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Research Study to Look at How Well the Drug Concizumab Works in Your Body if You Have Haemophilia With Inhibitors (explorer7)

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ClinicalTrials.gov Identifier: NCT04083781
Recruitment Status : Recruiting
First Posted : September 10, 2019
Last Update Posted : April 13, 2021
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Study Description
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Brief 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. The group will be 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 have to inject themselves with study medicine every day under the skin. This 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 three years. Participants will have to come to the clinic for up to 33 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. At all visits, blood samples will be taken. Participants will be asked to record information into an electronic diary during the study and may also be asked to wear an activity tracker.

Condition or disease Intervention/treatment Phase
Haemophilia A With Inhibitors Haemophilia B With Inhibitors Drug: Concizumab Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 136 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients will be randomised to concizumab prophylaxis (ppx) or no ppx or assigned into the non-randomised treatment arms, based on their treatment regimen before entering the trial. The main part of the trial is completed for a patient when the patient has completed at least 24 weeks of participation (screening period not included) for patients in arm 1 or 32 weeks of participation (screening period not included) for patients in arms 2,3 and 4. After the main part of the trial, all patients will be offered to continue in the extension part of the trial and receive treatment with concizumab for up to an additional 128 weeks (arms 2-4) or 136 weeks (arm 1). After up to 128/136 weeks in extension part the patient will enter the safety follow-up part of the trial. The patient will receive his last dose at home on the day of visit 26a (week 160). The follow-up part of the trial lasts for 7 weeks and the patient will continue to report bleeding episodes until visit 27a (week 167).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of Concizumab Prophylaxis in Patients With Haemophilia A or B With Inhibitors
Actual Study Start Date : October 21, 2019
Estimated Primary Completion Date : November 17, 2021
Estimated Study Completion Date : June 20, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm 1: No prophylaxis
Haemophilia A with inhibitors (HAwI) and haemophilia B with inhibitors (HBwI) patients, previously treated on-demand, will be randomised 1:2 to no prophylaxis versus concizumab prophylaxis. In the extension part, patients in arm 1 will receive daily concizumab subcutaneous (s.c., under the skin) injections.
 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).
Experimental: Arm 2: Concizumab prophylaxis
HAwI and HBwI patients, previously treated on-demand, will be randomised 1:2 to no prophylaxis versus concizumab prophylaxis.
 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).
Experimental: Arm 3: Concizumab prophylaxis
The HAwI and HBwI patients enrolled into the concizumab phase 2 trial (NN7415-4310) at time of transfer will be offered enrolment into this trial. It is required that these patients are on concizumab prophylaxis up until enrolment into the trial. These patients will continue concizumab prophylaxis.
 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).
Experimental: Arm 4: Concizumab prophylaxis
Patients previously on prophylaxis with by-passing agents and on-demand patients who are screened at a timepoint where the required number of patients in arms 1 and 2 have been randomised. These patients will, if eligible, be enrolled into the trial and will initiate concizumab prophylaxis at visit 2a (week 0).
 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).


Outcome Measures
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Primary Outcome Measures :
  1. The number of treated spontaneous and traumatic bleeding episodes [ Time Frame: 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) ]
    This will be presented as 'count of episodes'.


Secondary Outcome Measures :
  1. Change in 36 Item short form health survey version 2 (SF36v2) bodily pain [ Time Frame: 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. ]
    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.

  2. Change in SF36v2 physical functioning [ Time Frame: 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. ]
    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.

  3. Number of treated spontaneous bleeding episodes [ Time Frame: 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) ]
    This will be presented as 'count of episodes'.

  4. Number of treated spontaneous and traumatic joint bleeds [ Time Frame: 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) ]
    This will be presented as 'count of episodes'.

  5. Number of treated spontaneous and traumatic target joint bleeds [ Time Frame: 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) ]
    This will be presented as 'count of episodes'.

  6. Number of thromboembolic events [ Time Frame: Timeframe is presented under 'outcome measure description' ]
    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.

  7. Number of thromboembolic events [ Time Frame: 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 (week 167). ]
    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).

  8. Number of hypersensitivity type reactions [ Time Frame: Timeframe is presented under 'outcome measure description' ]
    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.

  9. Number of hypersensitivity type reactions [ Time Frame: 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 (week 167). ]
    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).

  10. Number of injection site reactions [ Time Frame: Timeframe is presented under 'outcome measure description' ]
    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.

  11. Number of injection site reactions [ Time Frame: 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 (week 167). ]
    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).

  12. Number of patients with antibodies to concizumab [ Time Frame: Timeframe is presented under 'outcome measure description' ]
    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.

  13. Number of patients with antibodies to concizumab [ Time Frame: 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 (week 167). ]
    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).

  14. Pre-dose (trough) concizumab plasma concentration (Ctrough) [ Time Frame: Prior to the concizumab administration at week 24 (after restart) ]
    This will be measured in 'ng/mL'.

  15. Pre-dose thrombin peak [ Time Frame: Prior to the concizumab administration at week 24 (after restart) ]
    This will be measured in 'nmol/L'.

  16. Pre-dose free tissue factor pathway inhibitor (TFPI) concentration [ Time Frame: Prior to the concizumab administration at week 24 (after restart) ]
    This will be measured in 'ng/mL'.

  17. Maximum concizumab plasma concentration (Cmax) [ Time Frame: From 0 to 24 hours where 0 is time of the concizumab dose at week 24 (after restart) ]
    This will be measured in 'ng/mL'.

  18. Area under the concizumab plasma concentration-time curve (AUC) [ Time Frame: From 0 to 24 hours where 0 is time of the concizumab dose at week 24 (after restart) ]
    This will be measured in 'ng*hr/mL'.


Eligibility Criteria
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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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.)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04083781


Contacts
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Contact: Novo Nordisk (+1) 866-867-7178 clinicaltrials@novonordisk.com

Locations
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Sponsors and Collaborators
Novo Nordisk A/S
Investigators
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Study Director: Clinical Reporting Anchor and Disclosure (1452) Novo Nordisk A/S
More Information
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Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT04083781    
Other Study ID Numbers: NN7415-4311
U1111-1225-9670 ( Other Identifier: World Health Organization (WHO) )
2018-004889-34 ( Registry Identifier: European Medicines Agency (EudraCT) )
First Posted: September 10, 2019    Key Record Dates
Last Update Posted: April 13, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com
URL: http://novonordisk-trials.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hemophilia A
Hemophilia B
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
 Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Genetic Diseases, X-Linked