Clinical Trial Results:
Prospective, open-label, multicentre phase 3b study to assess the efficacy and safety of individually tailored prophylaxis with Human-cl rhFVIII in previously treated adult patients with severe haemophilia A
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Summary
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EudraCT number |
2013-001556-35 |
Trial protocol |
GB SK CZ HU BG AT ES DE PL |
Global end of trial date |
16 Jan 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Jan 2017
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First version publication date |
06 Jan 2017
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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 |
GENA-21
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01863758 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Octapharma AG
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Sponsor organisation address |
Seidenstraße 2, Lachen, Switzerland, CH-8853
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Public contact |
Johann Bichler, Octapharma AG, +41 55451 21 77, johann.bichler@octapharma.ch
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Scientific contact |
Johann Bichler, Octapharma AG, +41 55451 21 77, johann.bichler@octapharma.ch
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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 |
13 Jan 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Jan 2015
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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 |
The main objective of the trial was to compare the annualized total bleeding rate of individually tailored prophylaxis with the historical bleeding rate observed in patients having received on-demand treatment with Human-cl rhFVIII from study GENA-01. Thereafter, patients were treated prophylactically every other day or 3x/week with a dose of 30–40 IU/kg body weight for about 1–3 months until PK data have been analysed and discussed with the investigator (Phase-I). Then, patients were treated prophylactically for 6 months (Phase-II) whereby the prophylactic dose and dosing interval were recommended for each patient based on the analysis of individual PK data obtained at the Initial PK visit. Specifically, it was calculated for how long a certain dose will provide FVIII:C plasma concentrations (one-stage assay) of ≥0.01 IU/mL.
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Protection of trial subjects |
The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, and ICH-GCP, and national regulatory requirements. In- and exclusion criteria were carefully defined in order to protect subjects from contraindications, interactions with other medication and safety factors associated with the investigational medicinal product. Throughout the study safety was assessed, such as occurrence of adverse events, measurement of vital signs and physical examinations. In particular, patients were checked whether they had developed an inhibitor to factor VIII.
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Background therapy |
NA | ||
Evidence for comparator |
NA | ||
Actual start date of recruitment |
29 Aug 2013
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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 |
Poland: 9
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Country: Number of subjects enrolled |
Romania: 9
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Country: Number of subjects enrolled |
Slovakia: 2
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Country: Number of subjects enrolled |
United Kingdom: 6
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Country: Number of subjects enrolled |
Austria: 1
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Country: Number of subjects enrolled |
Bulgaria: 31
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Country: Number of subjects enrolled |
Germany: 4
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Country: Number of subjects enrolled |
Hungary: 4
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Worldwide total number of subjects |
66
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EEA total number of subjects |
66
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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) |
0
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Adults (18-64 years) |
65
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment period August 2013 - June 2014 In total, 66 patients previously treated with with Human-cl rhFVIII suffering from haemophilia A were enrolled in 20 study centers in Austria, Bulgaria, Germany, Hungary, Poland, Romania, Slovakia and United Kingdom. | ||||||||||||||||||||
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Pre-assignment
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Screening details |
Severe haemophilia A (FVIII:C <1%), Male patients ≥18 years of age, previous treatment with a FVIII concentrate for at least 150 exposure days (EDs), Good documentation regarding dosing and bleeding frequency in the 6 months preceding study start, Immunocompetence (CD4+ count >200/μL), negative for HIV, freely given informed consent. | ||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (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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Are arms mutually exclusive |
No
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Arm title
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Initial PK Evaluation Phase | ||||||||||||||||||||
Arm description |
Duration: 72 hours | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Human-cl rhFVIII
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Investigational medicinal product code |
Nuwiq
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Dose: 60 +/- 5 IU/kg
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Arm title
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Prophylactic Treatment - Phase I | ||||||||||||||||||||
Arm description |
Patients were to be treated prophylactically every other day or 3x/week with a dose of 30–40 IU/kg body weight (BW) for about 1–3 months until PK data have been analysed and discussed with the investigator. Dose escalations were allowed in case of an inadequate frequency and severity of breakthrough bleeding episodes in accordance with the Institution’s standard clinical care. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Human-cl rhFVIII
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Investigational medicinal product code |
Nuwiq
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Dose: 30 - 40 IU/kg every other day or 3x/week
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Arm title
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Prophylactic Treatment - Phase II | ||||||||||||||||||||
Arm description |
Patients were to be treated prophylactically for 6 months. The prophylactic dose and dosing interval were recommended for each patient based on the analysis of individual PK data obtained at the Initial PK Visit. Specifically, it was calculated for how long a certain dose will provide FVIII:C plasma concentrations (one-stage assay) of ≥0.01 IU/mL using calculated elimination half-lives. The goal was to determine the maximum regular prophylactic dosing interval that can be achieved with a dose of not more than 60–80 IU/kg and that is capable of maintaining a trough level of ≥0.01 IU/mL. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Human-cl rhFVIII
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Investigational medicinal product code |
Nuwiq
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Dose and dosing interval: individually PK tailored
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
PROPH analysis set
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Subject analysis set type |
Sub-group analysis | |||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All patients in the ITT population who entered the Prophylactic Treatment—Phase II of the study (i.e. had at least one prophylactic treatment in Phase II)
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Subject analysis set title |
PROPH-PP analysis set
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Subject analysis set type |
Sub-group analysis | |||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All patients in the PP population who entered the Prophylactic Treatment—Phase II of the study
– who had evaluable initial PK results for the evaluation of the individual prophylactic treatment schedule
– with at least 6 months (–2 weeks) of individual prophylactic treatment (Prophylactic Treatment—Phase II) with Human-cl rhFVIII
– who had no significant dosing or treatment errors, e.g. several unexplained interruptions of individual prophylaxis with Human-cl rhFVIII, e.g. >20% of prophylactic infusions were not given within the prescribed treatment intervals (± 1 day)
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End points reporting groups
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Reporting group title |
Initial PK Evaluation Phase
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Reporting group description |
Duration: 72 hours | ||
Reporting group title |
Prophylactic Treatment - Phase I
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Reporting group description |
Patients were to be treated prophylactically every other day or 3x/week with a dose of 30–40 IU/kg body weight (BW) for about 1–3 months until PK data have been analysed and discussed with the investigator. Dose escalations were allowed in case of an inadequate frequency and severity of breakthrough bleeding episodes in accordance with the Institution’s standard clinical care. | ||
Reporting group title |
Prophylactic Treatment - Phase II
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Reporting group description |
Patients were to be treated prophylactically for 6 months. The prophylactic dose and dosing interval were recommended for each patient based on the analysis of individual PK data obtained at the Initial PK Visit. Specifically, it was calculated for how long a certain dose will provide FVIII:C plasma concentrations (one-stage assay) of ≥0.01 IU/mL using calculated elimination half-lives. The goal was to determine the maximum regular prophylactic dosing interval that can be achieved with a dose of not more than 60–80 IU/kg and that is capable of maintaining a trough level of ≥0.01 IU/mL. | ||
Subject analysis set title |
PROPH analysis set
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
All patients in the ITT population who entered the Prophylactic Treatment—Phase II of the study (i.e. had at least one prophylactic treatment in Phase II)
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Subject analysis set title |
PROPH-PP analysis set
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
All patients in the PP population who entered the Prophylactic Treatment—Phase II of the study
– who had evaluable initial PK results for the evaluation of the individual prophylactic treatment schedule
– with at least 6 months (–2 weeks) of individual prophylactic treatment (Prophylactic Treatment—Phase II) with Human-cl rhFVIII
– who had no significant dosing or treatment errors, e.g. several unexplained interruptions of individual prophylaxis with Human-cl rhFVIII, e.g. >20% of prophylactic infusions were not given within the prescribed treatment intervals (± 1 day)
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End point title |
Comparision of Annualised Total Bleeding Rates (ABR) [1] | ||||||||||||
End point description |
The comparision of the annualized total bleeding rate of individually tailored prophylaxis with the historical bleeding rate observed in patients having received on-demand treatment with Human-cl rhFVIII from study GENA-01.
Reduction of the annualized total bleeding rate observed in the GENA-01 study (58.1 total bleeding episodes per patient per year) by 50% during individually tailored prophylaxis.
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End point type |
Primary
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End point timeframe |
from start of phase II to end of phase II
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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 confirmative 1-sided 1-sample Poisson-test demonstrated that the mean annualised total bleeding rate (ABR) in patients with individually tailored prophylaxis (3.13) is at least 50% below the mean ABR rate in GENA-01 trial (49.36), with the upper bound of the mean ABR 95% CI 3.80) and 97.5% CI (3.90) both lower than 50% of the mean ABR in GENA-01 (24.68). Excluding 1 patient with numerous BEs despite prophylaxis before study entry and during Phase-II (ABR 96 & 107, respectively) ABR is 1.5. |
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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 |
AE were reported throughout the whole study. 24 hours SAE reporting requirement. Waiver from 24 hours SAE reporting: hospitalization for the treatment of a (disease-related) BE assessed as unrelated to IMP treatment.
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Adverse event reporting additional description |
All SAEs, whether suspected to be related to study treatment or not, are reported by telephone, fax or e-mail immediately to the responsible Clinical Project Manager, study monitor, or to the responsible local CRO. AEs were evaluated at each patient visit.
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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 |
17.1
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Reporting groups
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Reporting group title |
Safety anaylsis population SAF
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Reporting group description |
All patients who received at least one dose of Human-cl rhFVIII. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 1.5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 Jan 2014 |
Amendment 02
• One of the objectives of the study was to assess the TGA in terms of its usefulness in individualising therapy for patients on prophylaxis. Unfortunately, the TGA samples from the PK assessment of 31 patients could not be analysed because samples thawed during transit to the laboratory. In order to end up with a reasonable number of patients for whom this parameter could be analysed it was decided to increase the number of patients from approximately 55 patients enrolled with the aim to have evaluable data on 50 patients, to 65 patients enrolled with the aim to have evaluable data on 60 patients.
• The efficacy analysis plan was supplemented with a secondary analysis regarding the analysis of the bleeding rate and treatment of bleeding episodes as requested by FDA for the completed GENA studies GENA-01, GENA-03 and GENA-08.
• The wording was modified to better explain the BLEED and BLEED-PP population i.e. that the populations were those of treated bleeds. |
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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 | |||
