E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Haemophilia A
Hemofilia A |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018937 |
E.1.2 | Term | Haemophilia A |
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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 |
- To evaluate the efficacy of N8 in bleeding prevention in subjects with haemophilia A. - To evaluate the efficacy of N8 in on-demand treatment of bleeding episodes in subjects with haemophilia A
Additional Primary Objective for Part A (only) - To describe the steady-state PK profile of N8 in the subjects who participated in NN7008-3522, 3 months after initial dose of N8.
Part C: - To evaluate the efficacy of N8 in bleeding prevention during surgical procedures in subjects with haemophilia A - To evaluate the haemostatic effect of N8 during surgical procedures and in the early postoperative period (Day 1 to Day 6) in subjects with haemophilia A |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety of N8 when used for prevention of bleeding episodes and on-demand treatment of bleeding episodes in subjects with haemophilia A. - To assess the frequency of development of inhibitors defined as clinically important inhibitors to FVIII (?0.6 BU/mL) - To assess and compare Patient Reported Outcomes (PROs)
Part C: - To evaluate the safety of N8 when used for prevention and treatment of bleeding during surgical procedures and in the early postoperative period in subjects with haemophilia A - To assess the frequency of inhibitor development defined as clinically important inhibitors to FVIII when used for prevention and treatment of bleeding during surgical procedures and in the early postoperative period in subjects with haemophilia A - To assess and compare PRO |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: Efficacy and Safety of N8 in Prevention and Treatment of Bleeding during Surgical Procedures in Subjects with Haemophilia A
Date: 11 Feb 2009 Version: 6
Objectives: The primary objectives are: - To evaluate the efficacy of N8 in bleeding prevention during surgical procedures in subjects with haemophilia A - To evaluate the haemostatic effect of N8 during surgical procedures and in the early postoperative period (Day 1 to Day 6) in subjects with haemophilia A |
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E.3 | Principal inclusion criteria |
Part A 1. Completion of the phase 1 PK trial NN7008-3522 2. Informed consent obtained prior to any trial-related activities. (Trial-related activities are any procedure that would not have been performed during normal management of the subject.) 3. Male subjects with the diagnosis of severe (baseline FVIII?1%) haemophilia A from age 12 to 56 years having a weight of 10 to 120 kg. 4. Willing to undergo a bleeding preventive regimen of 75 exposure days 5. Non-bleeding state (i.e. no clinical manifestation of active bleed) at the time of administration of trial product for measurement of recovery in relation to administration of the first dose and the PK session 6. Documented history of at least 150 exposure days to any other FVIII products (prevention or on-demand treatment) (Please refer to section 8.6.2.3) 7. No history of FVIII inhibitors ?0.6 BU/mL measured regularly since the first treatment of haemophilia A prior to entering the trial or the time period should cover at least 8 years (Please refer to section 8.6.2.2) 8. No detectable inhibitors to FVIII ( ?0.6 BU/mL) (as assessed by central laboratory at the investigative site at the time of screening) 9. Hepatitis C Virus (HCV) seronegative or if HCV seropositive, viral load <200.000 IU/mL and CD4+ lymphocyte count ? 200/µL. 10. Lupus anticoagulant negative 11. HIV-1 seronegative or if HIV-1 seropositive, the viral load <400.000 copies/mL and the CD4+ lymphocyte count ?200/µL. Part B 1. Informed consent obtained prior to any trial-related activities (Trial-related activities are any procedure that would not have been performed during normal management of the subject). 2.Male subjects with the diagnosis of severe (baseline FVIII?1%) haemophilia A from age 12 to 65 years having a weight of 10 to 120 kg. 3. Willing to undergo a bleeding preventive regimen of 75 exposure days 4. Non-bleeding state (i.e. no clinical manifestation of active bleed) at the time of administration of trial product for measurement of recovery in relation to administration of the first dose 5. Documented history of at least 150 exposure days to any other FVIII products (prevention or on-demand treatment) (Please refer to section 8.6.2.3) 6. No history of FVIII inhibitors ?0.6 BU/mL measured regularly since the first treatment of haemophilia A prior to entering the trial or the time period should cover at least 8 years (Please refer to History of Inhibitors in section 8.6.2.2) 7. No detectable inhibitors to FVIII ( ?0.6 BU/mL) (as assessed by central laboratory at the time of screening) 8. HCV seronegative and or if HCV seropositive, viral load <200.000 IU/mL and CD4+ lymphocyte count ? 200/µL. 9. Lupus anticoagulant negative 10. HIV-1 seronegative or if HIV-1 seropositive, the viral load <400.000 copies/mL and the CD4+ lymphocyte count ?200/µL. Part C: 12.Scheduled to undergo major or minor surgical procedures 13.Surgical procedure requiring at least 6 days of infusion of N8 concentrate post-operatively. Subjects will only participate in Part C when they have been included in either Part A or Part and have received at least one dose of trial product (N8). |
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E.4 | Principal exclusion criteria |
1. Subjects on Immune Tolerance Treatment (ITT) regimens 2.Pharmaceutical treatment of a mild and moderate bleeding episode within one week prior to first dose 3. Pharmaceutical treatment of a severe bleeding episode within one week prior to first dose 4. Known pseudo-tumours 5. Platelet count <50,000 platelets/µL (based on medical records) at trial entry 6. Severe current hepatic dysfunction or severe hepatic disease during the last 12 months 7. ALAT > than 4 times of the upper limit of normal reference range (as defined by central laboratory ranges 8. Septicaemia, e.g. febrile illness within 5 days prior to trial product administration 9. Current dialysis therapy 10. Creatinine levels 50% above normal level (according to central laboratory range) 11. Congenital or acquired coagulation disorders other than haemophilia A 12. Previous arterial thrombotic events (Myocardial Infarction and Intra Cranial Thrombosis) (as defined by medical records). 13. Known or suspected allergy to trial product (N8) or related products 14. Surgery within one month prior to first administration of trial product (catheter, stents, ports, and dental extractions do not count as surgeries, i.e. they will not exclude the subject) 15. Use of Coagulation Factors: FVIII concentrates or other FVIII containing products within four days prior to first administration of trial product 16. Use of Anticoagulants: Heparin, vitamin-K antagonists, and direct thrombin inhibitors one week prior to first administration of trial product 17. Use of non-prescribed opiate substances 18. Regular use of cannabis (only for subjects in Part A) 19. Use of platelet inhibitors including NSAID one week prior to first administration of trial product 20. The receipt of any investigational drug within 30 days prior to administration of trial product except subjects who have completed NN7008-3522 21. Previous participation in the current trial (defined as withdrawal) or withdrawn subjects from NN7008-3522 after administration of trial product 22. Any disease or condition which, according to the Investigator?s judgement, could imply a potential hazard to the subject, interfere with the trial participation or trial outcome 23. Mental incapacity, unwillingness or language barriers precluding adequate understanding or cooperation |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy Endpoints Total consumption of N8 (prevention and on-demand) per month and/or year Prevention - Assessment of the actual consumption of N8 (IU/kg BW/months) for prevention - Assessment of the average number of break-through bleeds per month reported during the preventative regimen On-Demand - Assessment of the actual consumption of N8 (IU/kg BW/bleeding episode). - Assessment of the haemostatic response (none, moderate, good or excellent) when haemostasis has been achieved. Part C: - Assessment of the actual consumption of N8 (IU/kg BW) o Time period Day 1 to Day 6 o Time period Day 7 to return to prevention regimen - Assessment of haemostatic effect when haemostasis has been achieved - Haemoglobin level prior to surgery and after surgery - Amount of blood or blood product for transfusion - Loss of blood |
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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 | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |