E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Haemophilia A Haemophilia B |
Hemofilija A Hemofilija B |
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E.1.1.1 | Medical condition in easily understood language |
Bleeding disorder, inherited deficiency in clotting factor VIII Bleeding disorder, inherited deficiency in clotting factor IX |
Poremećaj krvarenja, nasljedni nedostatak faktora zgrušavanja VIII Poremećaj krvarenja, nasljedni nedostatak faktora zgrušavanja faktora IX |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018938 |
E.1.2 | Term | Haemophilia A (Factor VIII) |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018939 |
E.1.2 | Term | Haemophilia B (Factor IX) |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. To compare effect of concizumab prophylaxis to no prophylaxis (on-demand treatment with factor) in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia A without inhibitors 2. To compare effect of concizumab prophylaxis to no prophylaxis (on-demand treatment with factor) in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia B without inhibitors |
1.Usporedba učinka na smanjenje broja krvarenja profilaktički primijenjenog koncizumaba u odnosu na liječenje prema potrebi (eng. on-demand) faktorima zgrušavanja kod adolescenata i odraslih ispitanika s hemofilijom A bez inhibitora 2.Usporedba učinka na smanjenje broja krvarenja profilaktički primijenjenog koncizumaba u odnosu na liječenje prema potrebi (eng. on-demand) faktorima zgrušavanja kod adolescenata i odraslih ispitanika s hemofilijom B bez inhibitora |
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E.2.2 | Secondary objectives of the trial |
1. To compare the effect of concizumab prophylaxis to the patients’ previous prophylaxis treatment in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia A without inhibitors 2. To compare the effect of concizumab prophylaxis to the patients’ previous prophylaxis treatment in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia B without inhibitors 3. To investigate the safety of concizumab prophylaxis in adult and adolescent patients with haemophilia A or B without inhibitors 4. To investigate the PK and PD parameters of concizumab prophylaxis in adult and adolescent patients with haemophilia A or B without inhibitors |
1.Usporedba učinka na smanjenje broja krvarenja profilaktički primijenjenog koncizumaba u odnosu na prijašnje profilaktičko liječenje faktorima zgrušavanja kod adolescenata i odraslih ispitanika s hemofilijom A bez inhibitora 2.Usporedba učinka na smanjenje broja krvarenja profilaktički primijenjenog koncizumaba u odnosu na prijašnje profilaktičko liječenje faktorima zgrušavanja kod adolescenata i odraslih ispitanika s hemofilijom B bez inhibitora 3.Procjena sigurnosti profilaktičke primjene koncizumaba u adolescenata i odraslih ispitanika s hemofilijom A ili B bez inhibitora 4.Procjena farmakokinetičkih i farmakodinamičkih parametara koncizumaba u prevenciji krvarenja kod adolescenata i odraslih ispitanika s hemofilijom A ili B bez inhibitora |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 less than 1%) or B (FIX 2% or less) |
-Informirani pristanak dobiven prije bilo kakvih aktivnosti vezanih uz ispitivanje. Te aktivnosti su bilo kakvi postupci provedeni kao dio ispitivanja, uključujući postupke za procjenu prikladnosti za ispitivanje -muškarci u dobi ≥12 godina u trenutku potpisivanja informiranog pristanka -prirođena teška hemofilija A (FVIII <1%) ili B (FIX ≤2%) |
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E.4 | Principal 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.) |
Poznata preosjetljivost ili sumnja na svaku sastavnicu ispitivanog lijeka ili srodnih lijekova -Poznati nasljedni ili stečeni poremećaj krvarenja različit od kongenitalne hemofilije -Potvrđena prisutnost inhibitora 0.6 BU ili veća na probiru - Povijest tromboembolijskih bolesti (uključuje arterijsku i vensku trombozu kao i infarkt miokarda, plućnu emboliju, cerebralni infarkt/tromboza, duboku vensku trombozu, ostale klinički značajne tromboembolijske događaje te okluziju perifernih arterija. Trenutne kliničke znakove ili liječenje tromboembolijskih bolesti. Pacijenti koji su prema procijeni ispitivača u skupini visokog rizika za razvoj tromboembolijskog događaja (Rizični faktori za tromboembolijski događaj mogu uključivati, ali nisu ograničeni na: hiperkolesterolemiju, šećernu bolest, hipertenziju, pretilost, pušenje, obiteljsku anamnezu tromboembolijskih događaja, arteriosklerozu, ostala stanja povezana s povišenim rizikom za razvoj tromboembolijskog događaja.)
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E.5 End points |
E.5.1 | Primary end point(s) |
1. For haemophilia A patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes 2. For haemophilia B patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes |
1. Za ispitanike s hemofilijom A bez inhibitora: Broj liječenih spontanih i traumatskih epizoda krvarenja 2. Za ispitanike s hemofilijom B bez inhibitora: Broj liječenih spontanih i traumatskih epizoda krvarenja
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-2. On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24). Concizumab (arm 2 and 4): From start of the new concizumab dosing regimen (week 0) up until the confirmatory analyses cut-off (at least 32 weeks) |
1-2. Prema potrebi (grana 1): Od randomizacije nakon pauze (tjedan 0) sve do početka terapije koncizumabom (tjedan 24) Koncizumab (grana 2 i 4): Od početka novog režima doziranja koncizumabom (tjedan 0) sve do točke potvrdne analize (najmanje 32 tjedna)
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E.5.2 | Secondary end point(s) |
1. For haemophilia A patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes 2. For haemophilia B patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes 3. For haemophilia A patients without inhibitors: Number of treated spontaneous bleeding episodes 4. For haemophilia B patients without inhibitors: Number of treated spontaneous bleeding episodes 5. For haemophilia A patients without inhibitors: Number of treated joint bleeds 6. For haemophilia B patients without inhibitors: Number of treated joint bleeds 7. For haemophilia A patients without inhibitors: Number of treated target joint bleeds 8. For haemophilia B patients without inhibitors: Number of treated target joint bleeds 9. Number of thromboembolic events 10. Number of thromboembolic events 11. Number of hypersensitivity type reactions 12. Number of hypersensitivity type reactions 13. Number of injection site reactions 14. Number of injection site reactions 15. Number of patients with antibodies to concizumab 16. Number of patients with antibodies to concizumab 17. Pre-dose (trough) concizumab plasma concentration (Ctrough) 18. Pre-dose peak thrombin generation 19. Pre-dose free tissue factor pathway inhibitor (TFPI) concentration 20. Maximum concizumab plasma concentration (Cmax) 21. Area under the concizumab plasma concentration-time curve (AUC) |
1. Za pacijente s hemofilijom A bez inhibitora: Broj liječenih spontanih i traumatskih epizoda krvarenja 2. Za pacijente s hemofilijom B bez inhibitora: Broj liječenih spontanih i traumatskih epizoda krvarenja 3. Za pacijente s hemofilijom A bez inhibitora: Broj liječenih spontanih epizoda krvarenja 4. Za pacijente s hemofilijom B bez inhibitora: Broj liječenih spontanih epizoda krvarenja 5. Za pacijente s hemofilijom A bez inhibitora: Broj liječenih krvarenja u zglobovima 6. Za pacijente s hemofilijom B bez inhibitora: Broj liječenih krvarenja u zglobovima 7. Za pacijente s hemofilijom A bez inhibitora: Broj liječenih krvarenja u ciljnim zglobovima 8. Za pacijente s hemofilijom B bez inhibitora: Broj liječenih krvarenja u ciljnim zglobovima 9. Broj tromboembolijskih događaja 10. Broj tromboembolijskih događaja 11. Broj reakcija preosjetljivosti 12. Broj reakcija preosjetljivosti 13. Broj reakcija na mjestu injiciranja 14. Broj reakcija na mjestu injiciranja 15. Broj pacijenata s protutijelima na koncizumab 16. Broj pacijenata s protutijelima na koncizumab 17. Koncentracija koncizumaba u plazmi prije doziranja 18. Najviši iznos parametra stvaranja trombina prije doziranja 19. Koncentracija slobodnog TFPI faktor inhibitora (TFPI – tissue factor pathway inhibitor) prije doziranja 20. Maksimalna plazmatska koncentracija koncizumaba (Cmax) 21. Površina ispod krivulje ovisnosti koncentracije koncizumaba o vremenu (AUC)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-2.Arm 4:patients on stable prophylaxis (PPX) min.24wks in trial 4322: -Previous PPX (in 4322):PPX stable-end of trial -Concizumab (Conci) PPX (in 4307):Maintenance dose is confirmed/increased/decreased–conf. analyses (CA) (min.24wks) 3-8.On demand (arm 1):Randomisation post-pause (wk0)-dose start (wk24) -Conci (arm 2 & 4):New regimen start (wk0)–CA (min.32 wks) 9,11,13,15. On demand (arm 1 main part): -Randomisation–on demand treatment up to start of dose Conci (arms 2-4): -Pre-pause:Dose start (wk0)–7 wks post treatment pause -Post-pause:Dose start (wk0)–the CA (min.32 wks) 10,12,14,16. Conci: -Before pause:Dose at wk0–7 wks after treatment pause -Post-pause:Start of dose–end of trial (wk 167) 17-19.Prior to dose at wk24 (after restart) 20-21.0-24 hrs (0:dose at wk24 (after restart)) |
1-2.Grana4:pacijenti na stabilnoj profilaksi (PPX) min.24tj u 4322: -Prethodna PPX (u 4322):PPX stabilna na kraju ispitivanja -Koncizumab (Konci) PPX (u 4307):Održavanje doze je potvrđeno/povećano/smanjeno-potvrdna analiza (PA) (min.24tj) 3-8.Po potrebi (grana1):Randomizacija nakon pauze (tj0)-početak doze (tj24) -Konci(grana 2i4):Novi režim početak (tj0)- PA (min.32tj) 9,11,13,15. Po potrebi (grana 1 glavni dio) -Randomizacija-po potrebi do početka doze Konci (grana 2-4) -Prije doze:Početak doze (tj0)- 7tj nakon pauze terapije Poslije doze:Početak doze (th0)-do PA (min.32tj) 10,12,14,16. Konci -Prije pauze:Doza na tj0- 7tj nakon pauze -Nakon pauze:Početak doze- kraj ispitivanja (tj167) 17-19.Prije doze u tj24 (nakon restarta) 20-21.0-24hr (0:doza u tj24 (nakon restarta))
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
dvije randomizirane skupine na lijeku (profilaksa/ ne profilaksa) i dvije nerandomizirane skupine |
2 randomised treatment arms (ppx/no ppx) and two non-randomised treatment arms |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Ovisno o režimu liječenja prije ulaska u ispitivanje ispitanici će biti podiieljeni u jednu od četir |
Treatment regimen before entering the trial will determine the assignment to the four treatment arms |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 59 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Algeria |
Australia |
Canada |
European Union |
India |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Russian Federation |
Serbia |
South Africa |
Thailand |
Turkey |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 8 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 8 |