Trial Outcomes & Findings for 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 (NCT NCT00357656)

Last Updated: 2021-05-19

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

85 participants

Primary outcome timeframe

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

Results posted on

2021-05-19

Participant Flow

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

Of 85 participants enrolled,15 were screen failures (2 after PK), 4 discontinued on the basis of the PK study in the preoperative period, 1 died, 1 was discontinued by physician decision (imprisonment), and 1 was discontinued per sponsor decision. Eventually, 63 participants were randomized to treatment by continuous (n=32) or bolus infusion (n=31)

Participant milestones

Participant milestones
Measure	Bolus Infusion Bolus infusion of ADVATE (rAHF-PFM)	Continuous Infusion Continuous infusion of ADVATE (rAHF-PFM)
Overall Study STARTED	31	32
Overall Study COMPLETED	31	29
Overall Study NOT COMPLETED	0	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Bolus Infusion Bolus infusion of ADVATE (rAHF-PFM)	Continuous Infusion Continuous infusion of ADVATE (rAHF-PFM)
Overall Study Other, No surgery performed	0	3

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bolus Infusion n=31 Participants Bolus infusion of ADVATE (rAHF-PFM)	Continuous Infusion n=32 Participants Continuous infusion of ADVATE (rAHF-PFM)	Total n=63 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	31 Participants n=5 Participants	32 Participants n=7 Participants	63 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	38.6 Years STANDARD_DEVIATION 9.76 • n=5 Participants	39.0 Years STANDARD_DEVIATION 11.52 • n=7 Participants	38.8 Years STANDARD_DEVIATION 10.61 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	31 Participants n=5 Participants	32 Participants n=7 Participants	63 Participants n=5 Participants

PRIMARY outcome

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

Population: All subjects who were randomized to receive BI or CI and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids. The overall number of participants treated by BI and CI comprises the number of participants in Stratum A, B and C for BI and CI.

Outcome measures

Outcome measures
Measure	Bolus Infusion n=28 Participants Bolus infusion of ADVATE (rAHF-PFM)	Continuous Infusion n=26 Participants Continuous infusion of ADVATE (rAHF-PFM)	BI Stratum A n=22 Participants Participants who underwent unilateral knee replacement and were treated by bolus infusion	BI Stratum B n=2 Participants Participants who underwent hip surgery and were treated by bolus infusion	BI Stratum C n=4 Participants Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion	CI Stratum A n=23 Participants Participants who underwent unilateral knee replacement and were treated by continuous infusion	CI Stratum B n=1 Participants Participants who underwent hip surgery and were treated by continuous infusion	CI Stratum C n=2 Participants Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion
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)	3.632 Tera per Liter Standard Deviation 0.971	3.383 Tera per Liter Standard Deviation 0.632	3.718 Tera per Liter Standard Deviation 0.978	2.855 Tera per Liter Standard Deviation 1.732	3.548 Tera per Liter Standard Deviation 0.577	3.345 Tera per Liter Standard Deviation 0.616	3.400 Tera per Liter Standard Deviation NA Stratum B for continuous infusion has only one subject with available data, therefore standard deviation is not available.	3.820 Tera per Liter Standard Deviation 1.103

SECONDARY outcome

Timeframe: During the first 24 postoperative hours blood loss was measured every 8 hours ± 30 minutes

Population: All subjects who were randomized to receive BI or CI and have observed drainage volumes up to 24 hours. The overall number of participants treated by BI and CI comprises the number of participants in Stratum A, B and C for BI and CI.

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. Units: Milliliter of blood

Outcome measures

Outcome measures
Measure	Bolus Infusion n=31 Participants Bolus infusion of ADVATE (rAHF-PFM)	Continuous Infusion n=29 Participants Continuous infusion of ADVATE (rAHF-PFM)	BI Stratum A n=24 Participants Participants who underwent unilateral knee replacement and were treated by bolus infusion	BI Stratum B n=2 Participants Participants who underwent hip surgery and were treated by bolus infusion	BI Stratum C n=5 Participants Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion	CI Stratum A n=24 Participants Participants who underwent unilateral knee replacement and were treated by continuous infusion	CI Stratum B n=2 Participants Participants who underwent hip surgery and were treated by continuous infusion	CI Stratum C n=3 Participants Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion
Actual Postoperative Blood Loss During the First 24 Hours Compared With the Average Blood Loss as Predicted Preoperatively by the Operating Surgeon	709.28 Milliliter Standard Deviation 150.103	811.11 Milliliter Standard Deviation 79.511	724.48 Milliliter Standard Deviation 66.367	265 Milliliter Standard Deviation 49.497	814.03 Milliliter Standard Deviation 171.019	819.22 Milliliter Standard Deviation 66.992	713.49 Milliliter Standard Deviation 0	811.25 Milliliter Standard Deviation 163.027

SECONDARY outcome

Timeframe: 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 estimated expected blood loss for the surgery in a hemostatically normal individual of the same sex, age, and stature as the study subject for the first 24 hours postoperatively, and for the postoperative period until drain removal, if drainage continued beyond 24 hours. Units: Milliliter of blood

Outcome measures

Outcome measures
Measure	Bolus Infusion n=30 Participants Bolus infusion of ADVATE (rAHF-PFM)	Continuous Infusion n=28 Participants Continuous infusion of ADVATE (rAHF-PFM)	BI Stratum A n=23 Participants Participants who underwent unilateral knee replacement and were treated by bolus infusion	BI Stratum B n=2 Participants Participants who underwent hip surgery and were treated by bolus infusion	BI Stratum C n=5 Participants Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion	CI Stratum A n=23 Participants Participants who underwent unilateral knee replacement and were treated by continuous infusion	CI Stratum B n=2 Participants Participants who underwent hip surgery and were treated by continuous infusion	CI Stratum C n=3 Participants Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion
Actual Postoperative Blood Loss Compared to the Expected Average Blood Loss Until Drain Removal as Predicted Preoperatively by the Surgeon	766.73 Milliliter Standard Deviation 182.463	929.49 Milliliter Standard Deviation 167.662	752.91 Milliliter Standard Deviation 42.343	341.5 Milliliter Standard Deviation 135.075	1000.37 Milliliter Standard Deviation 259.239	899.83 Milliliter Standard Deviation 45.459	921.1 Milliliter Standard Deviation 42.906	1162.48 Milliliter Standard Deviation 514.033

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Bolus Infusion n=31 Participants Bolus infusion of ADVATE (rAHF-PFM)	Continuous Infusion n=29 Participants Continuous infusion of ADVATE (rAHF-PFM)	BI Stratum A n=24 Participants Participants who underwent unilateral knee replacement and were treated by bolus infusion	BI Stratum B n=2 Participants Participants who underwent hip surgery and were treated by bolus infusion	BI Stratum C n=5 Participants Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion	CI Stratum A n=24 Participants Participants who underwent unilateral knee replacement and were treated by continuous infusion	CI Stratum B n=2 Participants Participants who underwent hip surgery and were treated by continuous infusion	CI Stratum C n=3 Participants Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion
Number of Bleeding Episodes During Treatment With Continuous or Bolus Infusion	0.10 Bleeding Episodes Standard Deviation 0.301	0.03 Bleeding Episodes Standard Deviation 0.186	0.08 Bleeding Episodes Standard Deviation 0.282	0.50 Bleeding Episodes Standard Deviation 0.707	0.00 Bleeding Episodes Standard Deviation 0.000	0.00 Bleeding Episodes Standard Deviation 0.000	0.50 Bleeding Episodes Standard Deviation 0.707	0.00 Bleeding Episodes Standard Deviation 0.000

SECONDARY outcome

Timeframe: During the first postoperative 24 hours

Outcome measures

Outcome measures
Measure	Bolus Infusion n=31 Participants Bolus infusion of ADVATE (rAHF-PFM)	Continuous Infusion n=29 Participants Continuous infusion of ADVATE (rAHF-PFM)	BI Stratum A n=24 Participants Participants who underwent unilateral knee replacement and were treated by bolus infusion	BI Stratum B n=2 Participants Participants who underwent hip surgery and were treated by bolus infusion	BI Stratum C n=5 Participants Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion	CI Stratum A n=24 Participants Participants who underwent unilateral knee replacement and were treated by continuous infusion	CI Stratum B n=2 Participants Participants who underwent hip surgery and were treated by continuous infusion	CI Stratum C n=3 Participants Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion
Number of Units of Packed Red Blood Cells Transfused	0.9 PRBC Units Standard Deviation 1.2	1.3 PRBC Units Standard Deviation 1.4	1.0 PRBC Units Standard Deviation 1.3	1.5 PRBC Units Standard Deviation 2.1	0.2 PRBC Units Standard Deviation 0.4	1.2 PRBC Units Standard Deviation 1.3	3.5 PRBC Units Standard Deviation 2.1	0.7 PRBC Units Standard Deviation 1.2

SECONDARY outcome

Timeframe: From first study drug exposure until study completion/discontinuation (approximately 9-26 weeks per subject)

Population: Participants in the Safety Analysis Set treated with at least one ADVATE infusion.

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.

Outcome measures

Outcome measures
Measure	Bolus Infusion n=31 Participants Bolus infusion of ADVATE (rAHF-PFM)	Continuous Infusion n=32 Participants Continuous infusion of ADVATE (rAHF-PFM)	BI Stratum A n=72 Participants Participants who underwent unilateral knee replacement and were treated by bolus infusion	BI Stratum B Participants who underwent hip surgery and were treated by bolus infusion	BI Stratum C Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion	CI Stratum A Participants who underwent unilateral knee replacement and were treated by continuous infusion	CI Stratum B Participants who underwent hip surgery and were treated by continuous infusion	CI Stratum C Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion
Number of Adverse Events Related to the Administration of the Study Product.	6 Adverse Events	8 Adverse Events	14 Adverse Events	—	—	—	—	—

SECONDARY outcome

Timeframe: Throughout the study period of approximately 9-26 weeks per participant

Population: Participants in the Safety Analysis Set treated with at least one ADVATE infusion.

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

Outcome measures

Outcome measures
Measure	Bolus Infusion n=31 Participants Bolus infusion of ADVATE (rAHF-PFM)	Continuous Infusion n=32 Participants Continuous infusion of ADVATE (rAHF-PFM)	BI Stratum A n=72 Participants Participants who underwent unilateral knee replacement and were treated by bolus infusion	BI Stratum B Participants who underwent hip surgery and were treated by bolus infusion	BI Stratum C Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion	CI Stratum A Participants who underwent unilateral knee replacement and were treated by continuous infusion	CI Stratum B Participants who underwent hip surgery and were treated by continuous infusion	CI Stratum C Participants who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion
Incidence of Factor VIII Inhibitory Antibody (≥0.4 Bethesda Units Using the Nijmegen Modification of the Bethesda Assay Formation)	2 Participants	2 Participants	4 Participants	—	—	—	—	—

Adverse Events

Bolus Infusion

Serious events: 3 serious events

Other events: 22 other events

Deaths: 0 deaths

Continuous Infusion

Serious events: 6 serious events

Other events: 20 other events

Deaths: 0 deaths

Not Assigned Participants

Serious events: 1 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Bolus Infusion n=31 participants at risk All participants who were randomized to receive bolus infusion (BI) of ADVATE (rAHF-PFM). At total of 31 participants were randomized and received at least one ADVATE (rAHF-PFM) dose.	Continuous Infusion n=32 participants at risk All participants who were randomized to receive continuous infusion (CI) of ADVATE (rAHF-PFM). At total of 32 participants were randomized and received at least one ADVATE (rAHF-PFM) dose.	Not Assigned Participants n=9 participants at risk All participants who were not assigned to either bolus infusion or continuous infusion but received at least one ADVATE (rAHF-PFM) dose during pharmacokinetic evaluation. A total of 9 participants received only the pharmacokinetic infusion and were not randomized.
Blood and lymphatic system disorders Factor VIII inhibition	6.5% 2/31 • Number of events 2 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	6.2% 2/32 • Number of events 2 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
General disorders Multi-organ failure	0.00% 0/31 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/32 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	11.1% 1/9 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Infections and infestations Febrile infection	0.00% 0/31 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	3.1% 1/32 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Infections and infestations Pseudomembranous colitis	0.00% 0/31 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	3.1% 1/32 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Musculoskeletal and connective tissue disorders Hemarthrosis	3.2% 1/31 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/32 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Musculoskeletal and connective tissue disorders Joint swelling	0.00% 0/31 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	3.1% 1/32 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Musculoskeletal and connective tissue disorders Muscle hemorrhage	0.00% 0/31 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	3.1% 1/32 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.

Other adverse events

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Agreements with PIs may vary per requirements of individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication. Baxalta requires a review of results communication (e.g. for confidential information) \>= 30 days prior to submission. Baxalta may request an additional delay of \<=120 days (e.g. for intellectual property protection).
Publication restrictions are in place

Restriction type: OTHER

Measure	Bolus Infusion n=31 participants at risk All participants who were randomized to receive bolus infusion (BI) of ADVATE (rAHF-PFM). At total of 31 participants were randomized and received at least one ADVATE (rAHF-PFM) dose.	Continuous Infusion n=32 participants at risk All participants who were randomized to receive continuous infusion (CI) of ADVATE (rAHF-PFM). At total of 32 participants were randomized and received at least one ADVATE (rAHF-PFM) dose.	Not Assigned Participants n=9 participants at risk All participants who were not assigned to either bolus infusion or continuous infusion but received at least one ADVATE (rAHF-PFM) dose during pharmacokinetic evaluation. A total of 9 participants received only the pharmacokinetic infusion and were not randomized.
Injury, poisoning and procedural complications Procedural pain	32.3% 10/31 • Number of events 10 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	50.0% 16/32 • Number of events 16 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Blood and lymphatic system disorders Anemia	32.3% 10/31 • Number of events 10 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	21.9% 7/32 • Number of events 7 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	11.1% 1/9 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
General disorders Pyrexia	32.3% 10/31 • Number of events 10 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	15.6% 5/32 • Number of events 5 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
General disorders Pain	16.1% 5/31 • Number of events 5 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	9.4% 3/32 • Number of events 3 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Musculoskeletal and connective tissue disorders Arthralgia	16.1% 5/31 • Number of events 5 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	6.2% 2/32 • Number of events 2 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Gastrointestinal disorders Constipation	3.2% 1/31 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	12.5% 4/32 • Number of events 4 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Blood and lymphatic system disorders Thrombocytosis	9.7% 3/31 • Number of events 3 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	3.1% 1/32 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Cardiac disorders Tachycardia	6.5% 2/31 • Number of events 2 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	6.2% 2/32 • Number of events 2 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Nervous system disorders Headache	3.2% 1/31 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	9.4% 3/32 • Number of events 3 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Psychiatric disorders Insomnia	3.2% 1/31 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	9.4% 3/32 • Number of events 3 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Infections and infestations Tooth Infection	0.00% 0/31 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/32 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	11.1% 1/9 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenoma benign	0.00% 0/31 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/32 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	11.1% 1/9 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Skin and subcutaneous tissue disorders Erythema	0.00% 0/31 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/32 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	11.1% 1/9 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Musculoskeletal and connective tissue disorders Muscle Hemorrhage	0.00% 0/31 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/32 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	11.1% 1/9 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Infections and infestations Influenza	0.00% 0/31 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	6.2% 2/32 • Number of events 2 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Injury, poisoning and procedural complications Anaemia postoperative	0.00% 0/31 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	6.2% 2/32 • Number of events 2 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Gastrointestinal disorders Nausea	9.7% 3/31 • Number of events 3 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/32 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Gastrointestinal disorders Vomiting	6.5% 2/31 • Number of events 2 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	3.1% 1/32 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Infections and infestations Urinary tract infection	6.5% 2/31 • Number of events 2 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	3.1% 1/32 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Musculoskeletal and connective tissue disorders Haemarthrosis	6.5% 2/31 • Number of events 2 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	3.1% 1/32 • Number of events 1 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.
Psychiatric disorders Anxiety	6.5% 2/31 • Number of events 2 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/32 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.	0.00% 0/9 • Throughout the study period. Overall: 9 years and 6 months. Per participant: 9-26 weeks.