Efficacy and Safety of Turoctocog Alfa Pegol (N8-GP) for Prophylaxis and Treatment of Bleeding Episodes in Previously Treated Chinese Patients With Haemophilia A (pathfinder10)

Haemophilia A Clinical Trial

— Pathfinder10  

Official title:

A Multi-centre, Open-label Trial Evaluating Efficacy, Safety and Pharmacokinetics of Turoctocog Alfa Pegol (N8-GP) When Used for Treatment and Prophylaxis of Bleeding Episodes in Previously Treated Chinese Patients With Haemophilia A

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05082116
• Other study ID #: NN7088-4595
• Secondary ID: U1111-1235-59052
• Status: Completed
• Phase: Phase 3
• Start date: September 27, 2021
• Est. completion date: December 28, 2022

Study information

• Verified date: December 2023
• Source: Novo Nordisk A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study investigates how well the medicine called turoctocog alfa pegol (N8-GP) works in previously treated Chinese patients with severe haemophilia A.

Participants will be treated with N8-GP. This is a medicine that doctors can already prescribe in other countries.

The medicine will be injected into a vein (intravenous injections) and blood samples will be collected.

The study will last for about 7-8 months. Participants will have between 8 and 15 visits to the clinic and possibly a number of phone calls with the study doctor.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: December 28, 2022
• Est. primary completion date: December 28, 2022
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

• Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.

• Male Chinese patient with severe congenital haemophilia A with a FVIII activity below 1% according to medical records.

• Aged greater than or equal to 12 years at the time of signing informed consent.

• History of at least 150 exposure days (EDs) to other FVIII products.

• The patient and/or caregiver is capable of assessing a bleeding episode, keeping a diary, performing home treatment of bleeding episodes and otherwise following the trial procedures at the discretion of the investigator.

Exclusion Criteria:

• Known or suspected hypersensitivity to trial product or related products.

• Previous participation in this trial. Participation is defined as signed informed consent.

• Participation in any clinical trial of an approved or non-approved investigational medicinal product within 5 half-lives or 30 days from screening, whichever is longer.

• Known history of FVIII inhibitors based on existing medical records, laboratory report reviews and patient and/or caregiver interviews.

• Current FVIII inhibitors greater than or equal to 0.6 BU.

• Congenital or acquired coagulation disorder other than haemophilia According to medical records.

• HIV positive, defined by medical records, with CD4+ count less than or equal 200/L and a viral load greater than 200 particles/µl or greater than 400000 copies/mL within 6 months of the trial entry. If the data are not available in medical records within last 6 months, then the test must be performed at screening visit.

• Previous significant thromboembolic events (e.g. myocardial infarction, cerebrovascular disease or deep venous thrombosis) as defined by available medical records.

• Hepatic dysfunction defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) greater than 3 times limit of normal combined with total bilirubin greater than 1.5 times the upper limit of normal at screening, as defined by central laboratory

• Renal impairment defined as estimated glomerular filtration rate (eGFR) below or equal to 30 mL/min/1.73 m^2 for serum creatinine measured at screening, as defined by central laboratory.

• Platelet count below 50×109/L at screening based on central laboratory values at screening.

• Ongoing immune modulating or chemotherapeutic medication.

• Any disorder, except for conditions associated with haemophilia A, which in the investigator's opinion might jeopardise the patient's safety or compliance with the protocol.

• Mental incapacity, unwillingness or language barriers precluding adequate understanding or cooperation.

Related Conditions & MeSH terms

• Haemophilia A
• Hemophilia A

Intervention

Drug:
• turoctocog alfa pegol (N8-GP)
N8-GP will be injected into a vein (intravenous injections) every 4 days in at least 28 weeks

Locations

Country	Name	City	State
China	Novo Nordisk Investigational Site	Beijing	Beijing
China	Novo Nordisk Investigational Site	Fuzhou	Fujian
China	Novo Nordisk Investigational Site	Guangzhou	Guangdong
China	Novo Nordisk Investigational Site	Guiyang	Guizhou
China	Novo Nordisk Investigational Site	Jin'an	Shandong
China	Novo Nordisk Investigational Site	Kunming	Yunnan
China	Novo Nordisk Investigational Site	Tianjin	Tianjin
China	Novo Nordisk Investigational Site	Xining	Qinghai

Sponsors (1)

Lead Sponsor	Collaborator
Novo Nordisk A/S

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Bleeding Episodes Per Year (Annualised Bleeding Rate)	Number of bleeding episodes per year (Annualised Bleeding Rate) data is reported. Annualised bleeding rate (ABR) is the number of bleeding episodes per year.	From start of treatment (Week 0) until Week 28
Secondary	Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None)	Haemostatic effect of N8-GP for treatment of bleeding episodes was assessed by 4-point response scale: none, moderate, good or excellent. Evaluation during trial was done by participant and/or parent(s)/caregiver within approximately 8 hours after a single injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hrs after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hrs after a single injection, but possibly requiring more than one injection for complete resolution; Moderate: Probable or slight beneficial effect within approximately 8 hours after the first injection, but usually requiring more than one injection; None: No improvement, or worsening of symptoms.	From start of treatment (Week 0) until Week 28
Secondary	Number of Injections Needed to Treat Bleeding Episodes	The mean number of injections of N8-GP used for treatment of a bleed from start to stop of a bleed was reported.	From start of treatment (Week 0) until Week 28
Secondary	Consumption of N8-GP for Prophylaxis	The mean consumption of N8-GP for prophylaxis per year per participant was reported and it was measured in international units per kilogram per year (IU/kg/year).	From start of treatment (Week 0) until Week 28
Secondary	FVIII Trough Activity During Prophylaxis	Trough levels of FVIII was reported for all participnats who received prophylaxis treatment. Chromogenic assay was performed with N8-GP product specific standard (PSS) as a calibrator. The analysis is based on a mixed model on the log transformed plasma FVIII activity with age group as fixed effect and participant as a random effect. The mean trough is presented back-transformed to the natural scale.	From start of treatment (Week 0) (excluding the first exposure) until Week 28
Secondary	Percentage of Participants With Incidence Rate of Confirmed FVIII Inhibitors =0.6 BU	Percentage of participants who developed inhibitory antibodies against FVIII was presented. A participant was said to have FVIII-inhibitors if two consecutive tests, preferably within 2 weeks, were positive (greater than or equal to (=) 0.6 bethesda unit (BU)). For the calculation of the inhibitor rate the numerator was included for all participants with neutralising antibodies while the denominator was included for all participants with a minimum of 50 exposures plus any participants with less than 50 exposures but with neutralising inhibitor.	From start of treatment (Week 0) until Week 28
Secondary	Number of Adverse Events (AEs)	An adverse event (AE) was defined as any unfavorable 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 presented AEs are treatment-emergent. A treatment-emergent adverse event was defined as an event with onset after first N8-GP administration.	From start of treatment (Week 0) until end of trial (Week 32)
Secondary	Number of Serious Adverse Events (SAEs)	A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, or is life-threatening, or requires inpatient hospitalization or causes prolongation of existing hospitalization results in persistent or significant disability/incapacity, or may have caused a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage. All presented SAEs are treatment-emergent (any serious adverse events which occurred after trial product administration).	From start of treatment (Week 0) until end of trial (Week 32)
Secondary	Incremental Recovery (IR)	The incremental recovery was calculated by subtracting the FVIII activity (IU/mL) measured in plasma at time 0 from that measured at time 30 min after dosing and dividing this difference by the dose injected at time 0 expressed as IU/kg body weight. FVIII activity was measured with a chromogenic assay.	30 min post-injection at Week 0, Week 28
Secondary	FVIII Activity 30 Min Post-injection (C30min)	FVIII plasma activity was measured after 30 mins of injection. FVIII activity was measured with a chromogenic assay.	30 min post-injection at Week 0, Week 28
Secondary	FVIII Trough Activity 96 h Post-injection (C96h)	FVIII plasma activity was measured after 96 h of injection. This was measured at two time points Week 0 and Week 28 during the study. Chromogenic assay was performed.	Single-dose: 96 h ± 8 h post-injection at Week 0, Steady-state: 96 h ± 8 h post-injection at Week 28
Secondary	Area Under the Curve (AUC0-inf)	Area under the plasma activity versus time profile from time zero to infinity (AUC0-inf) was measured.	0-96 hours post-injection at Week 0 and Week 28
Secondary	Area Under the Curve (0-t)	Area under the plasma activity versus time profile from time zero to last measurable activity (AUC0-t) was measured.	0-96 hours post-injection at Week 0 and Week 28
Secondary	Area Under the Curve (0-96h)	Area under the plasma activity versus time profile from time zero to 96 hours (AUC0-96h) was measured.	0-96 hours post-injection at Week 0 and Week 28
Secondary	Accumulation Ratio	Accumulation ratio was calculated as AUC(0-96h) at steady state/AUC(0-96h) at single dose. AUC(0-96) is the area under the plasma activity versus time profile from time zero to 96 hours.	0-96 hours post-injection on Week 28
Secondary	Terminal Half-life (t½)	Terminal half life was calculated as ln(2)/?z; where ?z is the terminal elimination rate constant. The terminal elimination rate constant was estimated using linear regression on the terminal part of the log (activity) versus time profile.	0-96 hours post-injection on Week 0 and Week 28
Secondary	Clearance (CL)	Clearance (CL) of drug after intravenous administration was reported. Clearance was calculated using the formula CL= Dose / AUC(0-inf) for single dose and CL= Dose / AUC(0-96) h for steady state.	Single-dose: 0-96 h post-injection at Week 0, Steady-state: 0-96 h post-injection at Week 28
Secondary	Apparent Volume of Distribution (Vz) Based on the Terminal Phase	Apparent volume of distribution (Vz) based on the terminal phase was measured. Apparent volume of distribution was calculated using formula: total plasma clearance divided by terminal elimination rate constant (Vz= CL/?z).	0-96 hours post-injection on Week 0 and Week 28
Secondary	Apparent Volume of Distribution (Vss) Based on Steady-state	Apparent volume of distribution (Vss) at steady-state was measured. Apparent volume of distribution (Vss) was calculated using formula: total plasma clearance multiplied by mean residence time (Vss=CL*MRT).	0-96 h post-injection at Week 28
Secondary	Extrapolated Area Under the Curve (AUC Percent [%] Extrap	Percentage of AUC(0-inf) determined by extrapolation. It was calulating using formula: Area under the plasma activity versus time profile from given measurable time to infinity (AUCt-inf)/Area under the plasma activity versus time profile from time zero to infinity (AUC0-inf).	0-96 hours post-injection on Week 0 and Week 28
Secondary	Mean Residence Time	Mean residence time (MRT) calculated as area under the first moment plasma concentration-time curve (AUMC [0-inf]) divided by AUC (0-inf). (AUMC [0-inf]) is the area under the first moment plasma concentration-time curve from time 0 to infinity.	0-96 hours post-injection on Week 0 and Week 28
Secondary	Terminal Elimination Rate Constant (?z)	The terminal elimination rate constant was estimated using linear regression on the terminal part of the log(activity) versus time profile.	0-96 hours post-injection on Week 0 and Week 28