Maximum post-infusion plasma concentration of FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours. |
| Area Under the Curve (0-inf) | Pre-infusion to 50 hours post-infusion | Area under plasma concentration curve, FIX activity-time profile from time zero extrapolated to infinity. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours. |
| Mean Residence Time (MRT) | Pre-infusion to 50 hours post-infusion | MRT is the average time the molecules of drug reside in the body before elimination. |
| Clearance (CL) | Pre-infusion to 50 hours post-infusion | Clearance is a measure of the volume of plasma from which FIX activity is removed per unit time. Weight normalized clearance calculated as CL=Dose/AUC 0-inf. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Non-Inhibitory Factor IX Antibodies (Overall) | Exposure Day 1 through study completion (up to 2.5 years) | Incidence of APVO101 immunogenicity response (development of inhibitory, non-inhibitory factor IX binding antibodies and incidence of antibodies to Chinese hamster ovary cell proteins \[CHOP\]) |
| Occurrence of Anti-CHOP Antibodies (Overall) | Exposure Day 1 through study completion (up to 2.5 years) | Incidence of APVO101 immunogenicity response (development of inhibitory, non-inhibitory factor IX binding antibodies and incidence of antibodies to Chinese hamster ovary cell proteins \[CHOP\]) |
| Thrombogenicity Assessment - D-Dimer | Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion | This study included testing of thrombogenic markers at the PK stage to evaluate for thrombotic risk. |
| Thrombogenicity Assessment - Thrombin/Antithrombin (TAT) Complex | Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion | This study included testing of thrombogenic markers at the PK stage to evaluate for thrombotic risk. |
| Thrombogenicity Assessment - Prothrombin Fragment 1+2 | Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion | This study included testing of thrombogenic markers at the PK stage to evaluate for thrombotic risk. |
| Spontaneous Annualized Bleeding Rate (Treatment Phase) | Exposure Day 1 up to 50 exposure days (approximately 6 months) | Includes annualized bleeding rate for spontaneous bleeding (i.e. bleeds that occur without obvious cause). |
| Spontaneous Annualized Bleeding Rate (Overall) | Exposure Day 1 through study completion (up to 2.5 years) | Includes annualized bleeding rate for spontaneous bleeding (i.e. bleeds that occur without obvious cause). |
| Occurrence of Inhibitory Factor IX Antibodies (Overall) | Exposure Day 1 through study completion (up to 2.5 years) | Incidence of APVO101 immunogenicity response (development of inhibitory, non-inhibitory factor IX binding antibodies and incidence of antibodies to Chinese hamster ovary cell proteins \[CHOP\]) |
Countries
Brazil, Georgia, Moldova, South Africa, Turkey (Türkiye), Ukraine
Participant flow
Pre-assignment details
Pediatric patients (less than 11.5 years of age at first dose) with severe to moderately severe hemophilia B. Participants had a minimum of 50 exposure days of factor IX (FIX) replacement therapy prior to enrollment.
Participants by arm
| Arm | Count |
|---|---|
| APVO101 Prophylaxis - Safety Population Following a four day washout period or three half-lives washout of a factor IX product with a prolonged half-life, all study participants entered the PK Phase.
* PK Phase - PK evaluation consisted of administration of a single 75 (±5) IU/kg dose, followed by factor IX activity and safety assessments up to 50 hours post-infusion.
* Treatment Phase - after completion of the PK Phase, participants (safety population) received APVO101 prophylaxis (starting prophylaxis dose was to be determined based on APVO101 recovery; ideally within the recommended dose range: 35 to 75 IU/kg, twice weekly or at a frequency determined as appropriate by the Investigator) for 50 exposure days (approximately 6 months).
* Continuation Phase - participants could continue APVO101 prophylaxis (recommended dose range: 35 to 75 IU/kg, twice weekly) for an additional 50 or more exposure days (approximately 6 months). | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Continuation Phase | Adverse Event | 1 |
| Continuation Phase | Protocol Violation | 1 |
| Continuation Phase | Sponsor Concluded Study | 1 |
| Treatment Phase | Adverse Event | 1 |
| Treatment Phase | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | APVO101 Prophylaxis - Safety Population | — |
|---|---|---|
| Age, Customized Age Group: < 6 | 10 Participants | — |
| Age, Customized Age Group: 6 to < 12 | 11 Participants | — |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | — |
| Race (NIH/OMB) Asian | 0 Participants | — |
| Race (NIH/OMB) Black or African American | 3 Participants | — |
| Race (NIH/OMB) More than one race | 0 Participants | — |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | — |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | — |
| Race (NIH/OMB) White | 18 Participants | — |
| Region of Enrollment Brazil | 3 Participants | — |
| Region of Enrollment Georgia | 2 Participants | — |
| Region of Enrollment Moldova | 1 Participants | — |
| Region of Enrollment South Africa | 3 Participants | — |
| Region of Enrollment Turkey | 4 Participants | — |
| Region of Enrollment Ukraine | 8 Participants | — |
| Retrospective Annualized Bleeding Rate | — | — bleeding episodes per year |
| Sex: Female, Male Female | 0 Participants | — |
| Sex: Female, Male Male | 21 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 21 |
| other Total, other adverse events | 16 / 21 |
| serious Total, serious adverse events | 2 / 21 |
Outcome results
Primary
Annualized Bleeding Rate (ABR)
The primary efficacy variable was the ABR while on prophylaxis to prevent bleeding episodes. The ABR was defined as the number of bleeding episodes per year.
Time frame: Exposure Day 1 up to 50 exposure days (approximately 6 months)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form and received at least one dose of APVO101.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APVO101 - Safety Population | Annualized Bleeding Rate (ABR) | 2.93 bleeding episodes per year | Standard Deviation 4.59 |
Primary
Annualized Bleeding Rate (ABR) Overall
The primary efficacy variable was the ABR while on prophylaxis to prevent bleeding episodes. The ABR was defined as the number of bleeding episodes per year.
Time frame: Exposure Day 1 through study completion (up to 2.5 years)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form and received at least one dose of APVO101.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APVO101 - Safety Population | Annualized Bleeding Rate (ABR) Overall | 2.34 bleeding episodes per year | Standard Deviation 4.23 |
Secondary
Area Under the Curve (0-inf)
Area under plasma concentration curve, FIX activity-time profile from time zero extrapolated to infinity. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.
Time frame: Pre-infusion to 50 hours post-infusion
Population: Analysis population included all participants for whom legally acceptable representative had signed informed consent/assent form, were in non-bleeding state, participated in single PK assessment at start of study and for whom an adequate PK profile had been obtained. Number analyzed signifies participants evaluable at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APVO101 - Safety Population | Area Under the Curve (0-inf) | 1170 IU/dL/hr | Standard Deviation 231 |
Secondary
Clearance (CL)
Clearance is a measure of the volume of plasma from which FIX activity is removed per unit time. Weight normalized clearance calculated as CL=Dose/AUC 0-inf. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.
Time frame: Pre-infusion to 50 hours post-infusion
Population: Analysis population included all participants for whom legally acceptable representative had signed informed consent/assent form, were in non-bleeding state, participated in single PK assessment at start of study and for whom an adequate PK profile had been obtained. Number analyzed signifies participants evaluable at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APVO101 - Safety Population | Clearance (CL) | 6.8 mL/(kg*hr) | Standard Deviation 1.5 |
Secondary
Concentration (Cmax)
Maximum post-infusion plasma concentration of FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.
Time frame: Pre-infusion to 50 hours post-infusion
Population: Analysis population included all participants for whom legally acceptable representative had signed informed consent/assent form, were in non-bleeding state, participated in single PK assessment at start of study and for whom an adequate PK profile had been obtained. Number analyzed signifies participants evaluable at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APVO101 - Safety Population | Concentration (Cmax) | 60.1 IU/dL | Standard Deviation 12.2 |
Secondary
Incremental Recovery (IR)
Incremental recovery was the increase in circulating FIX activity for every international unit (IU) of APVO101 administered per kilogram of body weight of participant. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.
Time frame: Pre-infusion to 50 hours post-infusion
Population: Analysis population included all participants for whom legally acceptable representative had signed informed consent/assent form, were in non-bleeding state, participated in single PK assessment at start of study and for whom an adequate PK profile had been obtained. Number analyzed signifies participants evaluable at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APVO101 - Safety Population | Incremental Recovery (IR) | 0.790 IU/dL per IU/kg | Standard Deviation 0.156 |
Secondary
Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Overall)
Of the bleeding episodes requiring treatment, the investigator considered the site, severity and type of the bleeding episode while evaluating efficacy for control and management of the bleeding episode. The investigator's efficacy assessment categories control of bleeding episodes included: 'effective', 'partially effective' and 'not effective'.
Time frame: Exposure Day 1 through study completion (up to 2.5 years)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form, received at least one dose of APVO101 and who had experienced at least one bleeding episode.
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| APVO101 - Safety Population | Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Overall) | Effective | 35 efficacy for control of bleeding episode |
| APVO101 - Safety Population | Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Overall) | Partially effective | 0 efficacy for control of bleeding episode |
| APVO101 - Safety Population | Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Overall) | Not effective | 0 efficacy for control of bleeding episode |
Secondary
Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Treatment Phase)
Of the bleeding episodes requiring treatment, the investigator considered the site, severity and type of the bleeding episode while evaluating efficacy for control and management of the bleeding episode. The investigator's efficacy assessment categories control of bleeding episodes included: 'effective', 'partially effective' and 'not effective'.
Time frame: Exposure Day 1 up to 50 exposure days (approximately 6 months)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form, received at least one dose of APVO101 and who had experienced at least one bleeding episode.
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| APVO101 - Safety Population | Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Treatment Phase) | Effective | 16 efficacy for control of bleeding episode |
| APVO101 - Safety Population | Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Treatment Phase) | Partially effective | 0 efficacy for control of bleeding episode |
| APVO101 - Safety Population | Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Treatment Phase) | Not effective | 0 efficacy for control of bleeding episode |
Secondary
Investigator Rating of APVO101 Prophylaxis Efficacy (Overall)
The investigator will indicate the overall assessment of APVO101 prophylaxis efficacy, considering the absence of bleeding episodes, site, severity and types of bleeding episodes treated, and other factors that might influence the therapeutic response. The investigator's efficacy assessment categories for prophylaxis will include: 'effective', 'partially effective' and 'not effective'.
Time frame: Exposure Day 1 through study completion (up to 2.5 years)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form and had received at least one dose of APVO101.
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| APVO101 - Safety Population | Investigator Rating of APVO101 Prophylaxis Efficacy (Overall) | Effective | 167 prophylactic efficacy assessment |
| APVO101 - Safety Population | Investigator Rating of APVO101 Prophylaxis Efficacy (Overall) | Partially Effective | 3 prophylactic efficacy assessment |
| APVO101 - Safety Population | Investigator Rating of APVO101 Prophylaxis Efficacy (Overall) | Not Effective | 0 prophylactic efficacy assessment |
Secondary
Investigator Rating of APVO101 Prophylaxis Efficacy (Treatment Phase)
The investigator will indicate the overall assessment of APVO101 prophylaxis efficacy, considering the absence of bleeding episodes, site, severity and types of bleeding episodes treated, and other factors that might influence the therapeutic response. The investigator's efficacy assessment categories for prophylaxis will include: 'effective', 'partially effective' and 'not effective'.
Time frame: Exposure Day 1 up to 50 exposure days (approximately 6 months)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form and had received at least one dose of APVO101.
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| APVO101 - Safety Population | Investigator Rating of APVO101 Prophylaxis Efficacy (Treatment Phase) | Effective | 80 prophylactic efficacy assessment |
| APVO101 - Safety Population | Investigator Rating of APVO101 Prophylaxis Efficacy (Treatment Phase) | Partially Effective | 1 prophylactic efficacy assessment |
| APVO101 - Safety Population | Investigator Rating of APVO101 Prophylaxis Efficacy (Treatment Phase) | Not Effective | 0 prophylactic efficacy assessment |
Secondary
Mean Residence Time (MRT)
MRT is the average time the molecules of drug reside in the body before elimination.
Time frame: Pre-infusion to 50 hours post-infusion
Population: Analysis population included all participants for whom legally acceptable representative had signed informed consent/assent form, were in non-bleeding state, participated in single PK assessment at start of study and for whom an adequate PK profile had been obtained. Number analyzed signifies participants evaluable at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APVO101 - Safety Population | Mean Residence Time (MRT) | 20 hours | Standard Deviation 2.53 |
Secondary
Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Overall)
Subjects rated APVO101 efficacy for each bleeding episode based on a four-point scale: 1. Excellent: a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size 2. Good: pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution; 3. Fair: probable or slight beneficial response usually requiring one of more additional infusions for resolution; 4. Poor: no improvement or condition worsens.
Time frame: Exposure Day 1 through study completion (up to 2.5 years)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form, received at least one dose of APVO101 and who had experienced at least one bleeding episode.
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| APVO101 - Safety Population | Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Overall) | Excellent | 28 bleeding episodes |
| APVO101 - Safety Population | Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Overall) | Good | 13 bleeding episodes |
| APVO101 - Safety Population | Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Overall) | Fair | 0.0 bleeding episodes |
| APVO101 - Safety Population | Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Overall) | Poor | 0.0 bleeding episodes |
| APVO101 - Safety Population | Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Overall) | No infusions required to treat bleeding episode | 9 bleeding episodes |
| APVO101 - Safety Population | Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Overall) | Missing | 2 bleeding episodes |
Secondary
Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Treatment Phase)
Subjects rated APVO101 efficacy for each bleeding episode based on a four-point scale: 1. Excellent: a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size 2. Good: pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution; 3. Fair: probable or slight beneficial response usually requiring one of more additional infusions for resolution; 4. Poor: no improvement or condition worsens.
Time frame: Exposure Day 1 up to 50 exposure days (approximately 6 months)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form, received at least one dose of APVO101 and who had experienced at least one bleeding episode.
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| APVO101 - Safety Population | Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Treatment Phase) | Excellent | 10 bleeding episodes |
| APVO101 - Safety Population | Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Treatment Phase) | Good | 5 bleeding episodes |
| APVO101 - Safety Population | Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Treatment Phase) | Fair | 0.0 bleeding episodes |
| APVO101 - Safety Population | Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Treatment Phase) | Poor | 0.0 bleeding episodes |
| APVO101 - Safety Population | Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Treatment Phase) | No infusions required to treat bleeding episode | 7 bleeding episodes |
| APVO101 - Safety Population | Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Treatment Phase) | Missing | 2 bleeding episodes |
Secondary
Terminal Half-Life (t 1/2)
Terminal half-life is the length of time required for the concentration of drug to decrease by one half of its starting dose in the body. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.
Time frame: Pre-infusion to 50 hours post-infusion
Population: Analysis population included all participants for whom legally acceptable representative had signed informed consent/assent form, were in non-bleeding state, participated in single PK assessment at start of study and for whom an adequate PK profile had been obtained. Number analyzed signifies participants evaluable at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APVO101 - Safety Population | Terminal Half-Life (t 1/2) | 16.3 hours | Standard Deviation 2.2 |
Secondary
Volume of Distribution at Steady-State (Vdss)
Volume of distribution is defined as the theoretical volume in which the total amount of FIX would need to be uniformly distributed to produce the observed plasma concentration of FIX. Steady state volume of distribution (Vdss) is the apparent volume of distribution at steady-state. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.
Time frame: Pre-infusion to 50 hours post-infusion
Population: Analysis population included all participants for whom legally acceptable representative had signed informed consent/assent form, were in non-bleeding state, participated in single PK assessment at start of study and for whom an adequate PK profile had been obtained. Number analyzed signifies participants evaluable at specified time points.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APVO101 - Safety Population | Volume of Distribution at Steady-State (Vdss) | 134 mL/kg | Standard Deviation 30.6 |
Other Pre-specified
Occurrence of Anti-CHOP Antibodies (Overall)
Incidence of APVO101 immunogenicity response (development of inhibitory, non-inhibitory factor IX binding antibodies and incidence of antibodies to Chinese hamster ovary cell proteins \[CHOP\])
Time frame: Exposure Day 1 through study completion (up to 2.5 years)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form and received at least one dose of APVO101.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| APVO101 - Safety Population | Occurrence of Anti-CHOP Antibodies (Overall) | 3 Participants |
Other Pre-specified
Occurrence of Inhibitory Factor IX Antibodies (Overall)
Incidence of APVO101 immunogenicity response (development of inhibitory, non-inhibitory factor IX binding antibodies and incidence of antibodies to Chinese hamster ovary cell proteins \[CHOP\])
Time frame: Exposure Day 1 through study completion (up to 2.5 years)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form and received at least one dose of APVO101.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| APVO101 - Safety Population | Occurrence of Inhibitory Factor IX Antibodies (Overall) | 0 Participants |
Other Pre-specified
Occurrence of Non-Inhibitory Factor IX Antibodies (Overall)
Incidence of APVO101 immunogenicity response (development of inhibitory, non-inhibitory factor IX binding antibodies and incidence of antibodies to Chinese hamster ovary cell proteins \[CHOP\])
Time frame: Exposure Day 1 through study completion (up to 2.5 years)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form and received at least one dose of APVO101.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| APVO101 - Safety Population | Occurrence of Non-Inhibitory Factor IX Antibodies (Overall) | 3 Participants |
Other Pre-specified
Spontaneous Annualized Bleeding Rate (Overall)
Includes annualized bleeding rate for spontaneous bleeding (i.e. bleeds that occur without obvious cause).
Time frame: Exposure Day 1 through study completion (up to 2.5 years)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form and received at least one dose of APVO101.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APVO101 - Safety Population | Spontaneous Annualized Bleeding Rate (Overall) | 0.63 spontaneous bleeding episodes | Standard Deviation 1.26 |
Other Pre-specified
Spontaneous Annualized Bleeding Rate (Treatment Phase)
Includes annualized bleeding rate for spontaneous bleeding (i.e. bleeds that occur without obvious cause).
Time frame: Exposure Day 1 up to 50 exposure days (approximately 6 months)
Population: Analysis population included all participants for whom a legally acceptable representative had signed the informed consent/assent form and received at least one dose of APVO101.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APVO101 - Safety Population | Spontaneous Annualized Bleeding Rate (Treatment Phase) | 0.81 spontaneous bleeding episodes | Standard Deviation 1.93 |
Other Pre-specified
Thrombogenicity Assessment - D-Dimer
This study included testing of thrombogenic markers at the PK stage to evaluate for thrombotic risk.
Time frame: Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion
Population: To accommodate blood volume limitations for participants less than 17 kg, no thrombogenicity assessments were performed during the PK Phase. Participants weighing 17 kg to 19 kg, the 4 to 6 hour post-infusion timepoint was not collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| APVO101 - Safety Population | Thrombogenicity Assessment - D-Dimer | 4 to 6 hours post-infusion | 0.452 mg/L | Standard Deviation 0.2955 |
| APVO101 - Safety Population | Thrombogenicity Assessment - D-Dimer | Day 1, pre-infusion | 0.432 mg/L | Standard Deviation 0.232 |
| APVO101 - Safety Population | Thrombogenicity Assessment - D-Dimer | 15 to 30 minutes post-infusion | 0.422 mg/L | Standard Deviation 0.1999 |
| APVO101 - Safety Population | Thrombogenicity Assessment - D-Dimer | 24 to 26 hours post-infusion | 0.578 mg/L | Standard Deviation 0.2766 |
| Change From Baseline | Thrombogenicity Assessment - D-Dimer | 15 to 30 minutes post-infusion | 0.006 mg/L | Standard Deviation 0.1071 |
| Change From Baseline | Thrombogenicity Assessment - D-Dimer | 4 to 6 hours post-infusion | 0.045 mg/L | Standard Deviation 0.2051 |
| Change From Baseline | Thrombogenicity Assessment - D-Dimer | 24 to 26 hours post-infusion | 0.114 mg/L | Standard Deviation 0.2586 |
Other Pre-specified
Thrombogenicity Assessment - Prothrombin Fragment 1+2
This study included testing of thrombogenic markers at the PK stage to evaluate for thrombotic risk.
Time frame: Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion
Population: To accommodate blood volume limitations for participants less than 17 kg, no thrombogenicity assessments were performed during the PK Phase. Participants weighing 17 kg to 19 kg, the 4 to 6 hour post-infusion timepoint was not collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| APVO101 - Safety Population | Thrombogenicity Assessment - Prothrombin Fragment 1+2 | 24 to 26 hours post-infusion | 223.0 pmol/L | Standard Deviation 246.46 |
| APVO101 - Safety Population | Thrombogenicity Assessment - Prothrombin Fragment 1+2 | 4 to 6 hours post-infusion | 238.6 pmol/L | Standard Deviation 330.63 |
| APVO101 - Safety Population | Thrombogenicity Assessment - Prothrombin Fragment 1+2 | Day 1, pre-infusion | 99.9 pmol/L | Standard Deviation 41.59 |
| APVO101 - Safety Population | Thrombogenicity Assessment - Prothrombin Fragment 1+2 | 15 to 30 minutes post-infusion | 318.0 pmol/L | Standard Deviation 433.64 |
| Change From Baseline | Thrombogenicity Assessment - Prothrombin Fragment 1+2 | 24 to 26 hours post-infusion | 123.1 pmol/L | Standard Deviation 251.48 |
| Change From Baseline | Thrombogenicity Assessment - Prothrombin Fragment 1+2 | 4 to 6 hours post-infusion | 139.5 pmol/L | Standard Deviation 303.66 |
| Change From Baseline | Thrombogenicity Assessment - Prothrombin Fragment 1+2 | 15 to 30 minutes post-infusion | 218.1 pmol/L | Standard Deviation 439.48 |
Other Pre-specified
Thrombogenicity Assessment - Thrombin/Antithrombin (TAT) Complex
This study included testing of thrombogenic markers at the PK stage to evaluate for thrombotic risk.
Time frame: Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion
Population: To accommodate blood volume limitations for participants less than 17 kg, no thrombogenicity assessments were performed during the PK Phase. Participants weighing 17 kg to 19 kg, the 4 to 6 hour post-infusion timepoint was not collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| APVO101 - Safety Population | Thrombogenicity Assessment - Thrombin/Antithrombin (TAT) Complex | 24 to 26 hours post-infusion | 12.45 ug/L | Standard Deviation 16.459 |
| APVO101 - Safety Population | Thrombogenicity Assessment - Thrombin/Antithrombin (TAT) Complex | 4 to 6 hours post-infusion | 12.17 ug/L | Standard Deviation 15.986 |
| APVO101 - Safety Population | Thrombogenicity Assessment - Thrombin/Antithrombin (TAT) Complex | Day 1, pre-infusion | 5.92 ug/L | Standard Deviation 2.579 |
| APVO101 - Safety Population | Thrombogenicity Assessment - Thrombin/Antithrombin (TAT) Complex | 15 to 30 minutes post-infusion | 17.92 ug/L | Standard Deviation 22.971 |
| Change From Baseline | Thrombogenicity Assessment - Thrombin/Antithrombin (TAT) Complex | 4 to 6 hours post-infusion | 6.63 ug/L | Standard Deviation 17.399 |
| Change From Baseline | Thrombogenicity Assessment - Thrombin/Antithrombin (TAT) Complex | 15 to 30 minutes post-infusion | 12.71 ug/L | Standard Deviation 24.252 |
| Change From Baseline | Thrombogenicity Assessment - Thrombin/Antithrombin (TAT) Complex | 24 to 26 hours post-infusion | 6.78 ug/L | Standard Deviation 17.081 |