Trial Outcomes & Findings for Non-interventional Post-authorisation Study to Document the Immunogenicity, Safety, and Efficacy of NUWIQ (NCT NCT02962765)

NCT ID: NCT02962765

Last Updated: 2021-10-21

Results Overview

FVIII inhibitors will be determined based on clinical observations and confirmed by FVIII inhibitor testing in the laboratory.

• Recruitment status: COMPLETED
• Target enrollment: 80 participants
• Primary outcome timeframe: Screening through to study completion (minimum 1.7 months; maximum 31.6 months)
• Results posted on: 2021-10-21

Participant Flow

Participant milestones

Measure	Nuwiq® (Human-cl rhFVIII) A total of 80 patients were enrolled in this study. Of the 80 patients enrolled into the study, 2 were excluded because they had not received any treatment with Nuwiq, leaving 78 patients in the full analysis population (FAS) and safety population (SAF). Of these, 77 patients were part of the prophylactic treatment group and 2 patients were in the on-demand treatment group. One patient changed regimen from on-demand treatment to prophylactic treatment and back to on-demand treatment while in the study. Corresponding data for this patient in included in both the prophylactic and on-demand treatment groups. The treatment regimen, doses, dosing intervals and dose adjustments were determined at the discretion of the treating physician. A usual dose for long-term prophylaxis against bleeding in patients with severe hemophilia A is 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. Of the 78 total patients, 17 were excluded for the reasons summarized below.
Overall Study STARTED	78
Overall Study FAS Population	78
Overall Study SAF Population	78
Overall Study Prophylactic Treatment Group	77
Overall Study On Demand Treatment Group	2
Overall Study SURG Population	4
Overall Study COMPLETED	61
Overall Study NOT COMPLETED	17

Reasons for withdrawal

Measure	Nuwiq® (Human-cl rhFVIII) A total of 80 patients were enrolled in this study. Of the 80 patients enrolled into the study, 2 were excluded because they had not received any treatment with Nuwiq, leaving 78 patients in the full analysis population (FAS) and safety population (SAF). Of these, 77 patients were part of the prophylactic treatment group and 2 patients were in the on-demand treatment group. One patient changed regimen from on-demand treatment to prophylactic treatment and back to on-demand treatment while in the study. Corresponding data for this patient in included in both the prophylactic and on-demand treatment groups. The treatment regimen, doses, dosing intervals and dose adjustments were determined at the discretion of the treating physician. A usual dose for long-term prophylaxis against bleeding in patients with severe hemophilia A is 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. Of the 78 total patients, 17 were excluded for the reasons summarized below.
Overall Study Protocol Violation	9
Overall Study Withdrawal by Subject	3
Overall Study Lost to Follow-up	1
Overall Study Death	1
Overall Study Limited access to study medication	3

Baseline Characteristics

Non-interventional Post-authorisation Study to Document the Immunogenicity, Safety, and Efficacy of NUWIQ

Baseline characteristics by cohort

Measure	Nuwiq® (Human-cl rhFVIII) SAF Population n=78 Participants The safety (SAF) population consist of all patients who received at least one infusion of Human-cl rhFVIII (n=78)
Age, Customized Age · <12 yrs	40 Participants n=5 Participants
Age, Customized Age · 12-<18 yrs	12 Participants n=5 Participants
Age, Customized Age · >18 yrs	26 Participants n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	78 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	25 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	53 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race/Ethnicity, Customized Patient race · American Indian or Alaska Native	7 Participants n=5 Participants
Race/Ethnicity, Customized Patient race · Asian	0 Participants n=5 Participants
Race/Ethnicity, Customized Patient race · Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race/Ethnicity, Customized Patient race · Black or African American	1 Participants n=5 Participants
Race/Ethnicity, Customized Patient race · White	61 Participants n=5 Participants
Race/Ethnicity, Customized Patient race · More than one race	0 Participants n=5 Participants
Race/Ethnicity, Customized Patient race · Other	9 Participants n=5 Participants
Height <12 yrs	112 centimeters STANDARD_DEVIATION 17.59 • n=5 Participants
Height 12-<18 yrs	168.8 centimeters STANDARD_DEVIATION 9.73 • n=5 Participants
Height >18 yrs	172.9 centimeters STANDARD_DEVIATION 7.88 • n=5 Participants
Weight <12 yrs	21.7 kilograms STANDARD_DEVIATION 8.30 • n=5 Participants
Weight 12-<18 yrs	67.1 kilograms STANDARD_DEVIATION 15.55 • n=5 Participants
Weight >18 yrs	76.6 kilograms STANDARD_DEVIATION 17.21 • n=5 Participants
BMI <12 yrs	17.0 kg/m^2 STANDARD_DEVIATION 3.34 • n=5 Participants
BMI 12-<18 yrs	23.6 kg/m^2 STANDARD_DEVIATION 5.46 • n=5 Participants
BMI >18 yrs	25.5 kg/m^2 STANDARD_DEVIATION 4.65 • n=5 Participants
Severity of Haemophilia A Moderate	10 Participants n=5 Participants
Severity of Haemophilia A Severe	68 Participants n=5 Participants
Family history of Haemophilia Yes	47 Participants n=5 Participants
Family history of Haemophilia No	31 Participants n=5 Participants
Factor VIII Inhibitor History Yes	10 Participants n=5 Participants
Factor VIII Inhibitor History No	68 Participants n=5 Participants
Factor VIII gene defect Intron 22-Inversion	17 Participants n=5 Participants
Factor VIII gene defect Large Deletion/Insertion	1 Participants n=5 Participants
Factor VIII gene defect Small Deletion/Insertion	5 Participants n=5 Participants
Factor VIII gene defect Stop-Mutation	4 Participants n=5 Participants
Factor VIII gene defect Nonsense Mutation	4 Participants n=5 Participants
Factor VIII gene defect Missense Mutation	2 Participants n=5 Participants
Factor VIII gene defect Other	9 Participants n=5 Participants
Factor VIII gene defect Unknown	36 Participants n=5 Participants

PRIMARY outcome

Timeframe: Screening through to study completion (minimum 1.7 months; maximum 31.6 months)

Population: FVIII inhibitor testing could be carried out at any time at the physician's discretion. Patients were checked for clinical symptoms suggesting FVIII inhibitor development, any suspicion of inhibitor formation was to be investigated by FVIII inhibitor testing. No symptoms led to suspicion of inhibitor formation in any patient treated with Nuwiq®. Within the FAS population, inhibitor levels were tested in 40 patients at screening, 44 between screening and completion and 21 at study completion.

FVIII inhibitors will be determined based on clinical observations and confirmed by FVIII inhibitor testing in the laboratory.

Outcome measures

Measure	FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® n=40 Participants FVIII inhibitors detected in the FAS population at screening.	FVIII Inhibitors Detected Between Screening and Completion in Patients Treated With Nuwiq® n=44 Participants FVIII inhibitors detected in the FAS population between screening and study completion	FVIII Inhibitors Detected at Completion in Patients Treated With Nuwiq® (Human-cl rhFVIII) n=21 Participants FVIII inhibitors detected in the FAS population at study completion
Number of Patients With FVIII Inhibitors	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Recorded from screening through to study completion (minimum 1.7 months; maximum 31.6 months)

Adverse drug reactions (ADRs) including hypersensitivity reactions will be recorded by patients in treatment diaries which will be reviewed at each Follow-up Visit.

Outcome measures

Measure	FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® n=78 Participants FVIII inhibitors detected in the FAS population at screening.	FVIII Inhibitors Detected Between Screening and Completion in Patients Treated With Nuwiq® FVIII inhibitors detected in the FAS population between screening and study completion	FVIII Inhibitors Detected at Completion in Patients Treated With Nuwiq® (Human-cl rhFVIII) FVIII inhibitors detected in the FAS population at study completion
Number of Patients With Adverse Drug Reactions	0 Participants	—	—

SECONDARY outcome

Timeframe: Monitored throughout the study from screening through to study completion (minimum 3.7 months; maximum 21.2 months)

Population: Of the 77 participants within the prophylactic treatment group, 74 patients had at least 3 months under a prophylactic regimen and had at least one bleeding episode and were analyzed.

Total number of bleeding episodes under prophylaxis treatment divided by the duration of prophylactic phase (in years)

Outcome measures

Measure	FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® n=252 Number of bleeding episodes FVIII inhibitors detected in the FAS population at screening.	FVIII Inhibitors Detected Between Screening and Completion in Patients Treated With Nuwiq® FVIII inhibitors detected in the FAS population between screening and study completion	FVIII Inhibitors Detected at Completion in Patients Treated With Nuwiq® (Human-cl rhFVIII) FVIII inhibitors detected in the FAS population at study completion
Annualized Rate of Breakthrough Bleeds to Assess Efficacy in Prophylactic Treatment All bleeding events	2.39 Number of bleeding episodes per year Interval 0.0 to 4.87	—	—
Annualized Rate of Breakthrough Bleeds to Assess Efficacy in Prophylactic Treatment Spontaneous bleeding events	0.00 Number of bleeding episodes per year Interval 0.0 to 2.47	—	—
Annualized Rate of Breakthrough Bleeds to Assess Efficacy in Prophylactic Treatment Traumatic bleeding events	0.00 Number of bleeding episodes per year Interval 0.0 to 1.93	—	—

SECONDARY outcome

Timeframe: Monitored throughout the study from screening through to study completion (minimum 1.7 months; maximum 31.6 months)

At the end of a BE, treatment efficacy was to be assessed either by the patient (or the patient's parent or legal guardian) or by the treating physician in case of on-site treatment using a 4-point scale including the four items 'excellent,' 'good,' moderate,' and 'none.' Excellent result was defined as abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection. Good was definite pain relief and/or improvement in signs of bleeding within approximately 8-12 hours after an injection requiring up to 2 injections for complete resolution. Moderate was probable or slight beneficial effect within approximately 12 hours after the first injection requiring more than two injections for complete resolution. None was no improvement after 12 hours, or worsening of symptoms, requiring more than 2 injections for complete resolution.

Outcome measures

Measure	FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® n=55 Number of bleeding episodes FVIII inhibitors detected in the FAS population at screening.	FVIII Inhibitors Detected Between Screening and Completion in Patients Treated With Nuwiq® FVIII inhibitors detected in the FAS population between screening and study completion	FVIII Inhibitors Detected at Completion in Patients Treated With Nuwiq® (Human-cl rhFVIII) FVIII inhibitors detected in the FAS population at study completion
Assessment of the Efficacy of On-demand Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale Excellent	50 Number of Bleeding episodes	—	—
Assessment of the Efficacy of On-demand Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale Good	4 Number of Bleeding episodes	—	—
Assessment of the Efficacy of On-demand Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale Moderate	1 Number of Bleeding episodes	—	—
Assessment of the Efficacy of On-demand Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale None	0 Number of Bleeding episodes	—	—

SECONDARY outcome

Timeframe: From start of surgery until end of post-operative period

Population: A total of 4 patients had 6 surgeries that were treated with Nuwiq®. Two of these surgeries were minor and 4 were major. Five surgeries had an overall efficacy assessment performed jointly by the hematologist and surgeon. One of the six surgeries was treated pre-op with another FVIII product and post-op with Nuwiq® and therefore an assessment of Nuwiq® efficacy could not be performed

At the end of the postoperative period, an overall assessment of the efficacy of treatment in the pre-, peri-, and postoperative periods using the 'excellent,' 'good,' moderate,' and 'none' scale will be done jointly by the surgeon and the hematologist. Based on this assessment, efficacy ratings assessed as either 'excellent' or 'good' will be considered 'successfully treated'.

Outcome measures

Measure	FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® n=5 Surgeries FVIII inhibitors detected in the FAS population at screening.	FVIII Inhibitors Detected Between Screening and Completion in Patients Treated With Nuwiq® FVIII inhibitors detected in the FAS population between screening and study completion	FVIII Inhibitors Detected at Completion in Patients Treated With Nuwiq® (Human-cl rhFVIII) FVIII inhibitors detected in the FAS population at study completion
Overall Assessment of the Effectiveness of Surgical Prophylaxis by the Treating Physicians Excellent	5 Surgeries	—	—
Overall Assessment of the Effectiveness of Surgical Prophylaxis by the Treating Physicians Good	0 Surgeries	—	—
Overall Assessment of the Effectiveness of Surgical Prophylaxis by the Treating Physicians Moderate	0 Surgeries	—	—
Overall Assessment of the Effectiveness of Surgical Prophylaxis by the Treating Physicians None	0 Surgeries	—	—

SECONDARY outcome

Timeframe: Recorded from screening through to study completion (minimum 1.7 months; maximum 31.6 months)

Population: Analysis was only performed on patients in the prophylactic treatment group who experienced bleeding episode that required treatment with Nuwiq. Of the 77 patients in the prophylactic treatment group, 48 patients experienced a BE that required treatment with Nuwiq and were assessed using the 4-point efficacy scale

At the end of a BE, treatment efficacy was to be assessed either by the patient (or the patient's parent or legal guardian) or by the treating physician in case of on-site treatment using a 4-point scale including the four items 'excellent', 'good', 'moderate', and 'none.'

Excellent result was defined as abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection. Good was definite pain relief and/or improvement in signs of bleeding within approximately 8-12 hours after an injection requiring up to 2 injections for complete resolution. Moderate was probable or slight beneficial effect within approximately 12 hours after the first injection requiring more than two injections for complete resolution. None was no improvement after 12 hours, or worsening of symptoms, requiring more than 2 injections for complete resolution.

Outcome measures

Measure	FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® n=246 Number of treated Bleeding episodes FVIII inhibitors detected in the FAS population at screening.	FVIII Inhibitors Detected Between Screening and Completion in Patients Treated With Nuwiq® FVIII inhibitors detected in the FAS population between screening and study completion	FVIII Inhibitors Detected at Completion in Patients Treated With Nuwiq® (Human-cl rhFVIII) FVIII inhibitors detected in the FAS population at study completion
Assessment of the Efficacy of Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale Excellent	167 Bleeding episodes	—	—
Assessment of the Efficacy of Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale Good	50 Bleeding episodes	—	—
Assessment of the Efficacy of Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale Moderate	26 Bleeding episodes	—	—
Assessment of the Efficacy of Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale None	3 Bleeding episodes	—	—

Adverse Events

Nuwiq® (Human-cl rhFVIII) SAF Population

Serious events: 0 serious events

Other events: 0 other events

Deaths: 1 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Sigurd Knaub, Senior VP CR&D Haematology

Octapharma

Phone: 01554512141

Email: Sigurd.Knaub@octapharma.com

Results disclosure agreements

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