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Clinical Trial Results:
A prospective, open-label, phase I/III study investigating pharmacokinetic properties of BT524 and efficacy and safety of BT524 in the treatment and prophylaxis of bleeding in patients with congenital fibrinogen deficiency

Summary
EudraCT number	2011-004154-25
Trial protocol	IT DE BG
Global end of trial date	18 May 2020

Results information
Results version number	v1(current)
This version publication date	11 Sep 2021
First version publication date	11 Sep 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

984

ISRCTN number

US NCT number

NCT02065882

WHO universal trial number (UTN)

Sponsor organisation name

Biotest AG

Sponsor organisation address

Landsteinerstraße 5, Dreieich, Germany, 63303

Public contact

Corporate Clinical Research & Development, Biotest AG, 0049 6103801492, andrea.wartenberg-demand@biotest.com

Scientific contact

Corporate Clinical Research & Development, Biotest AG, 0049 6103801497, andrea.wartenberg-demand@biotest.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001931-PIP16-02

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

02 Jul 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 May 2020

Global end of trial reached?

Yes

Global end of trial date

18 May 2020

Was the trial ended prematurely?

Main objective of the trial

To investigate the 14 day single-dose pharmacokinetics of BT524 following intravenous infusion in patients with congenital fibrinogen deficiency (afibrinogenemia or severe hypofibrinogenemia).

Protection of trial subjects

The study was conducted in accordance with the ICH-GCP guidelines, the most recent version of the Declaration of Helsinki, and with local regulatory requirements. Children and adolescents (≥ 6 to < 18 years) were to be enrolled, only after completion of dosing interval and the associated 7-day dosing-free safety interval of the first 10 adult patients enrolled into the study and after the Data Monitoring Committee (DMC) had reviewed the data from these 10 adult patients. Subsequently, after the first 20 patients ≥ 6 to ≤ 75 years had finished PK/PD part I, 3 additional patients < 6 years were planned to be enrolled in study part I and subsequently in the part II. Prior to enrolment of any children < 6 years into the study the DMC had to review and to assess all available safety and PK/PD data from adults and children ≥ 6 years enrolled in the study at that time. Implementation of Stopping rule: The DMC was expected to review all safety relevant information for each participating subject individually with the purpose to identify safety issues that were pertinent to the decision whether the study could be continued as intended or whether the safety relevant methods and procedures needed to be adjusted.

Background therapy

None

Evidence for comparator

None

Actual start date of recruitment

11 Mar 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Lebanon: 39

Country: Number of subjects enrolled

Egypt: 12

Country: Number of subjects enrolled

Tunisia: 13

Country: Number of subjects enrolled

Bulgaria: 2

Country: Number of subjects enrolled

Germany: 1

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

First Patient enrolled March 2013, last Patient completed May 2020

Screening details

Male or female aged 0 to 75 Diagnosis: Known congenital afibrinogenemia or severe congenital hypofibrinogenemia

Number of subjects started

35 ^[1]

Number of subjects completed

Reason: Number of subjects

Consent withdrawn by subject: 2

Reason: Number of subjects

screen failures: 5

Reason: Number of subjects

No IMP available: 1

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The study was divided into part I and part II. Patients in part I who received treatment and completed part I were subsequently enrolled in part II. 35 patients were enrolled in part I, thereof 27 patients were enrolled in part II. In addition, 32 patients were directly enrolled in part II, without participation in PK part I. Overall, 67 patients were enrolled in this study (35 patients in part I and additional 32 patients in part II).

Period 1 title

PK Part I

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

BT524

Arm description

IV administration of BT524 (fibrinogen concentrate from human plasma)

Arm type

Intervention

Investigational medicinal product name

BT524 (fibrinogen concentrate from human plasma)

Investigational medicinal product code

BT524

Other name

Fibrinogen concentrate

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Injection , Infusion , Intravenous use

Dosage and administration details

The dosage and duration of the substitution therapy depended on the severity of the disorder, location and extent of the bleeding and the patient’s clinical condition. Besides, dosage was based on individual body weight (BW) and individual fibrinogen baseline level. Similar dosage strategy was applied to patients aged < 6 years, as for patients aged ≥ 6 to ≤ 75 years. The dosage regimen for surgical interventions and spontaneous bleedings targeted (functional) fibrinogen levels recommended by the core Summary of Product Characteristics (SmPC) for human fibrinogen products. PK Part I: 70 mg/kg BW, single IV infusion

Number of subjects in period 1 ^[2]	BT524
Started	27
Completed	27

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Baseline characteristics are only available separate for treated patients in study part I (n=27) and for treated patients in study part II (n=36).

Period 2 title

Part II

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

BT524

Arm description

IV administration of BT524 (fibrinogen concentrate from human plasma)

Arm type

Intervention

Investigational medicinal product name

BT524 (fibrinogen concentrate from human plasma)

Investigational medicinal product code

BT524

Other name

Fibrinogen concentrate

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Infusion , Injection , Intravenous use

Dosage and administration details

Number of subjects in period 2	BT524
Started	27
Completed	36
Not completed	23
Consent withdrawn by subject	1
Adverse event, non-fatal	1
Study termination due to local authority decision	3
Screen failure	7
Without bleeding event	11
Joined	32
New recruitment directly in study part II	32

Baseline characteristics

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Reporting group title

PK Part I

Reporting group description

Demographic data were documented at screening. The analysis was performed in the Safety Analysis Set (SAF I) for all patients completed part I (n=27).

Reporting group values	PK Part I	Total
Number of subjects	27	27
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	3	3
Children (2-11 years)	6	6
Adolescents (12-17 years)	3	3
Adults (18-64 years)	15	15
From 65-84 years	0	0
85 years and over	0	0
Gender categorical
Units: Subjects
Female	13	13
Male	14	14

Subject analysis set title

SAF I

Subject analysis set type

Safety analysis

Subject analysis set description

The safety analysis set I (SAF I) comprises of all patients who were exposed to BT524 in part I of the study.

Subject analysis set title

SAF II

Subject analysis set type

Safety analysis

Subject analysis set description

The safety analysis set II (SAF II) comprises of all patients who were exposed to BT524 in part II of the study.

Subject analysis set title

PK Set

Subject analysis set type

Full analysis

Subject analysis set description

The Pharmacokinetic analysis set (PK) consists of all patients of part I with PK data.

Subject analysis sets values	SAF I	SAF II	PK Set
Number of subjects	27	36	27
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	3	1	3
Children (2-11 years)	6	11	6
Adolescents (12-17 years)	3	4	3
Adults (18-64 years)	15	20	15
From 65-84 years	0	0	0
85 years and over	0	0	0
Age continuous
Units:
	±	±	±
Gender categorical
Units: Subjects
Female	13	14	13
Male	14	22	14

End points

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Reporting group title

BT524

Reporting group description

IV administration of BT524 (fibrinogen concentrate from human plasma)

Reporting group title

BT524

Reporting group description

IV administration of BT524 (fibrinogen concentrate from human plasma)

Subject analysis set title

SAF I

Subject analysis set type

Safety analysis

Subject analysis set description

The safety analysis set I (SAF I) comprises of all patients who were exposed to BT524 in part I of the study.

Subject analysis set title

SAF II

Subject analysis set type

Safety analysis

Subject analysis set description

The safety analysis set II (SAF II) comprises of all patients who were exposed to BT524 in part II of the study.

Subject analysis set title

PK Set

Subject analysis set type

Full analysis

Subject analysis set description

The Pharmacokinetic analysis set (PK) consists of all patients of part I with PK data.

Primary: Single-dose PK of FiAg: Terminal Elimination Half-life (t1/2)

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End point title

Single-dose PK of FiAg: Terminal Elimination Half-life (t1/2) ^[1]

End point description

Terminal Elimination Half-live (t1/2) was assessed after a single IV infusion of 70 mg/kg body weight of BT524. t1/2 of fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. t1/2 was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).

End point type

Primary

End point timeframe

Pre-dose, end of infusion (EoI), 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 96 h, 168 h, 240 h and 336 h post-EoI.

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: Analysis of the study data for the primary endpoint was descriptive only. PK parameters were summarized by descriptive statistics. No confirmatory testing was performed on the PK parameters in part I.

End point values	BT524	PK Set
Number of subjects analysed	27	27
Units: hours
arithmetic mean (standard deviation)	67.9 ± 15.3	67.9 ± 15.3

No statistical analyses for this end point

Primary: Single-dose PK of FiAg: Time to Maximum Concentration (tmax)

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End point title

Single-dose PK of FiAg: Time to Maximum Concentration (tmax) ^[2]

End point description

Time to reach Maximum Concentration (tmax) was assessed after a single IV infusion of 70 mg/kg body weight of BT524. Time of occurence of Cmax relative to dosing (Tmax) for fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. Tmax was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).

End point type

Primary

End point timeframe

Pre-dose, end of infusion (EoI), 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 96 h, 168 h, 240 h and 336 h post-EoI.

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: Analysis of the study data for the primary endpoint was descriptive only. PK parameters were summarized by descriptive statistics. No confirmatory testing was performed on the PK parameters in part I.

End point values	BT524	PK Set
Number of subjects analysed	27	27
Units: hours
arithmetic mean (standard deviation)	0.843 ± 0.361	0.843 ± 0.361

No statistical analyses for this end point

Primary: Single-dose PK of FiAg: Maximum Concentration (Cmax)

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End point title

Single-dose PK of FiAg: Maximum Concentration (Cmax) ^[3]

End point description

Maximum Concentration (Cmax) was assessed after a single IV infusion of 70 mg/kg body weight of BT524. Maximum observed plasma concentration (Cmax) for fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. Cmax was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).

End point type

Primary

End point timeframe

Pre-dose, end of infusion (EoI), 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 96 h, 168 h, 240 h and 336 h post-EoI.

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: Analysis of the study data for the primary endpoint was descriptive only. PK parameters were summarized by descriptive statistics. No confirmatory testing was performed on the PK parameters in part I.

End point values	BT524	PK Set
Number of subjects analysed	27	27
Units: g/L
arithmetic mean (standard deviation)	1.81 ± 0.423	1.81 ± 0.423

No statistical analyses for this end point

Primary: Single-Dose PK for FiAg: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz)

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End point title

Single-Dose PK for FiAg: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz) ^[4]

End point description

AUC0-tz was assessed after a single IV infusion of 70 mg/kg body weight of BT524. AUC0-tz: Area under the time course of the plasma concentrations calculated from time zero up to the last quantifiable plasma concentration for fibrinogen antigen (FiAg), was determined from samples taken at several time points during the 14 day sampling period. AUC0-tz was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).

End point type

Primary

End point timeframe

Pre-dose, end of infusion (EoI), 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 96 h, 168 h, 240 h and 336 h post-EoI.

Notes
[4] - 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: Analysis of the study data for the primary endpoint was descriptive only. PK parameters were summarized by descriptive statistics. No confirmatory testing was performed on the PK parameters in part I.

End point values	BT524	PK Set
Number of subjects analysed	27	27
Units: g*h/L
arithmetic mean (standard deviation)	144 ± 38.9	144 ± 38.9

No statistical analyses for this end point

Primary: Single-dose PK of FiAg: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞)

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End point title

Single-dose PK of FiAg: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞) ^[5]

End point description

Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞) was assessed after a single IV infusion of 70 mg/kg body weight of BT524. AUC0-∞: AUC from time 0 to infinity for fibrinogen antigen, was determined from samples taken at several time points during the 14 day sampling period. AUC0-∞ was derived from time-concentration profiles using adapted methodology (noncompartmental analysis, compartment analysis, or population modeling, as appropriate/required).

End point type

Primary

End point timeframe

Pre-dose, end of infusion (EoI), 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 96 h, 168 h, 240 h and 336 h post-EoI.

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: Analysis of the study data for the primary endpoint was descriptive only. PK parameters were summarized by descriptive statistics. No confirmatory testing was performed on the PK parameters in part I.

End point values	BT524	PK Set
Number of subjects analysed	27	27
Units: g*h/L
arithmetic mean (standard deviation)	173 ± 45.4	173 ± 45.4

No statistical analyses for this end point

Primary: Single-dose PK of FiAg: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞)

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End point title

Single-dose PK of FiAg: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞) ^[6]

End point description

Mean Residence Time (MRT) extrapolated to infinity (MRT0-∞) was assessed after a single IV infusion of 70 mg/kg body weight of BT524. MRT0-∞: Mean Residence Time (MRT) extrapolated to infinity for fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. MRT0-∞ was derived from time-concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).

End point type

Primary

End point timeframe

Pre-dose, end of infusion (EoI), 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 96 h, 168 h, 240 h and 336 h post-EoI.

Notes
[6] - 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: Analysis of the study data for the primary endpoint was descriptive only. PK parameters were summarized by descriptive statistics. No confirmatory testing was performed on the PK parameters in part I.

End point values	BT524	PK Set
Number of subjects analysed	27	27
Units: hours
arithmetic mean (standard deviation)	133 ± 17.4	133 ± 17.4

No statistical analyses for this end point

Primary: Single-dose PK of FiAg: Clearance (CL)

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End point title

Single-dose PK of FiAg: Clearance (CL) ^[7]

End point description

Clearance (CL) was assessed after a single IV infusion of 70 mg/kg body weight of BT524. CL: Total clearance (CL) for fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. CL was derived from time concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).

End point type

Primary

End point timeframe

Pre-dose, end of infusion (EoI), 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 96 h, 168 h, 240 h and 336 h post-EoI.

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: Analysis of the study data for the primary endpoint was descriptive only. PK parameters were summarized by descriptive statistics. No confirmatory testing was performed on the PK parameters in part I.

End point values	BT524	PK Set
Number of subjects analysed	27	27
Units: L/h
arithmetic mean (standard deviation)	0.0206 ± 0.00961	0.0206 ± 0.00961

No statistical analyses for this end point

Primary: Single-dose PK of FiAg: Volume of distribution (Vdss)

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End point title

Single-dose PK of FiAg: Volume of distribution (Vdss) ^[8]

End point description

Volume of distribution at presumed steady-state (Vdss) per kg BW was assessed after a single IV infusion of 70 mg/kg body weight of BT524. Volume of distribution at presumed steady-state (Vdss) per kg BW for fibrinogen antigen was determined from samples taken at several time points during the 14 day sampling period. Vdss was derived from time concentration profiles using adapted methodology (non-compartmental analysis, compartment analysis, or population modeling, as appropriate/ required).

End point type

Primary

End point timeframe

Pre-dose, end of infusion (EoI), 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 96 h, 168 h, 240 h and 336 h post-EoI.

Notes
[8] - 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: Analysis of the study data for the primary endpoint was descriptive only. PK parameters were summarized by descriptive statistics. No confirmatory testing was performed on the PK parameters in part I.

End point values	BT524	PK Set
Number of subjects analysed	27	27
Units: mL/kg
arithmetic mean (standard deviation)	57.8 ± 19.1	57.8 ± 19.1

No statistical analyses for this end point

Primary: Single-dose PK of FiAg: Incremental Recovery (IR)

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End point title

Single-dose PK of FiAg: Incremental Recovery (IR) ^[9]

End point description

IR was assessed after a single IV infusion of 70 mg/kg body weight of BT524. IR is the dose-adjusted maximum fibrinogen increase in plasma within 4 hours after the end of infusion and reported as milligram per deciliter per milligram per kilogram [mg/dL]/[mg/kg].

End point type

Primary

End point timeframe

Pre-infusion to 4 hours post-infusion.

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: Analysis of the study data for the primary endpoint was descriptive only. PK parameters were summarized by descriptive statistics. No confirmatory testing was performed on the PK parameters in part I.

End point values	BT524	PK Set
Number of subjects analysed	27	27
Units: (mg/dL)/(mg/kg)
arithmetic mean (standard deviation)	2.63 ± 0.652	2.63 ± 0.652

No statistical analyses for this end point

Primary: Single dose PK of FibAg: Classical in vivo recovery (CIR)

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End point title

Single dose PK of FibAg: Classical in vivo recovery (CIR) ^[10]

End point description

CIR was assessed after a single IV infusion of 70 mg/kg body weight of BT524. Classical in vivo recovery (CIR) is the maximum fibrinogen increase in plasma within 4 hours after the end of infusion divided by the maximum theoretical fibrinogen increase (Maximum concentration0-4h /(dose/plasma volume)). A plasma volume of 45 mL/kg body weight will be used in these calculations.

End point type

Primary

End point timeframe

Pre-infusion to 4 hours post-infusion.

Notes
[10] - 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: Analysis of the study data for the primary endpoint was descriptive only. PK parameters were summarized by descriptive statistics. No confirmatory testing was performed on the PK parameters in part I.

End point values	BT524	PK Set
Number of subjects analysed	27	27
Units: percent volume/volume
arithmetic mean (standard deviation)	118 ± 29.4	118 ± 29.4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

For Treatment emergent AEs (TEAEs): After administration of BT524 and until the last study visit (Day 49) in study part I and II. Non-TEAEs: after patient’s signature of Informed Consent and before first administration of BT524 per study part.

Adverse event reporting additional description

PK part I: TEAEs were reported from the time of single dose administration of BT524 for PK assessments to Day 49 (PK safety visit). Part II: TEAEs were reported from the time of BT524 administration for treatment of a bleeding event to Day 49 (Safety visit for this bleeding event).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

03/2018

Reporting group title

PK Part I

Reporting group description

Reporting group title

Part II

Reporting group description

Serious adverse events	PK Part I	Part II
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 27 (7.41%)	7 / 36 (19.44%)
number of deaths (all causes)	0	1
number of deaths resulting from adverse events	0	1
Injury, poisoning and procedural complications
Extra dural hematoma
subjects affected / exposed	0 / 27 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Traumatic haemorrhage
subjects affected / exposed	0 / 27 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 27 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Hypertensive Encephalopathy
subjects affected / exposed	1 / 27 (3.70%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 27 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	0 / 27 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Pancreatitis
subjects affected / exposed	0 / 27 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Menorrhagia
subjects affected / exposed	0 / 27 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Portal vein thrombosis
subjects affected / exposed	0 / 27 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Post streptococcal glomerulonephritis
subjects affected / exposed	1 / 27 (3.70%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Haematoma muscle
subjects affected / exposed	0 / 27 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 27 (3.70%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	PK Part I	Part II
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 27 (37.04%)	25 / 36 (69.44%)
Injury, poisoning and procedural complications
Procedural haemorrhage
subjects affected / exposed	0 / 27 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	2
Procedural pain
subjects affected / exposed	0 / 27 (0.00%)	9 / 36 (25.00%)
occurrences all number	0	30
Skin wound
subjects affected / exposed	0 / 27 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	2
Subcutaneous haematoma
subjects affected / exposed	1 / 27 (3.70%)	6 / 36 (16.67%)
occurrences all number	1	10
Traumatic haematoma
subjects affected / exposed	0 / 27 (0.00%)	3 / 36 (8.33%)
occurrences all number	0	3
Vascular disorders
Haematoma
subjects affected / exposed	0 / 27 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	3
Nervous system disorders
Headache
subjects affected / exposed	1 / 27 (3.70%)	2 / 36 (5.56%)
occurrences all number	1	2
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 27 (3.70%)	3 / 36 (8.33%)
occurrences all number	1	3
Swelling face
subjects affected / exposed	0 / 27 (0.00%)	3 / 36 (8.33%)
occurrences all number	0	3
Gastrointestinal disorders
Gingival bleeding
subjects affected / exposed	1 / 27 (3.70%)	2 / 36 (5.56%)
occurrences all number	1	3
Toothache
subjects affected / exposed	2 / 27 (7.41%)	3 / 36 (8.33%)
occurrences all number	2	3
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	0 / 27 (0.00%)	4 / 36 (11.11%)
occurrences all number	0	4
Skin and subcutaneous tissue disorders
Ecchymosis
subjects affected / exposed	0 / 27 (0.00%)	3 / 36 (8.33%)
occurrences all number	0	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 27 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	2
Back pain
subjects affected / exposed	3 / 27 (11.11%)	4 / 36 (11.11%)
occurrences all number	4	5
Haemarthrosis
subjects affected / exposed	0 / 27 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	2
Osteorrhagia
subjects affected / exposed	0 / 27 (0.00%)	3 / 36 (8.33%)
occurrences all number	0	9
Pain in extremity
subjects affected / exposed	0 / 27 (0.00%)	4 / 36 (11.11%)
occurrences all number	0	8
Infections and infestations
Rhinitis
subjects affected / exposed	1 / 27 (3.70%)	2 / 36 (5.56%)
occurrences all number	1	2

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Were there any global substantial amendments to the protocol? Yes

16 Jan 2013

Modification of the involved countries and sites. Date of first patient in. Introduction of two additional flowcharts for the newly defined subgroups of children with different BW: Children Group I (6 to 18 years, BW > 43 kg) and Children Group II (6 to 18 years, BW between 22 and 43 kg). Reduction of time points of blood draw in children Group I (> 43 kg BW) for the assessment of Coagulation, Hematology and Biochemistry. Reduction of time points of blood draw in children Group II (22-43 kg BW) for the assessment of Coagulation, Hematology and Biochemistry as well as of PK and PD. Addition of a new chapter concerning Pregnancy Reporting.

16 Sep 2013

Clinical Study Protocol Tunisia, only adults included in study 984

15 Jun 2014

Introduction of a DMC to approve the inclusion of children and adolescents after the 10th adult patient treated and to survey the study as a whole. Implementation of an appropriate procedure and a related stopping rule. Inclusion criterion 1 (now 1 and 2) and exclusion criterion 12 were modified to clarify the target population. Extension of study duration due to slow patient recruitment. Furthermore, study patients already on trial were offered to extend their study participation (in part II) until the last patient enrolled has finished study part II. Modified method for determination of Fibrinogen Antigen (Assay); ELISA changed to nephelometry. Assessments of risk and burden in children and adolescents and a justification regarding the risks and burden these age groups are exposed by the clinical trial. Implementation of risk minimization measures for all study patients as well as for the enrolment and treatment of children and adolescents. Determination of Fibrinogen inhibitory antibodies was stated more precisely. Addition of requirement to report the development of Fibrinogen inhibitory antibodies as SAEs.

15 Jul 2015

Treatment of at least 10 additional patients into part II (without part I PK/PD). Calculation of the BT524 dose to be administered to the patients was revised in regard to the specifications in the COA. Treatment of at least 10 additional patients into part II (without part I PK/PD). Implementation of the DMC Modified method for determination of Fibrinogen Antigen (Assay); ELISA changed to nephelometry Calculation of the BT524 dose to be administered to the patient was revised in regard to the specifications in the COA Implementation of risk minimization measures for all study patients Determination of fibrinogen inhibitory antibodies was stated more precisely. Addition of a requirement to report the development of fibrinogen inhibitory antibodies as SAEs.

15 Mar 2017

Based on the agreement of the PIP (EMEA-001931-PIP01-16) the extension of the ongoing study 984 was introduced. Detailed description of the inclusion and treatment of children aged 0 to < 6 years. Update of study synopsis and introduction of 6 additional flowcharts for the newly defined groups of children aged < 6 years (Pre-school Children Group III and Newborns/ Infants and Toddlers Group IV)

08 May 2018

Adaption of exclusion criterion 12 in order to clarify that this criterion is only applicable for patients in PK part I. Adaption of exclusion criterion 13 in order to harmonize the 'lower BW limit' (the 5th percentile of the normal range) between all children age groups. Information regarding the WHO Child Growth Standards was included in CSP appendix 20.2. Introduction of new sections 'Adverse Event of Special Interest (AESI)' and 'Follow-up of Adverse Events'. Correction of Sample Calculation as this section was adapted within amendment 3 (CSP Version 4.0) to the new patient numbers in error. The investigator was asked to classify any bleeding event post-dose as minor or major.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A prospective, open-label, phase I/III study investigating pharmacokinetic properties of BT524 and efficacy and safety of BT524 in the treatment and prophylaxis of bleeding in patients with congenital fibrinogen deficiency

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Single-dose PK of FiAg: Terminal Elimination Half-life (t1/2)

Primary: Single-dose PK of FiAg: Terminal Elimination Half-life (t1/2)

Primary: Single-dose PK of FiAg: Time to Maximum Concentration (tmax)

Primary: Single-dose PK of FiAg: Time to Maximum Concentration (tmax)

Primary: Single-dose PK of FiAg: Maximum Concentration (Cmax)

Primary: Single-dose PK of FiAg: Maximum Concentration (Cmax)

Primary: Single-Dose PK for FiAg: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz)

Primary: Single-Dose PK for FiAg: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz)

Primary: Single-dose PK of FiAg: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞)

Primary: Single-dose PK of FiAg: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞)

Primary: Single-dose PK of FiAg: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞)

Primary: Single-dose PK of FiAg: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞)

Primary: Single-dose PK of FiAg: Clearance (CL)

Primary: Single-dose PK of FiAg: Clearance (CL)

Primary: Single-dose PK of FiAg: Volume of distribution (Vdss)

Primary: Single-dose PK of FiAg: Volume of distribution (Vdss)

Primary: Single-dose PK of FiAg: Incremental Recovery (IR)

Primary: Single-dose PK of FiAg: Incremental Recovery (IR)

Primary: Single dose PK of FibAg: Classical in vivo recovery (CIR)

Primary: Single dose PK of FibAg: Classical in vivo recovery (CIR)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Finland
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Greece
Hungary
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Ireland
Italy
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Luxembourg
Malta
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Slovakia
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Outside EU/EEA

Clinical trials

Clinical Trial Results: A prospective, open-label, phase I/III study investigating pharmacokinetic properties of BT524 and efficacy and safety of BT524 in the treatment and prophylaxis of bleeding in patients with congenital fibrinogen deficiency

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Single-dose PK of FiAg: Terminal Elimination Half-life (t1/2)

Primary: Single-dose PK of FiAg: Terminal Elimination Half-life (t1/2)

Primary: Single-dose PK of FiAg: Time to Maximum Concentration (tmax)

Primary: Single-dose PK of FiAg: Time to Maximum Concentration (tmax)

Primary: Single-dose PK of FiAg: Maximum Concentration (Cmax)

Primary: Single-dose PK of FiAg: Maximum Concentration (Cmax)

Primary: Single-Dose PK for FiAg: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz)

Primary: Single-Dose PK for FiAg: Area Under the Curve (AUC) Calculated to the Last Measured Concentration (AUC0-tz)

Primary: Single-dose PK of FiAg: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞)

Primary: Single-dose PK of FiAg: Area Under the Curve (AUC) From Time 0 to Infinity (AUC0-∞)

Primary: Single-dose PK of FiAg: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞)

Primary: Single-dose PK of FiAg: Mean Residence Time (MRT) Extrapolated to Infinity (MRT0-∞)

Primary: Single-dose PK of FiAg: Clearance (CL)

Primary: Single-dose PK of FiAg: Clearance (CL)

Primary: Single-dose PK of FiAg: Volume of distribution (Vdss)

Primary: Single-dose PK of FiAg: Volume of distribution (Vdss)

Primary: Single-dose PK of FiAg: Incremental Recovery (IR)

Primary: Single-dose PK of FiAg: Incremental Recovery (IR)

Primary: Single dose PK of FibAg: Classical in vivo recovery (CIR)

Primary: Single dose PK of FibAg: Classical in vivo recovery (CIR)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A prospective, open-label, phase I/III study investigating pharmacokinetic properties of BT524 and efficacy and safety of BT524 in the treatment and prophylaxis of bleeding in patients with congenital fibrinogen deficiency