Clinical trial • Phase III • Haematology|Rare Disease

CONCIZUMAB for Haemophilia A | Haemophilia B

Phase III trial of CONCIZUMAB for Haemophilia A | Haemophilia B.

Overview

Trial Therapeutic Area
Haematology|Rare Disease
Trial Disease
Haemophilia A | Haemophilia B
Trial Stage
Phase III
Drug Modality
Monoclonal antibody
Paediatric Trial
Yes

Key dates

Initial CTIS Submission Date
15-12-2023
First CTIS Authorization Date
07-02-2024

Trial design

Randomised, on demand treatment with coagulation factor (no prophylaxis) as comparator arm (arm 1); concizumab prophylaxis in interventional arms (arm 2 and others) - doses/schedules not specified in the ctis summary-controlled Phase III trial in Denmark, Portugal, Lithuania and others.

Randomised
Yes
Comparator
On demand treatment with coagulation factor (no prophylaxis) as comparator arm (arm 1); concizumab prophylaxis in interventional arms (arm 2 and others) - doses/schedules not specified in the CTIS summary
Target Sample Size
115

Eligibility

Recruits 115 paediatric patients.

Vulnerable Population
Adolescents (aged 12–17) are included (inclusion criterion: Male aged ≥12 years). Informed consent is required before any trial-related activities. Country-specific subject information and informed consent forms for adolescents and for parents/legal representatives are listed (e.g. adolescent SI-IC forms and Parents LARs documents), indicating parental/legal representative involvement for minors and age-specific information materials in multiple languages.

Inclusion criteria

  • {"criterion_text":"- 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"}
  • {"criterion_text":"- Male aged ≥12 years at the time of signing informed consent"}
  • {"criterion_text":"- Body weight >25 kg at screening"}
  • {"criterion_text":"- Congenital severe haemophilia A (FVIII < 1%) or moderate/severe B (FIX ≤ 2%)."}
  • {"criterion_text":"- Documented treatment with coagulation factor containing product in the last 24 weeks (not applicable for NN7415-4255 (explorer5) patients enrolled prior to the treatment pause)."}

Exclusion criteria

  • {"criterion_text":"- Known or suspected hypersensitivity to any constituent of the trial product or related products"}
  • {"criterion_text":"- A known systemic inflammatory condition requiring systemic treatment at screening"}
  • {"criterion_text":"- Treatment with emicizumab within 180 days before screening"}
  • {"criterion_text":"- Presence of confirmed inhibitor ≥0.6 BU at screening"}
  • {"criterion_text":"- Known history of inhibitors ≥0.6 BU in the last 5 years according to the medical records."}
  • {"criterion_text":"- Any disorder, except for conditions associated with haemophilia, which in the investigator’s opinion might jeopardise patient’s safety or compliance with the protocol"}
  • {"criterion_text":"- Previous participation in this trial. Participation is defined as signed informed consent. However, this is not applicable for patients who were screen failed at Sponsor’s decision due to the treatment pause"}
  • {"criterion_text":"- Participation in any clinical trial of an approved or non-approved investigational medicinal product within 5 half-lives or 30 days from screening, whichever is longer (not applicable for NN7415-4255 patients enrolled prior to the treatment pause)."}
  • {"criterion_text":"- Platelets ≤100x109/L at screening"}
  • {"criterion_text":"- Fibrinogen below laboratory lower normal limit at screening"}
  • {"criterion_text":"- Hepatic dysfunction defined as AST and/or ALT >3 times the upper limit combined with total bilirubin > 1,5 times the upper limit at screening"}
  • {"criterion_text":"- Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) ≤30 ml/min/1.73 m2 for serum creatinine measured at screening"}
  • {"criterion_text":"- Known inherited or acquired coagulation disorder other than congenital haemophilia"}
  • {"criterion_text":"- History of thromboembolic disease. 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"}

Endpoints

Primary endpoints

  • {"endpoint_text":"- For haemophilia A patients without inhibitors: the number of treated spontaneous and traumatic bleeding episodes On demand (arm 1) From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2) From start of the new concizumab dosing regimen (week 0) up until the confirmatory analyses cut-off (at least 32 weeks)","definition_or_measurement_approach":"Counts of treated spontaneous and traumatic bleeding episodes in haemophilia A patients without inhibitors; measured over the specified time windows for each arm (on-demand arm: from randomisation after pause to start of concizumab; concizumab arm: from start of maintenance dosing to confirmatory analysis cut-off of at least 32 weeks)."}
  • {"endpoint_text":"- For haemophilia B patients without inhibitors: the number of treated spontaneous and traumatic bleeding episodes On demand (arm 1) From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2) From start of the new concizumab dosing regimen (week 0) up until the confirmatory analyses cut-off (at least 32 weeks)","definition_or_measurement_approach":"Counts of treated spontaneous and traumatic bleeding episodes in haemophilia B patients without inhibitors; measured over the specified time windows for each arm (on-demand arm: from randomisation after pause to start of concizumab; concizumab arm: from start of maintenance dosing to confirmatory analysis cut-off of at least 32 weeks)."}

Secondary endpoints

  • {"endpoint_text":"- For haemophilia A patients without inhibitors: The number of treated spontaneous and traumatic bleeding 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. 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).","definition_or_measurement_approach":"Number of treated spontaneous and traumatic bleeding episodes in haemophilia A patients with prior stable prophylaxis (PPX) or on concizumab PPX, measured from the time PPX is stable (or concizumab maintenance dose confirmation/change) to end of study or confirmatory cut-off (≥24 weeks)."}
  • {"endpoint_text":"- For haemophilia B patients without inhibitors: The number of treated spontaneous and traumatic bleeding 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. 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).","definition_or_measurement_approach":"Number of treated spontaneous and traumatic bleeding episodes in haemophilia B patients with prior stable prophylaxis (PPX) or on concizumab PPX, measured from the time PPX is stable (or concizumab maintenance dose confirmation/change) to end of study or confirmatory cut-off (≥24 weeks)."}
  • {"endpoint_text":"- For haemophilia A patients without inhibitors: Number of treated spontaneous bleeding episodes On demand (arm 1) From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2) From start of the new concizumab dosing regimen (week 0) up until the confirmatory analyses cut-off (at least 32 weeks)","definition_or_measurement_approach":"Count of treated spontaneous bleeding episodes in haemophilia A patients measured over arm-specific time windows as defined."}
  • {"endpoint_text":"- For haemophilia B patients without inhibitors: Number of treated spontaneous bleeding episodes On demand (arm 1) From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2) From start of the new concizumab dosing regimen (week 0) up until the confirmatory analyses cut-off (at least 32 weeks)","definition_or_measurement_approach":"Count of treated spontaneous bleeding episodes in haemophilia B patients measured over arm-specific time windows as defined."}
  • {"endpoint_text":"- For haemophilia A patients without inhibitors: Number of treated spontaneous and traumatic joint bleeds On demand (arm 1) From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2) From start of the new concizumab dosing regimen (week 0) up until the confirmatory analyses cut-off (at least 32 weeks)","definition_or_measurement_approach":"Count of treated spontaneous and traumatic joint bleeds in haemophilia A patients over specified arm time windows."}
  • {"endpoint_text":"- For haemophilia B patients without inhibitors: Number of treated spontaneous and traumatic joint bleeds On demand (arm 1) From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2) From start of the new concizumab dosing regimen (week 0) up until the confirmatory analyses cut-off (at least 32 weeks)","definition_or_measurement_approach":"Count of treated spontaneous and traumatic joint bleeds in haemophilia B patients over specified arm time windows."}
  • {"endpoint_text":"- For haemophilia A patients without inhibitors: Number of treated spontaneous and traumatic target joint bleeds On demand (arm 1) From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2) From start of the new concizumab dosing regimen (week 0) up until the confirmatory analyses cut-off (at least 32 weeks)","definition_or_measurement_approach":"Count of treated spontaneous and traumatic target joint bleeds in haemophilia A patients over specified arm time windows."}
  • {"endpoint_text":"- For haemophilia B patients without inhibitors: Number of treated spontaneous and traumatic target joint bleeds On demand (arm 1) From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2) From start of the new concizumab dosing regimen (week 0) up until the confirmatory analyses cut-off (at least 32 weeks)","definition_or_measurement_approach":"Count of treated spontaneous and traumatic target joint bleeds in haemophilia B patients over specified arm time windows."}
  • {"endpoint_text":"- Number of thromboembolic events On demand (arm 1 main part) From randomisation to on demand treatment until start of concizumab treatment Concizumab (arms 2-4) Before the pause: From start of concizumab treatment up until 7 weeks after the treatment was paused and After the pause: From start of concizumab treatment up until the confirmatory analyses cut-off (at least 32 weeks) Concizumab (arm 1 extension part) From start of concizumab treatment up until the confirmatory analysis cut-off","definition_or_measurement_approach":"Number of thromboembolic events captured for specified arms and time windows (on-demand main part; concizumab arms before and after pause; extension part) with defined observation windows (including up to 7 weeks after pause and at least 32 weeks for confirmatory analyses)."}
  • {"endpoint_text":"- Number of thromboembolic events Concizumab Before the pause: From start of treatment (week 0) up until 7 weeks after the treatment was paused as well as After the pause: From start of concizumab treatment up until the end of trial (up to 384 weeks)","definition_or_measurement_approach":"Number of thromboembolic events on concizumab, observed in two periods: before the pause (start to 7 weeks after pause) and after the pause (start to end of trial, up to 384 weeks)."}
  • {"endpoint_text":"- Number 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 up until 7 weeks after the treatment was paused and After the pause: From start of concizumab treatment up until the confirmatory analyses cut-off (at least 32 weeks) Concizumab (arm 1 extension) From start of concizumab treatment up until the confirmatory analysis cut-off","definition_or_measurement_approach":"Count of hypersensitivity-type reactions captured per arm/time-window definitions (on-demand main part; concizumab arms before and after pause; extension part)."}
  • {"endpoint_text":"- Number of hypersensitivity type reactions Concizumab Before the pause: From start of treatment (week 0) up until 7 weeks after the treatment was paused as well as After the pause: From start of concizumab treatment up until the end of trial (up to 384 weeks)","definition_or_measurement_approach":"Count of hypersensitivity reactions on concizumab separated into before-pause (start to 7 weeks after pause) and after-pause (start to end of trial up to 384 weeks)."}
  • {"endpoint_text":"- Number of injection site reactions On demand (arm 1 main part) From randomisation to on demand treatment until start of concizumab treatment Concizumab (arms 2-4) Before the pause: From start of concizumab treatment up until 7 weeks after the treatment was paused and After the pause: From start of concizumab treatment up until the confirmatory analyses cut-off (at least 32 weeks) Concizumab (arm 1 extension part) From start of concizumab treatment up until the confirmatory analysis cut-off","definition_or_measurement_approach":"Number of injection site reactions recorded per arm and defined time windows (on-demand main part; concizumab arms before and after pause; extension part)."}
  • {"endpoint_text":"- Number of injection site reactions Concizumab Before the pause: From start of treatment (week 0) up until 7 weeks after the treatment was paused as well as After the pause: From start of concizumab treatment up until the end of trial (up to 384 weeks)","definition_or_measurement_approach":"Number of injection site reactions on concizumab observed before-pause (start to 7 weeks post-pause) and after-pause (start to end of trial up to 384 weeks)."}
  • {"endpoint_text":"- Number of patients with antibodies to concizumab Concizumab (arms 2-4) Before the pause: From start of concizumab treatment (week 0) up until 7 weeks after the treatment was paused as well as 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 (visit 9a) up until the confirmatory analysis cut-off","definition_or_measurement_approach":"Number of patients developing antibodies to concizumab, measured per arm and defined observation windows (before pause up to 7 weeks after pause; after pause up to confirmatory analysis cut-off of ≥32 weeks; extension part from visit 9a)."}
  • {"endpoint_text":"- Number of patients with antibodies to concizumab Concizumab Before the pause: From start of treatment (week 0) up until 7 weeks after the treatment was paused as well as After the pause: From start of concizumab treatment up until the end of trial (up to 384 weeks)","definition_or_measurement_approach":"Number of patients with anti-concizumab antibodies observed before-pause (start to 7 weeks post-pause) and after-pause (start to end of trial up to 384 weeks)."}
  • {"endpoint_text":"- Pre-dose (trough) concizumab plasma concentration (Ctrough) prior to the concizumab administration at week 24 (after restart)","definition_or_measurement_approach":"Pharmacokinetic measurement: pre-dose (trough) plasma concizumab concentration measured prior to dosing at week 24 after restart."}
  • {"endpoint_text":"- Pre-dose thrombin peak prior to the concizumab administration at week 24 (after restart)","definition_or_measurement_approach":"Pharmacodynamic measurement: thrombin peak measured pre-dose prior to concizumab administration at week 24 after restart."}
  • {"endpoint_text":"- Pre-dose free TFPI concentration prior to the concizumab administration at week 24 (after restart)","definition_or_measurement_approach":"Pharmacodynamic measurement: pre-dose free TFPI concentration measured prior to concizumab administration at week 24 after restart."}
  • {"endpoint_text":"- Maximum concizumab plasma concentration (Cmax) from 0 to 24 hours where 0 is time of the concizumab dose at week 24 (after restart)","definition_or_measurement_approach":"PK measurement: Cmax in the 0-24 hour interval after the concizumab dose at week 24 after restart."}
  • {"endpoint_text":"- Area under the concizumab plasma concentration-time curve (AUC) from 0 to 24 hours where 0 is time of the concizumab dose at week 24 (after restart)","definition_or_measurement_approach":"PK measurement: AUC(0-24h) following concizumab dose at week 24 after restart."}

Recruitment

Planned Sample Size
115
Recruitment Window Months
79
Consent Approach
Informed consent must be obtained before any trial-related activities. Country-specific subject information and consent forms are provided for adults and adolescents (e.g. adolescents 12-15y, 16-17y), parent/legal representative (LAR) forms are available where relevant, and BYOD consent/addenda and future research consent documents are provided. SI-IC documents are available in multiple country languages as listed in the CTIS documents (examples include English, Portuguese, French, Spanish, Polish, Hungarian, Lithuanian, German, Italian, Swedish, Estonian).

Geography

Total Number Of Sites
16
Total Number Of Participants
41

Denmark

Earliest CTIS Part Ii Submission Date
19-01-2024
Latest Decision Or Authorization Date
07-02-2024
Processing Time Days
19
Number Of Sites
1
Number Of Participants
2

Sites

Site Name
Rigshospitalet
Contact Person Name
Eva Funding
Contact Person Email
eva.funding@regionh.dk

Portugal

Earliest CTIS Part Ii Submission Date
19-01-2024
Latest Decision Or Authorization Date
07-02-2024
Processing Time Days
19
Number Of Sites
1
Number Of Participants
2

Sites

Site Name
Centro Hospitalar Universitario Sao Joao E.P.E.
Contact Person Name
Manuela Carvalho

Lithuania

Earliest CTIS Part Ii Submission Date
27-03-2024
Latest Decision Or Authorization Date
18-03-2024
Number Of Sites
1
Number Of Participants
3

Sites

Site Name
Vilniaus universiteto ligonine Santaros klinikos VšĪ
Contact Person Name
Sonata Saulyte Trakymiene
Contact Person Email
sonatrak@gmail.com

Hungary

Earliest CTIS Part Ii Submission Date
19-01-2024
Latest Decision Or Authorization Date
08-02-2024
Processing Time Days
20
Number Of Sites
1
Number Of Participants
2

Sites

Site Name
Central Hospital Of Northern Pest Military Hospital
Contact Person Name
Laszlo Nemes
Contact Person Email
lnemes@t-online.hu

Germany

Earliest CTIS Part Ii Submission Date
19-01-2024
Latest Decision Or Authorization Date
09-02-2024
Processing Time Days
21
Number Of Sites
1
Number Of Participants
7

Sites

Site Name
Universitaet Des Saarlandes
Contact Person Name
Hermann Eichler
Contact Person Email
hermann.eichler@uks.eu

France

Earliest CTIS Part Ii Submission Date
19-01-2024
Latest Decision Or Authorization Date
12-02-2024
Processing Time Days
24
Number Of Sites
1
Number Of Participants
1

Sites

Site Name
Centre Hospitalier Regional Et Universitaire De Brest
Contact Person Name
Brigitte Pan Petesch

Italy

Earliest CTIS Part Ii Submission Date
19-01-2024
Latest Decision Or Authorization Date
08-02-2024
Processing Time Days
20
Number Of Sites
1
Number Of Participants
2

Sites

Site Name
Azienda Ospedaliera Universitaria Citta' Della Salute E Della Scienza Di Torino
Contact Person Name
Alessandra Borchiellini

Sweden

Earliest CTIS Part Ii Submission Date
19-01-2024
Latest Decision Or Authorization Date
08-02-2024
Processing Time Days
20
Number Of Sites
1
Number Of Participants
2

Sites

Site Name
Region Skane Skanes Universitetssjukhus
Department Name
Koagulationsmottagning, VO Hematologi, Skånes Universitetssjukhus
Contact Person Name
Jan Astermark
Contact Person Email
Jan.Astermark@med.lu.se

Spain

Earliest CTIS Part Ii Submission Date
19-01-2024
Latest Decision Or Authorization Date
08-02-2024
Processing Time Days
20
Number Of Sites
3
Number Of Participants
6

Sites

Site Name
Hospital Universitario La Paz
Contact Person Name
Víctor Jiménez Yuste
Contact Person Email
vjimenez.hulp@salud.madrid.org
Site Name
University Hospital Virgen Del Rocio S.L.
Contact Person Name
Ramiro Núñez
Site Name
Hospital Universitario Regional De Malaga
Contact Person Name
Francisco Lopez Jaime

Poland

Earliest CTIS Part Ii Submission Date
19-01-2024
Latest Decision Or Authorization Date
13-02-2024
Processing Time Days
25
Number Of Sites
4
Number Of Participants
12

Sites

Site Name
Uniwersytecki Szpital Kliniczny W Poznaniu
Department Name
Oddział Hematologii i Transplantologii
Contact Person Name
Lidia Gil
Contact Person Email
lidia.gil@skpp.edu.pl
Site Name
Instytut Hematologii I Transfuzjologii
Department Name
Klinika Zaburzen Hemostazy i Chorob Wewnetrznych
Contact Person Name
Jerzy Windyga
Contact Person Email
jwindyga@ihit.waw.pl
Site Name
Samodzielny Publiczny Zaklad Opieki Zdrowotnej Szpital Uniwersytecki W Krakowie
Department Name
Oddział Kliniczny Hematologii
Contact Person Name
Joanna Zdziarska
Contact Person Email
jzdziarska@su.krakow.pl
Site Name
Samodzielny Publiczny Szpital Kliniczny Nr 1 W Lublinie
Contact Person Name
Justyna Kozinska
Contact Person Email
justynakozinska@vp.pl

Estonia

Earliest CTIS Part Ii Submission Date
19-01-2024
Latest Decision Or Authorization Date
12-02-2024
Processing Time Days
24
Number Of Sites
1
Number Of Participants
2

Sites

Site Name
North Estonia Medical Centre Foundation
Contact Person Name
Keidi Suursaar

Sponsor

Primary sponsor

Full Name
Novo Nordisk A/S
Organisation Type
Pharmaceutical company
Country Of Registered Address
Denmark

Contract research organisations

Name
Syneos Health Inc.
Responsibilities
Special Laboratory
Name
WCG Clinical Inc.
Responsibilities
code 10 (statistical/other role indicated by code in CTIS export)

Third parties

  • {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"Special Laboratory","organisation_type":"Pharmaceutical company"}
  • {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"code 7 (role not elaborated in CTIS export)","organisation_type":"Pharmaceutical company"}
  • {"country":"United Kingdom","full_name":"Perceptive Eclinical Limited","duties_or_roles":"IWRS Helpdesk","organisation_type":"Pharmaceutical company"}
  • {"country":"United States","full_name":"Oracle America Inc.","duties_or_roles":"code 7 (role not elaborated in CTIS export)","organisation_type":"Pharmaceutical company"}
  • {"country":"United States","full_name":"Actigraph LLC","duties_or_roles":"Activity tracker device Supplier","organisation_type":"Pharmaceutical company"}
  • {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"Central laboratory","organisation_type":"Pharmaceutical company"}
  • {"country":"United Kingdom","full_name":"Calyx","duties_or_roles":"IWRS Supplier","organisation_type":"Industry"}
  • {"country":"Switzerland","full_name":"Celerion Switzerland AG","duties_or_roles":"Special Laboratory","organisation_type":"Pharmaceutical company"}
  • {"country":"United States","full_name":"WCG Clinical Inc.","duties_or_roles":"code 10 (role not elaborated in CTIS export)","organisation_type":"Pharmaceutical company"}

Investigational products

Investigational Product Name
Concizumab C 40 mg/mL PDS290
Active Substance
CONCIZUMAB
Modality
Monoclonal antibody
Routes Of Administration
SUBCUTANEOUS
Route
SUBCUTANEOUS
Authorisation Status
Not authorised
Investigational Product Name
Concizumab C 100 mg/mL PDS290
Active Substance
CONCIZUMAB
Modality
Monoclonal antibody
Routes Of Administration
SUBCUTANEOUS
Route
SUBCUTANEOUS
Authorisation Status
Not authorised

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