Trial Outcomes & Findings for Assess the Efficacy and Safety of Personalized Prophylaxis Human-cl rhFVIII in Patients With Severe Haemophilia A (NCT NCT02256917)

NCT ID: NCT02256917

Last Updated: 2021-01-19

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 58 participants
• Primary outcome timeframe: 6 months
• Results posted on: 2021-01-19

Participant Flow

Participant milestones

Measure	Human-cl rhFVIII The study consisted of 3 phases: 1. Pharmacokinetic (PK) Phase: 58 previously treated (≥150 exposure days) immunocompetent adults with severe hemophilia A without inhibitors patients started and completed the PK phase (PK population). Patients were treated with single dose of FVIII (60±5 IU/kg). One patient discontinued after single PK administration. 2. Prophylactic Treatment Phase I: 57 patients started and 56 completed Phase I; Patients were treated prophylactically every other day or 3x/week with a dose of 30-40 IU/kg BW for 1-3 months until PK data had been analysed. 3. Prophylactic Treatment Phase II: 56 patients started and 52 completed Phase II. Patients were treated prophylactically for 6 months using the dose and dosing interval based on individual PK data. All 58 patients were included in the safety (SAF) and the intention-to-treat (ITT) populations.
Pharmacokinetic (PK) Evaluation Phase STARTED	58
Pharmacokinetic (PK) Evaluation Phase COMPLETED	58
Pharmacokinetic (PK) Evaluation Phase NOT COMPLETED	0
Prophylactic Treatment Phase I STARTED	57
Prophylactic Treatment Phase I COMPLETED	56
Prophylactic Treatment Phase I NOT COMPLETED	1
Prophylactic Treatment Phase II STARTED	56
Prophylactic Treatment Phase II COMPLETED	52
Prophylactic Treatment Phase II NOT COMPLETED	4

Reasons for withdrawal

Measure	Human-cl rhFVIII The study consisted of 3 phases: 1. Pharmacokinetic (PK) Phase: 58 previously treated (≥150 exposure days) immunocompetent adults with severe hemophilia A without inhibitors patients started and completed the PK phase (PK population). Patients were treated with single dose of FVIII (60±5 IU/kg). One patient discontinued after single PK administration. 2. Prophylactic Treatment Phase I: 57 patients started and 56 completed Phase I; Patients were treated prophylactically every other day or 3x/week with a dose of 30-40 IU/kg BW for 1-3 months until PK data had been analysed. 3. Prophylactic Treatment Phase II: 56 patients started and 52 completed Phase II. Patients were treated prophylactically for 6 months using the dose and dosing interval based on individual PK data. All 58 patients were included in the safety (SAF) and the intention-to-treat (ITT) populations.
Prophylactic Treatment Phase I Lost to Follow-up	1
Prophylactic Treatment Phase II Lost to Follow-up	1
Prophylactic Treatment Phase II Withdrawn Consent	1
Prophylactic Treatment Phase II Did not attend completion visit	1
Prophylactic Treatment Phase II Discontinued medication	1

Baseline Characteristics

Assess the Efficacy and Safety of Personalized Prophylaxis Human-cl rhFVIII in Patients With Severe Haemophilia A

Baseline characteristics by cohort

Measure	SAF/ITT Population n=58 Participants All patients who received at least one infusion of Human-cI rhFVIII
Age, Continuous	40.1 years STANDARD_DEVIATION 13.5 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	58 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	14 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants
Race (NIH/OMB) White	39 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants
Region of Enrollment Canada	4 participants n=5 Participants
Region of Enrollment Netherlands	2 participants n=5 Participants
Region of Enrollment United States	23 participants n=5 Participants
Region of Enrollment Japan	11 participants n=5 Participants
Region of Enrollment Finland	4 participants n=5 Participants
Region of Enrollment North Macedonia	4 participants n=5 Participants
Region of Enrollment Slovenia	2 participants n=5 Participants
Region of Enrollment France	6 participants n=5 Participants
Region of Enrollment Croatia	2 participants n=5 Participants
Weight	77.0 kg STANDARD_DEVIATION 17.0 • n=5 Participants
Body mass index (BMI)	25.7 kg/m^2 STANDARD_DEVIATION 5.0 • n=5 Participants
Hemophilia Joint Health Score	32.3 units on a scale STANDARD_DEVIATION 20.2 • n=5 Participants
Blood group O	20 Participants n=5 Participants
Blood group A	26 Participants n=5 Participants
Blood group AB	1 Participants n=5 Participants
Blood group B	7 Participants n=5 Participants
Blood group Unknown/missing	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=56 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 n=22 Participants All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Annualized Total Bleeding Rate of Individually Tailored Prophylaxis	4.67 Bleeding events per year (ABR) Standard Deviation 6.46	58.08 Bleeding events per year (ABR) Standard Deviation 30.78

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=56 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 n=22 Participants All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis	2.98 Bleeding events per year (ABR) Standard Deviation 5.76	38.46 Bleeding events per year (ABR) Standard Deviation 28.07

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=29 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 n=22 Participants All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis	4.82 Bleeding events per year (ABR) Standard Deviation 6.98	58.08 Bleeding events per year (ABR) Standard Deviation 30.78

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=56 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Median Prophylactic Dosing Interval	83.9 hours Interval 53.5 to 96.1	—

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=56 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Mean Prophylactic Dosing Interval	83.0 hours Standard Deviation 22.37	—

SECONDARY outcome

Timeframe: 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.

AUCnorm of Human-cl rhFVIII measured using the one-stage (OS) assay

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=47 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
AUC Divided by the Dose (AUCnorm) of Human-cl rhFVIII	0.302 hr*IU/mL/(IU/kg) Standard Deviation 0.116	—

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=47 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
In-vivo Recovery (IVR) of Human-cl rhFVIII	1.775 % per IU/kg Standard Deviation 0.421	—

SECONDARY outcome

Timeframe: 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.

T1/2 of Human-cl rhFVIII measured using the one-stage (OS) assay

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=47 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Half Life (t1/2) of Human-cl rhFVIII	15.725 hours Standard Deviation 4.029	—

SECONDARY outcome

Timeframe: 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.

MRT of Human-cl rhFVIII measured using the one-stage (OS) assay

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=47 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Mean Residence Time (MRT) of Human-cl rhFVIII	20.762 hours Standard Deviation 5.997	—

SECONDARY outcome

Timeframe: 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.

CL of Human-cl rhFVIII measured using the one-stage (OS) assay

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=47 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Clearance (CL) of Human-cl rhFVIII	3.859 mL/hr/kg Standard Deviation 1.670	—

SECONDARY outcome

Timeframe: 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.

Vss of Human-cl rhFVIII measured using the one-stage (OS) assay

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=47 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Volume of Distribution at Steady State (Vss) of Human-cl rhFVIII	72.901 mL/kg Standard Deviation 16.454	—

SECONDARY outcome

Timeframe: 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.

Average weekly consumption of Human-cl rhFVIII reported as IU/kg BW per week per patient was determined during individualized prophylactic treatment

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=56 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Usage of Human-cl rhFVIII (FVIII IU/kg BW Per Week Per Patient)	83.7 IU/kg per week Standard Deviation 25.7	—

SECONDARY outcome

Timeframe: 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

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

Outcome measures

Measure	Individualized Prophylaxis in GENA-21b n=58 Participants Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis	GENA-01 All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Number of Patients With Adverse Events (AEs) AE	34 Participants	—
Number of Patients With Adverse Events (AEs) No AE	24 Participants	—

Adverse Events

SAF/ITT Population

Serious events: 4 serious events

Other events: 34 other events

Deaths: 0 deaths

Serious adverse events

Measure	SAF/ITT Population n=58 participants at risk All patients who received at least one infusion of Human-cI rhFVIII
Musculoskeletal and connective tissue disorders Back pain	1.7% 1/58 • Number of events 1 • At each study visit over the study duration (7-9 months)
Blood and lymphatic system disorders Subdural haematoma	1.7% 1/58 • Number of events 1 • At each study visit over the study duration (7-9 months)
Metabolism and nutrition disorders Hypokalemia	1.7% 1/58 • Number of events 1 • At each study visit over the study duration (7-9 months)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basosquamous carcinoma	1.7% 1/58 • Number of events 1 • At each study visit over the study duration (7-9 months)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Large B-cell lymphoma	1.7% 1/58 • Number of events 1 • At each study visit over the study duration (7-9 months)
General disorders Pyrexia	1.7% 1/58 • Number of events 1 • At each study visit over the study duration (7-9 months)

Other adverse events

Measure	SAF/ITT Population n=58 participants at risk All patients who received at least one infusion of Human-cI rhFVIII
Infections and infestations Nasopharyngitis	20.7% 12/58 • At each study visit over the study duration (7-9 months)
Infections and infestations Influenza	5.2% 3/58 • At each study visit over the study duration (7-9 months)
Infections and infestations Urinary tract infection	5.2% 3/58 • At each study visit over the study duration (7-9 months)
Gastrointestinal disorders Diarrhea	5.2% 3/58 • At each study visit over the study duration (7-9 months)
Gastrointestinal disorders Dyspepsia	3.4% 2/58 • At each study visit over the study duration (7-9 months)
Gastrointestinal disorders Gastritis	3.4% 2/58 • At each study visit over the study duration (7-9 months)
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.2% 3/58 • At each study visit over the study duration (7-9 months)
Respiratory, thoracic and mediastinal disorders Nasal congestion	3.4% 2/58 • At each study visit over the study duration (7-9 months)
Musculoskeletal and connective tissue disorders Arthralgia	6.9% 4/58 • At each study visit over the study duration (7-9 months)
Musculoskeletal and connective tissue disorders Bone pain	3.4% 2/58 • At each study visit over the study duration (7-9 months)
Musculoskeletal and connective tissue disorders Pain in extremity	3.4% 2/58 • At each study visit over the study duration (7-9 months)
General disorders Pyrexia	6.9% 4/58 • At each study visit over the study duration (7-9 months)
Nervous system disorders Headache	8.6% 5/58 • At each study visit over the study duration (7-9 months)
Nervous system disorders Dizziness	3.4% 2/58 • At each study visit over the study duration (7-9 months)
Blood and lymphatic system disorders Anemia	3.4% 2/58 • At each study visit over the study duration (7-9 months)
Blood and lymphatic system disorders Lymphadenopathy	3.4% 2/58 • At each study visit over the study duration (7-9 months)
Psychiatric disorders Depression	3.4% 2/58 • At each study visit over the study duration (7-9 months)
Psychiatric disorders Insomnia	3.4% 2/58 • At each study visit over the study duration (7-9 months)

Additional Information

Sylvia Werner

Octapharma

Phone: 415 260-9577

Email: sylvia.werner@octapharma.com

Results disclosure agreements

• Principal investigator is a sponsor employee Octapharma agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Octapharma supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial. Octapharma also reserves the right to review data prior to publishing and provide comments/changes within a certain time period.
• Publication restrictions are in place

Restriction type: OTHER