Trial Outcomes & Findings for A Study of Safety and Efficacy of Fibrin Sealant Grifols as an Adjunct to Haemostasis During Surgery in Paediatric Participants (NCT NCT03461406)

Last Updated: 2023-04-14

Results Overview

Hemostasis is defined as Grade 0 bleeding per 5-point validated bleeding severity scale (0=no bleeding and 4=Unidentified or inaccessible spurting or gush) at the target bleeding site (TBS) according to the investigator's (surgeon's) judgment, so that the surgical closure of the exposed field could begin.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

186 participants

Primary outcome timeframe

From start of treatment until 4 minutes after treatment start (Day 1)

Results posted on

2023-04-14

Participant Flow

Participants took part in the study at 18 sites in the United States, Bulgaria, France, Hungary, Romania, Serbia, and United Kingdom, from 18 January 2019 (first participant enrolled to receive the study drug) to 20 May 2022 (last participant completed).

Paediatric participants with excessive bleeding during surgery were randomized into 1: 1 ratio to receive Fibrin Sealant (FS) Grifols and EVICEL. A total of 197 participants were screened, out of which 186 participants were randomized (Intent-to-treat population), 178 received study treatment (modified intent-to-treat population), 171 participants completed the study.

Participant milestones

Participant milestones
Measure	Fibrin Sealant Grifols Participants topically applied FS Grifols, which consisted of component 1: human fibrinogen (80 mg/mL) and component 2: human thrombin with calcium chloride (500 IU/mL) solutions filled in syringes and assembled on a syringe holder.	EVICEL Participants topically applied EVICEL, which consisted of component 1: Concentrate of human fibrinogen (BAC 2) (55-85 mg/mL) and component 2: human thrombin (800-1200 IU/mL) solutions. The 2 components (BAC2 and thrombin) were mixed and applied topically.
Overall Study STARTED	95	91
Overall Study Parenchymous Surgery	46	43
Overall Study Soft Tissue Surgery	45	44
Overall Study Safety Population	91	87
Overall Study COMPLETED	87	84
Overall Study NOT COMPLETED	8	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Fibrin Sealant Grifols Participants topically applied FS Grifols, which consisted of component 1: human fibrinogen (80 mg/mL) and component 2: human thrombin with calcium chloride (500 IU/mL) solutions filled in syringes and assembled on a syringe holder.	EVICEL Participants topically applied EVICEL, which consisted of component 1: Concentrate of human fibrinogen (BAC 2) (55-85 mg/mL) and component 2: human thrombin (800-1200 IU/mL) solutions. The 2 components (BAC2 and thrombin) were mixed and applied topically.
Overall Study Death	1	2
Overall Study Consent Withdrawn by Participant	0	1
Overall Study Screen Failure	3	1
Overall Study Reason not Specified	1	3
Overall Study Lost to Follow-up	3	0

Baseline Characteristics

A Study of Safety and Efficacy of Fibrin Sealant Grifols as an Adjunct to Haemostasis During Surgery in Paediatric Participants

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Fibrin Sealant Grifols n=95 Participants Participants topically applied FS Grifols, which consisted of component 1: human fibrinogen (80 mg/mL) and component 2: human thrombin with calcium chloride (500 IU/mL) solutions filled in syringes and assembled on a syringe holder.	EVICEL n=91 Participants Participants topically applied EVICEL, which consisted of component 1: Concentrate of human fibrinogen (BAC 2) (55-85 mg/mL) and component 2: human thrombin (800-1200 IU/mL) solutions. The 2 components (BAC2 and thrombin) were mixed and applied topically.	Total n=186 Participants Total of all reporting groups
Age, Continuous	8.43 years STANDARD_DEVIATION 6.108 • n=5 Participants	8.84 years STANDARD_DEVIATION 6.320 • n=7 Participants	8.63 years STANDARD_DEVIATION 6.199 • n=5 Participants
Sex: Female, Male Female	40 Participants n=5 Participants	30 Participants n=7 Participants	70 Participants n=5 Participants
Sex: Female, Male Male	55 Participants n=5 Participants	61 Participants n=7 Participants	116 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	13 Participants n=5 Participants	11 Participants n=7 Participants	24 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	82 Participants n=5 Participants	80 Participants n=7 Participants	162 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	6 Participants n=5 Participants	2 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) White	86 Participants n=5 Participants	89 Participants n=7 Participants	175 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: From start of treatment until 4 minutes after treatment start (Day 1)

Population: Modified ITT (mITT) population included all participants in the ITT population who meet the intra-operative enrollment criteria, and thus treated with any amount of investigational product (IP). Overall number analyzed are the number of participants with haemostasis by 4 minutes. Number analyzed are the number of participants with parenchymous and soft tissue surgery with data available for analysis. Percentage are rounded off the single decimal point.

Outcome measures

Outcome measures
Measure	Fibrin Sealant Grifols n=91 Participants Participants topically applied FS Grifols, which consisted of component 1: human fibrinogen (80 mg/mL) and component 2: human thrombin with calcium chloride (500 IU/mL) solutions filled in syringes and assembled on a syringe holder.	EVICEL n=87 Participants Participants topically applied EVICEL, which consisted of component 1: Concentrate of human fibrinogen (BAC 2) (55-85 mg/mL) and component 2: human thrombin (800-1200 IU/mL) solutions. The 2 components (BAC2 and thrombin) were mixed and applied topically.
Percentage of Participants Achieving Hemostasis Within 4 Minutes After Treatment Start (T4) Parenchymous Surgery	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants Achieving Hemostasis Within 4 Minutes After Treatment Start (T4) Soft Tissue Surgery	93.3 percentage of participants	90.9 percentage of participants

SECONDARY outcome

Timeframe: From start of treatment to 7 minutes after start of treatment (Day 1)

Population: mITT population included all participants in the ITT population who meet the intra-operative enrollment criteria, and thus treated with any amount of IP. Overall number analyzed are the number of participants with haemostasis by 4 minutes. Number analyzed are the number of participants with parenchymous and soft tissue surgery with data available for analysis. Percentages are rounded off a single decimal point.

Hemostasis is defined as Grade 0 bleeding at the TBS according to the investigator's (surgeon's) judgment, so that the surgical closure of the exposed field could begin. The cumulative percentage of participants achieving hemostasis at the TBS by the time points of T7 defined as an absence/cessation of bleeding (Grade 0) at the TBS by that time point without occurrence of rebleeding, Grade 3 or Grade 4 bleeding, use of alternative hemostatic treatment, and reapplication of study treatment after T4 and until TClosure.

Outcome measures

Outcome measures
Measure	Fibrin Sealant Grifols n=91 Participants Participants topically applied FS Grifols, which consisted of component 1: human fibrinogen (80 mg/mL) and component 2: human thrombin with calcium chloride (500 IU/mL) solutions filled in syringes and assembled on a syringe holder.	EVICEL n=87 Participants Participants topically applied EVICEL, which consisted of component 1: Concentrate of human fibrinogen (BAC 2) (55-85 mg/mL) and component 2: human thrombin (800-1200 IU/mL) solutions. The 2 components (BAC2 and thrombin) were mixed and applied topically.
Cumulative Percentage of Participants Achieving Hemostasis at the TBS by the 7 Minutes After Treatment Start (T7) Parenchymous Surgery	100.0 percentage of participants	100.0 percentage of participants
Cumulative Percentage of Participants Achieving Hemostasis at the TBS by the 7 Minutes After Treatment Start (T7) Soft Tissue Surgery	100.0 percentage of participants	100.0 percentage of participants

SECONDARY outcome

Timeframe: From start of treatment to 10 minutes after start of treatment (Day 1)

Population: mITT population included all participants in the ITT population who meet the intra-operative enrollment criteria and thus treated with any amount of IP. Overall number analyzed are the number of participants with haemostasis by 4 minutes. Number analyzed are the number of participants with parenchymous and soft tissue surgery with data available for analysis. Percentages are rounded off a single decimal point.

Hemostasis is defined as Grade 0 bleeding at the TBS according to the investigator's (surgeon's) judgment, so that the surgical closure of the exposed field could begin. The cumulative percentage of participants achieving hemostasis at the TBS by the time points of T10 defined as an absence/cessation of bleeding (Grade 0) at the TBS by that time point without occurrence of rebleeding, Grade 3 or Grade 4 bleeding, use of alternative hemostatic treatment, and reapplication of study treatment after T4 and until TClosure.

Outcome measures

Outcome measures
Measure	Fibrin Sealant Grifols n=90 Participants Participants topically applied FS Grifols, which consisted of component 1: human fibrinogen (80 mg/mL) and component 2: human thrombin with calcium chloride (500 IU/mL) solutions filled in syringes and assembled on a syringe holder.	EVICEL n=87 Participants Participants topically applied EVICEL, which consisted of component 1: Concentrate of human fibrinogen (BAC 2) (55-85 mg/mL) and component 2: human thrombin (800-1200 IU/mL) solutions. The 2 components (BAC2 and thrombin) were mixed and applied topically.
Cumulative Percentage of Participants Achieving Hemostasis at the Target Bleeding Site by 10 Minutes After Treatment Start (T10) Parenchymous Surgery	97.8 percentage of participants	100.0 percentage of participants
Cumulative Percentage of Participants Achieving Hemostasis at the Target Bleeding Site by 10 Minutes After Treatment Start (T10) Soft Tissue Surgery	100.0 percentage of participants	100.0 percentage of participants

SECONDARY outcome

Timeframe: From start of treatment to 10 minutes after start of treatment and until the time of completion of surgical closure (Day 1)

Participants were considered treatment failures if there is a. persistent bleeding at the TBS beyond T4 b. Grade 3 or Grade 4 breakthrough bleeding from the TBS that jeopardizes participant safety according to the investigator's judgment at any moment during the 10-minute observational period and until TClosure c. Use of alternative hemostatic treatments or maneuvers (other than the study treatment) at the TBS during the 10-minute observational period and until TClosure, or use of study treatment at the TBS beyond T4 and until TClosure d. Rebleeding (Grade ≥1) at the TBS after the assessment of the primary efficacy endpoint at T4 and until TClosure.

Outcome measures

Outcome measures
Measure	Fibrin Sealant Grifols n=91 Participants Participants topically applied FS Grifols, which consisted of component 1: human fibrinogen (80 mg/mL) and component 2: human thrombin with calcium chloride (500 IU/mL) solutions filled in syringes and assembled on a syringe holder.	EVICEL n=87 Participants Participants topically applied EVICEL, which consisted of component 1: Concentrate of human fibrinogen (BAC 2) (55-85 mg/mL) and component 2: human thrombin (800-1200 IU/mL) solutions. The 2 components (BAC2 and thrombin) were mixed and applied topically.
Percentage of Participants With Treatment Failures Parenchymous Surgery	0 percentage of participants	0 percentage of participants
Percentage of Participants With Treatment Failures Soft Tissue Surgery	0 percentage of participants	0 percentage of participants

Adverse Events

Fibrin Sealant Grifols

Serious events: 8 serious events

Other events: 20 other events

Deaths: 1 deaths

EVICEL

Serious events: 9 serious events

Other events: 13 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

Sandra Camprubi Gimenez

Instituto Grifols, S.A.

Phone: +34670923160

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Site may publish results from the Study, after providing Sponsor thirty days' notice prior to submitting a manuscript or other materials related to the Study to any outside party. At Sponsors' request, Site will remove any Confidential Information (other than Study results), and Site will upon Sponsors' request, delay publication or presentation for a period of up to one hundred twenty days to allow Sponsor to protect its interests in any Sponsor Inventions.
Publication restrictions are in place

Restriction type: OTHER

Measure	Fibrin Sealant Grifols n=91 participants at risk Participants topically applied FS Grifols, which consisted of component 1: human fibrinogen (80 mg/mL) and component 2: human thrombin with calcium chloride (500 IU/mL) solutions filled in syringes and assembled on a syringe holder.	EVICEL n=87 participants at risk Participants topically applied EVICEL, which consisted of component 1: Concentrate of human fibrinogen (BAC 2) (55-85 mg/mL) and component 2: human thrombin (800-1200 IU/mL) solutions. The 2 components (BAC2 and thrombin) were mixed and applied topically.
Injury, poisoning and procedural complications Post procedural haemorrhage	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Investigations Transaminases increased	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Cardiac disorders Cardiac arrest	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Respiratory, thoracic and mediastinal disorders Acute Respiratory Failure	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Immune system disorders Anaphylactic shock	2.2% 2/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Blood and lymphatic system disorders Pancytopenia	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
General disorders Pyrexia	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Ascites	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Diarrhoea	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Ileus	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Ileus paralytic	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Intussusception	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Vomiting	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Infections and infestations Postoperative wound infection	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Infections and infestations Respiratory syncytial virus infection	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Infections and infestations Respiratory tract infection	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Infections and infestations Sepsis	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Infections and infestations Staphylococcal infection	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Infections and infestations Wound infection	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.

Measure	Fibrin Sealant Grifols n=91 participants at risk Participants topically applied FS Grifols, which consisted of component 1: human fibrinogen (80 mg/mL) and component 2: human thrombin with calcium chloride (500 IU/mL) solutions filled in syringes and assembled on a syringe holder.	EVICEL n=87 participants at risk Participants topically applied EVICEL, which consisted of component 1: Concentrate of human fibrinogen (BAC 2) (55-85 mg/mL) and component 2: human thrombin (800-1200 IU/mL) solutions. The 2 components (BAC2 and thrombin) were mixed and applied topically.
Vascular disorders Hypertension	2.2% 2/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Injury, poisoning and procedural complications Anaemia postoperative	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Injury, poisoning and procedural complications Mechanical ventilation complication	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Injury, poisoning and procedural complications Procedural pain	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Injury, poisoning and procedural complications Procedural vomiting	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Injury, poisoning and procedural complications Wound complication	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Injury, poisoning and procedural complications Wound dehiscence	2.2% 2/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Investigations Blood magnesium decreased	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Investigations Haemoglobin decreased	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Investigations Oxygen saturation decreased	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Investigations Platelet count increased	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Respiratory, thoracic and mediastinal disorders Atelectasis	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Respiratory, thoracic and mediastinal disorders Bronchospasm	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Respiratory, thoracic and mediastinal disorders Epistaxis	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Respiratory, thoracic and mediastinal disorders Pleural effusion	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Respiratory, thoracic and mediastinal disorders Pneumothorax	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Blood and lymphatic system disorders Anaemia	2.2% 2/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	3.4% 3/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
General disorders Generalised oedema	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
General disorders Pyrexia	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	5.7% 5/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Abdominal distension	2.2% 2/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Abdominal pain	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Constipation	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Intra-abdominal fluid collection	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Melaena	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Nausea	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	2.3% 2/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Gastrointestinal disorders Vomiting	5.5% 5/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	3.4% 3/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Reproductive system and breast disorders Acquired hydrocele	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Skin and subcutaneous tissue disorders Rash	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Metabolism and nutrition disorders Acidosis	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Metabolism and nutrition disorders Decreased appetite	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Metabolism and nutrition disorders Hypoalbuminaemia	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Infections and infestations Bacteraemia	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Infections and infestations Pneumonia	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Infections and infestations Postoperative abscess	0.00% 0/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	1.1% 1/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Infections and infestations Wound infection	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.
Infections and infestations Upper respiratory tract infection	1.1% 1/91 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.	0.00% 0/87 • From signing informed consent form up to 7 days post study completion (Up to approximately 47 days) Safety population included all participants who received any amount of IP.