Severe Haemophilia A
Conditions
Brief summary
The rationale of this study is to further fine-tune and individualize prophylactic treatment of patients with severe Haemophilia A with the goal of keeping the trough FVIII level above 1% between doses. Because trough FVIII levels are likely to be important predictors of the efficacy of prophylaxis, the focus of this study is on pharmacokinetic (PK) data.
Interventions
BIOLOGICALHuman cl rhFVIII
Sponsors
Octapharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Severe Haemophilia A (FVIII:C \< 1%) * Male patients \>= 18 years of age * Previous treatment with a FVIII concentrate for at least 150 EDs * Good documentation regarding dosing and bleeding frequency in the 6 months preceding study start * Immunocompetence (CD4+ count \> 200/uL)
Exclusion criteria
* Any coagulation disorder other than Haemophilia A * Present of past FVIII inhibitor activity * Severe liver or kidney disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Total Bleeding Rate of Individually Tailored Prophylaxis | 6 months | Total annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis | 6 months | Total annualized bleeding rate (ABR) in patients with 2x/week (or less) prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII |
| Median Prophylactic Dosing Interval | 6 months | Median over median actual dosing intervals between two prophylactic treatments per patient. The median time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient |
| Mean Prophylactic Dosing Interval | 6 months | Mean over mean actual dosing intervals between two prophylactic treatments per patient. The mean time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient |
| AUC Divided by the Dose (AUCnorm) of Human-cl rhFVIII | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection | AUCnorm of Human-cl rhFVIII measured using the one-stage (OS) assay |
| In-vivo Recovery (IVR) of Human-cl rhFVIII | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection | IVR of Human-cl rhFVIII measured using the one-stage (OS) assay and will be determined from the FVIII level before the infusion and the peak level after the infusion of Human-cl rhFVIII |
| Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis | 6 months | Spontaneous annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII |
| Mean Residence Time (MRT) of Human-cl rhFVIII | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection | MRT of Human-cl rhFVIII measured using the one-stage (OS) assay |
| Clearance (CL) of Human-cl rhFVIII | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection | CL of Human-cl rhFVIII measured using the one-stage (OS) assay |
| Volume of Distribution at Steady State (Vss) of Human-cl rhFVIII | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection | Vss of Human-cl rhFVIII measured using the one-stage (OS) assay |
| Usage of Human-cl rhFVIII (FVIII IU/kg BW Per Week Per Patient) | 6 months | Average weekly consumption of Human-cl rhFVIII reported as IU/kg BW per week per patient was determined during individualized prophylactic treatment |
| Number of Patients With Adverse Events (AEs) | At each study visit over the study duration (7-9 months) | AEs were documented at each (scheduled or unscheduled) study visit. Severity and seriousness of all AEs were documented by the investigator according to pre-defined criteria |
| Half Life (t1/2) of Human-cl rhFVIII | Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection | T1/2 of Human-cl rhFVIII measured using the one-stage (OS) assay |
Countries
Canada, Croatia, Finland, France, Japan, Netherlands, North Macedonia, Slovenia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SAF/ITT Population All patients who received at least one infusion of Human-cI rhFVIII | 58 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Prophylactic Treatment Phase I | Lost to Follow-up | 1 |
| Prophylactic Treatment Phase II | Did not attend completion visit | 1 |
| Prophylactic Treatment Phase II | Discontinued medication | 1 |
| Prophylactic Treatment Phase II | Lost to Follow-up | 1 |
| Prophylactic Treatment Phase II | Withdrawn Consent | 1 |
Baseline characteristics
| Characteristic | SAF/ITT Population |
|---|---|
| Age, Continuous | 40.1 years STANDARD_DEVIATION 13.5 |
| Blood group A | 26 Participants |
| Blood group AB | 1 Participants |
| Blood group B | 7 Participants |
| Blood group O | 20 Participants |
| Blood group Unknown/missing | 4 Participants |
| Body mass index (BMI) | 25.7 kg/m^2 STANDARD_DEVIATION 5 |
| Hemophilia Joint Health Score | 32.3 units on a scale STANDARD_DEVIATION 20.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 14 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 | 2 Participants |
| Race (NIH/OMB) White | 39 Participants |
| Region of Enrollment Canada | 4 participants |
| Region of Enrollment Croatia | 2 participants |
| Region of Enrollment Finland | 4 participants |
| Region of Enrollment France | 6 participants |
| Region of Enrollment Japan | 11 participants |
| Region of Enrollment Netherlands | 2 participants |
| Region of Enrollment North Macedonia | 4 participants |
| Region of Enrollment Slovenia | 2 participants |
| Region of Enrollment United States | 23 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 58 Participants |
| Weight | 77.0 kg STANDARD_DEVIATION 17 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 58 |
| other Total, other adverse events | 34 / 58 |
| serious Total, serious adverse events | 4 / 58 |
Outcome results
Primary
Annualized Total Bleeding Rate of Individually Tailored Prophylaxis
Total annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII
Time frame: 6 months
Population: The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. Their annualized bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Prophylaxis in GENA-21b | Annualized Total Bleeding Rate of Individually Tailored Prophylaxis | 4.67 Bleeding events per year (ABR) | Standard Deviation 6.46 |
| GENA-01 | Annualized Total Bleeding Rate of Individually Tailored Prophylaxis | 58.08 Bleeding events per year (ABR) | Standard Deviation 30.78 |
95% CI: [4.06, 5.79]one-sided one-sample Poisson-test
p-value: <0.000195% CI: [7.5, 18.86]Negative binomial regression model
p-value: <0.000195% CI: [6.12, 16.8]Poisson regression model
Secondary
Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis
Spontaneous annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII
Time frame: 6 months
Population: The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. Their annualized spontaneous bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Prophylaxis in GENA-21b | Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis | 2.98 Bleeding events per year (ABR) | Standard Deviation 5.76 |
| GENA-01 | Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis | 38.46 Bleeding events per year (ABR) | Standard Deviation 28.07 |
95% CI: [2.48, 3.87]One-sided one-sample Poisso
Secondary
Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis
Total annualized bleeding rate (ABR) in patients with 2x/week (or less) prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII
Time frame: 6 months
Population: The analysis population comprised 29 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial at intervals of 2x/week or less. Their annualized spontaneous bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Prophylaxis in GENA-21b | Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis | 4.82 Bleeding events per year (ABR) | Standard Deviation 6.98 |
| GENA-01 | Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis | 58.08 Bleeding events per year (ABR) | Standard Deviation 30.78 |
95% CI: [3.9, 6.39]One-sided one-sample Poisson-test
Secondary
AUC Divided by the Dose (AUCnorm) of Human-cl rhFVIII
AUCnorm of Human-cl rhFVIII measured using the one-stage (OS) assay
Time frame: Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
Population: The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Prophylaxis in GENA-21b | AUC Divided by the Dose (AUCnorm) of Human-cl rhFVIII | 0.302 hr*IU/mL/(IU/kg) | Standard Deviation 0.116 |
Secondary
Clearance (CL) of Human-cl rhFVIII
CL of Human-cl rhFVIII measured using the one-stage (OS) assay
Time frame: Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
Population: The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Prophylaxis in GENA-21b | Clearance (CL) of Human-cl rhFVIII | 3.859 mL/hr/kg | Standard Deviation 1.67 |
Secondary
Half Life (t1/2) of Human-cl rhFVIII
T1/2 of Human-cl rhFVIII measured using the one-stage (OS) assay
Time frame: Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
Population: The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Prophylaxis in GENA-21b | Half Life (t1/2) of Human-cl rhFVIII | 15.725 hours | Standard Deviation 4.029 |
Secondary
In-vivo Recovery (IVR) of Human-cl rhFVIII
IVR of Human-cl rhFVIII measured using the one-stage (OS) assay and will be determined from the FVIII level before the infusion and the peak level after the infusion of Human-cl rhFVIII
Time frame: Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
Population: The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Prophylaxis in GENA-21b | In-vivo Recovery (IVR) of Human-cl rhFVIII | 1.775 % per IU/kg | Standard Deviation 0.421 |
Secondary
Mean Prophylactic Dosing Interval
Mean over mean actual dosing intervals between two prophylactic treatments per patient. The mean time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient
Time frame: 6 months
Population: The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Prophylaxis in GENA-21b | Mean Prophylactic Dosing Interval | 83.0 hours | Standard Deviation 22.37 |
Secondary
Mean Residence Time (MRT) of Human-cl rhFVIII
MRT of Human-cl rhFVIII measured using the one-stage (OS) assay
Time frame: Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
Population: The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Prophylaxis in GENA-21b | Mean Residence Time (MRT) of Human-cl rhFVIII | 20.762 hours | Standard Deviation 5.997 |
Secondary
Median Prophylactic Dosing Interval
Median over median actual dosing intervals between two prophylactic treatments per patient. The median time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient
Time frame: 6 months
Population: The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Individualized Prophylaxis in GENA-21b | Median Prophylactic Dosing Interval | 83.9 hours |
Secondary
Number of Patients With Adverse Events (AEs)
AEs were documented at each (scheduled or unscheduled) study visit. Severity and seriousness of all AEs were documented by the investigator according to pre-defined criteria
Time frame: At each study visit over the study duration (7-9 months)
Population: The SAF population included 58 patients who received at least one infusion of Human-c1 rhFVIII in the GENA-21b trial
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Individualized Prophylaxis in GENA-21b | Number of Patients With Adverse Events (AEs) | AE | 34 Participants |
| Individualized Prophylaxis in GENA-21b | Number of Patients With Adverse Events (AEs) | No AE | 24 Participants |
Secondary
Usage of Human-cl rhFVIII (FVIII IU/kg BW Per Week Per Patient)
Average weekly consumption of Human-cl rhFVIII reported as IU/kg BW per week per patient was determined during individualized prophylactic treatment
Time frame: 6 months
Population: The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Prophylaxis in GENA-21b | Usage of Human-cl rhFVIII (FVIII IU/kg BW Per Week Per Patient) | 83.7 IU/kg per week | Standard Deviation 25.7 |
Secondary
Volume of Distribution at Steady State (Vss) of Human-cl rhFVIII
Vss of Human-cl rhFVIII measured using the one-stage (OS) assay
Time frame: Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
Population: The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Prophylaxis in GENA-21b | Volume of Distribution at Steady State (Vss) of Human-cl rhFVIII | 72.901 mL/kg | Standard Deviation 16.454 |