Clinical Trial Results:
Open Label Phase II Evaluation of Pharmacokinetics, Efficacy, and Safety of Kedrion Human Plasma-derived Antihaemophilic Double Virus inactivated and Nanofiltered Factor IX Administered to Previously Treated Severe or Moderately Severe Hemophilia B Patients
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Summary
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EudraCT number |
2005-006186-14 |
Trial protocol |
IT |
Global end of trial date |
06 Jan 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Apr 2017
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First version publication date |
20 Apr 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 |
KB037
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Kedrion SpA
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Sponsor organisation address |
Località Ai Conti, Barga/Lucca, Italy, 55051
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Public contact |
Chiara Guarnieri/Roberta Macchia
Kedrion SpA, Kedrion SpA, +39 0583767326, r.macchia@kedrion.com
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Scientific contact |
Chiara Guarnieri/Roberta Macchia
Kedrion SpA, Kedrion SpA, +39 0583767320, c.guarnieri@kedrion.com
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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 |
21 Dec 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
06 Jan 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Jan 2016
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Pharmacokinetics (PK) evaluation in vivo incremental recovery; area under the curve (AUC);area under the moment curve (AUMC); plasma half-life (tœ),determination of the time necessary to reach the peak plasma concentration (Tmax),clearance (CL), mean permanence time (MRT),distribution volume at steady state (Vdss),peak plasma concentration (Cmax) Efficacy and Safety evaluation Efficacy: 1) Evaluation of the haemostatic efficacy of Kedrion human plasma-derived double virus inactivated and nanofiltered factor IX (henceforth: Investigational Medicinal Product- IMP) in the management of acute bleeding events. Safety: 1) Assessment of the risk of inhibitor (neutralizing anti factor IX antibodies) development in conjunction with infusion of the IMP throughout the study period 2) Assessment of thrombogenicity of the IMP 3) Assessment of the short and medium term safety of the IMP, when administered to severe/moderately severe Previously Treated Patients
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Protection of trial subjects |
Subjects may withdraw their consent for participation in the study at any time without prejudice. Additionally, the Investigator may withdraw a subject if, in his/her clinical judgment, it is in the best interest of the subject or if the subject cannot comply with the protocol. Wherever possible, the tests and evaluations listed for the termination visit should be carried out. The sponsor should be notified of all study withdrawals within 24 hours.
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
29 Jun 2010
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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 |
Romania: 9
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Country: Number of subjects enrolled |
Italy: 6
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Country: Number of subjects enrolled |
Turkey: 1
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Worldwide total number of subjects |
16
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EEA total number of subjects |
15
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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) |
16
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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 |
- | ||||||
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Pre-assignment
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Screening details |
- | ||||||
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Pre-assignment period milestones
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Number of subjects started |
16 | ||||||
Number of subjects completed |
16 | ||||||
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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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Arm title
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single arm | ||||||
Arm description |
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Arm type |
Experimental | ||||||
Investigational medicinal product name |
Nanofiltered Factor IX
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Pharmacokinetic: 50 + 5 IU/Kg BW
Prophylactic regimen:
The frequency of FIX was twice/week. The IMP was administered iv at a maximum infusion rate of 10 ml/min. The dose administered was 30-40 IU/kg BW with the exact dose determined by the Investigator and rounded up to the nearest whole vial.
Once the prophylactic dose and regimen have been established, every effort had to be made to maintain that regimen throughout the study period. Changes in the dosing regimen might have been made at the Investigator’s discretion.
On-Demand regimen
In the event that the subject experienced a bleed that requires infusion of FIX, the subjects had to be treated exclusively with the IMP, administered iv at a maximum infusion rate of 10 mL/min. The dose and time intervals between doses used to treat the bleed will be at the discretion of the Investigator.
The required initial dosage may eventually be determined using the following formula:
BW (kg) x desired Factor IX increase% x 1.2
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Baseline characteristics reporting groups
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Reporting group title |
overall trial (overall period)
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Reporting group description |
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Subject analysis sets
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Subject analysis set title |
full population
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
-All enrolled patients population: all enrolled subjects in the trial (16)
-Efficacy population: all enrolled subjects, who received at least one infusion of IMP, completing the planned minimum 6 months exposure days, plus additional 6 months or 50 exposure days (whichever comes first) (14)
-Per Protocol population: all Efficacy population subjects with no major protocol violations (14)
-PK population: all enrolled subjects who received at least one infusion of IMP and participated in the PK phase (two PK determinations, once at the study entry and the second one after 6 months) (14)
-Safety population: all enrolled subjects who received at least one infusion of IMP. An early termination does not result in the exclusion of patients from this population (16)
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End points reporting groups
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Reporting group title |
single arm
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Reporting group description |
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Subject analysis set title |
full population
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
-All enrolled patients population: all enrolled subjects in the trial (16)
-Efficacy population: all enrolled subjects, who received at least one infusion of IMP, completing the planned minimum 6 months exposure days, plus additional 6 months or 50 exposure days (whichever comes first) (14)
-Per Protocol population: all Efficacy population subjects with no major protocol violations (14)
-PK population: all enrolled subjects who received at least one infusion of IMP and participated in the PK phase (two PK determinations, once at the study entry and the second one after 6 months) (14)
-Safety population: all enrolled subjects who received at least one infusion of IMP. An early termination does not result in the exclusion of patients from this population (16)
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End point title |
FIX concentration at 6 months (6 h post infusion) [1] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
First PK at Time 0
Second PK after 6 months
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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: Pharmacokinetic Analyses: PK parameters were evaluated using a non-compartmental model. Different types of paramenters were estimated: Slope, Rate constant, Elinination rate constant, α and β half life, Cmax, Tmax, AUC, AUMC and MRT, Vdss, Vd, Cl Each parameter was summarized by mean and SD of the mean. The differences of means (baseline vs 6 months) will be evaluated using paired T test. All PK concentrations were summarized by means of summary statistics for each timepoint |
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End point title |
Efficacy endpoint(mean of bleed/month) [2] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
mean number of new bleeds per month (both the total number and those secondary to trauma) during the all study period
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| Notes [2] - 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: Efficacy Analysis: Efficacy data reported on the CRF and on the patient diary was combined and evaluated by analyzing: - the number of new bleeds per month during the study, total or those secondary to trauma. These parameters were summarized by means and 95% confidence interval of mean |
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Adverse events information
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Timeframe for reporting adverse events |
AEs were reported for all the study period
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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 |
18.1
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Reporting groups
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Reporting group title |
Safety population
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Reporting group description |
All patients who received at least 1 infusion with IMP | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0.44% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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23 Dec 2009 |
Amendment 1 main changes:
1. Monitoring and Quality activities were outsourced to the CRO Sintesi Research S.r.l.
2. Number of patients updated from “not less than 20” to “at least 20” according to
CPMP/BPWG/198/95 rev. 1 Guideline
3. Exclusion of adolescent patients from 12 to 18 years, and consequently deletion of the inclusion criteria “weight>35 Kg”
4. PK evaluations: wash-out period changed from “4-7 days” to “at least 4 (7 if possible)”, according to the reference Guideline.
5. Safety: Inhibitors evaluations: IgE, IgG1, IgG2, IgG3 ed IgG4 dosage against FIX was added in case of patients who develop anaphylaxis and/or inhibitors according to
CPMP/BPWG/198/95 rev. 1 “Note for Guidance on the Clinical Investigation of Human Plasma Derived Factor VIII and IX Products”
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27 Feb 2012 |
Amendment 2 main changes:
Only administrative changes |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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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 | |||||||
