Safety and Efficacy of NNC-0156-0000-0009 After Long-Term Exposure in Patients With Haemophilia B: An Extension to Trials NN7999-3747 and NN7999-3773

Safety and Efficacy of NNC-0156-0000-0009 After Long-Term Exposure in Patients With Haemophilia B

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01395810

Acronym

paradigm™ 4

Enrollment

Registered

2011-07-18

Start date

2012-04-15

Completion date

2014-03-30

Last updated

2018-05-09

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

Conditions

Congenital Bleeding Disorder, Haemophilia B

Brief summary

This trial is conducted in Asia, Europe, Japan, North America and South Africa. The aim is to evaluate the safety and efficacy of nonacog beta pegol (NNC-0156-0000-0009) after long-term exposure in patients with haemophilia B. This trial is an extension to trials NN7999-3747 (NCT01333111/paradigm™ 2) and NN7999-3773 (NCT01386528/paradigm™ 3).

Interventions

DRUGnonacog beta pegol

One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

MALE

Age

13 Years to 70 Years

Healthy volunteers

Inclusion criteria

* Previous participation in NN7999-3747 (NCT01333111) and/or NN7999-3773

Exclusion criteria

* Known history of FIX inhibitors based on existing medical records, laboratory report reviews and patient and LAR (legal acceptable representative) interviews * Current FIX inhibitors above or equal to 0.6 BU (Bethesda Units) * Congenital or acquired coagulation disorders other than haemophilia B * Previous arterial thrombotic events (e.g. myocardial infarction and intracranial thrombosis) or previous deep venous thrombosis or pulmonary embolism (as defined by available medical records) * Any disease (liver, kidney, inflammatory and mental disorders included) or condition which, according to the Investigator's (trial physician) judgement, could imply a potential hazard to the patient, interfere with trial participation, or interfere with trial outcome

Design outcomes

Primary

Measure	Time frame	Description
Incidence of Inhibitory Antibodies Against FIX Defined as Titre Above or Equal to 0.6 BU (Bethesda Units)	From Day 1 up to 2 years	The primary endpoint was incidence of inhibitors against coagulation factor nine (FIX) defined as titre ≥0.6 Bethesda unit (BU). Number of subjects who developed inhibitors against FIX are reported.

Secondary

Measure	Time frame	Description
Haemostatic Effect of Nonacog Beta Pegol When Used for Treatment of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate, Poor)	From Day 1 up to 2 years	The haemostatic effect was evaluated by a four-point scale where an excellent or good outcome translated into a successful treatment, and a moderate or poor outcome was considered a treatment failure. The values mentioned below do not include bleeds with missing response.
Number of Bleeding Episodes During Routine Prophylaxis	From Day 1 up to 2 years	Annualized bleeding rate is the total number of bleeding episodes/total exposure time. It is analysed by a Poisson regression model with dose as a factor allowing for over-dispersion and using treatment duration as an offset. Median annualized bleeding rate is the median of individual annualized bleeding rates. Numbers are based on the treatment arm at the time of each bleed.
FIX Trough Levels	From Day 1 up to 2 years	During the trial, the pre-dose FIX levels was measured with the one-stage clotting assay. Measurements taken at least 5 days and no more than 10 days after last dose as well as at least 14 days after last bleeding episode were included in this analysis. The mean FIX trough levels were estimated based on the mixed effects model on the log-transformed plasma concentration with subject as a random effect. The mean FIX trough level was presented back-transformed to the natural scale.
Incidence of Adverse Events (AEs)	From Day 1 up to 2 years	AEs were summarized by frequency of events and frequency of patients with any event. Incidence of AEs was expressed as number of AEs per subject years of exposure (total number of events /total time in trial).
Incidence of Serious Adverse Events (SAEs)	From Day 1 up to 2 years	AEs were summarized by frequency of events and frequency of patients with any event. Incidence of serious AEs was expressed as number of serious AEs per subject years of exposure (total number of events /total time in trial).

Countries

Austria, France, Germany, Greece, Italy, Japan, Malaysia, Netherlands, North Macedonia, Romania, Russia, South Africa, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States

Participant flow

Recruitment details

The trial was conducted at 41 sites in 15 countries as follows: France: 1 site; Germany: 3 sites; Italy: 2 sites; Japan: 4 sites; Macedonia: 2 sites; Malaysia: 1 site; Netherlands: 1 site; Romania: 1 site, Russia: 1 site; South Africa: 1 site; Taiwan: 1 site, Thailand: 2 sites; Turkey: 3 sites; United Kingdom: 5 sites; United States: 13 sites

Pre-assignment details

A total of 71 unique subjects were dosed during this trial. During the trial, subjects were free to switch between treatment arms if agreed between the investigator and the subject. Subjects who switched arms were represented in multiple arms.

Participants by arm

Arm	Count
Prophylaxis 10 IU/kg Subjects were given 10 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	18
Prophylaxis 40 IU/kg Subjects were given 40 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	48
Prophylaxis 80 IU/kg Subjects were dosed with 80 IU/kg every second week. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	0
On-demand Subjects in the on-demand group were administered with the single dose of 40 IU/kg of nonacog beta pegol. The recommended dose for treatment of a mild or moderate bleeding episode, for example a joint bleed, was a single dose of 40 IU/kg nonacog beta pegol. If there was no observed effect of 40 IU/kg, the investigator was to be contacted prior to administration of the second dose of 40 IU/kg. The recommended dose for severe bleeds was 80 IU/kg nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.	5
Total	71

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	0	1
Overall Study	Lack of Efficacy	0	1
Overall Study	Unclassified	2	0
Overall Study	Withdrawal criteria	0	2

Baseline characteristics

Characteristic	Prophylaxis 10 IU/kg	Prophylaxis 40 IU/kg	On-demand	Total	Prophylaxis 80 IU/kg
Age, Continuous	32.2 Years STANDARD_DEVIATION 13.6	31.4 Years STANDARD_DEVIATION 14.4	37.6 Years STANDARD_DEVIATION 15.4	32.0 Years STANDARD_DEVIATION 14.2	—
Age, Customized 13 - 17 years	3 Participants	12 Participants	0 Participants	15 Participants	—
Age, Customized 18 - 70 years	15 Participants	36 Participants	5 Participants	56 Participants	—
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	18 Participants	48 Participants	5 Participants	71 Participants	0 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	— / —	— / —	— / —	— / —
other Total, other adverse events	8 / 21	8 / 52	0 / 2	5 / 5
serious Total, serious adverse events	1 / 21	5 / 52	0 / 2	0 / 5

Outcome results

Primary

Incidence of Inhibitory Antibodies Against FIX Defined as Titre Above or Equal to 0.6 BU (Bethesda Units)

The primary endpoint was incidence of inhibitors against coagulation factor nine (FIX) defined as titre ≥0.6 Bethesda unit (BU). Number of subjects who developed inhibitors against FIX are reported.