A Research Study Looking at How a Factor VIII Medicine Called Turoctocog Alfa Pegol (N8-GP) Works in People With Haemophilia A

Safety and Efficacy of Turoctocog Alfa Pegol (N8-GP) in Prophylaxis and Treatment of Bleeds in Previously N8-GP Treated Patients With Severe Haemophilia A

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03528551

Acronym

pathfinder8

Enrollment

160

Registered

2018-05-18

Start date

2018-04-30

Completion date

2020-12-03

Last updated

2022-12-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Congenital Bleeding Disorder, Haemophilia A

Brief summary

This study will look at how a known study medicine N8-GP works in previously N8-GP treated people with haemophilia A. The aim is to look at how N8-GP works during regular use. Participants will get N8-GP. N8-GP has been tested in more than 200 people with haemophilia A for several years. Participants will get an injection of N8-GP into a blood vessel, one, two or three times weekly. Participants will get more doses if they bleed or if they will need a surgery. The study will last for about 2 years. Participants will have at least 9 visits with the study doctor. If participants agree to be in this study, they will get their first injection (in this study) at the first visit. Participants will also get an injection at visit 3, 5 and 7. Participants will be trained to give all other injections themselves. Participants must not use any clotting factors other than N8-GP or any anticoagulants (blood thinners) during the study.

Interventions

DRUGTuroctocog alfa pegol

Turoctocog alfa pegol 75 IU/kg body weight will be administered once weekly as intravenous injections for a duration of 2 years.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

MALE

Healthy volunteers

Inclusion criteria

* Male patients of all ages with the diagnosis of severe congenital haemophilia A (coagulation Factor VIII \[FVIII\] activity less than 1%) based on medical records * On-going participation in NN7088-3859 (pathfinder2), or NN7088-3885 (pathfinder5) at the time of transfer

Exclusion criteria

* Known or suspected hypersensitivity to trial product including allergy to hamster protein or related products * Any disorder, except for conditions associated with haemophilia, which in the investigator's opinion might jeopardise patient's safety or compliance with the protocol - Current participation in any clinical trial (except NN7088-3859 (pathfinder2) or NN7088-3885 (pathfinder5)) of an approved or non-approved investigational medicinal product

Design outcomes

Primary

Measure	Time frame	Description
Number of Adverse Events Reported	Week 0 to week 108	An adverse event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. All AEs mentioned here are treatment emergent adverse events (TEAEs). The TEAE is defined as an event reported from date of first trial product administration until end of the treatment visit (week 104) or follow-up visit if relevant (1 month after end of the treatment).

Secondary

Measure	Time frame	Description
Number of Bleeding Episodes on Prophylaxis	Week 0 to week 104	Number of bleeding episodes per participant in the prophylaxis regimen was evaluated during 104 weeks.
Number of Spontaneous Bleeding Episodes on Prophylaxis	Week 0 to week 104	Spontaneous bleeding referred as bleeding episodes that occurred without apparent cause. The number of spontaneous bleeding episodes were evaluated during 104 weeks.
Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes Assessed as: Excellent, Good, Moderate, or None	Week 0 to week 104	The haemostatic effect after treatment of a bleed with N8-GP was assessed using a 4-point scale: 'excellent', 'good', 'moderate' or 'none'. The evaluation was done as follows: 1. Excellent: Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection. 2. Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after an injection, but possibly requiring more than one injection for complete resolution. 3. Moderate: Probable or slight beneficial effect within approximately 8 hours after the first injection; usually requiring more than one injection 4. None: No improvement or worsening of symptoms.
Mean Number of N8-GP Injections Required Per Bleeding Episode	Week 0 to week 104	The mean number of N8-GP injections required per bleeding episode from start to stop of a bleed for participants was presented from week 0 to week 104.
Pre-dose FVIII Activity Levels on N8-GP Prophylaxis	Week 0 to week 104	The pre-dose FVIII activity levels were assessed in International units per millilitre (IU/mL) units from week 0 to week 104 to get an estimate of the pre-dose level for N8-GP at steady-state using mixed model.
Number of Participants With Inhibitory Antibodies Against Coagulation Factor VIII (FVIII) ≥0.6 Bethesda Units (BU)	Week 0 to week 104	The Incidence of inhibitors against coagulation factor eight (FVIII) is defined as titre greater than or equal to (≥) 0.6 Bethesda unit. The inhibitor antibodies were measured using a heat modified Nijmegen FVIII Bethesda assay. The number of participants who developed inhibitors against FVIII are reported.
Haemostatic Response During Major Surgical Interventions Assessed as: Excellent, Good, Moderate, or None	Week 0 to week 104	The Haemostatic response to N8-GP during major surgical interventions was assessed using a 4-point scale: 'excellent', 'good', 'moderate' or 'none'. The evaluation was done as follows: 1. Excellent: Better than expected/predicted in this type of procedure. 2. Good: As expected in this type of procedure 3. Moderate: Less than optimal for the type of procedure but haemostatic response maintained without change of treatment regimen 4. None: Bleeding due to inadequate therapeutic response with adequate dosing, change of regimen required. This endpoint was measured from week 0 to week 104.
Consumption of N8-GP Per Bleed	Week 0 to week 104	The average dose of N8-GP consumed for treatment of bleed was assessed in International units per kilogram per bleed(IU/kg/bleed). This endpoint was evaluated from week 0 to week 104.
Consumption of N8-GP During Prophylaxis Treatment	Week 0 to week 104	The average dose of N8-GP consumed for prevention of bleed was assessed. This endpoint was evaluated from week 0 to week 104.
Change From Start Till End of Trial in Treatment Satisfaction (Based on Hemo-SAT Score)	Week 0, Week 104	The treatment satisfaction of a bleed with N8-GP was assessed using HEMO-SAT assessment tool which contains a questionnaire with 6 domains (Ease and convenience, efficacy, burden, specialist/nurses, centre/hospital, general satisfaction), with a scale of 0-100. The lower scores reflecting greater treatment satisfaction. In other words, decrease in the score would mean improvement. The summary of change presented was based on individual changes since week 0. Data is presented for total score.
Change in Joint Health Status From Start to End of Trial (Based on Haemophilia Joint Health Score)	Week 0, Week 104	Haemophilia Joint Health Score is a validated outcome tool developed for the assessment of joint health in patients with hemophilia. It comprises an evaluation of the elbow, knee and ankle joints with regards to swelling, muscular atrophy, crepitation and range of motion, joint pain, strength, motion and axial alignment. The score range is from 0 to 24 points (a score of 0 indicates no joint damage. Higher the score higher the joint damage). Change from week 0 to end of trial (week 104) in the domain scores was presented.

Countries

Australia, Brazil, Canada, Croatia, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Japan, Lithuania, Malaysia, Netherlands, Norway, Portugal, Puerto Rico, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States

Participant flow

Recruitment details

The trial was conducted at 66 sites in 25 countries: Australia(2), Brazil(1), Canada(1), Croatia(1), Denmark(1), France(2), Germany(2), Greece(1), Hungary(2), Israel(1), Italy(2), Japan(3), Korea(1), Lithuania(1), Malaysia(1), Netherlands(2), Norway(1), Portugal(1), Spain(2), Switzerland(4), Taiwan(1), Turkey(5), Ukraine(1), United Kingdom (8), United States (USA) (19).

Pre-assignment details

Out of 160 participants enrolled in this study, 102 came from trial NN7088-3859 and 58 came from trial NN7088-3885. The participants received turoctocog alfa pegol (N8-GP) injections either as once-weekly, twice weekly or three times weekly during the 104 weeks treatment period. Despite 160 participants started the trial, the total number of participants considered are 167 as 2 participants switched to twice weekly and 5 participants switched to three times weekly regimen.

Participants by arm

Arm	Count
N8-GP, Once Weekly Participants received once weekly (dosing every 7 day) prophylaxis doses of N8-GP, 75 IU/kg (International Units per kilogram) intravenous injections for 104 weeks. Participants treated with N8-GP once weekly or were on the on demand regimen in the previous trial NN7088-3859 (pathfinder2) were included in this arm. At the investigator's discretion an intensification of the dosing regimen to twice weekly was allowed if the participant experienced more than 2 bleeds within an 8 week period or experienced a severe bleed requiring hospitalization.	25
N8-GP, Twice Weekly Participants received twice weekly (dosing every 3 and 4 days) prophylaxis doses of N8-GP intravenous injections for 104 weeks: N8-GP, 50 IU/kg for participants aged ≥ 12 years and N8-GP, 60 IU/kg for participants aged \< 12 years. Participants treated with N8-GP in the previous trials NN7088-3859 (pathfinder2) and NN7088-3885 (pathfinder5) were included in this arm. At the investigator's discretion, an intensification of the dosing regimen to thrice weekly was allowed if the participant experienced spontaneous bleeding episodes. Participants in this arm were permitted to switch to three times weekly at any time if clinically justified. Otherwise any treatment regimen was preferably be kept for a minimum of 6 months.	133
N8-GP, Three Times Weekly Participants received three times weekly (dosing every 2, 2 and 3 days) prophylaxis doses of N8-GP, 50 IU/kg as intravenous injections for a duration of 104 weeks. Participants treated with N8-GP in the previous trials NN7088-3859 (pathfinder2) and NN7088-3885 (pathfinder5) were included in this arm. Participants in this arm were permitted to switch to twice weekly at any time if clinically justified. Otherwise any treatment regimen was preferably be kept for a minimum of 6 months.	2
Total	160

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	0	1
Overall Study	Protocol Violation	0	3
Overall Study	Transferred to other arm/group	2	3
Overall Study	Withdrawal by parent/guardian	0	5
Overall Study	Withdrawal by Subject	0	7

Baseline characteristics

Characteristic	N8-GP, Once Weekly	N8-GP, Twice Weekly	N8-GP, Three Times Weekly	Total
Age, Continuous	35.1 Years STANDARD_DEVIATION 12.7	27.3 Years STANDARD_DEVIATION 16.8	25.3 Years STANDARD_DEVIATION 17.8	28.4 Years STANDARD_DEVIATION 16.4
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	8 Participants	0 Participants	8 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	25 Participants	124 Participants	2 Participants	151 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	3 Participants	17 Participants	1 Participants	21 Participants
Race (NIH/OMB) Black or African American	1 Participants	4 Participants	0 Participants	5 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	4 Participants	0 Participants	4 Participants
Race (NIH/OMB) White	21 Participants	108 Participants	1 Participants	130 Participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	25 Participants	133 Participants	2 Participants	160 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 25	1 / 135	0 / 7	1 / 160
other Total, other adverse events	9 / 25	46 / 135	4 / 7	56 / 160
serious Total, serious adverse events	4 / 25	15 / 135	0 / 7	19 / 160

Outcome results

Primary

Number of Adverse Events Reported

An adverse event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. All AEs mentioned here are treatment emergent adverse events (TEAEs). The TEAE is defined as an event reported from date of first trial product administration until end of the treatment visit (week 104) or follow-up visit if relevant (1 month after end of the treatment).

Time frame: Week 0 to week 108

Population: Safety analysis set (SAS) included all enrolled participants who were exposed to the trial product.

Arm	Measure	Value (NUMBER)
N8-GP, Once Weekly	Number of Adverse Events Reported	58 Events
N8-GP, Twice Weekly	Number of Adverse Events Reported	444 Events
N8-GP, Three Times Weekly	Number of Adverse Events Reported	8 Events

Secondary

Change From Start Till End of Trial in Treatment Satisfaction (Based on Hemo-SAT Score)

The treatment satisfaction of a bleed with N8-GP was assessed using HEMO-SAT assessment tool which contains a questionnaire with 6 domains (Ease and convenience, efficacy, burden, specialist/nurses, centre/hospital, general satisfaction), with a scale of 0-100. The lower scores reflecting greater treatment satisfaction. In other words, decrease in the score would mean improvement. The summary of change presented was based on individual changes since week 0. Data is presented for total score.

Time frame: Week 0, Week 104

Population: FAS included all participants exposed to at least one dose of trial product in the current trial. 'Overall Number of Participants Analyzed' = participants with available data. Number analysed = Number of participants who contributed to the analysis. In the N8-GP, once weekly arm; none of the subjects were aged \<=16 years. Hence the number analyzed is mentioned as zero.

Arm	Measure	Group	Value (MEAN)	Dispersion
N8-GP, Once Weekly	Change From Start Till End of Trial in Treatment Satisfaction (Based on Hemo-SAT Score)	Total Score (participants aged >= 17 years)	-4.65 Score on a scale	Standard Deviation 8.16
N8-GP, Twice Weekly	Change From Start Till End of Trial in Treatment Satisfaction (Based on Hemo-SAT Score)	Total Score (participants aged <=16 years)	-1.78 Score on a scale	Standard Deviation 8.54
N8-GP, Twice Weekly	Change From Start Till End of Trial in Treatment Satisfaction (Based on Hemo-SAT Score)	Total Score (participants aged >= 17 years)	-2.11 Score on a scale	Standard Deviation 7.48
N8-GP, Three Times Weekly	Change From Start Till End of Trial in Treatment Satisfaction (Based on Hemo-SAT Score)	Total Score (participants aged >= 17 years)	-12.3 Score on a scale	Standard Deviation 23.78
N8-GP, Three Times Weekly	Change From Start Till End of Trial in Treatment Satisfaction (Based on Hemo-SAT Score)	Total Score (participants aged <=16 years)	1.43 Score on a scale	Standard Deviation 7.31

Secondary

Change in Joint Health Status From Start to End of Trial (Based on Haemophilia Joint Health Score)

Haemophilia Joint Health Score is a validated outcome tool developed for the assessment of joint health in patients with hemophilia. It comprises an evaluation of the elbow, knee and ankle joints with regards to swelling, muscular atrophy, crepitation and range of motion, joint pain, strength, motion and axial alignment. The score range is from 0 to 24 points (a score of 0 indicates no joint damage. Higher the score higher the joint damage). Change from week 0 to end of trial (week 104) in the domain scores was presented.

Time frame: Week 0, Week 104

Population: FAS included all participants exposed to at least one dose of trial product in the current trial. 'Overall Number of Participants Analyzed' = participants with available data.

Arm	Measure	Value (MEAN)	Dispersion
N8-GP, Once Weekly	Change in Joint Health Status From Start to End of Trial (Based on Haemophilia Joint Health Score)	0.238 Score on a scale	Standard Deviation 7.75
N8-GP, Twice Weekly	Change in Joint Health Status From Start to End of Trial (Based on Haemophilia Joint Health Score)	-0.116 Score on a scale	Standard Deviation 7.4
N8-GP, Three Times Weekly	Change in Joint Health Status From Start to End of Trial (Based on Haemophilia Joint Health Score)	-10.0 Score on a scale	Standard Deviation 14.1

Secondary

Consumption of N8-GP During Prophylaxis Treatment

The average dose of N8-GP consumed for prevention of bleed was assessed. This endpoint was evaluated from week 0 to week 104.