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Clinical Trial Results:
A Phase I/II, randomized, prospective, controlled, multi-center, open-label, two arm study evaluating the safety and preliminary efficacy of sFilm-FS in controlling liver bleeding during elective surgery.

Summary
EudraCT number	2018-000434-34
Trial protocol	SI AT
Global end of trial date	18 May 2023

Results information
Results version number	v1(current)
This version publication date	24 Jan 2025
First version publication date	24 Jan 2025
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

HEM-01-17

ISRCTN number

US NCT number

NCT04660721

WHO universal trial number (UTN)

Sponsor organisation name

Sealantium Medical Ltd.

Sponsor organisation address

Ha'Amal 11 St., Rosh Ha'Ayin, Israel,

Public contact

Prof. Orgad Laub, Sealantium Medical Ltd., +972 0544434387, orgad@sealantium-med.com

Scientific contact

Prof. Orgad Laub, Sealantium Medical Ltd., +972 0544434387, orgad@sealantium-med.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

18 May 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 May 2023

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study is to evaluate the safety of sFilm-FS versus an active-comparator (TACHOSIL®) when used as adjunct to conventional hemostatic techniques during elective hepatic surgery. Safety will be assessed from randomization of patients until the last follow-up visit and will include evaluation of treatment emergent adverse events. The secondary endpoints of the study are related to product hemostatic efficacy. For this purpose, hemostasis and treatment failure are defined. Hemostasis is defined as an absence/cessation of bleeding at the target bleeding site (TBS) according to the surgeon’s judgement, so that the surgical closure of the field could be started.

Protection of trial subjects

None

Background therapy

Evidence for comparator

TACHOSIL® is a fibrin sealant patch composed of an equine collagen patch coated with Human Fibrinogen and Human Thrombin. The product is ready for use and for the study it will be supplied in patch size of 4.8 x 4.8 cm (1.9 x 1.9 inch).

Actual start date of recruitment

12 May 2021

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 10

Country: Number of subjects enrolled

Slovenia: 6

Country: Number of subjects enrolled

Austria: 17

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

Patients undergoing elective, open abdominal surgery in which liver bleeding is expected, with presence of an appropriate target bleeding site (TBS) identified intra-operatively by the Investigator. 33 completed patients have been enrolled in this study.

Screening details

1. Patients (males or females) aged ≥ 18 years old 2. Patients requiring elective surgery in which liver bleeding will be encountered 3. Hemoglobin ≥ 8.0 g/dL within 24 hours prior to surgical procedure 4. Patients providing their informed consent prior to participation 5. Patients able to attend the visit and procedures foreseen in protocol

Period 1 title

Visit 1 (Screening)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group A

Arm description

sFilm-FS will be applied at the target bleeding site immediately after conventional methods of control have been exhausted. The sFilm-FS should cover adequately the entire TBS. Following application of sFilm-FS, the Investigator will immediately apply manual compression continuously for at least 2 minutes. A surgical sponge may be used to assist in providing adequate pressure. Hemostasis will be assessed after carefully releasing the compression at the site. sFilm-FS should not be removed once bleeding has stopped. A maximum of 4 units of sFilm-FS may be used per patient.

Arm type

Experimental

Investigational medicinal product name

sFilm-FS

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Intraabdominal use , Soft tissue use , Use in body cavities , Epilesional use

Dosage and administration details

sFilm-FS is a sterile bio-compatible bio-absorbable patch which consists of a polymeric film composed of a tri-block polymer (device component) containing Polyethylene Glycol (PEG) Poly-Caprolactone (PCL) and Poly-Lactide Acid (PLA), embedded with lyophilized powders of Human Fibrinogen, Human Thrombin (biological components) and calcium chloride. sFilm-FS is supplied ready to use in the patch size of 5 x 5 cm (~ 2 x 2 inch).

Group B

Arm description

TACHOSIL® will be applied at the target bleeding site immediately after conventional methods of control have been exhausted. TACHOSIL® should be applied as per the approved prescribing information, with manual compression for at least 3 minutes. A maximum of 4 units of TACHOSIL® may be used per patient.

Arm type

Active comparator

Investigational medicinal product name

TACHOSIL®

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Intraabdominal use , Soft tissue use , Use in body cavities , Epilesional use

Dosage and administration details

Number of subjects in period 1	Group A	Group B
Started	17	16
Completed	17	16

Period 2 title

Visit 2 (Baseline)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group A

Arm description

Arm type

Experimental

Investigational medicinal product name

sFilm-FS

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Intraabdominal use , Soft tissue use , Use in body cavities , Epilesional use

Dosage and administration details

Group B

Arm description

Arm type

Active comparator

Investigational medicinal product name

TACHOSIL®

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Number of subjects in period 2	Group A	Group B
Started	17	16
Completed	8	8
Not completed	9	8
V2 skipped if V1 was performed one day before V3	9	-
V2 skipped if V1 was performed one day before V3	-	8

Period 3 title

Visit 3 (Surgery)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group A

Arm description

Arm type

Experimental

Investigational medicinal product name

sFilm-FS

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Group B

Arm description

Arm type

Active comparator

Investigational medicinal product name

TACHOSIL®

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Number of subjects in period 3	Group A	Group B
Started	8	8
Completed	17	16
Joined	9	8
As per protocol, V2 (Baseline) skipped in case V1	9	8

Period 4 title

Visit 4 (Post-Surgery)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group A

Arm description

Arm type

Experimental

Investigational medicinal product name

sFilm-FS

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Group B

Arm description

Arm type

Active comparator

Investigational medicinal product name

TACHOSIL®

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Number of subjects in period 4	Group A	Group B
Started	17	16
Completed	17	16

Period 5 title

Visit 5 (Hospital Discharge)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group A

Arm description

Arm type

Experimental

Investigational medicinal product name

sFilm-FS

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Group B

Arm description

Arm type

Active comparator

Investigational medicinal product name

TACHOSIL®

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Number of subjects in period 5	Group A	Group B
Started	17	16
Completed	16	16
Not completed	1	0
Adverse event, non-fatal	1	-

Period 6 title

Visit 6 (Follow-up Day 30)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group A

Arm description

Arm type

Experimental

Investigational medicinal product name

sFilm-FS

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Group B

Arm description

Arm type

Active comparator

Investigational medicinal product name

TACHOSIL®

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Number of subjects in period 6	Group A	Group B
Started	16	16
Completed	15	14
Not completed	1	2
Adverse event, serious fatal	-	1
Consent withdrawn by subject	-	1
Protocol deviation	1	-

Period 7 title

Visit 7 (Follow-up Day 60)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group A

Arm description

Arm type

Experimental

Investigational medicinal product name

sFilm-FS

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Group B

Arm description

Arm type

Active comparator

Investigational medicinal product name

TACHOSIL®

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Number of subjects in period 7	Group A	Group B
Started	15	14
Completed	11	7
Not completed	5	7
V7 and V8 were introduced with Protocol V5.0	5	7
Joined	1	0
One patient didn't attend V6 but continued study	1	-

Period 8 title

Visit 8 (Follow-up Day 120)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group A

Arm description

Arm type

Experimental

Investigational medicinal product name

sFilm-FS

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Group B

Arm description

Arm type

Active comparator

Investigational medicinal product name

TACHOSIL®

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Number of subjects in period 8	Group A	Group B
Started	11	7
Completed	11	8
Joined	0	1
V7 and V8 were introduced with Protocol V5.0	-	1

Period 9 title

Visit 9 (Follow-up Day 180)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group A

Arm description

Arm type

Experimental

Investigational medicinal product name

sFilm-FS

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Group B

Arm description

Arm type

Active comparator

Investigational medicinal product name

TACHOSIL®

Investigational medicinal product code

Other name

Pharmaceutical forms

Sealant

Routes of administration

Epilesional use, Intraabdominal use , Soft tissue use , Use in body cavities

Dosage and administration details

Number of subjects in period 9	Group A	Group B
Started	11	8
Completed	16	14
Joined	5	6
V9 was performed on all patients still in study	5	6

Baseline characteristics

Top of page

Reporting group title

Group A

Reporting group description

Reporting group title

Group B

Reporting group description

Reporting group values	Group A	Group B	Total
Number of subjects	17	16	33
Age categorical
Patients (males or females) aged ≥ 18 years old
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	10	10	20
From 65-84 years	7	5	12
85 years and over	0	1	1
Age continuous
Patients (males or females) aged ≥ 18 years old
Units: years
arithmetic mean (standard deviation)	63.5 ( 10.46 )	57.8 ( 19.28 )	-
Gender categorical
Patients (males or females) aged ≥ 18 years old
Units: Subjects
Female	8	7	15
Male	9	9	18

End points

Top of page

Reporting group title

Group A

Reporting group description

Reporting group title

Group B

Reporting group description

Reporting group title

Group A

Reporting group description

Reporting group title

Group B

Reporting group description

Reporting group title

Group A

Reporting group description

Reporting group title

Group B

Reporting group description

Reporting group title

Group A

Reporting group description

Reporting group title

Group B

Reporting group description

Reporting group title

Group A

Reporting group description

Reporting group title

Group B

Reporting group description

Reporting group title

Group A

Reporting group description

Reporting group title

Group B

Reporting group description

Reporting group title

Group A

Reporting group description

Reporting group title

Group B

Reporting group description

Reporting group title

Group A

Reporting group description

Reporting group title

Group B

Reporting group description

Reporting group title

Group A

Reporting group description

Reporting group title

Group B

Reporting group description

Subject analysis set title

Vital Signs: Systolic Blood Pressure

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of vital signs (Systolic Blood Pressure - mmHg)

Subject analysis set title

Vital Signs: Diastolic Blood Pressure

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of vital signs (Diastolic Blood Pressure - mmHg)

Subject analysis set title

Vital Signs: Heart Rate

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of vital signs (Heart Rate - beats/min)

Subject analysis set title

Vital Signs: Respiratory Rate

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of vital signs (Respiratory Rate - breaths/min)

Subject analysis set title

Vital Signs: Body Temperature

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of vital signs (Body Temperature - °C)

Subject analysis set title

Urine - pH

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of urine pH

Subject analysis set title

Urine - Specific Gravity

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of Urine Specific Gravity (g/L)

Subject analysis set title

Urine - Glucose

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Detection of Glucose in Urine.

Subject analysis set title

Urine - Proteins

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Detection of Proteins in Urine.

Subject analysis set title

Urine - Blood

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Detection of Blood in Urine.

Subject analysis set title

Urine - Ketones

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Detection of Ketones in Urine.

Subject analysis set title

Physical Abnormalities

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Detection of Physical Abnormalities.

Subject analysis set title

Blood/coagulation Parameters - MCHC

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Mean Cell Hemoglobin Concentration - g/L)

Subject analysis set title

Blood/coagulation Parameters - MCH

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Mean Cell Hemoglobin - pg)

Subject analysis set title

Blood/coagulation Parameters - MCV

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Mean Corpuscular Volume - fL)

Subject analysis set title

Blood/coagulation Parameters - Red Blood Cell

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Red Blood Cell - 10^12/L)

Subject analysis set title

Blood/coagulation Parameters - White Blood Cell

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (White Blood Cell - 10^9/L)

Subject analysis set title

Blood/coagulation Parameters - Platelet

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Platelet - 10^9/L)

Subject analysis set title

Blood/coagulation Parameters - Fibrinogen

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Fibrinogen - g/L)

Subject analysis set title

Blood/coagulation Parameters - D-Dimer

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (D-Dimer - microg/mL)

Subject analysis set title

Blood/coagulation Parameters - ESR

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Erythrocyte Sedimentation Rate - mm/hr)

Subject analysis set title

Blood/coagulation Parameters - CRP

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (C-Reactive Protein - mg/dL)

Subject analysis set title

Blood/coagulation Parameters - BUN

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Blood Urea Nitrogen - mmol/L)

Subject analysis set title

Blood/coagulation Parameters - Creatinine

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Creatinine - micromol/L)

Subject analysis set title

Blood/coagulation Parameters - Uric Acid

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Uric Acid - micromol/L)

Subject analysis set title

Blood/coagulation Parameters - Total Bilirubin

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Total Bilirubin - micromol/L)

Subject analysis set title

Blood/coagulation Parameters - LDH

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Lactate Dehydrogenase - microkat/L)

Subject analysis set title

Blood/coagulation Parameters - SGOT/AST

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Serum Glutamic Oxaloacetic Transaminase/Aspartate Aminotransferase - microkat/L)

Subject analysis set title

Blood/coagulation Parameters - SGPT/ALT

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Serum Glutamic Pyruvic Transaminase/Alanine Aminotransferase - microkat/L)

Subject analysis set title

Blood/coagulation Parameters - Gamma-GT

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Gamma-GT - microkat/L)

Subject analysis set title

Blood/coagulation Parameters - Sodium

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Sodium - mmol/L)

Subject analysis set title

Blood/coagulation Parameters - Calcium

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Calcium - mmol/L)

Subject analysis set title

Blood/coagulation Parameters - Phosphorous

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Phosphorous - mmol/L)

Subject analysis set title

Blood/coagulation Parameters - Glucose

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Glucose - mmol/L)

Subject analysis set title

Blood/coagulation Parameters - Albumin

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Albumin - g/L)

Subject analysis set title

Blood/coagulation Parameters - Total Protein

Subject analysis set type

Per protocol

Subject analysis set description

Eligibility Criteria evaluation. Measurement of blood/coagulation parameters (Total Protein - g/L)

Primary: Safety - Vital Signs (Diastolic Blood Pressure)

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End point title

Safety - Vital Signs (Diastolic Blood Pressure) ^[1]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by measuring Diastolic Blood Pressure (mmHg)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	13	14	12	16	15	15	14	11	7	11	8	16	14
Units: mmHg
arithmetic mean (standard deviation)	81.0 ( 10.59 )	76.0 ( 7.27 )	75.4 ( 8.33 )	81.7 ( 13.61 )	61.6 ( 14.60 )	62.3 ( 10.87 )	74.2 ( 12.23 )	75.6 ( 11.52 )	74.9 ( 9.50 )	79.9 ( 11.58 )	79.7 ( 7.90 )	81.6 ( 8.45 )	80.8 ( 9.96 )	81.4 ( 6.88 )	81.0 ( 11.86 )	82.7 ( 7.57 )	79.4 ( 9.58 )	82.3 ( 11.56 )

No statistical analyses for this end point

Primary: Safety - Vital Signs (Respiratory Rate)

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End point title

Safety - Vital Signs (Respiratory Rate) ^[2]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by measuring Respiratory Rate (breaths/min)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	12	11	15	14	11	7	11	8	16	14
Units: breaths/min
arithmetic mean (standard deviation)	14.5 ( 3.14 )	13.5 ( 1.83 )	14.5 ( 2.27 )	15.4 ( 2.56 )	15.8 ( 7.59 )	15.0 ( 3.13 )	15.0 ( 2.88 )	16.8 ( 3.76 )	15.4 ( 3.12 )	22.4 ( 27.55 )	13.7 ( 2.32 )	12.9 ( 1.00 )	13.1 ( 1.81 )	14.3 ( 1.80 )	14.6 ( 2.29 )	13.4 ( 1.41 )	13.6 ( 2.36 )	14.1 ( 1.44 )

No statistical analyses for this end point

Primary: Safety - Vital Signs (Heart Rate)

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End point title

Safety - Vital Signs (Heart Rate) ^[3]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by measuring Heart Rate (beats/min)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	13	14	12	16	15	15	14	11	7	11	8	16	14
Units: beats/min
arithmetic mean (standard deviation)	72.2 ( 13.44 )	74.6 ( 11.94 )	74.5 ( 12.39 )	79.0 ( 16.98 )	69.0 ( 19.94 )	79.2 ( 13.93 )	77.1 ( 11.17 )	80.9 ( 18.18 )	79.1 ( 11.56 )	84.2 ( 14.87 )	77.3 ( 16.62 )	78.1 ( 17.17 )	74.2 ( 14.26 )	83.1 ( 8.45 )	73.7 ( 10.11 )	74.4 ( 7.61 )	73.7 ( 16.23 )	73.7 ( 13.78 )

No statistical analyses for this end point

Primary: Safety - Vital Signs (Body Temperature)

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End point title

Safety - Vital Signs (Body Temperature) ^[4]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by measuring Body Temperature (°C)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	13	14	12	16	15	15	14	11	7	11	8	16	14
Units: °C
arithmetic mean (standard deviation)	36.5 ( 0.39 )	36.7 ( 0.33 )	36.6 ( 0.44 )	36.4 ( 0.40 )	36.4 ( 0.77 )	36.3 ( 0.61 )	36.6 ( 0.44 )	36.8 ( 0.51 )	36.7 ( 0.39 )	36.7 ( 0.52 )	36.4 ( 0.53 )	36.4 ( 0.43 )	36.5 ( 0.34 )	36.8 ( 0.17 )	36.3 ( 0.59 )	36.8 ( 0.20 )	36.5 ( 0.39 )	36.3 ( 0.30 )

No statistical analyses for this end point

Primary: Safety - Physical Examination

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End point title

Safety - Physical Examination ^[5]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by physical examination: the detection of the number of patients with clinical abnormalities in different body areas (abdomen, eyes, skin, cardiovascular)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	16	16	15	14	11	7	11	8	16	14
Units: number of abnormalities	6	7	3	5	6	5	4	5	6	5	6	4

No statistical analyses for this end point

Primary: Safety - Urine Analysis (pH)

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End point title

Safety - Urine Analysis (pH) ^[6]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by urine analysis (pH)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	14	15	8	8	14	12	11	10	13	13	15	13
Units: not applicable
arithmetic mean (standard deviation)	5.5 ( 0.60 )	5.9 ( 0.84 )	5.7 ( 0.59 )	5.9 ( 0.88 )	5.4 ( 0.68 )	5.9 ( 0.88 )	6.2 ( 1.01 )	6.7 ( 1.09 )	6.3 ( 1.01 )	5.8 ( 0.81 )	5.7 ( 0.78 )	6.0 ( 0.90 )

No statistical analyses for this end point

Primary: Safety - Vital Signs (Systolic Blood Pressure)

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End point title

Safety - Vital Signs (Systolic Blood Pressure) ^[7]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by measuring Systolic Blood Pressure (mmHg)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	13	14	13	16	15	15	14	11	7	11	8	16	14
Units: mmHg
arithmetic mean (standard deviation)	137.1 ( 12.63 )	129.8 ( 16.75 )	138.9 ( 11.89 )	133.0 ( 11.10 )	118.9 ( 20.50 )	111.4 ( 14.75 )	129.1 ( 16.97 )	131.4 ( 21.22 )	133.1 ( 20.14 )	130.7 ( 21.08 )	131.6 ( 13.53 )	123.6 ( 17.35 )	133.5 ( 12.52 )	130.0 ( 15.46 )	130.6 ( 17.12 )	133.4 ( 10.34 )	127.0 ( 19.49 )	134.5 ( 19.07 )

No statistical analyses for this end point

Primary: Safety - Urine Analysis (Specific Gravity)

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End point title

Safety - Urine Analysis (Specific Gravity) ^[8]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by urine analysis (Specific Gravity)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	13	12	8	8	14	12	11	10	10	9	12	8
Units: g/L
arithmetic mean (standard deviation)	1021.6 ( 9.52 )	1018.8 ( 7.25 )	1017.2 ( 4.65 )	1019.2 ( 8.61 )	1027.2 ( 11.07 )	1022.4 ( 7.59 )	1018.2 ( 8.94 )	1024.9 ( 21.39 )	1019.9 ( 7.62 )	1019.7 ( 8.96 )	1017.4 ( 6.02 )	1020.1 ( 7.61 )

No statistical analyses for this end point

Primary: Safety - Urine Analysis (Glucose)

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End point title

Safety - Urine Analysis (Glucose) ^[9]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by urine analysis (Presence of Glucose - Positive, Strong Positive and Traces)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	16	16	8	8	14	12	11	10	13	13	15	13
Units: Presence
Positive	0	1	0	0	0	0	1	0	0	0	0	0
Strong Positive	1	0	0	0	1	0	0	0	1	0	1	1
Traces	5	3	1	0	4	4	6	4	4	4	1	2

No statistical analyses for this end point

Primary: Safety - Urine Analysis (Proteins)

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End point title

Safety - Urine Analysis (Proteins) ^[10]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by urine analysis (Presence of Proteins - Positive, Strong Positive and Traces)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	14	16	8	8	14	12	11	9	13	14	15	13
Units: presence
Positive	2	0	0	0	1	0	0	0	0	1	0	0
Strong Positive	0	0	0	0	2	0	0	0	0	0	0	0
Traces	2	3	1	2	5	6	1	3	4	3	0	2

No statistical analyses for this end point

Primary: Safety - Urine Analysis (Ketones)

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End point title

Safety - Urine Analysis (Ketones) ^[11]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by urine analysis (Presence of Ketones - Positive, Strong Positive and Traces)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	16	16	8	8	14	12	11	10	13	13	15	13
Units: presence
Positive	0	1	0	0	0	0	0	0	1	0	0	0
Strong Positive	0	0	0	1	1	1	0	0	0	0	0	0
Traces	2	1	0	1	5	2	4	3	2	1	0	1

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Hb)

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End point title

Safety - Blood/Coagulation Parameters (Hb) ^[12]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Hemoglobin - g/L)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	14	11	7	10	8	16	14
Units: g/L
arithmetic mean (standard deviation)	136.1 ( 20.54 )	135.6 ( 14.00 )	138.0 ( 15.13 )	135.0 ( 15.60 )	118.8 ( 10.64 )	121.9 ( 12.74 )	104.5 ( 17.14 )	108.4 ( 15.96 )	106.8 ( 16.19 )	111.7 ( 19.80 )	117.3 ( 17.02 )	122.1 ( 15.45 )	118.8 ( 14.03 )	119.3 ( 14.66 )	126.8 ( 12.66 )	128.9 ( 18.64 )	129.7 ( 11.66 )	136.3 ( 18.77 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (MCH)

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End point title

Safety - Blood/Coagulation Parameters (MCH) ^[13]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Mean Cell Hemoglobin - pg)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	14	11	7	10	8	15	14
Units: pg
arithmetic mean (standard deviation)	29.8 ( 3.00 )	29.5 ( 2.27 )	31.3 ( 2.01 )	28.2 ( 2.22 )	30.4 ( 1.95 )	29.3 ( 2.17 )	30.1 ( 2.11 )	29.6 ( 2.05 )	30.1 ( 1.81 )	29.3 ( 2.45 )	28.7 ( 2.26 )	29.1 ( 2.89 )	28.7 ( 2.38 )	27.5 ( 3.00 )	28.8 ( 3.26 )	27.1 ( 3.10 )	29.4 ( 2.53 )	29.6 ( 3.27 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (MCHC)

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End point title

Safety - Blood/Coagulation Parameters (MCHC) ^[14]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Mean Cell Hemoglobin Concentration - g/L)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	14	11	7	10	8	16	14
Units: g/L
arithmetic mean (standard deviation)	337.3 ( 15.40 )	337.5 ( 11.83 )	335.5 ( 8.14 )	337.5 ( 8.40 )	338.3 ( 12.16 )	337.7 ( 12.56 )	336.6 ( 10.82 )	333.8 ( 11.41 )	335.9 ( 10.53 )	333.6 ( 12.87 )	322.6 ( 12.02 )	332.1 ( 12.48 )	324.9 ( 11.02 )	326.7 ( 16.71 )	329.8 ( 11.91 )	326.6 ( 8.88 )	329.9 ( 10.77 )	334.9 ( 15.16 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (MCV)

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End point title

Safety - Blood/Coagulation Parameters (MCV) ^[15]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Mean Corpuscular Volume - fL)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at east 6 months)

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	14	11	7	10	8	16	14
Units: f/L
arithmetic mean (standard deviation)	88.5 ( 6.83 )	87.8 ( 7.34 )	93.1 ( 4.70 )	84.3 ( 8.21 )	90.4 ( 5.84 )	86.8 ( 6.91 )	89.5 ( 5.62 )	88.9 ( 6.35 )	89.9 ( 4.51 )	87.6 ( 7.31 )	88.9 ( 5.43 )	87.9 ( 8.29 )	88.5 ( 6.51 )	84.3 ( 8.79 )	86.9 ( 7.83 )	82.9 ( 8.30 )	88.2 ( 6.96 )	88.8 ( 9.02 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Red Blood Cell)

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End point title

Safety - Blood/Coagulation Parameters (Red Blood Cell) ^[16]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Red Blood Cell - 10^12/L)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	14	11	7	10	8	16	14
Units: 10^12/L
arithmetic mean (standard deviation)	4.6 ( 0.57 )	4.6 ( 0.53 )	4.4 ( 0.40 )	4.8 ( 0.57 )	3.9 ( 0.41 )	4.2 ( 0.57 )	3.5 ( 0.58 )	3.7 ( 0.63 )	3.6 ( 0.61 )	3.8 ( 0.66 )	4.1 ( 0.58 )	4.2 ( 0.52 )	4.1 ( 0.43 )	4.4 ( 0.52 )	4.4 ( 0.34 )	4.8 ( 0.63 )	4.5 ( 0.31 )	4.6 ( 0.71 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (White Blood Cell)

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End point title

Safety - Blood/Coagulation Parameters (White Blood Cell) ^[17]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (White Blood Cell - 10^9/L)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	14	11	7	10	8	16	14
Units: 10^9/L
arithmetic mean (standard deviation)	7.2 ( 2.47 )	8.0 ( 2.58 )	8.1 ( 2.00 )	9.2 ( 3.21 )	11.9 ( 3.81 )	10.9 ( 6.43 )	9.5 ( 4.61 )	12.1 ( 6.26 )	8.2 ( 2.93 )	9.6 ( 5.23 )	6.8 ( 2.33 )	8.1 ( 2.01 )	6.2 ( 3.20 )	7.4 ( 2.47 )	6.3 ( 2.56 )	8.0 ( 2.24 )	8.4 ( 4.42 )	7.8 ( 1.53 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Platelet)

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End point title

Safety - Blood/Coagulation Parameters (Platelet) ^[18]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Platelet - 10^9/L)

End point type

Primary

End point timeframe

From Visit 1 to Visit 9 (at least 6 months)

Notes
[18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	14	11	7	10	8	16	14
Units: 10^9/L
arithmetic mean (standard deviation)	241.6 ( 104.69 )	278.7 ( 90.90 )	241.6 ( 82.68 )	308.2 ( 125.23 )	227.4 ( 100.21 )	275.0 ( 122.16 )	238.4 ( 104.66 )	312.6 ( 173.32 )	308.4 ( 153.07 )	403.5 ( 272.79 )	260.9 ( 111.99 )	330.1 ( 189.33 )	216.8 ( 114.38 )	397.3 ( 204.51 )	203.8 ( 115.82 )	342.9 ( 169.86 )	250.2 ( 98.07 )	276.4 ( 141.69 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Fibrinogen)

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End point title

Safety - Blood/Coagulation Parameters (Fibrinogen) ^[19]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Fibrinogen - g/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	12	13	15	13	11	7	10	8	16	14
Units: g/L
arithmetic mean (standard deviation)	4.1 ( 1.16 )	4.3 ( 1.88 )	3.8 ( 0.87 )	4.3 ( 0.82 )	3.0 ( 0.81 )	3.5 ( 0.63 )	4.9 ( 1.21 )	5.8 ( 2.48 )	5.2 ( 1.10 )	5.8 ( 2.46 )	4.7 ( 1.68 )	4.4 ( 1.88 )	3.7 ( 0.75 )	4.6 ( 2.05 )	3.6 ( 0.95 )	3.6 ( 0.71 )	3.8 ( 0.96 )	3.2 ( 0.47 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (D-Dimer)

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End point title

Safety - Blood/Coagulation Parameters (D-Dimer) ^[20]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (D-Dimer - microg/mL)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	15	8	8	14	12	14	12	13	12	15	13	11	7	10	8	16	14
Units: microg/mL
arithmetic mean (standard deviation)	1.1 ( 0.81 )	0.9 ( 0.90 )	0.8 ( 0.46 )	1.3 ( 1.51 )	3.8 ( 3.58 )	2.8 ( 2.57 )	5.0 ( 3.32 )	3.3 ( 1.76 )	4.8 ( 4.54 )	4.9 ( 3.69 )	2.3 ( 1.78 )	2.2 ( 3.09 )	1.1 ( 0.68 )	1.3 ( 1.33 )	1.2 ( 1.05 )	0.6 ( 0.30 )	1.4 ( 2.03 )	4.0 ( 11.25 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (ESR)

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End point title

Safety - Blood/Coagulation Parameters (ESR) ^[21]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Erythrocyte Sedimentation Rate - mm/hr)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	13	12	8	8	12	10	12	10	12	10	13	10	8	7	11	8	13	9
Units: mm/hr
arithmetic mean (standard deviation)	18.3 ( 11.60 )	23.7 ( 18.44 )	20.6 ( 14.29 )	21.9 ( 6.85 )	17.6 ( 12.87 )	18.9 ( 13.30 )	48.5 ( 25.46 )	53.7 ( 37.18 )	55.7 ( 31.99 )	61.9 ( 41.07 )	39.8 ( 28.87 )	55.1 ( 51.17 )	16.5 ( 10.56 )	46.9 ( 37.53 )	18.0 ( 14.13 )	28.1 ( 18.64 )	17.7 ( 13.24 )	18.0 ( 9.86 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (CRP)

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End point title

Safety - Blood/Coagulation Parameters (CRP) ^[22]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (C-Reactive Protein - mg/dL)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	15	16	7	8	14	12	14	12	13	13	15	14	11	7	11	8	16	14
Units: mg/dL
arithmetic mean (standard deviation)	1.1 ( 1.11 )	1.3 ( 2.30 )	1.2 ( 1.46 )	0.9 ( 0.66 )	0.7 ( 0.90 )	0.7 ( 0.48 )	8.2 ( 8.91 )	11.4 ( 10.02 )	5.6 ( 5.35 )	5.5 ( 6.64 )	2.6 ( 4.97 )	1.6 ( 2.02 )	0.8 ( 1.31 )	1.0 ( 1.17 )	0.5 ( 0.47 )	0.4 ( 0.14 )	0.6 ( 0.86 )	0.5 ( 0.35 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (BUN)

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End point title

Safety - Blood/Coagulation Parameters (BUN) ^[23]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Blood Urea Nitrogen - mmol/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	14	11	7	10	8	16	14
Units: mmol/L
arithmetic mean (standard deviation)	5.3 ( 1.58 )	5.2 ( 1.28 )	5.8 ( 1.09 )	4.6 ( 2.03 )	5.1 ( 1.34 )	4.7 ( 1.98 )	5.2 ( 3.98 )	4.9 ( 2.49 )	4.7 ( 2.14 )	4.3 ( 1.73 )	5.1 ( 2.08 )	4.6 ( 1.65 )	5.7 ( 1.53 )	4.1 ( 1.38 )	5.5 ( 1.32 )	4.7 ( 1.55 )	4.2 ( 1.42 )	4.2 ( 2.31 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Creatinine)

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End point title

Safety - Blood/Coagulation Parameters (Creatinine) ^[24]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Creatinine - micromol/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[24] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	14	11	7	10	8	16	14
Units: micromol/L
arithmetic mean (standard deviation)	73.6 ( 18.12 )	61.7 ( 11.56 )	82.1 ( 21.02 )	68.9 ( 10.62 )	71.9 ( 18.48 )	66.5 ( 19.42 )	67.6 ( 34.13 )	58.7 ( 19.73 )	66.7 ( 19.76 )	59.8 ( 14.82 )	69.0 ( 16.50 )	60.0 ( 7.58 )	71.7 ( 16.01 )	62.7 ( 13.46 )	73.4 ( 21.88 )	65.9 ( 15.73 )	72.4 ( 17.81 )	61.6 ( 9.91 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Uric Acid)

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End point title

Safety - Blood/Coagulation Parameters (Uric Acid) ^[25]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Uric Acid - micromol/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	7	8	14	12	14	12	12	12	15	14	11	7	11	8	16	13
Units: micromol/L
arithmetic mean (standard deviation)	434.0 ( 324.04 )	376.1 ( 306.72 )	320.4 ( 84.22 )	346.5 ( 102.24 )	534.2 ( 585.91 )	401.1 ( 296.09 )	505.9 ( 550.82 )	304.8 ( 153.16 )	426.7 ( 423.50 )	343.7 ( 210.83 )	358.1 ( 307.01 )	431.3 ( 435.82 )	317.9 ( 87.80 )	340.0 ( 59.81 )	321.4 ( 90.98 )	338.1 ( 124.09 )	401.6 ( 345.94 )	312.4 ( 111.15 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Total Bilirubin)

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End point title

Safety - Blood/Coagulation Parameters (Total Bilirubin) ^[26]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Total Bilirubin - micromol/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[26] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	14	11	7	9	8	16	14
Units: micromol/L
arithmetic mean (standard deviation)	10.9 ( 6.71 )	12.0 ( 6.93 )	10.8 ( 7.62 )	11.6 ( 4.63 )	18.5 ( 15.69 )	11.6 ( 6.25 )	16.9 ( 19.88 )	13.1 ( 12.01 )	9.8 ( 6.61 )	8.0 ( 4.57 )	9.4 ( 5.11 )	7.1 ( 2.51 )	8.7 ( 5.89 )	6.7 ( 2.15 )	10.1 ( 5.55 )	7.9 ( 5.51 )	11.0 ( 7.60 )	11.3 ( 6.10 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (LDH)

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End point title

Safety - Blood/Coagulation Parameters (LDH) ^[27]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Lactate Dehydrogenase - microkat/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	15	8	8	13	12	13	12	13	13	15	14	11	7	10	8	16	14
Units: microkat/L
arithmetic mean (standard deviation)	3.7 ( 0.68 )	3.9 ( 2.28 )	3.6 ( 0.50 )	3.4 ( 0.75 )	8.1 ( 6.18 )	5.5 ( 2.72 )	4.8 ( 2.30 )	4.6 ( 1.29 )	4.0 ( 0.92 )	4.5 ( 1.19 )	3.5 ( 0.64 )	3.6 ( 0.90 )	3.6 ( 0.44 )	3.7 ( 1.01 )	3.3 ( 1.63 )	3.0 ( 1.60 )	2.9 ( 0.83 )	3.1 ( 1.08 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (SGOT/AST)

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End point title

Safety - Blood/Coagulation Parameters (SGOT/AST) ^[28]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Serum Glutamic Oxaloacetic Transaminase/Aspartate Aminotransferase - microkat/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[28] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	15	8	8	14	12	14	12	13	13	15	14	11	7	9	8	16	14
Units: microkat/L
arithmetic mean (standard deviation)	0.6 ( 0.29 )	0.4 ( 0.23 )	0.5 ( 0.21 )	0.4 ( 0.11 )	4.2 ( 4.42 )	1.8 ( 1.58 )	2.3 ( 3.42 )	1.2 ( 1.07 )	0.7 ( 0.34 )	0.9 ( 0.62 )	0.5 ( 0.22 )	0.4 ( 0.14 )	0.5 ( 0.30 )	0.5 ( 0.16 )	0.5 ( 0.31 )	0.4 ( 0.24 )	0.5 ( 0.21 )	0.5 ( 0.21 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (SGPT/ALT)

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End point title

Safety - Blood/Coagulation Parameters (SGPT/ALT) ^[29]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Serum Glutamic Pyruvic Transaminase/Alanine Aminotransferase - microkat/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	15	8	8	14	12	14	12	13	13	15	14	11	7	10	8	16	14
Units: microkat/L
arithmetic mean (standard deviation)	0.6 ( 0.47 )	0.4 ( 0.23 )	0.4 ( 0.22 )	0.5 ( 0.17 )	3.2 ( 3.53 )	1.4 ( 1.34 )	2.9 ( 3.86 )	1.4 ( 1.53 )	0.8 ( 0.58 )	1.4 ( 1.28 )	0.7 ( 1.09 )	0.4 ( 0.23 )	0.5 ( 0.41 )	0.4 ( 0.23 )	0.5 ( 0.31 )	0.4 ( 0.14 )	0.5 ( 0.30 )	0.4 ( 0.20 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Gamma-GT)

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End point title

Safety - Blood/Coagulation Parameters (Gamma-GT) ^[30]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Gamma-GT - microkat/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[30] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	15	8	8	14	12	14	12	13	13	15	14	11	7	11	8	16	14
Units: microkat/L
arithmetic mean (standard deviation)	2.9 ( 7.82 )	1.1 ( 1.10 )	0.6 ( 0.33 )	0.8 ( 1.20 )	2.8 ( 7.85 )	0.7 ( 0.89 )	4.7 ( 7.43 )	1.1 ( 0.91 )	3.0 ( 6.16 )	1.7 ( 1.23 )	3.8 ( 7.12 )	1.3 ( 0.96 )	0.8 ( 0.82 )	0.8 ( 0.91 )	0.8 ( 0.95 )	0.8 ( 0.85 )	1.2 ( 1.18 )	0.9 ( 1.01 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Na)

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End point title

Safety - Blood/Coagulation Parameters (Na) ^[31]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Sodium - mmol/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	13	12	13	12	13	13	15	14	11	7	10	8	16	14
Units: mmol/L
arithmetic mean (standard deviation)	141.1 ( 2.26 )	139.9 ( 1.89 )	140.0 ( 3.59 )	139.0 ( 3.89 )	140.9 ( 2.72 )	139.8 ( 2.63 )	139.1 ( 3.19 )	139.7 ( 2.85 )	139.4 ( 3.38 )	140.6 ( 3.07 )	140.9 ( 2.00 )	139.1 ( 2.41 )	141.5 ( 2.54 )	139.9 ( 2.41 )	140.8 ( 2.10 )	140.5 ( 2.78 )	140.3 ( 1.62 )	140.6 ( 2.79 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Ca)

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End point title

Safety - Blood/Coagulation Parameters (Ca) ^[32]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Calcium - mmol/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[32] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	14	11	7	10	8	16	14
Units: mmol/L
arithmetic mean (standard deviation)	2.4 ( 0.10 )	2.3 ( 0.16 )	2.4 ( 0.11 )	2.3 ( 0.12 )	2.1 ( 0.11 )	2.1 ( 0.11 )	2.1 ( 0.14 )	2.1 ( 0.12 )	2.2 ( 0.16 )	2.2 ( 0.13 )	2.5 ( 0.45 )	3.0 ( 1.93 )	2.4 ( 0.11 )	2.4 ( 0.05 )	2.4 ( 0.16 )	2.4 ( 0.10 )	2.4 ( 0.16 )	2.4 ( 0.09 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (P)

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End point title

Safety - Blood/Coagulation Parameters (P) ^[33]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Phosphorous - mmol/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	13	15	7	8	14	12	14	12	12	12	15	14	11	7	10	8	16	14
Units: mmol/L
arithmetic mean (standard deviation)	1.0 ( 0.12 )	1.1 ( 0.21 )	1.2 ( 0.08 )	1.1 ( 0.16 )	1.2 ( 0.20 )	1.1 ( 0.33 )	0.90 ( 0.32 )	0.89 ( 0.24 )	1.0 ( 0.19 )	1.0 ( 0.30 )	1.1 ( 0.11 )	1.1 ( 0.19 )	1.1 ( 0.28 )	1.1 ( 0.17 )	1.0 ( 0.24 )	1.1 ( 0.15 )	1.2 ( 0.20 )	8.7 ( 28.57 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Glucose)

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End point title

Safety - Blood/Coagulation Parameters (Glucose) ^[34]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Glucose - mmol/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[34] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	14	14	11	7	10	8	16	14
Units: mmol/L
arithmetic mean (standard deviation)	6.5 ( 2.51 )	5.6 ( 1.27 )	6.7 ( 3.15 )	6.4 ( 3.78 )	8.1 ( 2.50 )	7.6 ( 2.65 )	6.1 ( 1.91 )	6.5 ( 2.23 )	6.4 ( 1.62 )	6.0 ( 1.50 )	6.2 ( 1.52 )	5.9 ( 1.91 )	5.9 ( 1.59 )	6.9 ( 3.83 )	5.2 ( 1.73 )	7.1 ( 5.50 )	6.0 ( 1.83 )	5.7 ( 3.37 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Albumin)

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End point title

Safety - Blood/Coagulation Parameters (Albumin) ^[35]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Albumin - g/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[35] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	12	11	7	10	8	16	14
Units: g/L
arithmetic mean (standard deviation)	42.4 ( 4.16 )	42.5 ( 5.67 )	42.6 ( 3.89 )	44.0 ( 4.99 )	32.8 ( 4.77 )	34.5 ( 4.95 )	28.6 ( 4.71 )	30.7 ( 5.08 )	32.4 ( 5.25 )	34.0 ( 6.81 )	40.0 ( 3.35 )	41.1 ( 4.85 )	41.7 ( 2.95 )	41.9 ( 3.93 )	42.9 ( 4.38 )	44.6 ( 5.01 )	43.2 ( 4.71 )	43.8 ( 4.92 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (Total Proteins)

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End point title

Safety - Blood/Coagulation Parameters (Total Proteins) ^[36]

End point description

Safety has been assessed from randomization of patients until the last follow-up visit by blood/coagulation parameters profiles analysis (Total Proteins - g/L)

End point type

Primary

End point timeframe

From visit 1 to visit 9 (at least 6 months)

Notes
[36] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B	Group A	Group B
Number of subjects analysed	17	16	8	8	14	12	14	12	13	13	15	12	11	7	10	8	16	14
Units: g/L
arithmetic mean (standard deviation)	73.2 ( 5.93 )	73.0 ( 9.29 )	71.1 ( 5.41 )	74.9 ( 8.89 )	56.6 ( 8.07 )	62.0 ( 8.83 )	54.9 ( 8.68 )	60.5 ( 10.16 )	63.2 ( 9.92 )	64.5 ( 9.60 )	75.0 ( 6.53 )	76.1 ( 9.44 )	72.4 ( 4.99 )	79.3 ( 8.28 )	75.1 ( 6.15 )	77.7 ( 8.10 )	74.8 ( 6.21 )	75.3 ( 5.42 )

No statistical analyses for this end point

Primary: Safety - Blood/Coagulation Parameters (anti-Fb antibodies)

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End point title

Safety - Blood/Coagulation Parameters (anti-Fb antibodies) ^[37]

End point description

End point type

Primary

End point timeframe

End of Trial

Notes
[37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Considering the exploratory nature of the study (Phase I/II) no a priori hypotheses testing were formulated; only descriptive statistics and 95% Confidence Limits between treatment have been calculated where appropriate.

End point values	Group A	Group B
Number of subjects analysed	16	14
Units: participants	2	2

No statistical analyses for this end point

Secondary: Evaluation the Hemostatic Efficacy of sFilm-FS in Controlling Parenchymal Bleeding During Surgery

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End point title

Evaluation the Hemostatic Efficacy of sFilm-FS in Controlling Parenchymal Bleeding During Surgery

End point description

Proportion of patients achieving hemostasis at TBS (absence of bleeding) at 2 (for sFilm-FS product only), 3, 5, 7 or 10 minutes following first product application, without the occurrence of re-bleeding, starting from 10 minutes after product application and until the completion of surgical closure

End point type

Secondary

End point timeframe

Day of Surgery

End point values	Group A	Group B
Number of subjects analysed	14	12
Units: participants
2 minutes after application (only for sFilm-FS)	11	0
3 minutes after application	12	12
5 minutes after application	12	12
7 minutes after application	12	12
10 minutes after application	14	12

No statistical analyses for this end point

Secondary: Evaluation the Hemostatic Efficacy of sFilm-FS in Controlling Parenchymal Bleeding During Surgery

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End point title

Evaluation the Hemostatic Efficacy of sFilm-FS in Controlling Parenchymal Bleeding During Surgery

End point description

Incidence of re-treatment (one or more additional patch of sFilm-FS or TACHOSIL®) at the TBS at the different time points (2 for sFilm-FS, 3, 5, 7, 10 minutes from first product application)

End point type

Secondary

End point timeframe

Day of surgery

End point values	Group A	Group B
Number of subjects analysed	14	12
Units: participants
2 minutes after application (only for sFilm-FS)	0	0
3 minutes after application	0	0
5 minutes after application	0	0
7 minutes after application	0	0
10 minutes after application	2	0

No statistical analyses for this end point

Secondary: Evaluation the Hemostatic Efficacy of sFilm-FS in Controlling Parenchymal Bleeding During Surgery

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End point title

Evaluation the Hemostatic Efficacy of sFilm-FS in Controlling Parenchymal Bleeding During Surgery

End point description

Percentage of total patients (patients that achieved hemostasis with a single patch application and patients that required additional patches) that have achieved hemostasis 10 minutes after first product application and therefore did not need to convert to standard of care treatment at the end of these 10 minutes

End point type

Secondary

End point timeframe

Day of surgery

End point values	Group A	Group B
Number of subjects analysed	14	12
Units: participants	14	12

No statistical analyses for this end point

Secondary: Evaluation the Hemostatic Efficacy of sFilm-FS in Controlling Parenchymal Bleeding During Surgery

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End point title

Evaluation the Hemostatic Efficacy of sFilm-FS in Controlling Parenchymal Bleeding During Surgery

End point description

Incidence of treatment failure, based on pre-defined treatment failure criteria (in case the bleeding at TBS (or re-bleeding) is still observed after 10 minutes following first application of study product; if hemostasis at TBS is achieved, but the Investigator decides that an additional treatment is required to ensure the durability of hemostasis; if there is a breakthrough bleeding requiring treatment other than the study product, at any time)

End point type

Secondary

End point timeframe

Day of surgery

End point values	Group A	Group B
Number of subjects analysed	14	12
Units: participants	2	0

No statistical analyses for this end point

Secondary: Evaluation the Hemostatic Efficacy of sFilm-FS in Controlling Parenchymal Bleeding During Surgery

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End point title

Evaluation the Hemostatic Efficacy of sFilm-FS in Controlling Parenchymal Bleeding During Surgery

End point description

Incidence of transfusion requirements in the 6 months follow-up period

End point type

Secondary

End point timeframe

From surgery, up to 6 months

End point values	Group A	Group B
Number of subjects analysed	16	14
Units: participants	1	1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Visit 1 to Visit 9 (at least 6 months)

Adverse event reporting additional description

All patients experienced at least one adverse event during the study, none of them related to the study intervention.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Group A

Reporting group description

Reporting group title

Group B

Reporting group description

Serious adverse events	Group A	Group B
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 17 (35.29%)	2 / 16 (12.50%)
number of deaths (all causes)	1	1
number of deaths resulting from adverse events	1	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to liver
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Disease progression
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal wall haematoma
subjects affected / exposed	2 / 17 (11.76%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatorenal failure
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Muscle atrophy
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Group A	Group B
Total subjects affected by non serious adverse events
subjects affected / exposed	17 / 17 (100.00%)	16 / 16 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adrenal gland cancer
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Cholangiocarcinoma
subjects affected / exposed	2 / 17 (11.76%)	0 / 16 (0.00%)
occurrences all number	2	0
Gallbladder cancer
subjects affected / exposed	0 / 17 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Haemangioma of spleen
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Metastases to liver
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Metastases to lung
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Neuroendocrine carcinoma metastatic
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Vascular disorders
Hypertension
subjects affected / exposed	3 / 17 (17.65%)	2 / 16 (12.50%)
occurrences all number	3	2
Hypotension
subjects affected / exposed	2 / 17 (11.76%)	2 / 16 (12.50%)
occurrences all number	3	5
Inferior vena cava dilatation
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Surgical and medical procedures
Blood volume expansion
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Colonic lavage
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Dermabrasion
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Haematoma evacuation
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Prophylaxis
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Chest pain
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Death
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Disease progression
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Fatigue
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Generalised oedema
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Impaired healing
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Inflammatory pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Oedema peripheral
subjects affected / exposed	1 / 17 (5.88%)	2 / 16 (12.50%)
occurrences all number	1	5
Pain
subjects affected / exposed	3 / 17 (17.65%)	5 / 16 (31.25%)
occurrences all number	4	11
Pyrexia
subjects affected / exposed	2 / 17 (11.76%)	3 / 16 (18.75%)
occurrences all number	2	3
Reproductive system and breast disorders
Genital haemorrhage
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Penile haematoma
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Penile pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Atelectasis
subjects affected / exposed	0 / 17 (0.00%)	3 / 16 (18.75%)
occurrences all number	0	3
Dyspnoea
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Hiccups
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Hypoxia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Lung infiltration
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Oropharyngeal pain
subjects affected / exposed	1 / 17 (5.88%)	3 / 16 (18.75%)
occurrences all number	2	3
Pleural effusion
subjects affected / exposed	1 / 17 (5.88%)	2 / 16 (12.50%)
occurrences all number	1	2
Pulmonary embolism
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Pulmonary hypertension
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Respiratory failure
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Psychiatric disorders
Agitation
subjects affected / exposed	2 / 17 (11.76%)	0 / 16 (0.00%)
occurrences all number	2	0
Anxiety
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Confusional state
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Depression
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Insomnia
subjects affected / exposed	2 / 17 (11.76%)	1 / 16 (6.25%)
occurrences all number	2	1
Restlessness
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Sleep disorder
subjects affected / exposed	3 / 17 (17.65%)	2 / 16 (12.50%)
occurrences all number	3	3
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Blood albumin increased
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Blood bilirubin increased
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	2	0
Haemoglobin decreased
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
White blood cell count increased
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Injury, poisoning and procedural complications
Confusional state
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Drain site complication
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Fall
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Hepatic seroma
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Lumbar vertebral bile leak
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Post procedural bile leak
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Procedural hypotension
subjects affected / exposed	3 / 17 (17.65%)	0 / 16 (0.00%)
occurrences all number	3	0
Procedural pain
subjects affected / exposed	11 / 17 (64.71%)	9 / 16 (56.25%)
occurrences all number	13	11
Seroma
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Thoracic vertebral fracture
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Wound
subjects affected / exposed	0 / 17 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	3
Wound complication
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Congenital, familial and genetic disorders
Factor II deficiency
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Cardiac disorders
Aortic valve incompetence
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Atrial fibrillation
subjects affected / exposed	2 / 17 (11.76%)	1 / 16 (6.25%)
occurrences all number	3	2
Atrial tachycardia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Bradycardia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Cor pulmonale
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Cardiomegaly
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Mitral valve incompetence
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Pericardial cyst
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Right ventricular enlargement
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Right ventricular failure
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Sinus bradycardia
subjects affected / exposed	2 / 17 (11.76%)	0 / 16 (0.00%)
occurrences all number	2	0
Supraventricular tachycardia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Systolic dysfunction
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Tachycardia
subjects affected / exposed	1 / 17 (5.88%)	3 / 16 (18.75%)
occurrences all number	2	4
Tricuspid valve incompetence
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Ventricular extrasystoles
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Ventricular hypokinesia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Nervous system disorders
Cognitive disorder
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Dizziness
subjects affected / exposed	0 / 17 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Hypoaesthesia
subjects affected / exposed	0 / 17 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Lethargy
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Polyneuropathy
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	2	0
Radiculopathy
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 17 (11.76%)	1 / 16 (6.25%)
occurrences all number	2	1
Blood loss anaemia
subjects affected / exposed	2 / 17 (11.76%)	0 / 16 (0.00%)
occurrences all number	2	0
Coagulopathy
subjects affected / exposed	2 / 17 (11.76%)	0 / 16 (0.00%)
occurrences all number	2	0
Iron deficiency anaemia
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Leukocytosis
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Splenic infarction
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Thrombocytopenia
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Thrombocytosis
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 17 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	3
Abdominal pain
subjects affected / exposed	2 / 17 (11.76%)	1 / 16 (6.25%)
occurrences all number	3	1
Abdominal pain upper
subjects affected / exposed	2 / 17 (11.76%)	0 / 16 (0.00%)
occurrences all number	2	0
Abdominal wall haematoma
subjects affected / exposed	2 / 17 (11.76%)	2 / 16 (12.50%)
occurrences all number	2	2
Abnormal faeces
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Constipation
subjects affected / exposed	3 / 17 (17.65%)	1 / 16 (6.25%)
occurrences all number	3	1
Diarrhoea
subjects affected / exposed	2 / 17 (11.76%)	2 / 16 (12.50%)
occurrences all number	2	5
Duodenal ulcer
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Duodenitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Dyspepsia
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Dysphagia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Gastric ileus
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Haematemesis
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Haemorrhoids
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Ileus
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Inflammatory bowel disease
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Intestinal obstruction
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Intra-abdominal haematoma
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Nausea
subjects affected / exposed	12 / 17 (70.59%)	5 / 16 (31.25%)
occurrences all number	14	5
Vomiting
subjects affected / exposed	2 / 17 (11.76%)	0 / 16 (0.00%)
occurrences all number	2	0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Hepatic failure
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Hepatic steatosis
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Hepatorenal failure
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Hyperbilirubinaemia
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	2	0
Hypertransaminasaemia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Skin and subcutaneous tissue disorders
Excessive granulation tissue
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Lipodystrophy acquired
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Pruritus allergic
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 17 (11.76%)	3 / 16 (18.75%)
occurrences all number	2	3
Oliguria
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Renal infarct
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Urinary incontinence
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Urinary retention
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Back pain
subjects affected / exposed	2 / 17 (11.76%)	0 / 16 (0.00%)
occurrences all number	2	0
Flank pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Intervertebral disc degeneration
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Muscle atrophy
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Pain in extremity
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Infections and infestations
Abdominal infection
subjects affected / exposed	2 / 17 (11.76%)	0 / 16 (0.00%)
occurrences all number	2	0
Bacterial infection
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Candida infection
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Clostridium difficile infection
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
COVID-19
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Infection susceptibility increased
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	2	0
Oral candidiasis
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Post procedural infection
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	2	0
Respiratory tract infection
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Staphylococcal infection
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Urinary tract infection
subjects affected / exposed	2 / 17 (11.76%)	3 / 16 (18.75%)
occurrences all number	3	5
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	2	1
Dehydration
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Diabetes mellitus
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Folate deficiency
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	2	0
Hypercholesterolaemia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Hyperglycaemia
subjects affected / exposed	1 / 17 (5.88%)	2 / 16 (12.50%)
occurrences all number	1	2
Hyperkalaemia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2
Hypoalbuminaemia
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Hypocalcaemia
subjects affected / exposed	0 / 17 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Hypokalaemia
subjects affected / exposed	8 / 17 (47.06%)	5 / 16 (31.25%)
occurrences all number	12	5
Hyponatraemia
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Hypophagia
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Hypophosphataemia
subjects affected / exposed	3 / 17 (17.65%)	3 / 16 (18.75%)
occurrences all number	4	3
Magnesium deficiency
subjects affected / exposed	5 / 17 (29.41%)	1 / 16 (6.25%)
occurrences all number	5	1
Malnutrition
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	2

More information

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Were there any global substantial amendments to the protocol? Yes

10 Apr 2019

FDA Immediate Response requests: Various updates/ clarifications/ alignments with regulatory requirements, including extended subject monitoring, immunogenicity testing and addition of secondary endpoints.

19 May 2021

Changes of Sponsor: • Various updates/ clarifications • Increase of sample size • Inclusion of U.S. site

05 Jul 2021

Removal of TEG testing and related exclusion criteria.

08 Jul 2021

Changes of Sponsor/ FDA requests: • Removal of TEG testing and related exclusion criteria • Various updates/ clarifications/ alignments with regulatory requirements, including additional stopping criteria, addition of follow up visits and addition of MRI assessment

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Phase I/II, randomized, prospective, controlled, multi-center, open-label, two arm study evaluating the safety and preliminary efficacy of sFilm-FS in controlling liver bleeding during elective surgery.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Safety - Vital Signs (Diastolic Blood Pressure)

Primary: Safety - Vital Signs (Diastolic Blood Pressure)

Primary: Safety - Vital Signs (Respiratory Rate)

Primary: Safety - Vital Signs (Respiratory Rate)

Primary: Safety - Vital Signs (Heart Rate)

Primary: Safety - Vital Signs (Heart Rate)

Primary: Safety - Vital Signs (Body Temperature)

Primary: Safety - Vital Signs (Body Temperature)

Primary: Safety - Physical Examination

Primary: Safety - Physical Examination

Primary: Safety - Urine Analysis (pH)

Primary: Safety - Urine Analysis (pH)

Primary: Safety - Vital Signs (Systolic Blood Pressure)

Primary: Safety - Vital Signs (Systolic Blood Pressure)

Primary: Safety - Urine Analysis (Specific Gravity)

Primary: Safety - Urine Analysis (Specific Gravity)

Primary: Safety - Urine Analysis (Glucose)

Primary: Safety - Urine Analysis (Glucose)

Primary: Safety - Urine Analysis (Proteins)

Primary: Safety - Urine Analysis (Proteins)

Primary: Safety - Urine Analysis (Ketones)

Primary: Safety - Urine Analysis (Ketones)

Primary: Safety - Blood/Coagulation Parameters (Hb)

Primary: Safety - Blood/Coagulation Parameters (Hb)

Primary: Safety - Blood/Coagulation Parameters (MCH)

Primary: Safety - Blood/Coagulation Parameters (MCH)

Primary: Safety - Blood/Coagulation Parameters (MCHC)

Primary: Safety - Blood/Coagulation Parameters (MCHC)

Primary: Safety - Blood/Coagulation Parameters (MCV)

Primary: Safety - Blood/Coagulation Parameters (MCV)

Primary: Safety - Blood/Coagulation Parameters (Red Blood Cell)

Primary: Safety - Blood/Coagulation Parameters (Red Blood Cell)

Primary: Safety - Blood/Coagulation Parameters (White Blood Cell)

Primary: Safety - Blood/Coagulation Parameters (White Blood Cell)

Primary: Safety - Blood/Coagulation Parameters (Platelet)

Primary: Safety - Blood/Coagulation Parameters (Platelet)

Primary: Safety - Blood/Coagulation Parameters (Fibrinogen)

Primary: Safety - Blood/Coagulation Parameters (Fibrinogen)

Primary: Safety - Blood/Coagulation Parameters (D-Dimer)

Primary: Safety - Blood/Coagulation Parameters (D-Dimer)

Primary: Safety - Blood/Coagulation Parameters (ESR)

Primary: Safety - Blood/Coagulation Parameters (ESR)

Primary: Safety - Blood/Coagulation Parameters (CRP)

Primary: Safety - Blood/Coagulation Parameters (CRP)

Primary: Safety - Blood/Coagulation Parameters (BUN)

Primary: Safety - Blood/Coagulation Parameters (BUN)

Primary: Safety - Blood/Coagulation Parameters (Creatinine)

Primary: Safety - Blood/Coagulation Parameters (Creatinine)

Primary: Safety - Blood/Coagulation Parameters (Uric Acid)

Primary: Safety - Blood/Coagulation Parameters (Uric Acid)

Primary: Safety - Blood/Coagulation Parameters (Total Bilirubin)

Primary: Safety - Blood/Coagulation Parameters (Total Bilirubin)

Primary: Safety - Blood/Coagulation Parameters (LDH)

Primary: Safety - Blood/Coagulation Parameters (LDH)

Primary: Safety - Blood/Coagulation Parameters (SGOT/AST)

Primary: Safety - Blood/Coagulation Parameters (SGOT/AST)

Primary: Safety - Blood/Coagulation Parameters (SGPT/ALT)

Primary: Safety - Blood/Coagulation Parameters (SGPT/ALT)

Primary: Safety - Blood/Coagulation Parameters (Gamma-GT)

Primary: Safety - Blood/Coagulation Parameters (Gamma-GT)

Primary: Safety - Blood/Coagulation Parameters (Na)

Primary: Safety - Blood/Coagulation Parameters (Na)

Primary: Safety - Blood/Coagulation Parameters (Ca)

Primary: Safety - Blood/Coagulation Parameters (Ca)

Primary: Safety - Blood/Coagulation Parameters (P)

Primary: Safety - Blood/Coagulation Parameters (P)

Primary: Safety - Blood/Coagulation Parameters (Glucose)

Primary: Safety - Blood/Coagulation Parameters (Glucose)

Primary: Safety - Blood/Coagulation Parameters (Albumin)

Primary: Safety - Blood/Coagulation Parameters (Albumin)

Clinical Trial Results:
A Phase I/II, randomized, prospective, controlled, multi-center, open-label, two arm study evaluating the safety and preliminary efficacy of sFilm-FS in controlling liver bleeding during elective surgery.