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Research Study to Look at How Well the Drug Concizumab Works in Your Body if You Have Haemophilia Without Inhibitors (explorer8)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04082429
Recruitment Status : Recruiting
First Posted : September 9, 2019
Last Update Posted : July 19, 2021
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Brief Summary:
This study will test how well a new medicine called concizumab works in the body of people with haemophilia A or B without 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 12months 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 Without Inhibitors Haemophilia B Without Inhibitors Drug: Concizumab Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 158 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 before the trial. Upon restart, patients who were randomised to arms 1/2 before the pause will enter arm 4. Patients who were allocated to arms 3 & 4 before the pause will re-enter the arm they were initially allocated to. The randomisation into arms 1/2 will be restarted with new patients. The main part of the trial is completed for a patient when the patient completed 24 wks (excluding screening) in arm 1 or 32 wks (excluding screening) in arms 2-4. After the main part, all patients will be offered to continue in the extension part of the trial and receive concizumab for up to an additional 128 wks (arms 2-4) or 136 wks (arm 1). The patient will receive his last dose at home on the day of visit 26a (Wk 160). The follow-up part of the trial lasts for 7 wks and the patient will continue to report bleeding episodes until visit 27a (Wk 167).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of Concizumab Prophylaxis in Patients With Haemophilia A or B Without Inhibitors
Actual Study Start Date : November 13, 2019
Estimated Primary Completion Date : May 19, 2022
Estimated Study Completion Date : December 19, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

Arm Intervention/treatment
Experimental: Arm 1: No prophylaxis
Haemophilia A (HA) and haemophilia B (HB) patients, previously treated on-demand, will be randomised 1:2 to no prophylaxis versus concizumab prophylaxis. In the extension phase, this group will receive treatment with concizumab.
Drug: Concizumab
When patients are randomised/allocated to concizumab prophylaxis, they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week (Wk) 0) (arm 2, 3 and 4) or visit 9a (Wk 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 (Wk 6) or 9a.3 (Wk 30) and will be based on the concizumab exposure level measured at the previous visit 4a (Wk 6) or 9a.2 (Wk 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 replacement therapy until visit 9a (week 24; end of main part). In the extension part, patients in arm 1 will receive daily concizumab subcutaneous injections.

Experimental: Arm 2: Concizumab prophylaxis
HA and HB patients, previously treated on-demand, will be randomised 1:2 to no prophylaxis versus concizumab prophylaxis.
Drug: Concizumab
When patients are randomised/allocated to concizumab prophylaxis, they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week (Wk) 0) (arm 2, 3 and 4) or visit 9a (Wk 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 (Wk 6) or 9a.3 (Wk 30) and will be based on the concizumab exposure level measured at the previous visit 4a (Wk 6) or 9a.2 (Wk 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 replacement therapy until visit 9a (week 24; end of main part). In the extension part, patients in arm 1 will receive daily concizumab subcutaneous injections.

Experimental: Arm 3: Concizumab prophylaxis
The HA patients enrolled into the concizumab phase 2 trial NN7415-4255 (explorer 5) will be offered enrolment into this arm.
Drug: Concizumab
When patients are randomised/allocated to concizumab prophylaxis, they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week (Wk) 0) (arm 2, 3 and 4) or visit 9a (Wk 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 (Wk 6) or 9a.3 (Wk 30) and will be based on the concizumab exposure level measured at the previous visit 4a (Wk 6) or 9a.2 (Wk 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 replacement therapy until visit 9a (week 24; end of main part). In the extension part, patients in arm 1 will receive daily concizumab subcutaneous injections.

Experimental: Arm 4: Concizumab prophylaxis

Arm 4 will include patients previously on prophylaxis with factor products with a minimum of 24 weeks observation in NN7415-4322 (explorer 6) (at least 30 HA and 30 HB patients).

In addition, arm 4 will also include: 1) Patients who were randomised to arms 1 and 2 before the treatment pause. 2) HA patients who were in NN7415-4255 (explorer 5) at the time of the treatment pause, and who have now completed explorer 5. 3) On demand patients included after arms 1 and 2 are closed.

Drug: Concizumab
When patients are randomised/allocated to concizumab prophylaxis, they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week (Wk) 0) (arm 2, 3 and 4) or visit 9a (Wk 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 (Wk 6) or 9a.3 (Wk 30) and will be based on the concizumab exposure level measured at the previous visit 4a (Wk 6) or 9a.2 (Wk 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 replacement therapy until visit 9a (week 24; end of main part). In the extension part, patients in arm 1 will receive daily concizumab subcutaneous injections.




Primary Outcome Measures :
  1. For haemophilia A patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes [ Time Frame: On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) ]
    This will be presented as 'count of episodes'.

  2. For haemophilia B patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes [ Time Frame: On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) ]
    This will be presented as 'count of episodes'.


Secondary Outcome Measures :
  1. For haemophilia A patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes [ Time Frame: Time frame is presented under 'outcome measure description' ]
    This will be presented as 'count of episodes'. Arm 4 patients who have been on stable PPX at least 24 weeks in study 4322. For previous PPX (study 4322): From the point in time where PPX is stable and up until the end of study. Stable is defined as the time after an initial period on PPX treatment of at least 24 weeks. For concizumab PPX (trial 4307): From the point in time where the concizumab maintenance dose is confirmed, increased or decreased and up until the confirmatory analyses cut-off (at least 24 weeks).

  2. For haemophilia B patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes [ Time Frame: Time frame is presented under 'outcome measure description' ]
    This will be presented as 'count of episodes'. Arm 4 patients who have been on stable PPX at least 24 weeks in study 4322. For previous PPX (study 4322): From the point in time where PPX is stable and up until the end of study. Stable is defined as the time after an initial period on PPX treatment of at least 24 weeks. For concizumab PPX (trial 4307): From the point in time where the concizumab maintenance dose is confirmed, increased or decreased and up until the confirmatory analyses cut-off (at least 24 weeks).

  3. For haemophilia A patients without inhibitors: Number of treated spontaneous bleeding episodes [ Time Frame: On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) ]
    This will be presented as 'count of episodes'.

  4. For haemophilia B patients without inhibitors: Number of treated spontaneous bleeding episodes [ Time Frame: On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) ]
    This will be presented as 'count of episodes'.

  5. For haemophilia A patients without inhibitors: Number of treated spontaneous and traumatic joint bleeds [ Time Frame: On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) ]
    This will be presented as 'count of episodes'.

  6. For haemophilia B patients without inhibitors: Number of treated spontaneous and traumatic joint bleeds [ Time Frame: On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) ]
    This will be presented as 'count of episodes'.

  7. For haemophilia A patients without inhibitors: Number of treated spontaneous and traumatic target joint bleeds [ Time Frame: On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) ]
    This will be presented as 'count of episodes'.

  8. For haemophilia B patients without inhibitors: Number of treated spontaneous and traumatic target joint bleeds [ Time Frame: On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) ]
    This will be presented as 'count of episodes'.

  9. Number of thromboembolic events [ Time Frame: Time frame is presented under 'outcome measure description'. ]
    This will be presented as 'count of 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 confirmatory analyses cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the confirmatory analysis cut-off. Week 0 before the pause is defined as the time of the initial randomisation to on-demand administration or time of start of the previous concizumab dosing regimen (0.25 mg/kg/day). Week 0 after the pause is defined as the time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.

  10. 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 events'. Week 0 before the pause is defined as the time of the initial randomisation to on-demand administration or time of start of the previous concizumab dosing regimen (0.25 mg/kg/day).

  11. Number of hypersensitivity type reactions [ Time Frame: Time frame 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 confirmatory analyses cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the confirmatory analysis cut-off. Week 0 before the pause is defined as the time of the initial randomisation to on-demand administration or time of start of the previous concizumab dosing regimen (0.25 mg/kg/day). Week 0 after the pause is defined as the time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.

  12. 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 the initial randomisation to on-demand administration or time of start of the previous concizumab dosing regimen (0.25 mg/kg/day).

  13. Number of injection site reactions [ Time Frame: Time frame 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 confirmatory analyses cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the confirmatory analysis cut-off. Week 0 before the pause is defined as the time of the initial randomisation to on-demand administration or time of start of the previous concizumab dosing regimen (0.25 mg/kg/day). Week 0 after the pause is defined as the time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.

  14. 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 the initial randomisation to on-demand administration or time of start of the previous concizumab dosing regimen (0.25 mg/kg/day).

  15. Number of patients with antibodies to concizumab [ Time Frame: Time frame is presented under 'outcome measure description'. ]
    This will be presented as 'count of participants'. 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 confirmatory analyses cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the confirmatory analysis cut-off. Week 0 before the pause is defined as the time of the initial randomisation to on-demand administration or time of start of the previous concizumab dosing regimen (0.25 mg/kg/day). Week 0 after the pause is defined as the time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.

  16. 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 participants'. Week 0 before the pause is defined as the time of the initial randomisation to on-demand administration or time of start of the previous concizumab dosing regimen (0.25 mg/kg/day).

  17. 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'.

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

  19. 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'.

  20. 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'.

  21. 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'.



Information from the National Library of Medicine

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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 severe haemophilia A (FVIII below 1%) or B (FIX equal to or below 2%).

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
  • Presence of confirmed inhibitors 0.6 BU or greater at screening
  • 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.)

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): NCT04082429


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
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Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT04082429    
Other Study ID Numbers: NN7415-4307
U1111-1225-9722 ( Other Identifier: World Health Organization (WHO) )
2018-004891-36 ( Registry Identifier: European Medicines Agency (EudraCT) )
First Posted: September 9, 2019    Key Record Dates
Last Update Posted: July 19, 2021
Last Verified: July 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