Clinical Trial Results:
A prospective, controlled, randomised, cross-over study investigating the pharmacokinetic properties, surrogate efficacy and safety of Octafibrin compared to Haemocomplettan® P/ RiaSTAPTM in subjects with congenital fibrinogen deficiency
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Summary
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EudraCT number |
2011-002403-15 |
Trial protocol |
GB DE IT |
Global end of trial date |
19 Jan 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
31 Jul 2016
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First version publication date |
31 Jul 2016
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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 |
Forma-01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01575756 | ||
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 |
Clinical Research and Development, Octapharma Pharmazeutika Produktionsgesellschaft m.b.H, 0043 1610320, clinical.department@octapharma.com
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Scientific contact |
Clinical Research and Development, Octapharma Pharmazeutika Produktionsgesellschaft m.b.H, 0043 1610320, clinical.department@octapharma.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-001208-PIP01-11 | ||
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 |
14 Aug 2015
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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 |
19 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 |
• To determine the single dose pharmacokinetics of Octafibrin and Haemocomplettan® P/RiaSTAPTM in subjects with congenital fibrinogen deficiency
• To determine maximum clot strength (maximum clot firmness [MCF]) as a surrogate marker for haemostatic efficacy before and after administration of Octafibrin and Haemocomplettan® P/ RiaSTAPTM in subjects with congenital fibrinogen deficiency.
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Protection of trial subjects |
This trial was conducted in accordance to the principles of GCP, ensuring that the rights, safety and well-being of patients are protected and in consistency with the the Declaration of Helsinki.
Inclusion 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 AEs, labvalues, vital signs and physical examinations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
04 Jun 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 |
United Kingdom: 3
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Country: Number of subjects enrolled |
Bulgaria: 1
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Country: Number of subjects enrolled |
India: 8
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Country: Number of subjects enrolled |
Iran, Islamic Republic of: 7
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Country: Number of subjects enrolled |
Switzerland: 1
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Country: Number of subjects enrolled |
United States: 2
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Worldwide total number of subjects |
22
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EEA total number of subjects |
4
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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) |
6
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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 |
22 | |||||||||
Number of subjects completed |
22 | |||||||||
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Period 1
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Period 1 title |
overall trial
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Octafibrin Followed by Haemocomplettan® P or RiaSTAPTM | |||||||||
Arm description |
Participants received a single dose of Octafibrin 70 mg/kg intravenously once followed by Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously 45 days later or Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously followed by Octafibrin 70 mg/kg intravenously 45 days later in a randomized crossover design | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Octafibrin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Octafibrin is a human plasma-derived fibrinogen concentrate for intravenous use.The product was packed and labelled according to local regulations in vials containing 1 g of lyophilised fibrinogen concentrate powder for reconstitution with 50 mL of water for injection (WFI). Octafibrin was administered at a dose of 70 mg/kg body weight (BW) It was administered as an intravenous bolus injection at a maximum speed of 5 mL/min.(based on the labelled potency).
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Investigational medicinal product name |
Haemocomplettan® P/RiaSTAPTM
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
The reference therapy in this study was Haemocomplettan® P/RiaSTAPTM, which is a marketed fibrinogen concentrate. It was administered intravenously at a dose of 70 mg/kg BW (based on the labelled potency).
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Arm title
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Haemocomplettan® P or RiaSTAPTM Followed by Octafibrin | |||||||||
Arm description |
Participants received a single dose of Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously in a randomized crossover design followed by Octafibrin 70 mg/kg intravenously 45 days later. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Haemocomplettan® P/RiaSTAPTM
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
The reference therapy in this study was Haemocomplettan® P/RiaSTAPTM, which is a marketed fibrinogen concentrate. It was administered intravenously at a dose of 70 mg/kg BW (based on the labelled potency).
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Investigational medicinal product name |
Octafibrin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Octafibrin is a human plasma-derived fibrinogen concentrate for intravenous use.The product was packed and labelled according to local regulations in vials containing 1 g of lyophilised fibrinogen concentrate powder for reconstitution with 50 mL of water for injection (WFI). Octafibrin was administered at a dose of 70 mg/kg body weight (BW) It was administered as an intravenous bolus injection at a maximum speed of 5 mL/min.(based on the labelled potency).
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Period 2
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Period 2 title |
Octafibrin
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Is this the baseline period? |
No | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Arm title
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Octafibrin | |||||||||
Arm description |
- | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Octafibrin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Octafibrin is a human plasma-derived fibrinogen concentrate for intravenous use.The product was packed and labelled according to local regulations in vials containing 1 g of lyophilised fibrinogen concentrate powder for reconstitution with 50 mL of water for injection (WFI). Octafibrin was administered at a dose of 70 mg/kg body weight (BW) It was administered as an intravenous bolus injection at a maximum speed of 5 mL/min.(based on the labelled potency).
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Period 3
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Period 3 title |
Haemocomplettan® P or RiaSTAPTM
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Is this the baseline period? |
No | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Arm title
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Haemocomplettan® P or RiaSTAPTM | |||||||||
Arm description |
- | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Haemocomplettan® P/RiaSTAPTM
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
The reference therapy in this study was Haemocomplettan® P/RiaSTAPTM, which is a marketed fibrinogen concentrate. It was administered intravenously at a dose of 70 mg/kg BW (based on the labelled potency).
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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 |
PK Analysis Set (PK-PP)
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Subject analysis set type |
Per protocol | |||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The PK analysis set will include all patients who completed the PK assessment per protocol (PP)
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Subject analysis set title |
Full Analysis Set (FAS)
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Subject analysis set type |
Full analysis | |||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The full analysis set, defined according to the intention-to-treat (ITT) principle, will include all randomized patients who received at least one infusion of study medication (Octafibrin and/or any part of an infusion of Haemocomplettan® P/ RiaSTAPTM) and for whom any post-treatment data is available.
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End points reporting groups
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Reporting group title |
Octafibrin Followed by Haemocomplettan® P or RiaSTAPTM
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Reporting group description |
Participants received a single dose of Octafibrin 70 mg/kg intravenously once followed by Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously 45 days later or Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously followed by Octafibrin 70 mg/kg intravenously 45 days later in a randomized crossover design | ||
Reporting group title |
Haemocomplettan® P or RiaSTAPTM Followed by Octafibrin
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Reporting group description |
Participants received a single dose of Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously in a randomized crossover design followed by Octafibrin 70 mg/kg intravenously 45 days later. | ||
Reporting group title |
Octafibrin
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Reporting group description |
- | ||
Reporting group title |
Haemocomplettan® P or RiaSTAPTM
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Reporting group description |
- | ||
Subject analysis set title |
PK Analysis Set (PK-PP)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The PK analysis set will include all patients who completed the PK assessment per protocol (PP)
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Subject analysis set title |
Full Analysis Set (FAS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The full analysis set, defined according to the intention-to-treat (ITT) principle, will include all randomized patients who received at least one infusion of study medication (Octafibrin and/or any part of an infusion of Haemocomplettan® P/ RiaSTAPTM) and for whom any post-treatment data is available.
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End point title |
Fibrinogen Activity Normalized Area Under the Curve Standardized [1] | ||||||||||||
End point description |
Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment. The normalized area under the curve was standardized to a dose of 70 mg/kg.
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End point type |
Primary
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End point timeframe |
Blood samples for the PK assessments were taken over a period of 14 days at baseline, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 312 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: The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment. The normalized area under the curve was standardized to a dose of 70 mg/kg. Because of the cross over design the statistical analyses of this endpoint is already reported as Fibrinogen Activity Normalized AUC. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in Maximum Clot Firmness 1 Hour Post-treatment From Baseline [2] | ||||||||||||
End point description |
Thromboelastometry (ROTEM®) was used to measure maximum clot firmness. Thromboelastometry is a method for the continuous measurement of clot formation. Maximum clot firmness is a functional parameter that depends on the activation of coagulation, the platelet and fibrinogen content of the blood sample, and the polymerisation and cross-linking of the fibrin network. In order to obtain comparable results from all study centres, maximum clot firmness data were assessed from frozen citrated plasma samples in a central laboratory. As these samples did not contain platelets that would be found in the whole blood assay, only the fibrinogen content defined the maximum clot firmness.
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End point type |
Primary
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End point timeframe |
baseline and 1 hour post-infusion
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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: For each time point and treatment group, the mean, SD, median and range has been provided for the absolute MCF values and the changes from baseline (i.e. from pre-infusion). Mean changes in MCF between baseline and the 1 hour value have been described with two-sided 95% CIs based on the paired t-test. Further, the intra-individual differences between the changes from BL for each treatment will be described; corresponding 95% CI intervals based on the paired t-test was generated. |
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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 |
AEs occurring from Day 1 up to Day 14 post administration in each study period and SAEs occurring from Day 1 to Day 45 in each study period
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Adverse event reporting additional description |
Treatment-emergent adverse events (TEAEs) were defined as AEs occurring from Day 1 up to Day 14 post administration in each study period. Additionally, SAEs were considered TEAEs from Day 1 in first study period until study completion on day 45
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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 |
18.0
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Reporting groups
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Reporting group title |
Octafibrin
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Reporting group description |
AEs occurring from Day 1 up to Day 14 post administration in each study period and SAEs occurring from Day 1 to Day 45 in each study period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Haemocomplettan® P/RiaSTAPTM
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Reporting group description |
AEs occurring from Day 1 up to Day 14 post administration in each study period and SAEs occurring from Day 1 to Day 45 in each study period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
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 | |||
