NCT00357656

Phase 3/4 Study of a Recombinant Protein-Free Factor VIII (rAHF-PFM): Comparison of Continuous Infusion Versus Intermittent Bolus Infusion in Hemophilia A Subjects Undergoing Major Orthopedic Surgery

Completed Phase 4 Results posted Last updated 19 May 2021

What this trial tests

Phase 4 trial testing Recombinant Protein-Free Factor VIII (rAHF-PFM) in Hemophilia A in 85 participants. Completed in 9 December 2015.

Timeline

29 May 2006

Primary endpoint
1 October 2015

9 December 2015

Quick facts

Lead sponsor	Baxalta now part of Shire
Phase	Phase 4
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	85
Start date	29 May 2006
Primary completion	1 October 2015
Estimated completion	9 December 2015
Sites	36 locations across France, Italy, Netherlands, Russia, Belgium, Austria, Sweden, Hungary

Drugs / interventions tested

• Recombinant Protein-Free Factor VIII (rAHF-PFM) — full drug profile →
• Recombinant Protein-Free Factor VIII (rAHF-PFM) — full drug profile →

Conditions studied

• Hemophilia A — all drugs for Hemophilia A →

Sponsor

Baxalta now part of Shire — full company profile →

Who can join

Adults 18 to 70, any sex, with Hemophilia A. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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 · During the first postoperative 24 hours every 8 hours ± 30 minutes the drainage fluid was to be recorded..

Drainage fluid volume was to be measured cumulatively and recorded every 8 hours ± 30 minutes during the first 24 hours following surgery. Unit of measure: Tera per Liter is the PRBC concentration in 10\^12 units per 1 liter of drainage fluid.

Group	Value	95% CI
Bolus Infusion	3.632	± 0.971
Continuous Infusion	3.383	± 0.632
BI Stratum A	3.718	± 0.978
BI Stratum B	2.855	± 1.732
BI Stratum C	3.548	± 0.577
CI Stratum A	3.345	± 0.616
CI Stratum B	3.400	± NA
CI Stratum C	3.820	± 1.103

Actual Postoperative Blood Loss During the First 24 Hours Compared With the Average Blood Loss as Predicted Preoperatively by the Operating Surgeon Secondary · During the first 24 postoperative hours blood loss was measured every 8 hours ± 30 minutes

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

Group	Value	95% CI
Bolus Infusion	709.28	± 150.103
Contiuous Infusion	811.11	± 79.511
BI Stratum A	724.48	± 66.367
BI Stratum B	265	± 49.497
BI Stratum C	814.03	± 171.019
CI Stratum A	819.22	± 66.992
CI Stratum B	713.49	± 0
CI Stratum C	811.25	± 163.027

Actual Postoperative Blood Loss Compared to the Expected Average Blood Loss Until Drain Removal as Predicted Preoperatively by the Surgeon Secondary · From end of surgery (application of compressive dressing and release of tourniquet, if applicable) until drain removal (up to postoperative day 7).

The total blood loss for the postoperative period (from end of surgery until drain removal) was adjusted for the expected blood loss by applying a log-transformation of the blood loss data. The drainage volume was measured every 8 hours +/- 30 minutes during the first 24 hours. If the 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 estima

Group	Value	95% CI
Bolus Infusion	766.73	± 182.463
Continuous Infusion	929.49	± 167.662
BI Stratum A	752.91	± 42.343
BI Stratum B	341.5	± 135.075
BI Stratum C	1000.37	± 259.239
CI Stratum A	899.83	± 45.459
CI Stratum B	921.1	± 42.906
CI Stratum C	1162.48	± 514.033

Number of Bleeding Episodes During Treatment With Continuous or Bolus Infusion Secondary · Through Postoperative Day 7

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.

Group	Value	95% CI
Bolus Infusion	0.10	± 0.301
Continuous Infusion	0.03	± 0.186
BI Stratum A	0.08	± 0.282
BI Stratum B	0.50	± 0.707
BI Stratum C	0.00	± 0.000
CI Stratum A	0.00	± 0.000
CI Stratum B	0.50	± 0.707
CI Stratum C	0.00	± 0.000

Number of Units of Packed Red Blood Cells Transfused Secondary · During the first postoperative 24 hours

Group	Value	95% CI
Bolus Infusion	0.9	± 1.2
Continuous Infusion	1.3	± 1.4
BI Stratum A	1.0	± 1.3
BI Stratum B	1.5	± 2.1
BI Stratum C	0.2	± 0.4
CI Stratum A	1.2	± 1.3
CI Stratum B	3.5	± 2.1
CI Stratum C	0.7	± 1.2

Number of Adverse Events Related to the Administration of the Study Product. Secondary · From first study drug exposure until study completion/discontinuation (approximately 9-26 weeks per subject)

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 causal relationship (i.e., unrelated, possibly related or probably related) to the study product.

Group	Value	95% CI
Bolus Infusion	6
Continuous Infusion	8
Safety Analysis Set	14

Incidence of Factor VIII Inhibitory Antibody (≥0.4 Bethesda Units Using the Nijmegen Modification of the Bethesda Assay Formation) Secondary · Throughout the study period of approximately 9-26 weeks per participant

Number of participants that developed Factor VIII inhibitory antibody during the study.

Group	Value	95% CI
Bolus Infusion	2
Continuous Infusion	2
Safety Analysis Set	4

Adverse events — posted to ClinicalTrials.gov

Time frame: Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Bolus Infusion

Serious: 3/31 (10%)

Deaths: —

Continuous Infusion

Serious: 6/32 (19%)

Deaths: —

Not Assigned Participants

Serious: 1/9 (11%)

Deaths: —

Serious adverse events (7 terms)

Reaction	System	Bolus Infusion	Continuous Infusion	Not Assigned Participants
Factor VIII inhibition	Blood and lymphatic system disorders	—	—	—
Multi-organ failure	General disorders	—	—	—
Febrile infection	Infections and infestations	—	—	—
Pseudomembranous colitis	Infections and infestations	—	—	—
Hemarthrosis	Musculoskeletal and connective tissue disorders	—	—	—
Joint swelling	Musculoskeletal and connective tissue disorders	—	—	—
Muscle hemorrhage	Musculoskeletal and connective tissue disorders	—	—	—

Other adverse events (21 terms — click to expand)

Reaction	System	Bolus Infusion	Continuous Infusion	Not Assigned Participants
Procedural pain	Injury, poisoning and procedural complications	—	—	—
Anemia	Blood and lymphatic system disorders	—	—	—
Pyrexia	General disorders	—	—	—
Pain	General disorders	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Thrombocytosis	Blood and lymphatic system disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Insomnia	Psychiatric disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Tachycardia	Cardiac disorders	—	—	—
Influenza	Infections and infestations	—	—	—
Anaemia postoperative	Injury, poisoning and procedural complications	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Urinary tract infection	Infections and infestations	—	—	—
Haemarthrosis	Musculoskeletal and connective tissue disorders	—	—	—
Anxiety	Psychiatric disorders	—	—	—
Tooth Infection	Infections and infestations	—	—	—
Adenoma benign	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Erythema	Skin and subcutaneous tissue disorders	—	—	—
Muscle Hemorrhage	Musculoskeletal and connective tissue disorders	—	—	—

Most-reported serious reactions: Factor VIII inhibition, Multi-organ failure, Febrile infection, Pseudomembranous colitis, Hemarthrosis, Joint swelling, Muscle hemorrhage.

Data from ClinicalTrials.gov NCT00357656 adverse events section.

Sponsor's own description

The purpose of this study is to compare the hemostatic efficacy and safety of continuous infusion versus intermittent bolus infusion in the peri- and post-operative setting, employing rAHF-PFM, a recombinant antihemophilic factor manufactured without added human or animal proteins, in previously treated patients with severe or moderately severe hemophilia A (baseline factor VIII level \<= 2% of normal) who are undergoing unilateral major orthopedic surgery that requires drain placement. The total study period per subject (from consent to study completion) will vary from approximately 9 to 26 weeks and will involve clinical and laboratory assessments.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. Treatment for preventing bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgery.
   Coppola A, Windyga J, Tufano A, Yeung C, et al · · 2015 · cited 23× · PMID 25922858 · DOI 10.1002/14651858.cd009961.pub2
2. Results of a randomized phase III/IV trial comparing intermittent bolus versus continuous infusion of antihaemophilic factor (recombinant) in adults with severe or moderately severe haemophilia A undergoing major orthopaedic surgery.
   Pabinger I, Mamonov V, Windyga J, Engl W, et al · · 2021 · cited 4× · PMID 33772963 · DOI 10.1111/hae.14219