Research Study to Look at How Well the Drug Concizumab Works in Your Body if You Have Haemophilia With Inhibitors

Haemophilia A With Inhibitors Clinical Trial

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Official title:

Efficacy and Safety of Concizumab Prophylaxis in Patients With Haemophilia A or B With Inhibitors

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04083781
• Other study ID #: NN7415-4311
• Secondary ID: U1111-1225-96702
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 21, 2019
• Est. completion date: December 31, 2025

Study information

• Verified date: March 2024
• Source: Novo Nordisk A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will test how well a new medicine called concizumab works in the body of people with haemophilia A or B with inhibitors. The purpose is to show that concizumab can prevent bleeds in the body and is safe to use. Participants who usually only take medicine to treat bleeds (on-demand) will be placed in one of two groups. In one group, participants will get study medicine from the start of the study. In the other group, participants will continue with their normal medicine and get study medicine after 6 months. Which treatment the participant gets is decided by chance. Participants who usually take medicine to prevent bleeds (prophylaxis treatment) or who are already being treated with concizumab (study medicine) will receive the study medicine from the start of the study. Participants will get 1 injection with the study medicine every day under the skin. This participants will have to do themselves and can be done at home. The study doctor will hand out the medicine in the form of a pen-injector. The pen-injector will contain the study medicine. The study will last for about six years. The length of time the participants will be in the study depends on when they agreed to take part or when the medicine is available for purchase in their country (12 November 2025 at the latest). Participants will have to come to the clinic for up to 41 times. The time between visits will be approximately 4 weeks for the first 6 to 12 months, depending on the group participants are in and approximately 8 weeks for the rest of the study. Participants will be asked to record information into an electronic diary during the study and may also be asked to wear an activity tracker.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 136
• Est. completion date: December 31, 2025
• Est. primary completion date: December 27, 2021
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A 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 aged 12 years or older at the time of signing informed consent.
• Congenital Haemophilia A or B of any severity with documented history of inhibitor (equal to or above 0.6 Bethesda Units (BU).
• Patient has been prescribed, or in need of, treatment with bypassing agents in the last 24 weeks prior to screening (for patients not previously enrolled in NN7415-4310 (explorer 4)).

Exclusion Criteria:

• Known or suspected hypersensitivity to any constituent of the trial product or related products.
• Known inherited or acquired coagulation disorder other than congenital haemophilia.
• Ongoing or planned Immune Tolerance Induction treatment.
• History of thromboembolic disease (includes arterial and venous thrombosis including myocardial infarction, pulmonary embolism, cerebral infarction/thrombosis, deep vein thrombosis, other clinically significant thromboembolic events and peripheral artery occlusion). Current clinical signs of, or treatment for thromboembolic disease. Patients who in the judgement of the investigator are considered at high risk of thromboembolic events (thromboembolic risk factors could include, but are not limited to, hypercholesterolemia, diabetes mellitus, hypertension, obesity, smoking, family history of thromboembolic events, arteriosclerosis, other conditions associated with increased risk of thromboembolic events.)

Related Conditions & MeSH terms

• Haemophilia A With Inhibitors
• Haemophilia B With Inhibitors
• Hemophilia A
• Hemophilia B

Intervention

Drug:
• Concizumab
Concizumab will be administered daily subcutaneously (s.c., under the skin). When patients are randomised to concizumab prophylaxis they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week 0: arm 2, 3 & 4) or visit 9a (week 24: arm 1) followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5-8-week dose adjustment period on 0.20 mg/kg concizumab, the patients can be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab. A potential dose adjustment will take place at visit 4a.1 (week 6: arm 2, 3 & 4) or 9a.3 (week 30: arm 1) and will be based on the concizumab exposure level measured at the previous visit 4a (week 4) or 9a.2 (week 28). Patients who have concizumab exposure levels of 200-4000 ng/mL will stay at 0.20 mg/kg concizumab. Patients in arm 1 will continue on-demand treatment with their usual bypassing product until visit 9a (week 24: end of main part for arm 1).

Locations

Country	Name	City	State
Algeria	Haematology and Blood Bank Department	Algiers
Algeria	CHU Constantine IBN BADIS/ Hematology department	Constantine
Australia	The Alfred	Melbourne	Victoria
Australia	Fiona Stanley Hospital - Haemophilia and Haemostasis Centre	Murdoch	Western Australia
Austria	Klin. Abt. f. Hämatologie und Hämostaseologie, AKH Wien	Wien
Bulgaria	UMHAT "Tsaritsa Yoanna-ISUL"	Sofia
Croatia	KBC Zagreb, Rebro, Hemofilija centar	Zagreb
Croatia	KBC Zagreb, Zavod za pedijatrijsku hematologiju	Zagreb
Czechia	Fakultni nemocnice v Motole	Praha
Czechia	Ustav Hematologie a krevni tranfuze	Praha 2
Denmark	Skejby Blodsygdomme, blødercentret	Aarhus N
France	Hospices Civils de Lyon-Hopital Cardiologique Louis Pradel-1	Bron
France	Centre Hospitalier de Clermont-Ferrand-Hopital Estaing	Clermont-Ferrand
France	Ap-Hp-Hopital de Bicetre-1	Le Kremlin-Bicetre
France	Centre Hospitalier Universitaire de Rennes - Hopital Pontchaillou	Rennes
India	St. John's Medical college and Hospital	Bangalore	Karnataka
India	All India Institute of Medical Sciences_New Dehli	New Dehli	New Delhi
India	Sahyadri Speciality Hospital	Pune	Maharashtra
India	Sahyadri Super Speciality Hospital	Pune	Maharashtra
India	CMCV	Ranipet	Tamil Nadu
Italy	Oncoematologia IOV	Castelfranco Veneto
Italy	Dipartimento di Ematologia Univ. Firenze	Firenze	FI
Italy	Istituto di Medicina Int. A. Bianchi Bonomi Univ. Milano	Milano
Italy	Azienda OU "S.Maria della Misericordia"	Udine
Italy	Ospedale Donna Bambino U.O.C. Oncoematologia Pediatrica	Verona
Japan	Nagoya University Hospital_Blood Transfusion	Aichi
Japan	Kagoshima City Hospital	Kagoshima
Japan	St. Marianna University School of Medicine Hospital_Pediatrics	Kanagawa
Japan	Nara Medical University Hospital_Pediatrics	Nara
Japan	Saitama Medical Univ. Hospital	Saitama
Japan	Ogikubo Hospital_Pediatries & Blood	Tokyo
Korea, Republic of	Daejeon Eulji Medical Center, Eulji University	Daejeon
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Malaysia	Hospital Ampang	Ampang, Selangor
Malaysia	Hospital Pulau Pinang_Georgetown, Penang	Georgetown, Penang
Malaysia	Hospital Queen Elizabeth 1	Kota Kinabalu	Sabah
Mexico	Hospital Universitario Dr. José Eleuterio González	Monterrey	Nuevo León
Norway	Rikshospitalet - avdeling for blodsykdommer	Oslo
Poland	Szpital Uniwersytecki, Oddzial Kliniczny Hematologii	Kraków	Malopolskie
Poland	SPSK nr 1 Klinika Hematoonkologii i Transplantacji Szpiku	Lublin
Poland	Intytut Hematologii i Transfuzjologii	Warszawa	Mazowieckie
Poland	Uniwersytecki Szpital Kliniczny Im. Jana Mikulicza-Radeckiego We Wroclawiu	Wroclaw
Portugal	Centro Hospitalar de São João_Porto	Porto
Russian Federation	Children Regional Clinical Hospital	Krasnodar
Russian Federation	Morozovskaya municipal children hospital	Moscow
Russian Federation	National Medical Research institution of haemotology	Moscow
Russian Federation	Republican Hospital n.a. V. A. Baranov	Petrozavodsk
Russian Federation	City out-patient clinic 37, City Hemophilia Centre	Saint-Petersburg
Serbia	University Clinical Centre Kragujevac	Kragujevac
Slovakia	Nemocnica sv. Cyrila a Metoda, UNB,Klinika hemat. a transfuz	Bratislava
South Africa	Haematology Clinic	Durban	KwaZulu-Natal
South Africa	Charlotte Maxeke Johannesburg Academic Hospital	Parktown, Johannesburg	Gauteng
South Africa	Pietersburg Hospital	Polokwane	Limpopo
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Regional de Málaga	Málaga
Spain	Hospital Central de Asturias	Oviedo
Spain	Hospital Virgen del Rocío	Sevilla
Sweden	Koagulationsmottagning	Malmö
Sweden	Koagulationsmottagningen	Solna
Thailand	Ramathibodi Hospital_Bangkok_0	Bangkok
Thailand	Hematology and Oncology, Dept.of Pediatrics, CMU	Chiang Mai
Thailand	Sunpasitthiprasong Hospital	Ubon Ratchathani
Turkey	Acibadem Adana Hastanesi	Adana
Turkey	Cukurova Universitesi	Adana
Turkey	Akdeniz Universitesi	Antalya
Turkey	Istanbul University Oncology Institute	Capa-ISTANBUL
Ukraine	National specialized children clinic "OHMATDYT"	Kyiv
Ukraine	Institute of blood pathology and transfusion medicine	Lviv
United Kingdom	West Midlands Adult Comprehensive Care Haemophilia	Birmingham
United Kingdom	Great Ormond Street Hospital for Children	London
United Kingdom	Royal Hallamshire Hospital	Sheffield
United States	Emory University_Atlanta_1	Atlanta	Georgia
United States	St. Jude Affiliate Clinic at Novant Health Hemby Children's	Charlotte	North Carolina
United States	Indiana Hemophilia-Thromb Ctr	Indianapolis	Indiana
United States	TriStar Medical Group Children's Specialist	Nashville	Tennessee
United States	Center for Inherited Blood Dis	Orange	California
United States	Washington University School of Medicine_St. Louis	Saint Louis	Missouri
United States	University of Texas San Antonio	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Novo Nordisk A/S

Countries where clinical trial is conducted

United States,  Algeria,  Australia,  Austria,  Bulgaria,  Croatia,  Czechia,  Denmark,  France,  India,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Mexico,  Norway,  Poland,  Portugal,  Russian Federation,  Serbia,  Slovakia,  South Africa,  Spain,  Sweden,  Thailand,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The number of treated spontaneous and traumatic bleeding episodes	This will be presented as 'count of episodes'.	On demand (arm 1): From randomisation (week 0) up until start of concizumab treatment (at least 24 weeks). Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the primary analysis cut-off (at least 32 weeks)
Secondary	Change in 36 Item short form health survey version 2 (SF36v2) bodily pain	This will be presented as 'score on a scale'. The bodily pain subscale of the SF-36v2 questionnaire consists of 2 items. Subscale scores range from 0-100 and are transformed into population norm adjusted T-scores. A higher score indicates a better outcome on this subscale.	From start of treatment (week 0) until week 24. Week 0 is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen.
Secondary	Change in SF36v2 physical functioning	This will be presented as 'score on a scale'. The physical function subscale of the SF-36v2 questionnaire consists of 1 item with 10 subitems. Subscale scores range from 0-100 and are transformed into population norm adjusted T-scores. A higher score indicates a better outcome on this subscale.	From start of treatment (week 0) until week 24. Week 0 is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen.
Secondary	Number of treated spontaneous bleeding episodes	This will be presented as 'count of episodes'.	On demand (arm 1): From randomisation (week 0) up until start of concizumab treatment (at least 24 weeks) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the primary analysis cut-off (at least 32 weeks)
Secondary	Number of treated spontaneous and traumatic joint bleeds	This will be presented as 'count of episodes'.	On demand (arm 1): From randomisation (week 0) up until start of concizumab treatment (at least 24 weeks) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the primary analysis cut-off (at least 32 weeks)
Secondary	Number of treated spontaneous and traumatic target joint bleeds	This will be presented as 'count of episodes'.	On demand (arm 1): From randomisation (week 0) up until start of concizumab treatment (at least 24 weeks) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the primary analysis cut-off (at least 32 weeks)
Secondary	Number of thromboembolic events	This will be presented as 'count of thromboembolic events'. On demand (arm 1 main part): From randomisation to on demand treatment up until start of concizumab treatment. Concizumab (arms 2-4): Before the pause: From start of concizumab treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment (week 0) up until the primary analysis cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of the new concizumab dosing regimen (week 25) up until the primary analysis cut-off. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day). Week 0, after the pause is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen.	Timeframe is presented under 'outcome measure description'
Secondary	Number of thromboembolic events	This will be presented as 'count of thromboembolic events'. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day).	Concizumab: Before the pause: From start of treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment up until the end of trial (up to 280 weeks).
Secondary	Number of hypersensitivity type reactions	This will be presented as 'count of hypersensitivity type reactions'. On demand (arm 1 main part): From randomisation to on demand treatment up until start of concizumab treatment. Concizumab (arms 2-4): Before the pause: From start of concizumab treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment (week 0) up until the primary analysis cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of the new concizumab dosing regimen (week 25) up until the primary analysis cut-off. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day). Week 0, after the pause is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen.	Timeframe is presented under 'outcome measure description'
Secondary	Number of hypersensitivity type reactions	This will be presented as 'count of hypersensitivity type reactions'. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day).	Concizumab: Before the pause: From start of treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment up until the end of trial (up to 280 weeks).
Secondary	Number of injection site reactions	This will be presented as 'count of injection site reactions'. On demand (arm 1 main part): From randomisation to on demand treatment up until start of concizumab treatment. Concizumab (arms 2-4): Before the pause: From start of concizumab treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment (week 0) up until the primary analysis cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of the new concizumab dosing regimen (week 25) up until the primary analysis cut-off. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day). Week 0, after the pause is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen.	Timeframe is presented under 'outcome measure description'
Secondary	Number of injection site reactions	This will be presented as 'count of injection site reactions'. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day).	Concizumab: Before the pause: From start of treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment up until the end of trial (up to 280 weeks).
Secondary	Number of patients with antibodies to concizumab	This will be presented as 'count of patients'. Concizumab (arms 2-4): Before the pause: From start of concizumab treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment (week 0) up until the primary analysis cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of the new concizumab dosing regimen (week 25) up until the primary analysis cut-off. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day). Week 0, after the pause is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen.	Timeframe is presented under 'outcome measure description'
Secondary	Number of patients with antibodies to concizumab	This will be presented as 'count of patients'. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day).	Concizumab: Before the pause: From start of treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment up until the end of trial (up to 280 weeks).
Secondary	Pre-dose (trough) concizumab plasma concentration (Ctrough)	This will be measured in 'ng/mL'.	Prior to the concizumab administration at week 24 (after restart)
Secondary	Pre-dose thrombin peak	This will be measured in 'nmol/L'.	Prior to the concizumab administration at week 24 (after restart)
Secondary	Pre-dose free tissue factor pathway inhibitor (TFPI) concentration	This will be measured in 'ng/mL'.	Prior to the concizumab administration at week 24 (after restart)
Secondary	Maximum concizumab plasma concentration (Cmax)	This will be measured in 'ng/mL'.	From 0 to 24 hours where 0 is time of the concizumab dose at week 24 (after restart)
Secondary	Area under the concizumab plasma concentration-time curve (AUC)	This will be measured in 'ng*hr/mL'.	From 0 to 24 hours where 0 is time of the concizumab dose at week 24 (after restart)