Trial Outcomes & Findings for Clinical Study to Investigate the PK, Efficacy, and Safety of Wilate in Patients With Severe Hemophilia A (NCT NCT02954575)

NCT ID: NCT02954575

Last Updated: 2021-01-19

Results Overview

The total number of bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 57 participants
• Primary outcome timeframe: 6 months
• Results posted on: 2021-01-19

Participant Flow

Participant milestones

Measure	Wilate A total of 57 patients were enrolled in the study. For the PK assessment (PK population) a single dose of Wilate of 50 ±5 IU/kg BW was administered to 21 patients. For prophylactic treatment, Wilate was administered every 2 to 3 days at a dose of 20-40 IU/kg BW for 6 months. In case of unacceptably frequent spontaneous breakthrough BEs, the dose of Wilate was increased by approximately 5 IU/kg. The dose (and duration) of treatment for BEs was dependent on the location and extent of bleeding and on the clinical condition of the patient; range: 10-50 IU/kg every 12-24 hours or 8-24 hours until resolved. For the surgical prophylaxis population (SURG population), minor surgeries were treated with 15-30 IU/kg every 24 hours, at least 1 day, until healing iwas achieved. Major surgeries were treated with 40-50 IU/kg, repeat injection every 8-24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a FVIII activity of 30% to 60%.
Overall Study STARTED	57
Overall Study Received Treatment	55
Overall Study SAF Population	55
Overall Study FAS Population	55
Overall Study PP Population	52
Overall Study PK Population	21
Overall Study SURG Population	1
Overall Study COMPLETED	54
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Measure	Wilate A total of 57 patients were enrolled in the study. For the PK assessment (PK population) a single dose of Wilate of 50 ±5 IU/kg BW was administered to 21 patients. For prophylactic treatment, Wilate was administered every 2 to 3 days at a dose of 20-40 IU/kg BW for 6 months. In case of unacceptably frequent spontaneous breakthrough BEs, the dose of Wilate was increased by approximately 5 IU/kg. The dose (and duration) of treatment for BEs was dependent on the location and extent of bleeding and on the clinical condition of the patient; range: 10-50 IU/kg every 12-24 hours or 8-24 hours until resolved. For the surgical prophylaxis population (SURG population), minor surgeries were treated with 15-30 IU/kg every 24 hours, at least 1 day, until healing iwas achieved. Major surgeries were treated with 40-50 IU/kg, repeat injection every 8-24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a FVIII activity of 30% to 60%.
Overall Study Withdrawal by Subject	2
Overall Study Adverse Event	1

Baseline Characteristics

Clinical Study to Investigate the PK, Efficacy, and Safety of Wilate in Patients With Severe Hemophilia A

Baseline characteristics by cohort

Measure	Wilate n=55 Participants SAF population (All patients who received at least one administration of Wilate during the study (N=55)
Age, Continuous	35.0 years STANDARD_DEVIATION 12.3 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	55 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 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	0 Participants n=5 Participants
Race (NIH/OMB) White	55 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Weight	83.3 kg STANDARD_DEVIATION 21.4 • n=5 Participants
Body mass index (BMI)	26.8 kg/m2 STANDARD_DEVIATION 5.8 • n=5 Participants
Blood groups 0	19 Participants n=5 Participants
Blood groups A	23 Participants n=5 Participants
Blood groups AB	5 Participants n=5 Participants
Blood groups B	8 Participants n=5 Participants
von Willebrand factor antigen (VWF:Ag)	118.4 IU/dL STANDARD_DEVIATION 78.9 • n=5 Participants
von Willebrand factor activity (VWF:Ac)	103.7 IU/dL STANDARD_DEVIATION 39.5 • n=5 Participants
Previous Factor (F) VIII treatment On-demand	32 Participants n=5 Participants
Previous Factor (F) VIII treatment Prophylaxis	18 Participants n=5 Participants
Previous Factor (F) VIII treatment Combination	5 Participants n=5 Participants
Previous annualized bleeding rate (ABR)	32.98 No. BEs per patient per year STANDARD_DEVIATION 39.12 • n=5 Participants

PRIMARY outcome

Timeframe: 6 months

Population: The total annualized bleeding rate (TABR) was calculated for all patients included in the PP population (N=52).

The total number of bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel.

Outcome measures

Measure	Wilate n=57 No. of Bleeding Episodes (BEs) PP population
Total Annualized Bleeding Rate (TABR)	2.10 No. of BEs / year (ABR) Standard Deviation 3.44

SECONDARY outcome

Timeframe: 6 months

Population: The spontaneous annualized bleeding rate (SABR) was calculated for all patients included in the PP population (N=52).

The number of spontaneous bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel.

Outcome measures

Measure	Wilate n=41 No. of BEs PP population
Spontaneous Annualized Bleeding Rate (SABR)	1.51 No. of spontaneous BEs/year (SABR) Standard Deviation 3.03

SECONDARY outcome

Timeframe: 6 months

Population: In the PP population, efficacy of Wilate in the treatment of breakthrough BEs was analyzed for all patients experiencing breakthrough BEs (N=24)

The proportion of BEs successfully treated with Wilate were documented by the patient (together with the investigator in case of on-site treatments) in the patient diary for all BEs according to a 4-point hemostatic efficacy scale including the four items: 'excellent,' 'good,' moderate,' and 'none', where 'excellent' was defined as "Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection" (best outcome) and 'none' was defined as "No improvement within 12 hours, or worsening of symptoms, requiring more than two injections for complete resolution" (worst outcome). All efficacy ratings assessed as either 'excellent' or 'good' were considered 'successfully treated.'

Outcome measures

Measure	Wilate n=57 Number of BEs PP population
Efficacy of Wilate in the Treatment of Breakthrough BEs Excellent	16 Number of BEs
Efficacy of Wilate in the Treatment of Breakthrough BEs Good	32 Number of BEs
Efficacy of Wilate in the Treatment of Breakthrough BEs Moderate	9 Number of BEs

SECONDARY outcome

Timeframe: 6 months

The average consumption of Wilate per month of study (IU/kg) for all patients receiving prophylaxis.

Outcome measures

Measure	Wilate n=52 Participants PP population
Wilate Consumption Data (Average Total Normdose of FVIII IU/kg Per Month of Study) for Prophylaxis	405.06 IU/kg Standard Deviation 83.70

SECONDARY outcome

Timeframe: Initial PK visit (Day -1) and PK study completion visit (6 months); data collected 1 h prior to injection and 15 min, 1 h, 3 h, 6 h, 9 h, 24 h, 30 h and 48 h after the end of injection

Population: AUC divided by dose (IU\*h/dL per IU/kg)

PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The value of the AUCnorm of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.

Outcome measures

Measure	Wilate n=21 Participants PP population
Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Norm) of FVIII:C Initial PK	28.61 IU*h/dL per IU/kg Standard Deviation 9.31
Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Norm) of FVIII:C PK completion 6 months	30.75 IU*h/dL per IU/kg Standard Deviation 11.32

SECONDARY outcome

Timeframe: Initial PK assessment (Day -1) and PK study completion visit (6 months); data collected 1 h prior to infusion and 15 min, 1 h, 3 h, 6 h, 9 h, 24 h, 30 h and 48 h after the end of injection

PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The in vivo half-life of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.

Outcome measures

Measure	Wilate n=21 Participants PP population
Pharmacokinetic (PK) Assessment (in Vivo Half-Life (t1/2)) of FVIII:C Initial PK	10.82 Hours Standard Deviation 2.50
Pharmacokinetic (PK) Assessment (in Vivo Half-Life (t1/2)) of FVIII:C PK completion 6 months	11.50 Hours Standard Deviation 2.30

SECONDARY outcome

Timeframe: Initial PK assessment (Day -1) and 6 months

PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The maximum plasma concentration of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.

Outcome measures

Measure	Wilate n=21 Participants PP population
Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration [Cmax]) of FVIII:C Initial PK	106.70 IU/dL Standard Deviation 22.45
Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration [Cmax]) of FVIII:C PK completion 6 months	103.49 IU/dL Standard Deviation 26.53

SECONDARY outcome

Timeframe: Baseline, 3 and 6 months

The rise in FVIII activity in IU/dl per unit dose administered in IU/kg was determined from all patients at baseline, 3 and 6 months, using the OS assay.

Outcome measures

Measure	Wilate n=55 Participants PP population
Incremental in Vivo Recovery (IVR) of Wilate Over Time First PK/non-PK visit	2.14 kg/dL Standard Deviation 0.51
Incremental in Vivo Recovery (IVR) of Wilate Over Time 3 months	2.14 kg/dL Standard Deviation 0.49
Incremental in Vivo Recovery (IVR) of Wilate Over Time PK/non-PK completion 6 months	1.97 kg/dL Standard Deviation 0.64

SECONDARY outcome

Timeframe: 6 months

Analysis of variance (ANOVA) was used in an exploratory sense to assess an association between ABO blood type and the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay.

Outcome measures

Measure	Wilate n=21 Participants PP population
Association Between ABO Blood Type and the FVIII:C Half-life of Wilate (OS Assay)	15.867 Beta coefficient

SECONDARY outcome

Timeframe: 6 months

ANOVA was used in an exploratory sense to assess an association between VWF:Ag with the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay.

Outcome measures

Measure	Wilate n=21 Participants PP population
Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate	5.104 Beta coefficient

SECONDARY outcome

Timeframe: 6 months

Population: In the FAS population (N=55), the safety and tolerability of Wilate was analysed for all patients experiencing adverse events (AEs) throughout the study.

At each (scheduled or unscheduled) study visit, AEs were documented by the investigator throughout the study.

Outcome measures

Measure	Wilate n=55 Participants PP population
Safety and Tolerability of Wilate by Monitoring Adverse Events (AEs) Throughout the Study Number of AEs	17 Number of adverse events
Safety and Tolerability of Wilate by Monitoring Adverse Events (AEs) Throughout the Study Number of Treatment-emergent AEs	16 Number of adverse events

SECONDARY outcome

Timeframe: 6 months

FVIII inhibitor activity was determined at each study visit before the injection of Wilate using the modified Bethesda assay (Nijmegen modification).

Outcome measures

Measure	Wilate n=55 Participants PP population
Immunogenicity of Wilate by Testing for FVIII Inhibitors	0 Participants

SECONDARY outcome

Timeframe: 6 months

Population: In the FAS population (N=55), the viral safety of Wilate was analyzed for all patients at baseline.

Virus safety was evaluated by taking a plasma sample for parvovirus B19 antibody testing before the first injection of Wilate. All patients negative at screening were tested again at the study completion visit. The number with Parvovirus B19 seroconversions between BL and end of study was recorded.

Outcome measures

Measure	Wilate n=55 Participants PP population
Virus Safety Measured by the Number of Parvovirus B19 Seroconversions Between Baseline (BL) and End of Study	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Hemostatic efficacy was assessed at the end of surgery by the surgeon and at end of the postoperative period by the hematologist, using a 4-point hemostatic efficacy scale including the four items: 'excellent' (best possible outcome), 'good', 'moderate' and 'none' (worst outcome). Overall efficacy was assessed by the investigator, taking both the intra and postoperative assessments into account, and using the 'excellent,' 'good,' moderate,' and 'none' scale.

Outcome measures

Measure	Wilate n=1 Participants PP population
Efficacy of Wilate in Surgical Prophylaxis Excellent	0 Participants
Efficacy of Wilate in Surgical Prophylaxis Good	1 Participants
Efficacy of Wilate in Surgical Prophylaxis Moderate	0 Participants
Efficacy of Wilate in Surgical Prophylaxis None	0 Participants

Adverse Events

Wilate

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Wilate n=55 participants at risk SAF population
Infections and infestations Erysipelas	1.8% 1/55 • Number of events 1 • 6 months
Infections and infestations Nasopharyngitis	1.8% 1/55 • Number of events 1 • 6 months
Infections and infestations Viral upper respiratory tract infection	1.8% 1/55 • Number of events 1 • 6 months
Blood and lymphatic system disorders Thrombocytosis	3.6% 2/55 • Number of events 2 • 6 months
Immune system disorders Seasonal allergy	3.6% 2/55 • Number of events 2 • 6 months
Nervous system disorders Headache	1.8% 1/55 • Number of events 1 • 6 months
Skin and subcutaneous tissue disorders Eczema	1.8% 1/55 • Number of events 1 • 6 months
Musculoskeletal and connective tissue disorders Arthralgia	3.6% 2/55 • Number of events 5 • 6 months
General disorders Pain	1.8% 1/55 • Number of events 1 • 6 months
Injury, poisoning and procedural complications Limb injury	1.8% 1/55 • Number of events 1 • 6 months

Additional Information

Cristina Solomon

Octapharma AG

Phone: +41 (0)55 451 21 89

Email: Cristina.Solomon@octapharma.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place