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Clinical Trial Results:
Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method (rAHF PFM): A Phase 3/4, Prospective, Controlled, Randomized, Multi-Center Study to Compare the Efficacy and Safety of Continuous Infusion (CI) versus Intermittent Bolus Infusion (BI) in Subjects with Severe or Moderately Severe Hemophilia A Undergoing Major Orthopedic Surgery

Summary
EudraCT number	2005-005697-71
Trial protocol	AT SE BE PT ES HU NL GB IT PL
Global end of trial date	09 Dec 2015

Results information
Results version number	v1(current)
This version publication date	23 Dec 2016
First version publication date	23 Dec 2016
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

060402

ISRCTN number

US NCT number

NCT00357656

WHO universal trial number (UTN)

Sponsor organisation name

Baxalta US Inc.

Sponsor organisation address

One Baxter Way, Westlake Village, United States, CA 91362

Public contact

Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com

Scientific contact

Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com

Sponsor organisation name

Baxalta Innovations GmbH

Sponsor organisation address

Industriestrasse 67, Vienna, Austria, 1221

Public contact

Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com

Scientific contact

Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com

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

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

09 Dec 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Dec 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this trial is to compare the hemostatic efficacy of continuous infusion versus intermittent bolus infusion in the peri- and post-operative setting employing ADVATE (rAHF-PFM) in previously treated patients (PTPs) with severe or moderately severe hemophilia A (baseline FVIII level less or equal to 2% of normal) undergoing elective unilateral major orthopedic surgery that requires drain placement by assessing the cumulative packed red blood cell (PRBC) volume in the drainage fluid during the first 24 hours following surgery.

Protection of trial subjects

This study was conducted in accordance with the standards of Good Clinical Practice (GCP) in effect at the time of the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 May 2006

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 4

Country: Number of subjects enrolled

Austria: 5

Country: Number of subjects enrolled

Norway: 1

Country: Number of subjects enrolled

France: 1

Country: Number of subjects enrolled

Portugal: 5

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Spain: 4

Country: Number of subjects enrolled

Russian Federation: 27

Country: Number of subjects enrolled

Romania: 5

Country: Number of subjects enrolled

Hungary: 6

Country: Number of subjects enrolled

Poland: 13

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

Enrollment was conducted at 22 clinical sites in 12 countries (Austria, France, Hungary, Italy, Norway, Poland, Portugal, Romania, Russia, Spain, The Netherlands, USA). Of 85 subjects enrolled, 72 subjects participated in a PK study in the preoperative period; 63 subjects were then randomized to treatment by continuous or bolus infusion.

Screening details

Of 85 subjects enrolled, 15 were screen failures, 4 were discontinued on the basis of the PK study in the preoperative period, 1 subject died, 1 was discontinued by physician decision (imprisonment), and 1 was discontinued per sponsor decision. Eventually, 63 subjects were randomized to treatment by continuous (n=32) or bolus infusion (n=31).

Number of subjects started

Intermediate milestone: Number of subjects

PK infusion: 72

Number of subjects completed

Reason: Number of subjects

PK results: 4

Reason: Number of subjects

Physician decision (imprisonment): 1

Reason: Number of subjects

Sponsor decision: 1

Reason: Number of subjects

Death: 1

Reason: Number of subjects

Screen failure: 2

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Treatment by Continuous infusion

Arm description

This reporting group comprises all 32 subjects in the Full Analysis Set who were randomized to receive ADVATE (rAHF-PFM) by continuous infusion (CI).

Arm type

Experimental

Investigational medicinal product name

Advate

Investigational medicinal product code

Other name

rAHF-PFM (Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method)

Pharmaceutical forms

Powder and solvent for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects initially underwent a pharmacokinetic (PK) evaluation with ADVATE (dose: 50 IU ± 5 IU/kg). Prior to surgery, subjects received a loading dose with ADVATE (based on subject´s PK profile), to maintain a minimum target FVIII level of at least 80% of normal. After the loading dose(s), subjects received ADVATE either as intermittent bolus infusion (BI) or as continuous infusion (CI). The dose recommendations were provided by the sponsor and were based on the subject´s PK profile. For safety reasons, all subjects were to receive a rebolus in the recovery room to compensate for perioperative blood loss and increased FVIII consumption. The following minimum FVIII levels were to be targeted for both CI and BI treatment: at least 80% of normal for the first 72 hours after the initial loading dose, then at least 50% of normal until postoperative Day 7. For CI, ADVATE was to be administered with a syringe pump (infusion rate according to dosing regimen).

Treatment by Bolus infusion

Arm description

This reporting group comprises all 31 subjects in the Full Analysis Set who were randomized to receive ADVATE (rAHF-PFM) by intermittent bolus infusion (BI).

Arm type

Experimental

Investigational medicinal product name

Advate

Investigational medicinal product code

Other name

rAHF-PFM (Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method)

Pharmaceutical forms

Powder and solvent for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 1 ^[1]	Treatment by Continuous infusion	Treatment by Bolus infusion
Started	32	31
Completed	29	31
Not completed	3	0
No surgery performed	3	-

Notes
[1] - 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: Of 85 subjects enrolled, 72 subjects participated in a PK evaluation in the preoperative period; 63 subjects were then randomized to treatment by continuous or bolus infusion.

Baseline characteristics

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Reporting group title

Treatment by Continuous infusion

Reporting group description

This reporting group comprises all 32 subjects in the Full Analysis Set who were randomized to receive ADVATE (rAHF-PFM) by continuous infusion (CI).

Reporting group title

Treatment by Bolus infusion

Reporting group description

This reporting group comprises all 31 subjects in the Full Analysis Set who were randomized to receive ADVATE (rAHF-PFM) by intermittent bolus infusion (BI).

Reporting group values	Treatment by Continuous infusion	Treatment by Bolus infusion	Total
Number of subjects	32	31	63
Age categorical
Units: Subjects
Adults (18-64 years)	32	31	63
Age continuous
Units: years
log mean (standard deviation)	39 ± 11.52	38.6 ± 9.76	-
Gender categorical
Units:
Male	32	31	63
Female	0	0	0

Subject analysis set title

Full Analysis Set

Subject analysis set type

Full analysis

Subject analysis set description

The Full Analysis Set (FAS) comprises all subjects who were randomized to receive bolus infusion (BI) or continuous infusion (CI) of ADVATE (rAHF-PFM).

Subject analysis set title

Full Analysis Set - Continuous Infusion (CI)

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set comprises all subjects in the Full Analysis Set (FAS) who were randomized to receive continuous infusion (CI) of ADVATE (rAHF-PFM). This analysis set is identical to Reporting Group 1 (Treatment by Continuous Infusion).

Subject analysis set title

Full Analysis Set - Bolus Infusion (BI)

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set comprises all subjects in the FAS who were randomized to receive bolus infusion (BI) of ADVATE (rAHF-PFM). This analysis set is identical to Reporting Group 2 (Treatment by Bolus Infusion).

Subject analysis set title

Safety Analysis Set

Subject analysis set type

Safety analysis

Subject analysis set description

The Safety Analysis Set (SAS) comprises all subjects treated with at least one ADVATE (rAHF-PFM) dose. All safety analyses were performed on the SAS.

Subject analysis set title

Per Protocol Analysis Set

Subject analysis set type

Per protocol

Subject analysis set description

The Per Protocol Analysis Set (PPAS) comprises all subjects who were randomized to receive BI or CI of ADVATE (rAHF-PFM) and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids.

Subject analysis set title

Per Protocol Analysis Set - CI

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set comprises all subjects in the PPAS who were randomized to receive CI of ADVATE (rAHF-PFM) and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids.

Subject analysis set title

Per Protocol Analysis Set - BI

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set comprises all subjects in the PPAS who were randomized to receive BI of ADVATE (rAHF-PFM) and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids.

Subject analysis set title

Pharmacokinetic (PK) Full Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK Full Analysis Set (PKFAS) consists of all subjects who had a PK evaluation. If a subject had a repeat PK, the PK parameters of all evaluations were to be listed, but only the last value was to be used for summary statistics. This analysis set is identical to the Full Analysis Set (FAS).

Subject analysis set title

PKFAS - CI

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set comprises all subjects in the PKFAS who had a PK evaluation and were randomized to CI. This analysis set is identical to the FAS - CI.

Subject analysis set title

PKFAS - BI

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set comprises all subjects in the PKFAS who had a PK evaluation and were randomized to BI. This analysis set is identical to the FAS - BI.

Subject analysis set title

Stratum A - CI

Subject analysis set type

Per protocol

Subject analysis set description

Stratum A (CI) includes subjects in the per-protocol analysis set who underwent unilateral knee replacement and were treated by continuous infusion.

Subject analysis set title

Stratum B - CI

Subject analysis set type

Per protocol

Subject analysis set description

Stratum B (CI) includes subjects in the per-protocol analysis set who underwent hip surgery and were treated by continuous infusion.

Subject analysis set title

Stratum C - CI

Subject analysis set type

Per protocol

Subject analysis set description

Stratum C (CI) includes subjects in the per-protocol analysis set who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion.

Subject analysis set title

Stratum A - BI

Subject analysis set type

Per protocol

Subject analysis set description

Stratum A (BI) includes subjects in the per-protocol analysis set who underwent unilateral knee replacement and were treated by bolus infusion.

Subject analysis set title

Stratum B - BI

Subject analysis set type

Per protocol

Subject analysis set description

Stratum B (BI) includes subjects in the per-protocol analysis set who underwent hip surgery and were treated by bolus infusion.

Subject analysis set title

Stratum C - BI

Subject analysis set type

Per protocol

Subject analysis set description

Stratum C (BI) includes subjects in the per-protocol analysis set who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion.

Subject analysis sets values	Full Analysis Set	Full Analysis Set - Continuous Infusion (CI)	Full Analysis Set - Bolus Infusion (BI)	Safety Analysis Set	Per Protocol Analysis Set	Per Protocol Analysis Set - CI	Per Protocol Analysis Set - BI	Pharmacokinetic (PK) Full Analysis Set	PKFAS - CI	PKFAS - BI	Stratum A - CI	Stratum B - CI	Stratum C - CI	Stratum A - BI	Stratum B - BI	Stratum C - BI
Number of subjects	63	32	31	72	60	29	31	63	32	31	24	2	3	24	2	5
Age categorical
Units: Subjects
Adults (18-64 years)	63	32	31	72	60	29	31	63	32	31	24	2	3	24	2	5
Age continuous
Units: years
log mean (standard deviation)	38.8 ± 10.61	39 ± 11.52	38.6 ± 9.76	38.6 ± 10.49	38.7 ± 10.69	38.8 ± 11.77	38.6 ± 9.76	38.8 ± 10.61	39 ± 11.52	38.6 ± 9.76	38.4 ± 10.95	47 ± 14.14	36.3 ± 19.6	37.5 ± 9.06	55.5 ± 3.54	37.2 ± 9.34
Gender categorical
Units:
Male	63	32	31	72	60	29	31	63	32	31	24	2	3	24	2	5
Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

End points

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Reporting group title

Treatment by Continuous infusion

Reporting group description

This reporting group comprises all 32 subjects in the Full Analysis Set who were randomized to receive ADVATE (rAHF-PFM) by continuous infusion (CI).

Reporting group title

Treatment by Bolus infusion

Reporting group description

This reporting group comprises all 31 subjects in the Full Analysis Set who were randomized to receive ADVATE (rAHF-PFM) by intermittent bolus infusion (BI).

Subject analysis set title

Full Analysis Set

Subject analysis set type

Full analysis

Subject analysis set description

The Full Analysis Set (FAS) comprises all subjects who were randomized to receive bolus infusion (BI) or continuous infusion (CI) of ADVATE (rAHF-PFM).

Subject analysis set title

Full Analysis Set - Continuous Infusion (CI)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Full Analysis Set - Bolus Infusion (BI)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Safety Analysis Set

Subject analysis set type

Safety analysis

Subject analysis set description

The Safety Analysis Set (SAS) comprises all subjects treated with at least one ADVATE (rAHF-PFM) dose. All safety analyses were performed on the SAS.

Subject analysis set title

Per Protocol Analysis Set

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Per Protocol Analysis Set - CI

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Per Protocol Analysis Set - BI

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Pharmacokinetic (PK) Full Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

PKFAS - CI

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set comprises all subjects in the PKFAS who had a PK evaluation and were randomized to CI. This analysis set is identical to the FAS - CI.

Subject analysis set title

PKFAS - BI

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set comprises all subjects in the PKFAS who had a PK evaluation and were randomized to BI. This analysis set is identical to the FAS - BI.

Subject analysis set title

Stratum A - CI

Subject analysis set type

Per protocol

Subject analysis set description

Stratum A (CI) includes subjects in the per-protocol analysis set who underwent unilateral knee replacement and were treated by continuous infusion.

Subject analysis set title

Stratum B - CI

Subject analysis set type

Per protocol

Subject analysis set description

Stratum B (CI) includes subjects in the per-protocol analysis set who underwent hip surgery and were treated by continuous infusion.

Subject analysis set title

Stratum C - CI

Subject analysis set type

Per protocol

Subject analysis set description

Stratum C (CI) includes subjects in the per-protocol analysis set who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion.

Subject analysis set title

Stratum A - BI

Subject analysis set type

Per protocol

Subject analysis set description

Stratum A (BI) includes subjects in the per-protocol analysis set who underwent unilateral knee replacement and were treated by bolus infusion.

Subject analysis set title

Stratum B - BI

Subject analysis set type

Per protocol

Subject analysis set description

Stratum B (BI) includes subjects in the per-protocol analysis set who underwent hip surgery and were treated by bolus infusion.

Subject analysis set title

Stratum C - BI

Subject analysis set type

Per protocol

Subject analysis set description

Stratum C (BI) includes subjects in the per-protocol analysis set who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion.

Primary: Cumulative packed red blood cell (PRBC) volume in the drainage fluid during the first 24 hours following surgery in subjects receiving ADVATE (rAHF-PFM) by bolus (BI) or continuous infusion (CI)

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End point title

Cumulative packed red blood cell (PRBC) volume in the drainage fluid during the first 24 hours following surgery in subjects receiving ADVATE (rAHF-PFM) by bolus (BI) or continuous infusion (CI)

End point description

Drainage fluid volume was to be measured cumulatively and recorded every 8 hours +/- 30 minutes during the first 24 hours following surgery.

End point type

Primary

End point timeframe

During the first 24 postoperative hours

End point values	Treatment by Continuous infusion	Treatment by Bolus infusion	Per Protocol Analysis Set - CI	Per Protocol Analysis Set - BI	Stratum A - CI	Stratum B - CI	Stratum C - CI	Stratum A - BI	Stratum B - BI	Stratum C - BI
Number of subjects analysed	26	28	26	28	23	1	2	22	2	4
Units: T/L
arithmetic mean (standard deviation)	3.383 ± 0.632	3.632 ± 0.971	3.383 ± 0.632	3.632 ± 0.971	3.345 ± 0.616	3.4 ± 0	3.82 ± 1.103	3.718 ± 0.978	2.855 ± 1.732	3.548 ± 0.577

Non-inferiority of CI to BI

Statistical analysis description

The main analysis used a point estimate and a two-sided 95% confidence interval for ratio of the primary outcome measure of CI over BI combined over the three strata: stratum A: unilateral knee replacement, stratum B: hip surgery, stratum C: shoulder/elbow/ankle/knee (except knee replacement) surgery. Non-inferiority by the 200% margin of non-inferiority was demonstrated if the upper confidence limit of a 95% 2-sided confidence interval for the ratio of means did not exceed 200%.

Comparison groups

Treatment by Bolus infusion v Treatment by Continuous infusion

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001 ^[1]

Method

Hypothesis test

Parameter type

Mean ratio CI/BI

Point estimate

0.924

Confidence interval

level

95%

sides

2-sided

lower limit

0.816

upper limit

1.046

Notes
[1] - one-sided p-value against the null hypothesis of ratio >=200%

Secondary: Actual postoperative blood loss during the first 24 hours compared with the average blood loss as predicted preoperatively by the operating surgeon

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End point title

Actual postoperative blood loss during the first 24 hours compared with the average blood loss as predicted preoperatively by the operating surgeon

End point description

Drainage fluid volume was to be measured cumulatively and recorded every 8 hours +/- 30 minutes during the first 24 hours following surgery. Prior to surgery, the operating surgeon was to predict the estimated duration of surgery and the volume (mL) of the estimated expected blood loss for the surgery in a hemostatically normal individual of the same sex, age, and stature as the study subject 1) for the intraoperative procedure (defined as the time period from incision to application of compressive dressing and release of tourniquet, if applicable), 2) for the first 24 hours postoperatively, and 3) for the postoperative period until drain removal, if drainage continued beyond 24 hours.

End point type

Secondary

End point timeframe

During the first 24 postoperative hours

End point values	Treatment by Continuous infusion	Treatment by Bolus infusion	Per Protocol Analysis Set - CI	Per Protocol Analysis Set - BI	Stratum A - CI	Stratum B - CI	Stratum C - CI	Stratum A - BI	Stratum B - BI	Stratum C - BI
Number of subjects analysed	29	31	29	31	24	2	3	24	2	5
Units: millilitre (mL)
arithmetic mean (standard deviation)	811.11 ± 79.511	709.28 ± 150.103	811.11 ± 79.511	709.28 ± 150.103	819.22 ± 66.992	713.49 ± 0	811.25 ± 163.027	724.48 ± 66.367	265 ± 49.497	814.03 ± 171.019

No statistical analyses for this end point

Secondary: Actual postoperative blood loss compared to the expected average blood loss until drain removal as predicted preoperatively by the surgeon

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End point title

Actual postoperative blood loss compared to the expected average blood loss until drain removal as predicted preoperatively by the surgeon

End point description

If drainage continued beyond 24 hours, the PRBC volume and hemoglobin was to be measured cumulatively every 24 hours or whenever the drainage bottle was emptied and at the time of drain removal. Prior to surgery, the operating surgeon was to predict the estimated duration of surgery and the volume (mL) of the estimated expected blood loss for the surgery in a hemostatically normal individual of the same sex, age, and stature as the study subject 1) for the intraoperative procedure (defined as the time period from incision to application of compressive dressing and release of tourniquet, if applicable), 2) for the first 24 hours postoperatively, and 3) for the postoperative period until drain removal, if drainage continued beyond 24 hours.

End point type

Secondary

End point timeframe

Postoperatively until drain removal

End point values	Treatment by Continuous infusion	Treatment by Bolus infusion	Per Protocol Analysis Set - CI	Per Protocol Analysis Set - BI	Stratum A - CI	Stratum B - CI	Stratum C - CI	Stratum A - BI	Stratum B - BI	Stratum C - BI
Number of subjects analysed	28	30	28	30	23	2	3	23	2	5
Units: mL
arithmetic mean (standard deviation)	929.49 ± 167.662	766.73 ± 182.463	929.49 ± 167.662	766.73 ± 182.463	899.83 ± 45.459	921.1 ± 42.906	1162.48 ± 514.033	752.91 ± 42.343	341.5 ± 135.075	1000.37 ± 259.239

No statistical analyses for this end point

Secondary: Number of bleeding episodes during treatment with continuous or bolus infusion (through postoperative Day 7)

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End point title

Number of bleeding episodes during treatment with continuous or bolus infusion (through postoperative Day 7)

End point description

To simplify the results below: Bleeding episodes were reported for 4 subjects (3 subjects on bolus infusion: 2 in Stratum A and 1 in Stratum B, and 1 subject on continuous infusion/Stratum B). The 4 subjects had 1 bleeding episode each. No bleeding episodes were reported for Stratum C.

End point type

Secondary

End point timeframe

Postoperative Day 7

End point values	Treatment by Continuous infusion	Treatment by Bolus infusion	Per Protocol Analysis Set - CI	Per Protocol Analysis Set - BI	Stratum A - CI	Stratum B - CI	Stratum C - CI	Stratum A - BI	Stratum B - BI	Stratum C - BI
Number of subjects analysed	29	31	29	31	24	2	3	24	2	5
Units: Bleeding episodes
arithmetic mean (standard deviation)	0.03 ± 0.186	0.1 ± 0.301	0.03 ± 0.186	0.1 ± 0.301	0 ± 0	0.5 ± 0.707	0 ± 0	0.08 ± 0.282	0.5 ± 0.707	0 ± 0

No statistical analyses for this end point

Secondary: Number of units of packed red blood cells (PRBC) transfused

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End point title

Number of units of packed red blood cells (PRBC) transfused

End point description

End point type

Secondary

End point timeframe

During the first postoperative 24 hours

End point values	Treatment by Continuous infusion	Treatment by Bolus infusion	Per Protocol Analysis Set - CI	Per Protocol Analysis Set - BI	Stratum A - CI	Stratum B - CI	Stratum C - CI	Stratum A - BI	Stratum B - BI	Stratum C - BI
Number of subjects analysed	29	31	29	31	24	2	3	24	2	5
Units: PRBC units
arithmetic mean (standard deviation)	1.3 ± 1.4	0.9 ± 1.2	1.3 ± 1.4	0.9 ± 1.2	1.2 ± 1.3	3.5 ± 2.1	0.7 ± 1.2	1 ± 1.3	1.5 ± 2.1	0.2 ± 0.4

No statistical analyses for this end point

Secondary: Number of adverse events (AEs) related to the administration of the study product

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End point title

Number of adverse events (AEs) related to the administration of the study product

End point description

All AEs from the first study drug exposure until the study completion/ discontinuation date were to be recorded. Each AE was to be evaluated by the investigator for “seriousness”, “severity” and “causal relationship to the investigational product exposure or study procedure”.

End point type

Secondary

End point timeframe

From first study drug exposure until study completion/discontinuation (approx. 9-26 weeks per subject)

End point values	Treatment by Continuous infusion	Treatment by Bolus infusion	Safety Analysis Set
Number of subjects analysed	5	5	10
Units: adverse events (AEs)	8	6	14

No statistical analyses for this end point

Secondary: Incidence of Factor VIII inhibitory antibody (≥0.4 Bethesda Units using the Nijmegen modification of the Bethesda assay) formation

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End point title

Incidence of Factor VIII inhibitory antibody (≥0.4 Bethesda Units using the Nijmegen modification of the Bethesda assay) formation

End point description

End point type

Secondary

End point timeframe

Until study completion (approx. 9-26 weeks per subject)

End point values	Treatment by Continuous infusion	Treatment by Bolus infusion	Safety Analysis Set
Number of subjects analysed	2	2	4
Units: subjects	2	2	4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Overall: 9 years and 6 months Per subject: 9-26 weeks

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Safety Analysis Set (n=72)

Reporting group description

The Safety Analysis Set (SAS) comprises all 72 subjects treated with at least one ADVATE (rAHF-PFM) dose. A total of 72 subjects received ADVATE (rAHF-PFM) for the pharmacokinetic evaluation in the preoperative period. Of these, 32 subjects were subsequently randomized to treatment with continous infusion, and 31 subjects were randomized to treatment with intermittent bolus infusion.

Serious adverse events	Safety Analysis Set (n=72)
Total subjects affected by serious adverse events
subjects affected / exposed	10 / 72 (13.89%)
number of deaths (all causes)	1
number of deaths resulting from adverse events	0
Blood and lymphatic system disorders
Factor VIII inhibition
subjects affected / exposed	4 / 72 (5.56%)
occurrences causally related to treatment / all	4 / 4
deaths causally related to treatment / all	0 / 0
General disorders and administration site conditions
Multi-organ failure
subjects affected / exposed	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Musculoskeletal and connective tissue disorders
Hemarthrosis
subjects affected / exposed	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Joint swelling
subjects affected / exposed	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Muscle hemorrhage
subjects affected / exposed	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Infections and infestations
Febrile infection
subjects affected / exposed	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Pseudomembranous colitis
subjects affected / exposed	1 / 72 (1.39%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

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

Non-serious adverse events	Safety Analysis Set (n=72)
Total subjects affected by non serious adverse events
subjects affected / exposed	43 / 72 (59.72%)
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	26 / 72 (36.11%)
occurrences all number	32
Cardiac disorders
Tachycardia
subjects affected / exposed	4 / 72 (5.56%)
occurrences all number	4
Nervous system disorders
Headache
subjects affected / exposed	4 / 72 (5.56%)
occurrences all number	5
Blood and lymphatic system disorders
Anemia
subjects affected / exposed	18 / 72 (25.00%)
occurrences all number	21
Thrombocytosis
subjects affected / exposed	4 / 72 (5.56%)
occurrences all number	4
General disorders and administration site conditions
Pain
subjects affected / exposed	8 / 72 (11.11%)
occurrences all number	8
Pyrexia
subjects affected / exposed	15 / 72 (20.83%)
occurrences all number	21
Gastrointestinal disorders
Constipation
subjects affected / exposed	5 / 72 (6.94%)
occurrences all number	5
Psychiatric disorders
Insomnia
subjects affected / exposed	4 / 72 (5.56%)
occurrences all number	4
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	7 / 72 (9.72%)
occurrences all number	30

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Were there any global substantial amendments to the protocol? Yes

14 Nov 2007

Amendment 4: - Maximum subject age was raised from previously 65 to 70 years to allow the inclusion of subjects older than 65 years provided that their health status corresponds to NYHA classification less than or equal to II as defined by the New York Heart Association (NYHA) - The exclusion threshold for history of FVIII inhibitors in the Bethesda assay was raised from equal to or greater than 0.4 BU to equal to or greater than 0.5 BU.

02 Sep 2011

Amendment 5: Prior to Protocol Amendment 5 (version 02Sep2011), the study was performed in subjects undergoing unilateral primary total knee replacement. In Protocol Amendment 5, the surgeries were expanded to major orthopedic surgeries to increase the enrollment rate.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Cumulative packed red blood cell (PRBC) volume in the drainage fluid during the first 24 hours following surgery in subjects receiving ADVATE (rAHF-PFM) by bolus (BI) or continuous infusion (CI)

Primary: Cumulative packed red blood cell (PRBC) volume in the drainage fluid during the first 24 hours following surgery in subjects receiving ADVATE (rAHF-PFM) by bolus (BI) or continuous infusion (CI)

Secondary: Actual postoperative blood loss during the first 24 hours compared with the average blood loss as predicted preoperatively by the operating surgeon

Secondary: Actual postoperative blood loss during the first 24 hours compared with the average blood loss as predicted preoperatively by the operating surgeon

Secondary: Actual postoperative blood loss compared to the expected average blood loss until drain removal as predicted preoperatively by the surgeon

Secondary: Actual postoperative blood loss compared to the expected average blood loss until drain removal as predicted preoperatively by the surgeon

Secondary: Number of bleeding episodes during treatment with continuous or bolus infusion (through postoperative Day 7)

Secondary: Number of bleeding episodes during treatment with continuous or bolus infusion (through postoperative Day 7)

Secondary: Number of units of packed red blood cells (PRBC) transfused

Secondary: Number of units of packed red blood cells (PRBC) transfused

Secondary: Number of adverse events (AEs) related to the administration of the study product

Secondary: Number of adverse events (AEs) related to the administration of the study product

Secondary: Incidence of Factor VIII inhibitory antibody (≥0.4 Bethesda Units using the Nijmegen modification of the Bethesda assay) formation

Secondary: Incidence of Factor VIII inhibitory antibody (≥0.4 Bethesda Units using the Nijmegen modification of the Bethesda assay) formation

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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