Clinical Trial Results:
Efficacy and Safety of NNC 0129-0000-1003 (N8-GP) during Surgical Procedures in Patients with Haemophilia A
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Summary
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EudraCT number |
2011-001144-30 |
Trial protocol |
NL DE SE DK GB ES HU IT BG |
Global end of trial date |
10 Dec 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Jun 2019
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First version publication date |
22 Jun 2019
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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 |
NN7088-3860
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01489111 | ||
WHO universal trial number (UTN) |
U1111-1119-7326 | ||
Other trial identifiers |
Japanese trial registration number: 132215 | ||
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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 |
Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
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Scientific contact |
Clinical Reporting Anchor and Disclosure (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-001174-PIP02-12 | ||
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 |
21 May 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
10 Dec 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Dec 2018
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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 |
To evaluate the haemostatic effect of N8-GP during surgical procedures in patients with
haemophilia A
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki (Seoul, October 2008), ICH Good Clinical Practice, including archiving of essential documents (Geneva, May 1996), and 21 CFR 312.120.
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Background therapy |
Subjects were transferred from the pivotal trial (NN7088-3859), in which patients at inclusion were required to be with a documented history of at least 150 exposure days to other FVIII products. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
03 Aug 2012
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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 |
Australia: 2
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Country: Number of subjects enrolled |
Denmark: 1
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Country: Number of subjects enrolled |
France: 4
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Country: Number of subjects enrolled |
Hungary: 4
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Country: Number of subjects enrolled |
Israel: 1
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Country: Number of subjects enrolled |
Italy: 4
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Country: Number of subjects enrolled |
Japan: 4
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Country: Number of subjects enrolled |
Malaysia: 3
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Country: Number of subjects enrolled |
Netherlands: 2
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Country: Number of subjects enrolled |
Switzerland: 2
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Country: Number of subjects enrolled |
Turkey: 5
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Country: Number of subjects enrolled |
United Kingdom: 14
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Country: Number of subjects enrolled |
United States: 7
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Worldwide total number of subjects |
53
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EEA total number of subjects |
29
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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) |
1
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Adults (18-64 years) |
49
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial was conducted at 26 sites in 13 countries, as follows: Australia (1 site), Denmark (1 site), France (3 sites), Hungary (1 site), Israel (1 site), Italy (2 sites), Japan (2 sites), Malaysia (1 site), Netherlands (1 site), Switzerland (2 sites), Turkey (3 sites), United Kingdom (4 sites) and United States (4 sites). | ||||||||||
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Pre-assignment
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Screening details |
In this trial 36 subjects were exposed and all the results are analysed and presented based on surgery level (number of planned surgeries=53). | ||||||||||
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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 | ||||||||||
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Arms
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Arm title
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N8-GP | ||||||||||
Arm description |
Subjects (from trial NN7088-3859) undergoing major surgery received bleeding preventive treatment with N8-GP before, during and after surgery. The total duration of the trial was 2-5 weeks. Upon completion of this trial, subjects returned to trial NN7088-3859. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
N8-GP rFVIII
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Investigational medicinal product code |
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Other name |
ESPEROCT®
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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 |
The trial product was administered as a slow bolus intravenous injection. The administrations were performed both at home and in hospital. Dosing was done at the investigators’ discretion (except a fixed dose of 50 IU/kg at screening visit). The dose level of N8-GP during this trial was chosen following the coagulation factor 8 (FVIII) activity levels recommended by World Federation of Hemophilia (WFH) guidelines. Higher levels could be necessary depending on type of surgery and standard practice at site. The WFH guidelines for desired FVIII levels in major surgery are as follows: pre-surgery (day 0): 80−100%; post-surgery days 1−3: 60−80%; days 4−6: 40−60%; days 7−14: 30−50%. For treatment of a bleeding episode, all subjects were treated with doses between 20−75 IU/kg. The maximum dose to be administered to a subject within 24 hours was 200 IU/kg.
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Baseline characteristics reporting groups
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Reporting group title |
N8-GP
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Reporting group description |
Subjects (from trial NN7088-3859) undergoing major surgery received bleeding preventive treatment with N8-GP before, during and after surgery. The total duration of the trial was 2-5 weeks. Upon completion of this trial, subjects returned to trial NN7088-3859. | ||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
N8-GP
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Reporting group description |
Subjects (from trial NN7088-3859) undergoing major surgery received bleeding preventive treatment with N8-GP before, during and after surgery. The total duration of the trial was 2-5 weeks. Upon completion of this trial, subjects returned to trial NN7088-3859. | ||
Subject analysis set title |
N8-GP (completed surgeries)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects (from trial NN7088-3859) who completed major surgery received bleeding preventive treatment with N8-GP before, during and after surgery. The total duration of the trial was 2-5 weeks. Upon completion of this trial, patients returned to trial NN7088-3859.
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End point title |
Haemostatic effect during surgery evaluated by the four-point scale, assessed by the Investigator/surgeon at the day of surgery - Four-point response scale: excellent, good, moderate or none [1] | ||||||||||||||
End point description |
Haemostatic effect during surgery was evaluated on a four-point response scale as ‘none’, ‘moderate’, ‘good’ and ‘excellent’. This was assessed after completion of surgery (defined as “last stitch”).
Excellent: Better than expected/predicted in this type of procedure.
Good: As expected in this type of procedure.
Moderate: Less than optimal for the type of procedure but haemostatic response maintained without change of treatment regimen.
None: Bleeding due to inadequate therapeutic response with adequate dosing, change of regimen required.
Analysis population: Full analysis set included all subjects exposed to the trial drug (N8-GP) and completed surgeries.
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End point type |
Primary
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End point timeframe |
During surgery
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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: As the study includes only one arm, no statistical analysis is performed. All endpoints are summarised. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Average consumption of N8-GP during surgery | ||||||||
End point description |
Average consumption of N8-GP, during surgery is presented. The time during surgery is defined from ‘knife to skin’ until ‘last stitch’. Analysis population: Full analysis set included all subjects exposed to the trial drug (N8-GP) and completed surgeries.
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End point type |
Secondary
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End point timeframe |
The endpoint was analysed based on all available information until End of Trial (EOT) Visit and up to approximately 5 weeks for each patient.
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| No statistical analyses for this end point | |||||||||
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End point title |
Haemostatic effect of N8-GP during the post-operative period Days 1-6 and 7-14 | ||||||||||||||||||||||||
End point description |
Haemostatic effect during post-operative period Days 1-6 and 7-14 was evaluated on a four-point response scale as ‘none’, ‘moderate’, ‘good’ and ‘excellent’.
Excellent: Better than expected/predicted in this type of procedure.
Good: As expected in this type of procedure.
Moderate: Less than optimal for the type of procedure but haemostatic response maintained without change of treatment regimen.
None: Bleeding due to inadequate therapeutic response with adequate dosing, change of regimen required. Analysis population: Full analysis set included all subjects exposed to the trial drug (N8-GP).
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End point type |
Secondary
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End point timeframe |
The endpoint was analysed based on all available information until End of Trial (EOT) Visit and up to approximately 5 weeks for each patient.
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Average consumption of N8-GP during the post-operative period Days 1-6 | ||||||||
End point description |
Average consumption of N8-GP during post operative period days 1-6 is presented. Analysis population: Full analysis set included all subjects exposed to the trial drug (N8-GP) and completed surgery.
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End point type |
Secondary
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End point timeframe |
The endpoint was analysed based on all available information until End of Trial (EOT) Visit and up to approximately 5 weeks for each patient.
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| No statistical analyses for this end point | |||||||||
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End point title |
Incidence rate of inhibitors against factor VIII (FVIII) (≥0.6 BU/mL) | ||||||
End point description |
Incidence rate of inhibitors is the number of newly developed inhibitors per surgery. Development of FVIII inhibitors was measured by a validated Nijmegen modified Bethesda assay. A positive inhibitor test was defined as ≥0.6 bethesda unit. Number of surgeries with inhibitors at the end of trial is presented. Analysis population: safety analysis set (SAS) included all patients exposed to trial drug (N8-GP).
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End point type |
Secondary
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End point timeframe |
The endpoint was analysed based on all available information until End of Trial (EOT) Visit and up to approximately 5 weeks for each patient.
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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 |
From the first trial related activity (day 0) after the patient has signed the informed consent until the end of trial (earliest at day 14).
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Adverse event reporting additional description |
Adverse events were reported for the safety analysis set (SAS) which includes all subjects exposed to trial drug (N8-GP). The number of subjects refers to the number of surgeries.
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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 |
21
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Reporting groups
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Reporting group title |
N8-GP
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Reporting group description |
Subjects (from trial NN7088-3859) undergoing major surgery received bleeding preventive treatment with N8-GP before, during and after surgery. The total duration of the trial was 2-5 weeks. Upon completion of this trial, subjects returned to trial NN7088-3859. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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22 Dec 2011 |
Amendment was issued primarily as a response to a
Voluntary Harmonised Procedure (VHP)
assessment. Minor adjustment to the protocol have
been made. Also changes to the Subject
Information/Informed Consent are reflected in this
amendment |
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13 Apr 2012 |
This protocol amendment was issued primarily to change the requirement for the timing of the pre-operative loading dose and secondarily to align with the NN7088-3859
(pathfinderTM2) substantial protocol amendment issued simultaneously. In conjunction other minor clarifications to the protocol has also been included. |
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21 Jan 2014 |
1. Addition of a trial site
2. Decision that the present trial would remain open to
ensure that subjects participating in the NN7088-
3859 trial (including extension parts) would have
the opportunity to undergo major surgery. Thus,
patients would be offered to continue on N8-GP
until commercially available ensuring that they
could undergo surgery without having to switch
product.
3. Withdrawal criteria was amended to allow subjects
with a low titre inhibitor (≤5 BU), that did not
result in clinically ineffective treatment with
N8-GP, to continue in the trial.
4. Minor surgery definitions aligned with trial
NN7088-3859.
5. Israel added to country list.
6. Text updated to reflect what the subject had
consented to regarding storage of samples (if
allowed by local law).
7. Responsibilities regarding labelling and packing of
trial product were updated.
8. Text regarding serious adverse events was
specified. |
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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/28470862 |
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