Clinical Trial Results:
A Multi-Centre, Open-Label, Non-Controlled Trial on Safety and Efficacy of N8 (turoctocog alfa) in Prevention and Treatment of Bleeds in Previously Treated Subjects with Haemophilia A
Sub-Trial:
Safety and Efficacy of N8 (turoctocog alfa) in Prevention and Treatment of Bleeding during Surgical Procedures in Subjects with Haemophilia A
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Summary
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EudraCT number |
2008-003960-20 |
Trial protocol |
DE GB ES IT DK |
Global end of trial date |
21 Sep 2011
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Mar 2016
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First version publication date |
26 Jul 2015
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NN7008-3543
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00840086 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novo Nordisk A/S
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Sponsor organisation address |
Novo Allé, Bagsvaerd, Denmark, 2880
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Public contact |
Global Clinical Registry (GCR 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
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Scientific contact |
Global Clinical Registry (GCR 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000428-PIP01-08 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
08 Feb 2012
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Sep 2011
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Sep 2011
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Part A and Part B: 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 Objective for Part A To describe the steady-state PK profile of N8 in the subjects who participated in the phase 1 trial 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) for subjects with haemophilia A.
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki(2008) and ICH Good Clinical Practice (1996).
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Background therapy |
In accordance with the EMA guidelines on development of new FVIII products the clinical programme for turoctocog alfa was initiated with a pharmacokinetic trial (NN7008-3522) to document the essential pharmacokinetic characteristics of the product and to achieve initial safety information. The initial pharmacokinetic trial was designed as a comparative trial to the rFVIII product, Advate which is one of the commercially available rFVIII products. The pharmacokinetic parameters were based on FVIII coagulation activity measurements. This parameter is known to correlate to clinical efficacy of FVIII products. In the present trial, a pharmacokinetic session was performed 3-6 months after the first pharmacokinetic session with turoctocog alfa in NN7008-3522 using the same dose as the first pharmacokinetic session with turoctocog alfa, which is in accordance with the EMA guideline on development of new FVIII products. The main purpose of the second pharmacokinetic assessment was to evaluate changes in pharmacokinetic parameters as indicators of inhibitor information. This pharmacokinetic session was included in the present trial (NN7008-3543) for patients who completed the pharmacokinetic trial (NN7008-3522) mentioned above. The present trial consisted of three parts (part A, part B and part C). The only difference between part A and part B is the above described pharmacokinetic session. In the surgery sub-trial part C, the patients had the option to undergo surgery. The surgery part was also designed in accordance with the EMA guideline on development of new FVIII products. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
07 Apr 2009
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 4
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Country: Number of subjects enrolled |
United Kingdom: 3
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Country: Number of subjects enrolled |
Germany: 10
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Country: Number of subjects enrolled |
Italy: 7
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Country: Number of subjects enrolled |
Croatia: 11
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Country: Number of subjects enrolled |
Israel: 12
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Country: Number of subjects enrolled |
Japan: 9
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Country: Number of subjects enrolled |
Malaysia: 5
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Country: Number of subjects enrolled |
Russian Federation: 5
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Country: Number of subjects enrolled |
Serbia: 19
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Country: Number of subjects enrolled |
Switzerland: 5
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Country: Number of subjects enrolled |
Taiwan: 4
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Country: Number of subjects enrolled |
Turkey: 11
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Country: Number of subjects enrolled |
United States: 29
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Country: Number of subjects enrolled |
Brazil: 16
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Worldwide total number of subjects |
150
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EEA total number of subjects |
35
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
24
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Adults (18-64 years) |
126
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were recruited at 48 sites in 15 countries: Brazil (2 sites), Croatia (2 sites), Germany (4 sites), Israel (1 site), Italy (2 sites), Japan (8 sites), Malaysia (1 site), Russian Federation (1 site), Republic of Serbia (5 sites), Spain (2 sites), Switzerland (1 site), Taiwan (1 site), Turkey (5 sites), the UK (3 sites) and US (10 sites). | ||||||||||||||
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Pre-assignment
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Screening details |
Not applicable | ||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Blinding implementation details |
Not applicable
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Arms
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Arm title
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All Subjects treated with turoctocog alfa | ||||||||||||||
Arm description |
All subjects participating in the study (Part A + Part B + Part C). | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
N8
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Investigational medicinal product code |
NN7008
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects will receive bleeding preventive treatment (home treatment with self-injection i.v.) with turoctocog alfa at a dose of 20-40 IU/kg body weight every second day or 20-50 IU/kg body weight three times per week at the investigator's discretion
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Baseline characteristics reporting groups
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Reporting group title |
All Subjects treated with turoctocog alfa
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Reporting group description |
All subjects participating in the study (Part A + Part B + Part C). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Total (Part A+ Part B)
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Preventive treatment and treatment of bleeds: The doses were individualised based on the trough FVIII activity level. The doses could be adjusted by the investigator. The dose level chosen was 20-40 IU/kg every second day or 20-50 IU/kg three times per week (Part A + Part B). Subjects previously treated with turoctocog alpha were included in Part A.
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Subject analysis set title |
Part C
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Surgery sub-trial: This part of the trial included any of the patients from Part A and Part B that during the course of the trial needed to undergo a major or minor surgical procedure requiring at least 7 days of daily FVIII treatment, including the day of surgery. Patients received a preoperative loading dose of turoctocog alfa immediately prior to the surgical procedure. On the day of surgery and until Day 7 (included) turoctocog alfa was dose adjusted aiming for a trough level above 0.50 IU/mL. Day 8 to last day of the surgical recovery period (if relevant) turoctocog alfa was dosed according to local guidelines
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End points reporting groups
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Reporting group title |
All Subjects treated with turoctocog alfa
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Reporting group description |
All subjects participating in the study (Part A + Part B + Part C). | ||
Subject analysis set title |
Total (Part A+ Part B)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Preventive treatment and treatment of bleeds: The doses were individualised based on the trough FVIII activity level. The doses could be adjusted by the investigator. The dose level chosen was 20-40 IU/kg every second day or 20-50 IU/kg three times per week (Part A + Part B). Subjects previously treated with turoctocog alpha were included in Part A.
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Subject analysis set title |
Part C
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Surgery sub-trial: This part of the trial included any of the patients from Part A and Part B that during the course of the trial needed to undergo a major or minor surgical procedure requiring at least 7 days of daily FVIII treatment, including the day of surgery. Patients received a preoperative loading dose of turoctocog alfa immediately prior to the surgical procedure. On the day of surgery and until Day 7 (included) turoctocog alfa was dose adjusted aiming for a trough level above 0.50 IU/mL. Day 8 to last day of the surgical recovery period (if relevant) turoctocog alfa was dosed according to local guidelines
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End point title |
The incidence rate of FVIII inhibitors (greater than or equal to 0.6 Bethesda Units (BU)) [1] | |||||||||
End point description |
The incidence rate of FVIII inhibitors was calculated by having all patients with inhibitors in the nominator and including all patients with a minimum 50 exposure plus any patients with less than 50 exposures but with inhibitors in denominator.
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End point type |
Primary
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End point timeframe |
The adverse events were collected throughout the trial, corresponding to an average of 188 days per subject.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The trial was one-armed, so there were no comparison arms in the trial. The primary endpoint was incidence rate of FVIII inhibitors (≥0.6 BU). No FVIII inhibitors were detected during the trial. Furthermore, the 1-sided 97.5% upper confidence limit for the inhibitor incidence rate of zero was 2.46%, thus the primary test of adequate safety (upper confidence limit below 6.8%) succeeded. No further statistical analysis was done. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Frequency of Adverse Events (AEs) | ||||||||||||||||||||||||||||||||||||
End point description |
Adverse event was defined as events occurring after administration of trial product. Severe AEs: considerable interference with subject's daily activities, unacceptable. Moderate AEs: Marked symptoms, moderate interference with the patient’s daily activities. Mild AEs: No or transient symptoms, no interference with the patient’s daily activities. Serious AEs: AE that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalization, persistent/significant disability/incapacity/congenital anomaly/birth defect.
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End point type |
Secondary
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End point timeframe |
The adverse events were collected throughout the trial, corresponding to an average of 188 days per subject
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| Notes [2] - Adverse events reported during surgeries are listed in Part C. those outside are reported in A and B |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
The adverse events were collected throughout the trial, corresponding to an average of 188 days per subject.
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Adverse event reporting additional description |
Safety analysis set includes all subjects who received at least one dose of the investigational product.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
14.0
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Reporting groups
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Reporting group title |
All Subjects Treated With Turoctocog Alfa
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Reporting group description |
All subjects participating in the study (Part A + Part B + Part C). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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29 Jun 2009 |
Substantial amendment 9. The substantial amendment 9 to the NN7008-3543 protocol version 3.0 (dated 28-Aug-2008) and Subject Information/Informed Consent Form version 2.0 dated 28-Aug-2008: The purpose of this amendment is to clarify further the description of the protocol procedures which includes the addition of Appendix D, Surgery Guideline. Also the trial title was updated.
This amendment is applicable to all countries.
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02 Feb 2010 |
Substantial amendment 14. The current document is a substantial amendment to protocol NN7008-3543 version 3.0 (dated 28-Aug-2008) and Subject Information/Informed Consent Form version 5.0 (dated 18-May-2009). Changes are made to this protocol in response to comments from the FDA dated August 14, 2009 and to harmonize the protocol with EMEA guidelines on investigation of FVIII products, issued July 2009.
This amendment is applicable to all countries.
The most significant change is revision to the objectives and endpoints where safety (incidence of inhibitor development) is now the primary endpoint, and efficacy is secondary. As part of the new primary endpoint, a new hypothesis test is set, and inhibitor tests are added at visits 5, 6b, and 8 to ensure adequate safety follow-up. The requirement that subjects should be HCV negative and/or lupus anticoagulant negative if no other condition precludes trial participation has been removed in agreement with EMEA guidelines on investigation of FVIII products, issued July 2009. In addition, other minor changes have been made to further improve the clinical protocol.
Explanations of the changes are outlined below:
• Revision of order of objectives and endpoints: safety (incidence of inhibitor development) is now the primary endpoint, and efficacy endpoints are secondary. In development of FVIII products, PK is an accepted surrogate endpoint for efficacy, and is demonstrated in phase 1. In general, safety is the primary objective to address in phase 3 trials.
• Revision of title and re-ordering of sections addressing safety and efficacy, respectively.
• Addition of inhibitor tests at visits 5, 6b, and 8 to ensure adequate safety follow-up in accordance with the changed primary endpoint every 4-5 weeks during study participation.
• Introduction of hypothesis test for inhibitor development with upper limit of 6.8%, resulting in acceptance of max. 3 inhibitors in the trial. This change is in line with observed inhibitor |
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02 Feb 2010 |
Substantial amendment 15. The current document is a Substantial amendment to protocol NN7008-3543 version 3.0 (dated 28-Aug-2008) and Subject Information/Informed Consent Form version 5.0 (dated 18-May-2009).
Changes are made to this protocol in response to obtained results from the completed phase 1 trial, NN7008-3522, and to accommodate requests and comments from participating investigators.
This amendment is applicable to all countries.
The most significant changes are an increase of the maximum allowed dose from 100 IU/kg BW to 200 IU/kg BW and the limit of 14 days on maximum dose has been removed. The changes are made to accommodate sufficient haemostasis and to allow for a FVIII level above 0,5 IU/ml during surgery and post surgery. These changes are supported by CMC documentation.
Non-planned surgery is now allowed in Part C. Therefore emergency surgery is removed as withdrawal criterion.
The required assessments from day 8 to End of Recovery in Part C have been reduced in agreement with EMEA guidelines.
Viral safety assessment has been clarified and removed from visit 2b to avoid duplicate blood sampling.
For Switzerland Amendment 9 the section about birth control was rewritten excluding a requirement for a medically acceptable birth control. By mistake this was not excluded from the protocol at the same time. This has been corrected now.
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22 Apr 2010 |
Substantial amendment 17. This global substantial amendment has primarily been prepared to adjust the definition of inhibitor history. Due to historical laboratory cut-off values ≤ 1BU/mL for inhibitor testing in some countries we have decided to change our inclusion criterion #6 in Section 6.2.2 and Section 8.6.2.2 in order to clarify the inclusion requirement for the sites with above mentioned past practice.
Clarification of required registration of data during the Recovery Period has been added.
Furthermore, the wording ‘bleeding resolution’ will be changed to ‘stop of bleeding’ to be in alignment with the Case Record Form (CRF) and also minor mistakes will be corrected to be in alignment with the wording introduced with the previous global substantial amendment no.15.
Substantial Protocol Amendment no. 17 will be forwarded to Health Authorities and IRBs/Ethics Committees for approval.
The consolidated Protocol NN7008-3543 version 11.0 incorporates all changes.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/23647704 |
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