A Trial Evaluating the Efficacy and Safety of Prophylactic Administration of Concizumab in Haemophilia A and B Patients With Inhibitors (explorer™4)

A Multi-Centre, Randomised, Open-Label, Controlled Trial Evaluating the Efficacy and Safety of Prophylactic Administration of Concizumab in Haemophilia A and B Patients With Inhibitors

This trial is conducted in Africa, Asia, Europe and North America. The aim of the trial is to assess the efficacy of concizumab administered s.c. (subcutaneously, under the skin) once daily in preventing bleeding episodes in haemophilia A and B patients with inhibitors.

Study Overview

• Status: Completed
• Conditions: Congenital Bleeding Disorder; Haemophilia A With Inhibitors; Haemophilia B With Inhibitors
• Intervention / Treatment: Drug: Concizumab; Drug: Eptacog alfa

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria, 1090
    • Novo Nordisk Investigational Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B 1X1
      • Novo Nordisk Investigational Site
• Croatia
  • Zagreb, Croatia, 10 000
    • Novo Nordisk Investigational Site
• Denmark
  • Århus N, Denmark, 8200
    • Novo Nordisk Investigational Site
• Greece
  • Athens, Greece, GR-11527
    • Novo Nordisk Investigational Site
• Israel
  • Tel-Hashomer, Israel, 52621
    • Novo Nordisk Investigational Site
• Italy
  • Firenze, Italy, 50134
    • Novo Nordisk Investigational Site
  • Milano, Italy, 20124
    • Novo Nordisk Investigational Site
• Japan
  • Aichi, Japan, 466-8560
    • Novo Nordisk Investigational Site
  • Nara, Japan, 634-8522
    • Novo Nordisk Investigational Site
  • Tokyo, Japan, 167-0035
    • Novo Nordisk Investigational Site
• Malaysia
  • Georgetown, Penang, Malaysia, 10450
    • Novo Nordisk Investigational Site
  • Kota Kinabalu, Malaysia, 88586
    • Novo Nordisk Investigational Site
• Spain
  • Madrid, Spain, 28046
    • Novo Nordisk Investigational Site
  • Sevilla, Spain, 41013
    • Novo Nordisk Investigational Site
• Sweden
  • Solna, Sweden, 171 64
    • Novo Nordisk Investigational Site
• Ukraine
  • Lviv, Ukraine, 79044
    • Novo Nordisk Investigational Site
• United Kingdom
  • London, United Kingdom, SE1 7EH
    • Novo Nordisk Investigational Site
  • Sheffield, United Kingdom, S10 2JF
    • Novo Nordisk Investigational Site
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Novo Nordisk Investigational Site
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Novo Nordisk Investigational Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 the suitability for the trial - Male haemophilia A or B patients with inhibitors aged 18 years or older at the time of signing informed consent - Patients currently in need of treatment with bypassing agents Exclusion Criteria: - Known or suspected hypersensitivity to trial product(s) or related products - Known inherited or acquired bleeding disorder other than haemophilia - Ongoing or planned immune tolerance induction therapy or prophylaxis with FVIII or FIX

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Concizumab; Concizumab administered in both the main phase and extension phase, with eptacog alfa administered on-demand during bleeding episodes	Drug: Concizumab; A loading dose of 0.5 mg/kg will be given as the first dose, followed by 0.15 mg/kg (with potential stepwise dose escalation to 0.25 mg/kg) administered daily s.c. (subcutaneously, under the skin). Treatment duration is 24 weeks in the main trial, and up to 52 weeks in the extension phase; Drug: Eptacog alfa; A single dose of 90 μg/kg eptacog alfa one week after dosing with concizumab. On-demand treatment during bleeding episodes in both treatment arms
ACTIVE_COMPARATOR: Eptacog alfa and concizumab; Eptacog alfa administered on-demand during bleeding episodes as the only intervention during the main phase. Concizumab given in the extension phase	Drug: Concizumab; A loading dose of 0.5 mg/kg will be given as the first dose, followed by 0.15 mg/kg (with potential stepwise dose escalation to 0.25 mg/kg) administered daily s.c. (subcutaneously, under the skin). Treatment duration is 24 weeks in the main trial, and up to 52 weeks in the extension phase; Drug: Eptacog alfa; A single dose of 90 μg/kg eptacog alfa one week after dosing with concizumab. On-demand treatment during bleeding episodes in both treatment arms

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Bleeding Episodes	The number of bleeding episodes that were treated during at least 24 weeks from treatment onset (week 0) are presented.	During at least 24 weeks from treatment onset (week 0)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Bleeding Episodes	The number of bleeding episodes that were treated during at least 76 weeks from treatment onset (week 0) are presented. This outcome measure is applicable for only 'Concizumab' treatment arm.	During at least 76 weeks from treatment onset (week 0)
The Number of Spontaneous Bleeding Episodes	Bleeds that were not linked to a specific, known action or event are called spontaneous bleeding episodes. The number of spontaneous bleeding episodes that were treated during at least 24 weeks from treatment onset (week 0) are presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 24 weeks from treatment onset (week 0)
The Number of Spontaneous Bleeding Episodes	Bleeds that were not linked to a specific, known action or event are called spontaneous bleeding episodes. The number of spontaneous bleeding episodes that were treated during at least 76 weeks from treatment onset (week 0) are presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 76 weeks from treatment onset (week 0)
Number of Treatment-emergent Adverse Events (TEAEs) During at Least 24 Weeks From Treatment Onset	An adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal product, and which does not necessarily had a causal relationship with this treatment. A TEAE was defined as an event that had onset from the first exposure to treatment until the last visit in the trial. Number of TEAEs that occurred during at least 24 weeks from treatment onset (week 0) are presented. The data is presented per the dose level which the participants have reached at the time of event.	During at least 24 weeks from treatment onset (week 0)
Number of Treatment-emergent Adverse Events (TEAEs) During at Least 76 Weeks From Treatment Onset	An adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal product, and which does not necessarily had a causal relationship with this treatment. A TEAE was defined as an event that had onset from the first exposure to treatment until the last visit in the trial. Number of TEAEs that occurred during at least 76 weeks from treatment onset (week 0) are presented. The data is presented per the dose level which the participants have reached at the time of event.	During at least 76 weeks from treatment onset (week 0)
Number of Treatment-emergent Adverse Events (TEAEs) Within 24 Hours After Eptacog Alfa Administration	An adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal product, and which does not necessarily had a causal relationship with this treatment. A TEAE was defined as an event that had onset from the first exposure to treatment until the last visit in the trial. Number of TEAEs that occurred within 24 hours after eptacog alfa administration are presented. This outcome measure is applicable only for 'Eptacog alfa' treatment arm.	Within 24 hours after eptacog alfa administration
Occurrence of Anti-concizumab Antibodies During at Least 24 Weeks From Treatment Onset	Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset (week 0) is presented. This outcome measure is applicable for only 'Concizumab' treatment arm.	During at least 24 weeks from treatment onset (week 0)
Occurrence of Anti-concizumab Antibodies During at Least 76 Weeks From Treatment Onset	Occurrence of anti-concizumab antibodies during at least 76 weeks from treatment onset (week 0) is presented. This outcome measure is applicable for only 'Concizumab' treatment arm.	During at least 76 weeks from treatment onset (week 0)
Change in Fibrinogen	Change in fibrinogen during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 24 weeks from treatment onset (week 0)
Change in Fibrinogen	Change in fibrinogen during at least 76 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 76 weeks from treatment onset (week 0)
Change in D-dimer	Change in D-dimer during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 24 weeks from treatment onset (week 0)
Change in D-dimer	Change in D-dimer during at least 76 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 76 weeks from treatment onset (week 0)
Change in Prothrombin Fragment 1 + 2 (F1 + 2)	Change in F1 + 2 during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 24 weeks from treatment onset (week 0)
Change in Prothrombin Fragment 1 + 2 (F1 + 2)	Change in F1 + 2 during at least 76 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 76 weeks from treatment onset (week 0)
Change in Prothrombin Time (PT)	Change in PT during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 24 weeks from treatment onset (week 0)
Change in Prothrombin Time (PT)	Change in PT during at least 76 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 76 weeks from treatment onset (week 0)
Change in Activated Partial Thromboplastin Time (APTT)	Change in APTT during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 24 weeks from treatment onset (week 0)
Change in Activated Partial Thromboplastin Time (APTT)	Change in APTT during at least 76 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 76 weeks from treatment onset (week 0)
Change in Anti-thrombin (AT)	Change in AT during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	During at least 24 weeks from treatment onset (week 0)
Change in Anti-thrombin (AT)	Change in AT after at least 76 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	After at least 76 weeks from treatment onset (week 0)
Concentration of Concizumab	Concentration of concizumab prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	Prior to the last dose administration at 24 weeks
Concentration of Concizumab	Concentration of concizumab prior to the last dose administration after atleast 76 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	Prior to the last dose administration after atleast 76 weeks
Free Tissue Factor Pathway Inhibitor (TFPI) Concentration Value	Free TFPI (TFPI not bound to concizumab) concentration value prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	Prior to the last dose administration at 24 weeks
Free Tissue Factor Pathway Inhibitor (TFPI) Concentration Value	Free TFPI concentration value prior to the last dose administration after atleast 76 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	Prior to the last dose administration after atleast 76 weeks
Peak Thrombin Generation	Peak thrombin generation is the maximal concentration of thrombin formed at a given point in time. Peak thrombin generation prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	Prior to the last dose administration at 24 weeks
Peak Thrombin Generation	Peak thrombin generation is the maximal concentration of thrombin formed at a given point in time. Peak thrombin generation prior to the last dose administration after atleast 76 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	Prior to the last dose administration after atleast 76 weeks
Endogenous Thrombin Potential	Endogenous thrombin potential prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	Prior to the last dose administration at 24 weeks
Endogenous Thrombin Potential	Endogenous thrombin potential prior to the last dose administration after at least 76 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	Prior to the last dose administration after atleast 76 weeks
Thrombin Generation Velocity Index	Thrombin generation velocity index prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	Prior to the last dose administration at 24 weeks
Thrombin Generation Velocity Index	Thrombin generation velocity index prior to the last dose administration after at least 76 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.	Prior to the last dose administration after atleast 76 weeks

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Shapiro AD, Angchaisuksiri P, Astermark J, Benson G, Castaman G, Eichler H, Jimenez-Yuste V, Kavakli K, Matsushita T, Poulsen LH, Wheeler AP, Young G, Zupancic-Salek S, Oldenburg J, Chowdary P. Long-term efficacy and safety of subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors. Blood Adv. 2022 Jun 14;6(11):3422-3432. doi: 10.1182/bloodadvances.2021006403.
• Shapiro AD, Angchaisuksiri P, Astermark J, Benson G, Castaman G, Chowdary P, Eichler H, Jimenez-Yuste V, Kavakli K, Matsushita T, Poulsen LH, Wheeler AP, Young G, Zupancic-Salek S, Oldenburg J. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood. 2019 Nov 28;134(22):1973-1982. doi: 10.1182/blood.2019001542.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 10, 2017
• Primary Completion (ACTUAL): September 19, 2018
• Study Completion (ACTUAL): January 31, 2020

Study Registration Dates

• First Submitted: June 20, 2017
• First Submitted That Met QC Criteria: June 20, 2017
• First Posted (ACTUAL): June 22, 2017

Study Record Updates

• Last Update Posted (ACTUAL): October 22, 2021
• Last Update Submitted That Met QC Criteria: September 24, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Hemostatic Disorders; Hemophilia A; Hemophilia B; Blood Coagulation Disorders
• Other Study ID Numbers: NN7415-4310; U1111-1179-2925 (OTHER: World Health Organization (WHO)); 2016-000510-30 (EUDRACT_NUMBER); JapicCTI-173681 (REGISTRY: JAPIC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: According to disclosure commitment on novonordisk-trials.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No