Clinical Trial Results:
Multicenter, Prospective, Open-Label, Single-Arm Trial to Evaluate the Pharmacokinetics, Efficacy, and Safety of Human Plasma-Derived Fibrinogen (FIB Grifols) in Patients with Congenital Afibrinogenemia
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Summary
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EudraCT number |
2013-004343-23 |
Trial protocol |
IT |
Global end of trial date |
11 Nov 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Oct 2020
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First version publication date |
23 Oct 2020
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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 |
IG0902
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02281500 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Instituto Grifols, S.A.
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Sponsor organisation address |
Can Guasch, 2, Parets del Vallès, Barcelona, Spain, 08150
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Public contact |
Bioscience Clinical and Pharmacovigilance, Instituto Grifols, S.A., 0034 935712000, IGregulatory.affairs@grifols.com
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Scientific contact |
Bioscience Clinical and Pharmacovigilance, Instituto Grifols, S.A., 0034 935712000, IGregulatory.affairs@grifols.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 |
11 Nov 2019
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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 |
11 Nov 2019
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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 this study was to evaluate the pharmacokinetics (PK), efficacy, and safety of human plasma-derived fibrinogen concentrate FIB Grifols after a single-dose 70 milligrams/kilogram (mg/kg) body weight administration.
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Protection of trial subjects |
The ethical standards adopted by the XVIII World Medical Assembly (Helsinki, 1964) (and subsequent revisions) was strictly observed. The clinical trial likewise was performed in compliance with standards of ICH GCP guideline relating to trials involving investigational drugs.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Jul 2016
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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 |
India: 14
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Country: Number of subjects enrolled |
Lebanon: 7
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Country: Number of subjects enrolled |
United States: 1
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Worldwide total number of subjects |
22
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EEA total number of subjects |
0
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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) |
10
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
11
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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 |
The study was conducted in India, Lebanon, and the United States of America (USA) between 22 Jul 2016 (first subject first visit) and 11 Nov 2019 (last subject last visit). | ||||||
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Pre-assignment
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Screening details |
A total of 26 subjects were screened, out of which 24 subjects were enrolled, of them 2 subjects withdrawal the consent prior to receiving the study treatment, and the remaining 22 subjects received the study treatment. | ||||||
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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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FIB Grifols 70 mg/kg body weight | ||||||
Arm description |
Subjects received a single dose of slow intravenous infusion of Human Plasma-Derived Fibrinogen Concentrate Grifols (FIB Grifols) 70 milligram per kilogram (mg/kg) body weight, at a rate not exceeding 5 mL/minute, on Day 0. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Fibrinogen Grifols
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Investigational medicinal product code |
FIB Grifols
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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 drip use
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Dosage and administration details |
Subjects received a single dose of slow IV infusion of FIB Grifols 70mg/kg body weight, at a rate not exceeding 5 mL/minute, on Day 0.
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Baseline characteristics reporting groups
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Reporting group title |
FIB Grifols 70 mg/kg body weight
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Reporting group description |
Subjects received a single dose of slow intravenous infusion of Human Plasma-Derived Fibrinogen Concentrate Grifols (FIB Grifols) 70 milligram per kilogram (mg/kg) body weight, at a rate not exceeding 5 mL/minute, on Day 0. | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
FIB Grifols 70 mg/kg body weight
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Reporting group description |
Subjects received a single dose of slow intravenous infusion of Human Plasma-Derived Fibrinogen Concentrate Grifols (FIB Grifols) 70 milligram per kilogram (mg/kg) body weight, at a rate not exceeding 5 mL/minute, on Day 0. | ||
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End point title |
Area Under the Plasma Fibrinogen Concentration-time Curve (AUC) from Time Zero to 14 days (AUC0-14days) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [1] | ||||||||
End point description |
AUC(0-14days) was calculated by a combination of linear and logarithmic trapezoidal methods and expressed in the unit of concentration × time. The linear trapezoidal method used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method used for those arising from decreasing concentrations. Plasma fibrinogen activity determined by the Clauss method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The Pharmacokinetic (PK) analysis population included all subjects who have received study medication and had sufficient fibrinogen plasma concentration data to facilitate the calculation of pharmacokinetic parameters. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [2] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Plasma Fibrinogen Concentration-time Curve (AUC) from Time Zero to 14 days (AUC0-14days) of FIB Grifols Determined by Enzyme-Linked Immunosorbent Assay (ELISA) Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [3] | ||||||||
End point description |
AUC(0-14days) was calculated by a combination of linear and logarithmic trapezoidal methods and expressed in the unit of concentration × time. The linear trapezoidal method was used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations. Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [3] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [4] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
AUC from Time Zero To Infinite Time (AUC0-infinity) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [5] | ||||||||
End point description |
AUC0-infinity was calculated as AUC0-t + Ct/Kel, where (AUC0-t) was the area under the concentration vs. time curve from time 0 to the time of last quantifiable concentration (Ct), and Kel was the apparent terminal first-order elimination rate constant, determined by linear regression analysis of the natural log-linear segment of the plasma concentration-time curve, expressed in time-1 units (1/h). Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [5] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [6] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
AUC from Time Zero To Infinite Time (AUC0-infinity) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [7] | ||||||||
End point description |
AUC0-infinity was calculated as AUC0-t + Ct/Kel, where (AUC0-t) was the area under the concentration vs. time curve from time 0 to the time of last quantifiable concentration (Ct), and Kel was the apparent terminal first-order elimination rate constant, determined by linear regression analysis of the natural log-linear segment of the plasma concentration-time curve, expressed in time-1 units (1/h). Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [7] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [8] - PK analysis with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Maximum Observed Peak Plasma Fibrinogen Concentration (Cmax) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [9] | ||||||||
End point description |
Cmax was obtained directly from the experimental data without interpolation. Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study. PK analysis population included all subjects who have received study medication and had sufficient fibrinogen plasma concentration data to facilitate the calculation of pharmacokinetic parameters. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [9] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [10] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Maximum Observed Peak Plasma Fibrinogen Concentration (Cmax) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [11] | ||||||||
End point description |
Cmax was obtained directly from directly from the experimental data without interpolation. Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. PK analysis population included all subjects who have received study medication and had sufficient fibrinogen plasma concentration data to facilitate calculation of pharmacokinetic parameters. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [11] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [12] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Reach Maximum Plasma Fibrinogen Concentration (Tmax) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [13] | ||||||||
End point description |
Tmax was obtained directly from the experimental data without interpolation, expressed in time units (hour). Plasma fibrinogen activity was determined by the Clauss method in the central laboratory of the study. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [13] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [14] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Reach Maximum Plasma Fibrinogen Concentration (Tmax) of FIB Grifols Determined by ELISA Method [15] | ||||||||
End point description |
Tmax was obtained directly from the experimental data without interpolation, expressed in time units (hour). Plasma fibrinogen activity was determined by the ELISA method in the central laboratory of the study. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [15] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [16] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Apparent Terminal Half-life (t1/2) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [17] | ||||||||
End point description |
t1/2 was the time measured for the concentration to decrease by one half. t1/2 calculated by natural log 2 divided by Kel and expressed in time units (hour). PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [17] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [18] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Apparent Terminal Half-life (t1/2) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [19] | ||||||||
End point description |
t1/2 was the time measured for the concentration to decrease by one half. t1/2 calculated by natural log 2 divided by Kel and expressed in time units (hour). PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [19] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [20] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Mean Residence Time (MRT) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [21] | ||||||||
End point description |
MRT was calculated by AUC0-inf/AUC0-inf - (TI/2), where AUC0-inf was the area under the first moment of the concentration vs. time curve from time 0 extrapolated to infinite time and T1/2 was the apparent terminal half-life of infusion. PK analysis population included all subjects who have received study medication and had sufficient fibrinogen plasma concentration data to facilitate the calculation of pharmacokinetic parameters. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [21] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [22] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Mean Residence Time (MRT) of FIB Grifols Assessed Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [23] | ||||||||
End point description |
MRT was calculated by AUC0-inf/AUC0-inf - (TI/2), where AUC0-inf was the area under the first moment of the concentration vs. time curve from time 0 extrapolated to infinite time and T1/2 was the apparent terminal half life of infusion. PK analysis population included all subjects who have received study medication and had sufficient fibrinogen plasma concentration data to facilitate calculation of pharmacokinetic parameters. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [23] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [24] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Volume of Distribution (Vd) of FIB Grifols Determined by Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [25] | ||||||||
End point description |
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [25] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [26] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Volume of Distribution (Vd) of FIB Grifols Determined by ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [27] | ||||||||
End point description |
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [27] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [28] - PK analysis with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Clearance (Cl) of FIB Grifols Determined By Clauss Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [29] | ||||||||
End point description |
Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
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| Notes [29] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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| Notes [30] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Clearance (Cl) of FIB Grifols Determined By ELISA Method, Dose Normalized to 70 mg/kg and Corrected for Baseline Concentration [31] | ||||||||
End point description |
Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. PK parameters adjusted for baseline fibrinogen level calculated by deducting the pre-infusion fibrinogen concentration from the post-infusion concentrations before the calculation. The PK population used for the analyses of the PK parameters. Here, the “number of subjects analyzed” signifies subjects who were evaluable for this measure.
|
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End point type |
Primary
|
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
|
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| Notes [31] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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|
|||||||||
| Notes [32] - PK analysis with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
|
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End point title |
In Vivo Recovery (IVR) of FIB Grifols Determined by Clauss Method [33] | ||||||||
End point description |
Incremental IVR was calculated for fibrinogen levels from the peak level recorded within and included the first four hours after the end of infusion and reported as milligram per deciliter per milligram per kilogram [mg/dL]/[mg/kg]. IVR was determined for every subject using the following formula: ([FIB max (mg/dL)] - [FIB pre-infusion (mg/dL)])/FIB administered (mg)/Body weight (kg), where the FIB max is the peak FIB activity within the first four hours after the end of infusion and FIB pre-infusion was the baseline FIB activity level of the subject. FIB administered was the actual administered dose calculated using the actual volume administered to the subject, the declared potency, and the true concentration of FIB in the batch used. The PK population used for the analyses of the PK parameters.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
|
||||||||
| Notes [33] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
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|
|||||||||
| Notes [34] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
|
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End point title |
In Vivo Recovery (IVR) of FIB Grifols Determined by ELISA Method [35] | ||||||||
End point description |
Incremental IVR was calculated for fibrinogen levels from the peak level recorded within and included the first four hours after the end of infusion and reported as milligram per deciliter per milligram per kilogram [mg/dL]/[mg/kg]. IVR was determined for every subject using the following formula: ([FIB max (mg/dL)] - [FIB pre-infusion (mg/dL)])/FIB administered (mg)/Body weight (kg), where the FIB max is the peak FIB activity within the first four hours after the end of infusion and FIB pre-infusion was the baseline FIB activity level of the subject. FIB administered was the actual administered dose calculated using the actual volume administered to the subject, the declared potency, and the true concentration of FIB in the batch used. The PK population used for the analyses of the PK parameters.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 336 hours post-infusion
|
||||||||
| Notes [35] - 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: Statistical analysis was not performed since the descriptive statistical analysis was only planned for this endpoint. |
|||||||||
|
|||||||||
| Notes [36] - PK population with evaluable subjects for this end-point. |
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| No statistical analyses for this end point | |||||||||
|
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End point title |
Mean Change on Maximum Clot Firmness (MCF) from Baseline to 1-hour Post-infusion [37] | ||||||||
End point description |
MCF was as a functional parameter of blood's ability to coagulate, provides an indirect measure of hemostatic efficacy of replacement treatment with fibrinogen concentrates in subjects with fibrinogen deficiency. Rotational thromboelastography (ROTEM) was performed on frozen plasma samples by the central laboratory to measure MCF. Undetectable MCF values were set to 0. The Evaluable population included all subjects who received Investigational Product (IP) at any amount and who had at least two measurements, pre-infusion MCF and 1-hour post-infusion MCF measurements by ROTEM.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Baseline to 1 hour post-infusion
|
||||||||
| Notes [37] - 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: EudraCT database does not allow to report only one treatment group in the statistical analyses section. Due to this format constraint, inferential statistical analysis was not presented for this end-point. |
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|
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| No statistical analyses for this end point | |||||||||
|
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End point title |
Mean Change in Clotting Time (CT) from Baseline to 1-hour Post-infusion | ||||||||
End point description |
Improvement in adult subjects' plasma samples in CT from baseline to 1-hour post-infusion indicated the hemostatic efficacy of the treatment with fibrinogen concentrate in subjects with fibrinogen deficiency. The Evaluable population was used for the analyses. Here "99999" signifies that standard deviation could not be estimated as there was only 1 subject with detectable baseline CT value and thus analyzed, undetectable CT values were set to missing.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline to 1-hour post-infusion
|
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|
|||||||||
| Notes [38] - Evaluable population analysis with evaluable subject for this end-point. |
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| No statistical analyses for this end point | |||||||||
|
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End point title |
Clot Formation Time (CFT) at 1-hour Post-infusion | ||||||||
End point description |
Improvement in subjects plasma samples in CFT at 1-hour post-infusion indicated the hemostatic efficacy of the treatment with fibrinogen concentrate in subjects with fibrinogen deficiency. The Evaluable population was used for the analyses. Here "99999" signifies that standard deviation could not be estimated as there was only 1 subject with detectable baseline CFT value and thus analyzed, undetectable CFT values were set to missing.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
1 hour post-infusion
|
||||||||
|
|||||||||
| Notes [39] - Evaluable population analysis with evaluable subjects for this end-point. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Mean Change in Alpha angle (α) from Baseline to 1-hour Post-infusion | ||||||||
End point description |
Improvement in subjects plasma samples in alpha angle from baseline to 1-hour post-infusion indicated the hemostatic efficacy of the treatment with fibrinogen concentrate in subjects with fibrinogen deficiency. The Evaluable population was used for the analyses.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline to 1 hour post-infusion
|
||||||||
|
|||||||||
| Notes [40] - Evaluable population analysis with the eligible subjects for this end-point. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Mean Change in Prothrombin Time (PT) from Baseline to 1-hour Post-infusion | ||||||||
End point description |
Improvement in the subject’s plasma samples standard coagulation tests from baseline to 1-hour post-infusion indicated hemostatic efficacy of the treatment with fibrinogen concentrate in subjects with fibrinogen deficiency. The Evaluable population was used for the analyses.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline to 1 hour post-infusion
|
||||||||
|
|||||||||
| Notes [41] - Evaluable population with eligible subjects for this end-point. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Mean Change in Thrombin time (TT) from Baseline to 1-hour Post-infusion | ||||||||
End point description |
Improvement in the subject’s plasma samples standard coagulation tests from baseline to 1-hour post-infusion indicated hemostatic efficacy of the treatment with fibrinogen concentrate in subjects with fibrinogen deficiency. The Evaluable population was used for the analyses.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline to 1 hour post-infusion
|
||||||||
|
|||||||||
| Notes [42] - Evaluable population analysis with evaluable subjects for this end-point. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Mean Change in Activated Partial Thromboplastin Time (aPTT) from Baseline to 1-hour Post-infusion | ||||||||
End point description |
Improvement in subject’s plasma samples standard coagulation tests from baseline to 1-hour post-infusion indicated hemostatic efficacy of the treatment with a fibrinogen concentrate in subjects with fibrinogen deficiency. The Evaluable population was used for the analyses.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline to 1 hour post-infusion
|
||||||||
|
|||||||||
| Notes [43] - Evaluable population analysis with evaulable subjects for this end-point. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | ||||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered a study drug which may or may not have a causal relationship with the study drug. SAE was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-subject hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Treatment-emergent defined as adverse events/serious adverse events that started or worsened on or after the start of the investigational product infusion. The safety population included all subjects who received infusion (at any dose) of the IP.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From the start of the investigation product infusion up to Week 4
|
||||||||||||
|
|||||||||||||
| 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 start of the investigational product infusion up to Week 4
|
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Adverse event reporting additional description |
The safety population included all subjects who received infusion (at any dose) of the IP.
|
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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 |
FIB Grifols 70 mg/kg body weight
|
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Reporting group description |
Subjects received a single dose of slow IV infusion of FIB Grifols 70 mg/kg body weight, at a rate not exceeding 5 mL/minute, on Day 0. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
12 Feb 2016 |
Amendment #2.3 included clarification regarding subject eligibility determination and included additional details. 1.
In case fibrinogen levels determination for verification of the Inclusion/Exclusion criteria is performed at the Screening Visit, this sample will not be taken at Baseline Visit. Sample for PK will still be taken at Baseline Visit. 2. Fibrinogen levels: Plasma samples will be obtained for measurement of fibrinogen levels at those sites that cannot perform fibrinogen levels determinations by two methods: fibrinogen activity (Clauss method) and fibrinogen antigen locally. In these cases the subject will have a blood sample taken at Screening Visit and have it analyzed for this parameter by both methods at the central laboratory of the study for verification of the eligibility against the Inclusion/Exclusion criteria. In these cases, samples for the Inclusion/Exclusion criteria assessment will not be taken at Baseline Visit. Samples for PK will still be taken at Baseline Visit.
The subject discontinues his/her participation in the clinical trial without withdrawing his/her informed consent.
Any AE occurred during infusion or within 24 and 72 hours after completion of infusion will be considered temporally associated with the infusion and labeled as infusional AEs.
Thrombotic Events Risk Assessment included Wells Score which will be observed for evaluation and assessment of thrombotic events risk.
|
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
