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Clinical Trial Results:
Monocenter prospective open single-arm phase IV study of the effects of hawthorn extract WS® 1442 on arterial micro-vascular structure and macro-vascular function, persistance and erectile function of male patients with underlying cardiovascular disease and erectile dysfunction

Summary
EudraCT number	2014-001319-38
Trial protocol	DE
Global end of trial date	09 Sep 2020

Results information
Results version number	v1(current)
This version publication date	23 Sep 2021
First version publication date	23 Sep 2021
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

MW 051

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Dr. Willmar Schwabe GmbH & Co. KG

Sponsor organisation address

Willmar-Schwabe-Straße 4, Karlsruhe, Germany, 76227

Public contact

Medical Affairs, Dr. Willmar Schwabe GmbH & Co. KG, 0049 7214093 573, ute.paulsen@schwabe.de

Scientific contact

Medical Affairs, Dr. Willmar Schwabe GmbH & Co. KG, 0049 7214093 573, ute.paulsen@schwabe.de

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

23 Jun 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

09 Sep 2020

Global end of trial reached?

Yes

Global end of trial date

09 Sep 2020

Was the trial ended prematurely?

Yes

Main objective of the trial

• Description of the effects of hawthorn leaf and flower dry extract WS® 1442 on arterial micro-vascular structure and macro-vascular function and laboratory parameters of cardiac stress, endothelial function, oxidative stress and inflammation. • Analysis of the correlations of these effects with improvements in clinical symptoms, endurance performance and erectile function. • Description of the safety and tolerability of WS® 1442 in patients with underlying cardiovascular disease and erectile dysfunction.

Protection of trial subjects

Safety monitoring (adverse events [AEs], serious adverse events [SAEs], adverse drug reactions [ADRs]), assessment of laboratory data (blood chemistry, hematology), physical examination, ECG and vital signs.

Background therapy

Basic therapy of the underlying cardiovascular disease according to current guidelines.

Evidence for comparator

Not applicable.

Actual start date of recruitment

18 Aug 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 35

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

35 subjects were enrolled at one study center in Germany. Patients were recruited by cooperating clinics and medical practices which referred the patients to the study center. The duration of the recruitment phase was about 3.5 years and terminated early. First subject was screened on 18-Aug-2016, last patient completed on 25-Mar-2020.

Screening details

Suitable subjects were selected by the investigator according to the eligibility criteria specified in the protocol.

Number of subjects started

70 ^[1]

Number of subjects completed

Reason: Number of subjects

Failure meeting all inclusion criteria: 30

Reason: Number of subjects

Meeting at least one exclusion criterion: 5

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The total number of patients in the pre-assignment period reflects the number of screened patients. The total number of enrolled patients is different from the number of screened patients.

Period 1 title

Baseline

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

Not applicable.

WS® 1442

Arm description

Patients received hawthorn special extract WS® 1442, 450 mg p.o., b.i.d. (900 mg per day) for 8 weeks.

Arm type

Experimental

Investigational medicinal product name

hawthorn leaf and flower dry extract

Investigational medicinal product code

WS® 1442

Other name

Crataegutt® 450 mg Herz-Kreislauf Tabletten

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

450 mg, p.o. (oral), b.i.d. (twice daily)

Number of subjects in period 1	WS® 1442
Started	35
Completed	35

Period 2 title

Treatment

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

WS® 1442

Arm description

Patients received hawthorn special extract WS® 1442, 450 mg p.o., b.i.d. (900 mg per day) for 8 weeks.

Arm type

Experimental

Investigational medicinal product name

hawthorn leaf and flower dry extract

Investigational medicinal product code

WS® 1442

Other name

Crataegutt® 450 mg Herz-Kreislauf Tabletten

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

450 mg, p.o. (oral), b.i.d. (twice daily)

Number of subjects in period 2	WS® 1442
Started	35
Completed	31
Not completed	4
Consent withdrawn by subject	2
Withdrawal due to rejection of study procedure	1
COVID-19 pandemic related reasons	1

Baseline characteristics

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Reporting group title

Baseline

Reporting group description

Reporting group values	Baseline	Total
Number of subjects	35	35
Age categorical
Units: Subjects
Adults (18-64 years)	19	19
From 65-84 years	16	16
Age continuous
Units: years
arithmetic mean (standard deviation)	63.8 ± 8.43	-
Gender categorical
Units: Subjects
Female	0	0
Male	35	35

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

The Full Analysis Set (FAS) consists of all patients who received at least one dose of study medication and have results documented for the primary endpoint at visit 2 (baseline, Day 0) and visit 4 (completion, Day 53-59).

Subject analysis set title

Per Protocol Set (PPS)

Subject analysis set type

Per protocol

Subject analysis set description

The Per Protocol Set (PPS) consists of all patients in the Full Analysis Set with a study medication compliance of at least 80% and with no major protocol violation.

Subject analysis set title

Safety Analysis Set

Subject analysis set type

Safety analysis

Subject analysis set description

The Safety Analysis Set (SAF) consists of all patients who received at least one dose of study medication.

Subject analysis set title

Full Analysis Set (FAS) - Visit 2

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Per Protocol Set (PPS) - Visit 2

Subject analysis set type

Per protocol

Subject analysis set description

The Per Protocol Set (PPS) consists of all patients in the Full Analysis Set with a study medication compliance of at least 80% and with no major protocol violation.

Subject analysis set title

Full Analysis Set (FAS) - Visit 3

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Per Protocol Set (PPS) - Visit 3

Subject analysis set type

Per protocol

Subject analysis set description

The Per Protocol Set (PPS) consists of all patients in the Full Analysis Set with a study medication compliance of at least 80% and with no major protocol violation.

Subject analysis set title

Full Analysis Set (FAS) - Visit 4

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Per Protocol Set (PPS) - Visit 4

Subject analysis set type

Per protocol

Subject analysis set description

The Per Protocol Set (PPS) consists of all patients in the Full Analysis Set with a study medication compliance of at least 80% and with no major protocol violation.

Subject analysis set title

Full Analysis Set (FAS) - [Visit 2 to Visit 3 (excl.)]

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Per Protocol Set (PPS) - [Visit 2 to Visit 3 (excl.)]

Subject analysis set type

Per protocol

Subject analysis set description

The Per Protocol Set (PPS) consists of all patients in the Full Analysis Set with a study medication compliance of at least 80% and with no major protocol violation. Subject analysis set for SEP analysis.

Subject analysis set title

Full Analysis Set (FAS) - [Visit 3 (incl.) to Visit 4]

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Per Protocol Set (PPS) - [Visit 3 (incl.) to Visit 4]

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

RigiScan Analysis Set - Visit 2

Subject analysis set type

Sub-group analysis

Subject analysis set description

RigiScan Analysis Set comprises a subgroup of patients with optional RigiScan assessments at visit 2 (baseline, day 0) and visit 4 (completion, day 53-59).

Subject analysis set title

RigiScan Analysis Set - Visit 4

Subject analysis set type

Sub-group analysis

Subject analysis set description

RigiScan Analysis Set comprises a subgroup of patients with optional RigiScan assessments at visit 2 (baseline, day 0) and visit 4 (completion, day 53-59).

Subject analysis sets values	Full Analysis Set (FAS)	Per Protocol Set (PPS)	Safety Analysis Set	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 3	Per Protocol Set (PPS) - Visit 3	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4	Full Analysis Set (FAS) - [Visit 2 to Visit 3 (excl.)]	Per Protocol Set (PPS) - [Visit 2 to Visit 3 (excl.)]	Full Analysis Set (FAS) - [Visit 3 (incl.) to Visit 4]	Per Protocol Set (PPS) - [Visit 3 (incl.) to Visit 4]	RigiScan Analysis Set - Visit 2	RigiScan Analysis Set - Visit 4
Number of subjects	30	28	35	30	28	30	28	30	28	30	28	30	28	4	4
Age categorical
Units: Subjects
Adults (18-64 years)
From 65-84 years
Age continuous
Units: years
arithmetic mean (standard deviation)	63.7 ± 8.37	63.3 ± 7.72	63.8 ± 8.43	63.7 ± 8.37	63.3 ± 7.72	63.7 ± 8.37	63.3 ± 7.72	63.7 ± 8.37	63.3 ± 7.72	63.7 ± 8.37	63.3 ± 7.72	63.7 ± 8.37	63.3 ± 7.72	±	±
Gender categorical
Units: Subjects
Female	0	0	0	0	0	0	0	0	0	0	0	0	0
Male	30	28	35	30	28	30	28	30	28	30	28	30	28

End points

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Reporting group title

WS® 1442

Reporting group description

Patients received hawthorn special extract WS® 1442, 450 mg p.o., b.i.d. (900 mg per day) for 8 weeks.

Reporting group title

WS® 1442

Reporting group description

Patients received hawthorn special extract WS® 1442, 450 mg p.o., b.i.d. (900 mg per day) for 8 weeks.

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Per Protocol Set (PPS)

Subject analysis set type

Per protocol

Subject analysis set description

The Per Protocol Set (PPS) consists of all patients in the Full Analysis Set with a study medication compliance of at least 80% and with no major protocol violation.

Subject analysis set title

Safety Analysis Set

Subject analysis set type

Safety analysis

Subject analysis set description

The Safety Analysis Set (SAF) consists of all patients who received at least one dose of study medication.

Subject analysis set title

Full Analysis Set (FAS) - Visit 2

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Per Protocol Set (PPS) - Visit 2

Subject analysis set type

Per protocol

Subject analysis set description

The Per Protocol Set (PPS) consists of all patients in the Full Analysis Set with a study medication compliance of at least 80% and with no major protocol violation.

Subject analysis set title

Full Analysis Set (FAS) - Visit 3

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Per Protocol Set (PPS) - Visit 3

Subject analysis set type

Per protocol

Subject analysis set description

The Per Protocol Set (PPS) consists of all patients in the Full Analysis Set with a study medication compliance of at least 80% and with no major protocol violation.

Subject analysis set title

Full Analysis Set (FAS) - Visit 4

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Per Protocol Set (PPS) - Visit 4

Subject analysis set type

Per protocol

Subject analysis set description

The Per Protocol Set (PPS) consists of all patients in the Full Analysis Set with a study medication compliance of at least 80% and with no major protocol violation.

Subject analysis set title

Full Analysis Set (FAS) - [Visit 2 to Visit 3 (excl.)]

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Per Protocol Set (PPS) - [Visit 2 to Visit 3 (excl.)]

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Full Analysis Set (FAS) - [Visit 3 (incl.) to Visit 4]

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Per Protocol Set (PPS) - [Visit 3 (incl.) to Visit 4]

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

RigiScan Analysis Set - Visit 2

Subject analysis set type

Sub-group analysis

Subject analysis set description

RigiScan Analysis Set comprises a subgroup of patients with optional RigiScan assessments at visit 2 (baseline, day 0) and visit 4 (completion, day 53-59).

Subject analysis set title

RigiScan Analysis Set - Visit 4

Subject analysis set type

Sub-group analysis

Subject analysis set description

RigiScan Analysis Set comprises a subgroup of patients with optional RigiScan assessments at visit 2 (baseline, day 0) and visit 4 (completion, day 53-59).

Primary: Primary Endpoint - Change in AVR (Retinal arteriolar to venous ratio)

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End point title

Primary Endpoint - Change in AVR (Retinal arteriolar to venous ratio)

End point description

End point type

Primary

End point timeframe

Change from visit 2 (baseline, day 0) until visit 4 (completion, day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	30	28	30	28
Units: AVR
arithmetic mean (standard deviation)	0.813 ± 0.0607	0.812 ± 0.0620	0.814 ± 0.0620	0.811 ± 0.0624

Change in AVR (FAS)

Statistical analysis description

Change in AVR from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 4 v Full Analysis Set (FAS) - Visit 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[1]

Method

Parameter type

Change from baseline

Point estimate

0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.008

upper limit

0.011

Notes
[1] - N=30

Change in AVR (PPS)

Statistical analysis description

Change in AVR from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 4 v Per Protocol Set (PPS) - Visit 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[2]

Method

Parameter type

Change from baseline

Point estimate

-0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.011

upper limit

0.009

Notes
[2] - N=28

Secondary: SE | Microvascular structure| Central retinal arterial equivalent (CRAE)

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End point title

SE | Microvascular structure| Central retinal arterial equivalent (CRAE)

End point description

Three pictures of both eyes are taken at visits 2 and 4. CRAE was determined for each available picture. For each patient and visit, the arithmetic mean of all available CRAE values and the arithmetic mean of all CRAE values were calculated.

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	30	28	30	28
Units: CRAE (µm)
arithmetic mean (standard deviation)	146.8 ± 19.60	145.5 ± 17.53	148.2 ± 21.15	146.0 ± 15.91

Change in CRAE (FAS)

Statistical analysis description

Change in CRAE from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[3]

Method

Parameter type

Change from baseline

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

Notes
[3] - N=30

Change in CRAE (PPS)

Statistical analysis description

Change in CRAE from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[4]

Method

Parameter type

Change from baseline

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

2.6

Notes
[4] - N=28

Secondary: SE | Microvascular structure| Central retinal venous equivalent (CRVE)

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End point title

SE | Microvascular structure| Central retinal venous equivalent (CRVE)

End point description

Three pictures of both eyes are taken at visits 2 and 4. CRVE was determined for each available picture. For each patient and visit, the arithmetic mean of all available CRVE values and the arithmetic mean of all CRVE values were calculated.

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	30	28	30	28
Units: CRVE (µm)
arithmetic mean (standard deviation)	181.1 ± 22.89	179.7 ± 18.79	182.7 ± 26.40	180.9 ± 20.64

Change in CRVE (FAS)

Statistical analysis description

Change in CRVE from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[5]

Method

Parameter type

Change from baseline

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

3.8

Notes
[5] - N=30

Change in CRVE (PPS)

Statistical analysis description

Change in CRVE from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[6]

Method

Parameter type

Change from baseline

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

Notes
[6] - N=28

Secondary: SE | Macrovascular function | Cardio-ankle pulse wave velocity

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End point title

SE | Macrovascular function | Cardio-ankle pulse wave velocity

End point description

End point type

Secondary

End point timeframe

Change from visit 2 (baseline, day 0) until visit 4 (completion, day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	29 ^[7]	27 ^[8]	30	28
Units: PWV (m/s)
arithmetic mean (standard deviation)	13.52 ± 1.907	13.40 ± 1.906	14.18 ± 3.272	13.73 ± 2.173

Notes
[7] - Data of one patient missing.
[8] - Data of one patient missing.

Change in PWV (FAS)

Statistical analysis description

Change in PWV from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 4 v Full Analysis Set (FAS) - Visit 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[9]

Method

Parameter type

Change from baseline

Point estimate

0.58

Confidence interval

level

95%

sides

2-sided

lower limit

-0.31

upper limit

1.46

Notes
[9] - N=29

Change in PWV (PPS)

Statistical analysis description

Change in PWV from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[10]

Method

Parameter type

Change from baseline

Point estimate

0.22

Confidence interval

level

95%

sides

2-sided

lower limit

-0.21

upper limit

0.65

Notes
[10] - N=27

Secondary: SE | Macrovascular function | Cardio-ankle vascular index (CAVI)

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End point title

SE | Macrovascular function | Cardio-ankle vascular index (CAVI)

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	29 ^[11]	27 ^[12]	30	28
Units: CAVI (m/s)
arithmetic mean (standard deviation)	8.27 ± 1.079	8.19 ± 1.071	8.42 ± 1.352	8.28 ± 1.135

Notes
[11] - Data of one patient missing.
[12] - Data of one patient missing.

Change in CAVI (FAS)

Statistical analysis description

Change in CAVI from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[13]

Method

Parameter type

Change from baseline

Point estimate

0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.21

upper limit

0.39

Notes
[13] - N=29

Change in CAVI (PPS)

Statistical analysis description

Change in CAVI from baseline until visit 4 (week 8) for FAS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[14]

Method

Parameter type

Change from baseline

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.21

upper limit

0.24

Notes
[14] - N=27

Secondary: SE | Macrovascular function | Amplitude of the forward pulse wave (Pf)

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End point title

SE | Macrovascular function | Amplitude of the forward pulse wave (Pf)

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	28 ^[15]	26 ^[16]	30	28
Units: Pf (mmHg)
arithmetic mean (standard deviation)	24.29 ± 8.063	24.49 ± 8.084	26.51 ± 9.237	26.75 ± 9.361

Notes
[15] - Data of two patients missing.
[16] - Data of two patients missing.

Change in Pf (FAS)

Statistical analysis description

Change in Amplitude of the forward pulse wave from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[17]

Method

Parameter type

Change from baseline

Point estimate

1.96

Confidence interval

level

95%

sides

2-sided

lower limit

-0.63

upper limit

4.56

Notes
[17] - N=28

Change in Pf (PPS)

Statistical analysis description

Change in Amplitude of the forward pulse wave from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[18]

Method

Parameter type

Change from baseline

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.81

upper limit

4.81

Notes
[18] - N=26

Secondary: SE | Macrovascular function | Amplitude of the backward pulse wave (Pb)

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End point title

SE | Macrovascular function | Amplitude of the backward pulse wave (Pb)

End point description

End point type

Secondary

End point timeframe

Change from visit 2 (baseline, day 0) undtil visit 4 (completion, day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	28 ^[19]	26 ^[20]	30	28
Units: Pb (mmHg)
arithmetic mean (standard deviation)	14.35 ± 6.174	14.64 ± 6.267	16.15 ± 7.527	16.28 ± 7.711

Notes
[19] - Data of two patients missing.
[20] - Data of two patients missing

Change in Pb (FAS)

Statistical analysis description

Change in Amplitude of the backward pulse wave from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[21]

Method

Parameter type

Change from baseline

Point estimate

1.46

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

3.23

Notes
[21] - N=28

Change in Pb (PPS)

Statistical analysis description

Change in Amplitude of the backward pulse wave from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[22]

Method

Parameter type

Change from baseline

Point estimate

1.29

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

3.18

Notes
[22] - N=26

Secondary: SE | Macrovascular function | Central arterial blood pressure (systolic, diastolic, mean)

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End point title

SE | Macrovascular function | Central arterial blood pressure (systolic, diastolic, mean)

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	28 ^[23]	26 ^[24]	30	28
Units: mmHg
arithmetic mean (standard deviation)
Systolic	125.96 ± 16.262	126.02 ± 16.787	127.04 ± 19.051	127.83 ± 19.245
Diastolic	89.54 ± 8.252	89.06 ± 8.372	87.38 ± 8.591	87.89 ± 8.661
Mean	101.68 ± 9.789	101.38 ± 10.105	100.60 ± 10.823	101.20 ± 10.877

Notes
[23] - Data of two patients missing.
[24] - Data of two patients missing.

Change in central arterial BP - mean (FAS)

Statistical analysis description

Change in central arterial blood pressure from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[25]

Method

Parameter type

Change from baseline

Point estimate

-1.39

Confidence interval

level

95%

sides

2-sided

lower limit

-4.37

upper limit

1.59

Notes
[25] - N=28

Change in central arterial BP - mean (PPS)

Statistical analysis description

Change in central arterial blood pressure from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[26]

Method

Parameter type

Change from baseline

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-3.33

upper limit

2.39

Notes
[26] - N=26

Secondary: SE | Macrovascular function | Aortic pulse wave velocity (aoPWV)

Top of page

End point title

SE | Macrovascular function | Aortic pulse wave velocity (aoPWV)

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	28 ^[27]	26 ^[28]	30	28
Units: aoPWV (m/s)
arithmetic mean (standard deviation)	9.466 ± 1.4017	9.364 ± 1.2446	9.624 ± 1.5530	9.577 ± 1.4559

Notes
[27] - Data of two patients missing.
[28] - Data of two patients missing.

Change in aoPWV (FAS)

Statistical analysis description

Change in aoPWV from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[29]

Method

Parameter type

Change from baseline

Point estimate

0.015

Confidence interval

level

95%

sides

2-sided

lower limit

-0.117

upper limit

0.148

Notes
[29] - N=28

Change in aoPWV (PPS)

Statistical analysis description

Change in aoPWV from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[30]

Method

Parameter type

Change from baseline

Point estimate

0.056

Confidence interval

level

95%

sides

2-sided

lower limit

-0.073

upper limit

0.184

Notes
[30] - N=26

Secondary: SE | Macrovascular function | Aortic pulse pressure (aoPP)

Top of page

End point title

SE | Macrovascular function | Aortic pulse pressure (aoPP)

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	28 ^[31]	26 ^[32]	30	28
Units: aoPP (mm Hg)
arithmetic mean (standard deviation)	36.33 ± 12.955	36.90 ± 13.063	39.70 ± 15.406	39.96 ± 15.698

Notes
[31] - Data of two patients missing.
[32] - Data of two patients missing.

Change in aoPP (FAS)

Statistical analysis description

Change in aoPP from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[33]

Method

Parameter type

Change from baseline

Point estimate

2.68

Confidence interval

level

95%

sides

2-sided

lower limit

-0.85

upper limit

6.22

Notes
[33] - N=28

Change in aoPP (PPS)

Statistical analysis description

Change in aoPP from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[34]

Method

Parameter type

Change from baseline

Point estimate

2.34

Confidence interval

level

95%

sides

2-sided

lower limit

-1.45

upper limit

6.12

Notes
[34] - N=26

Secondary: SE | Macrovascular function | Augmentation pressure (AP)

Top of page

End point title

SE | Macrovascular function | Augmentation pressure (AP)

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	28 ^[35]	26 ^[36]	30	28
Units: AP (mmHg)
arithmetic mean (standard deviation)	13.26 ± 10.448	13.85 ± 10.625	14.13 ± 11.242	14.46 ± 11.564

Notes
[35] - Data of two patients missing.
[36] - Data of two patients missing.

Change in AP (FAS)

Statistical analysis description

Change in AP from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[37]

Method

Parameter type

Change from baseline

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-3.48

upper limit

3.59

Notes
[37] - N=28

Change in AP (PPS)

Statistical analysis description

Change in AP from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[38]

Method

Parameter type

Change from baseline

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-4.03

upper limit

3.57

Notes
[38] - N=26

Secondary: SE | Macrovascular function | Peripheral arterial blood pressure (systolic and diastolic)

Top of page

End point title

SE | Macrovascular function | Peripheral arterial blood pressure (systolic and diastolic)

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	29 ^[39]	27 ^[40]	30	28
Units: mmHg
arithmetic mean (standard deviation)
Systolic	135.59 ± 12.758	135.32 ± 13.196	136.15 ± 15.330	136.95 ± 15.408
Diastolic	86.84 ± 7.986	86.38 ± 8.070	85.07 ± 8.443	85.46 ± 8.609

Notes
[39] - Data of one patient missing.
[40] - Data of one patient missing.

Change in systolic PABP (FAS)

Statistical analysis description

Change in systolic PABP from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[41]

Method

Parameter type

Change from baseline

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-3.7

upper limit

3.32

Notes
[41] - N=29

Change in systolic PABP (PPS)

Statistical analysis description

Change in systolic PABP from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[42]

Method

Parameter type

Change from baseline

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

-2.43

upper limit

4.13

Notes
[42] - N=27

Change in diastolic PABP (FAS)

Statistical analysis description

Change in diastolic PABP from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[43]

Method

Parameter type

Change from baseline

Point estimate

-2.09

Confidence interval

level

95%

sides

2-sided

lower limit

-4.47

upper limit

0.28

Notes
[43] - N=29

Change in diastolic PABP (PPS)

Statistical analysis description

Change in diastolic PABP from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[44]

Method

Parameter type

Change from baseline

Point estimate

-1.25

Confidence interval

level

95%

sides

2-sided

lower limit

-3.43

upper limit

0.94

Notes
[44] - N=27

Secondary: SE | Macrovascular function | Cardiac ejection time

Top of page

End point title

SE | Macrovascular function | Cardiac ejection time

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	29 ^[45]	27 ^[46]	30	28
Units: Cardiac ejection time (sec.)
arithmetic mean (standard deviation)	302.82 ± 29.379	305.31 ± 28.402	306.41 ± 26.444	304.98 ± 26.266

Notes
[45] - Data of one patient missing.
[46] - Data of one patient missing.

Change in cardiac ejection time (FAS)

Statistical analysis description

Change in cardiac ejection time from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[47]

Method

Parameter type

Change from baseline

Point estimate

3.78

Confidence interval

level

95%

sides

2-sided

lower limit

-5.03

upper limit

12.58

Notes
[47] - N=29

Change in cardiac ejection time (PPS)

Statistical analysis description

Change in cardiac ejection time from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[48]

Method

Parameter type

Change from baseline

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-6.07

upper limit

5.69

Notes
[48] - N=27

Secondary: SE | Endurance performance in bicycle spiroergometry | Oxygen uptake at maximum burden (VO2 peak [ml/min])

Top of page

End point title

SE | Endurance performance in bicycle spiroergometry | Oxygen uptake at maximum burden (VO2 peak [ml/min])

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	29 ^[49]	27 ^[50]	25 ^[51]	25 ^[52]
Units: ml/min.
arithmetic mean (standard deviation)	1988.8 ± 581.06	2048.6 ± 556.54	2128.5 ± 476.52	2128.5 ± 476.52

Notes
[49] - Data of one patient missing.
[50] - Data of one patient missing
[51] - Data of five patients missing.
[52] - Data of three patients missing

Change in oxygen uptake (FAS)

Statistical analysis description

Change in oxygen uptake at maximum burden from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[53]

Method

Parameter type

Change from baseline

Point estimate

18.5

Confidence interval

level

95%

sides

2-sided

lower limit

-107.6

upper limit

144.6

Notes
[53] - N=24

Change in oxygen uptake (PPS)

Statistical analysis description

Change in oxygen uptake at maximum burden from baseline until visit 4 (week 8) for PPS

Comparison groups

Per Protocol Set (PPS) - Visit 4 v Per Protocol Set (PPS) - Visit 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[54]

Method

Parameter type

Change from baseline

Point estimate

18.5

Confidence interval

level

95%

sides

2-sided

lower limit

-107.6

upper limit

144.6

Notes
[54] - N=24

Secondary: SE | Endurance performance in bicycle spiroergometry | Power at maximum burden [watts]

Top of page

End point title

SE | Endurance performance in bicycle spiroergometry | Power at maximum burden [watts]

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	29 ^[55]	27 ^[56]	25 ^[57]	25 ^[58]
Units: watt
arithmetic mean (standard deviation)	153.4 ± 54.07	158.9 ± 51.99	165.2 ± 52.77	165.2 ± 52.77

Notes
[55] - Data of one patient missing.
[56] - Data of one patient missing
[57] - Data of five patients missing.
[58] - Data of three patients missing

Change in power at maximum burden (FAS)

Statistical analysis description

Change in power at maximum burden at maximum burden from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[59]

Method

Parameter type

Change from baseline

Point estimate

3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-16

upper limit

22.7

Notes
[59] - N=24

Change in power at maximum burden (PPS)

Statistical analysis description

Change in power at maximum burden at maximum burden from baseline until visit 4 (week 8) for PPS

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[60]

Method

Parameter type

Change from baseline

Point estimate

3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-16

upper limit

22.7

Notes
[60] - N=24

Secondary: SE | Endurance performance in bicycle spiroergometry | Increase of the product of systolic arterial blood pressure and heart rate between rest and 50 watts load

Top of page

End point title

SE | Endurance performance in bicycle spiroergometry | Increase of the product of systolic arterial blood pressure and heart rate between rest and 50 watts load

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	28 ^[61]	26 ^[62]	24 ^[63]	24 ^[64]
Units: Increase in rate pressure (mmHg/sec.)
arithmetic mean (standard deviation)	3550.3 ± 2623.53	3234.6 ± 2248.69	2529.6 ± 1361.56	2529.6 ± 1361.6

Notes
[61] - Data of two patients missing.
[62] - Data of two patients missing
[63] - Data of six patients missing.
[64] - Data of four patients missing

Change in rate pressure (FAS)

Statistical analysis description

Change in increase of the product of systolic arterial blood pressure and heart rate between rest and 50 watts load from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[65]

Method

Parameter type

Change from baseline

Point estimate

-767.8

Confidence interval

level

95%

sides

2-sided

lower limit

-1609.8

upper limit

74.2

Notes
[65] - N=22

Change in rate pressure (PPS)

Statistical analysis description

Change in increase of the product of systolic arterial blood pressure and heart rate between rest and 50 watts load from baseline until visit 4 (week 8) for PPS

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[66]

Method

Parameter type

Change from baseline

Point estimate

-767.8

Confidence interval

level

95%

sides

2-sided

lower limit

-1609.8

upper limit

74.2

Notes
[66] - N=22

Secondary: SE | Endurance performance in bicycle spiroergometry | Increase in blood lactate between rest and 50 watts load

Top of page

End point title

SE | Endurance performance in bicycle spiroergometry | Increase in blood lactate between rest and 50 watts load

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	30	28	26 ^[67]	26 ^[68]
Units: Increase of blood lactate (mmol/L)
arithmetic mean (standard deviation)	0.141 ± 0.2434	0.127 ± 0.2453	0.053 ± 0.1757	0.053 ± 0.1757

Notes
[67] - Data of four patients missing.
[68] - Data of two patients missing

Change in increase of blood lactate (FAS)

Statistical analysis description

Change in increase of in blood lactate between rest and 50 watts load from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[69]

Method

Parameter type

Change from baseline

Point estimate

-0.079

Confidence interval

level

95%

sides

2-sided

lower limit

-0.168

upper limit

0.011

Notes
[69] - N=26

Change in increase of blood lactate (PPS)

Statistical analysis description

Change in increase of blood lactate between rest and 50 watts load from baseline until visit 4 (week 8) for PPS

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[70]

Method

Parameter type

Change from baseline

Point estimate

-0.079

Confidence interval

level

95%

sides

2-sided

lower limit

-0.168

upper limit

0.011

Notes
[70] - N=26

Secondary: SE | Clinical Symptomatology | Sum Score in MLHFQ

Top of page

End point title

SE | Clinical Symptomatology | Sum Score in MLHFQ

End point description

The MLHFQ is scored according to MINNESOTA LIVING WITH HEART FAILURE® QUESTIONNAIRE Instructions for Data Collection and Scoring.

End point type

Secondary

End point timeframe

Measured at visit 2 (basleline), visit 3 (day 26-30) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 3	Per Protocol Set (PPS) - Visit 3	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	27 ^[71]	25 ^[72]	30	28	29 ^[73]	27 ^[74]
Units: MLHFQ Sum Score
arithmetic mean (standard deviation)	18.6 ± 16.33	15.4 ± 12.09	16.6 ± 17.18	13.8 ± 13.97	17.0 ± 18.96	13.8 ± 15.12

Notes
[71] - Data of three patients missing.
[72] - Data of three patients missing.
[73] - Data of one patient missing.
[74] - Data of one patient missing.

Change from BL to Visit 3 in MLHFQ (FAS)

Statistical analysis description

Change in MLHFQ Sum Score from baseline until visit 3 (week 4) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 3

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[75]

Method

Parameter type

Change from baseline

Point estimate

-3.6

Confidence interval

level

95%

sides

2-sided

lower limit

-6.9

upper limit

-0.4

Notes
[75] - N=27

Change from BL to Visit 4 in MLHFQ (FAS)

Statistical analysis description

Change in MLHFQ Sum Score from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[76]

Method

Parameter type

Change from baseline

Point estimate

-2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-7

upper limit

1.8

Notes
[76] - N=26

Change from BL to Visit 3 in MLHFQ (PPS)

Statistical analysis description

Change in MLHFQ Sum Score from baseline until visit 3 (week 4) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 3

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[77]

Method

Parameter type

Change from baseline

Point estimate

-3.7

Confidence interval

level

95%

sides

2-sided

lower limit

-7.2

upper limit

-0.2

Notes
[77] - N=25

Change from BL to Visit 4 in MLHFQ (PPS)

Statistical analysis description

Change in MLHFQ Sum Score from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[78]

Method

Parameter type

Change from baseline

Point estimate

-3

Confidence interval

level

95%

sides

2-sided

lower limit

-7.8

upper limit

1.7

Notes
[78] - N=24

Secondary: SE | Erectile function | Total Score in IIEF

Top of page

End point title

SE | Erectile function | Total Score in IIEF

End point description

The IIEF is scored according to Rosen R: SCALING AND SCORING OF THE INTERNATIONAL INDEX OF ERECTILE FUNCTION (IIEF), Final version October, 2004 revised Sept 2007 and July 2008.

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline), visit 3 (day 26-30) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 3	Per Protocol Set (PPS) - Visit 3	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	30	28	26 ^[79]	25 ^[80]	25 ^[81]	23 ^[82]
Units: IIEF Total Score
arithmetic mean (standard deviation)	27.8 ± 13.89	29.2 ± 13.32	30.8 ± 15.67	31.8 ± 15.13	38.5 ± 18.52	40.9 ± 17.20

Notes
[79] - Data of four patients missing.
[80] - Data of three patients missing.
[81] - Data of five patients missing.
[82] - Data of five patients missing.

Change from BL to V3 in IIEF | Total (FAS)

Statistical analysis description

Change in IIEF total score from baseline until visit 3 (week 4) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 3

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[83]

Method

Parameter type

Change from baseline

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

7.3

Notes
[83] - N=26

Change from BL to V4 in IIEF | Total (FAS)

Statistical analysis description

Change in IIEF total score from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[84]

Method

Parameter type

Change from baseline

Point estimate

8.9

Confidence interval

level

95%

sides

2-sided

lower limit

4.1

upper limit

13.7

Notes
[84] - N=25

Change from BL to V3 in IIEF | Total (PPS)

Statistical analysis description

Change in IIEF total score from baseline until visit 3 (week 4) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 3

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[85]

Method

Parameter type

Change from baseline

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

7.6

Notes
[85] - N=25

Change from BL to V4 in IIEF | Total (PPS)

Statistical analysis description

Change in IIEF total score from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 4 v Per Protocol Set (PPS) - Visit 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[86]

Method

Parameter type

Change from baseline

Point estimate

9.4

Confidence interval

level

95%

sides

2-sided

lower limit

4.3

upper limit

14.6

Notes
[86] - N=23

Secondary: SE | Erectile function | Value for erectile function in IIEF

Top of page

End point title

SE | Erectile function | Value for erectile function in IIEF

End point description

The IIEF is scored according to Rosen R: SCALING AND SCORING OF THE INTERNATIONAL INDEX OF ERECTILE FUNCTION (IIEF), Final version October, 2004 revised Sept 2007 and July 2008.

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline), visit 3 (day 26-30) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 3	Per Protocol Set (PPS) - Visit 3	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	30	28	28 ^[87]	26 ^[88]	28 ^[89]	26 ^[90]
Units: IIEF Domain Score
arithmetic mean (standard deviation)	9.3 ± 6.46	9.8 ± 6.40	10.4 ± 6.37	10.9 ± 6.35	13.9 ± 8.39	14.7 ± 8.14

Notes
[87] - Data of two patients missing.
[88] - Data of two patients missing.
[89] - Data of two patients missing.
[90] - Data of two patients missing.

Change from BL to V3 in IIEF | Erectile Func (FAS)

Statistical analysis description

Change in IIEF subscore erectile function from baseline until visit 3 (week 4) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 3

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[91]

Method

Parameter type

Change from baseline

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

3.3

Notes
[91] - N=28

Change from BL to V4 in IIEF | Erectile Func (FAS)

Statistical analysis description

Change in IIEF subscore erectile function from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[92]

Method

Parameter type

Change from baseline

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

1.4

upper limit

6.6

Notes
[92] - N=28

Change from BL to V3 in IIEF | Erectile Func (PPS)

Statistical analysis description

Change in IIEF subscore erectile function from baseline until visit 3 (week 4) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 3

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[93]

Method

Parameter type

Change from baseline

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

3.4

Notes
[93] - N=26

Change from BL to V4 in IIEF | Erectile Func (PPS)

Statistical analysis description

Change in IIEF subscore erectile function from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[94]

Method

Parameter type

Change from baseline

Point estimate

4.3

Confidence interval

level

95%

sides

2-sided

lower limit

1.5

upper limit

7.1

Notes
[94] - N=26

Secondary: SE | Erectile function | Question 1 in the SEP – proportion of positive responses to any responses for question 1

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End point title

SE | Erectile function | Question 1 in the SEP – proportion of positive responses to any responses for question 1

End point description

(1) Sexual Encounter Profile (SEP) Proportion of positive responses to any responses for question 1 at a particular visit; (2) SEP Change from [visit 2 to visit 3 (excluded)] to [visit 3 (included) to visit 4]

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline), visit 3 (day 26-30) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - [Visit 2 to Visit 3 (excl.)]	Per Protocol Set (PPS) - [Visit 2 to Visit 3 (excl.)]	Full Analysis Set (FAS) - [Visit 3 (incl.) to Visit 4]	Per Protocol Set (PPS) - [Visit 3 (incl.) to Visit 4]
Number of subjects analysed	16 ^[95]	16 ^[96]	16 ^[97]	16 ^[98]
Units: Proportion of positive responses (Q1)
arithmetic mean (standard deviation)	0.588 ± 0.4055	0.588 ± 0.4055	0.802 ± 0.2995	0.802 ± 0.2995

Notes
[95] - Data of 14 patients missing.
[96] - Data of twelve patients missing.
[97] - Data of 14 patients missing.
[98] - Data of twelve patients missing.

SEP1 - Change between periods | FAS

Statistical analysis description

Change in proportion of positive responses to SEP Q1 from [V2-V3 (excl.)] to [V3 (incl.)-V4] for FAS

Comparison groups

Full Analysis Set (FAS) - [Visit 3 (incl.) to Visit 4] v Full Analysis Set (FAS) - [Visit 2 to Visit 3 (excl.)]

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[99]

Method

Parameter type

Change from baseline

Point estimate

0.139

Confidence interval

level

95%

sides

2-sided

lower limit

-0.107

upper limit

0.384

Notes
[99] - N=13

SEP1 - Change between periods | PPS

Statistical analysis description

Change in proportion of positive responses to SEP Q1 from [V2-V3 (excl.)] to [V3 (incl.)-V4] for PPS

Comparison groups

Per Protocol Set (PPS) - [Visit 2 to Visit 3 (excl.)] v Per Protocol Set (PPS) - [Visit 3 (incl.) to Visit 4]

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[100]

Method

Parameter type

Change from baseline

Point estimate

0.139

Confidence interval

level

95%

sides

2-sided

lower limit

-0.107

upper limit

0.384

Notes
[100] - N=13

Secondary: SE | Erectile function | Question 2 in the SEP – proportion of positive responses for question 2 to any responses for question 1

Top of page

End point title

SE | Erectile function | Question 2 in the SEP – proportion of positive responses for question 2 to any responses for question 1

End point description

(1) Sexual Encounter Profile (SEP) Proportion of positive responses to any responses for question 2 at a particular visit; (2) SEP Change from [visit 2 to visit 3 (excluded)] to [visit 3 (included) to visit 4]

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline), visit 3 (day 26-30) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - [Visit 2 to Visit 3 (excl.)]	Per Protocol Set (PPS) - [Visit 2 to Visit 3 (excl.)]	Full Analysis Set (FAS) - [Visit 3 (incl.) to Visit 4]	Per Protocol Set (PPS) - [Visit 3 (incl.) to Visit 4]
Number of subjects analysed	16 ^[101]	16 ^[102]	16 ^[103]	16 ^[104]
Units: Proportion of positive responses (Q2)
arithmetic mean (standard deviation)	0.440 ± 0.3545	0.440 ± 0.3545	0.463 ± 0.4155	0.463 ± 0.4155

Notes
[101] - Data of 14 patients missing.
[102] - Data of twelve patients missing.
[103] - Data of 14 patients missing.
[104] - Data of twelve patients missing.

SEP2 - Change between periods | FAS

Statistical analysis description

Change in proportion of positive responses to SEP Q2 from [V2-V3 (excl.)] to [V3 (incl.)-V4] for FAS.

Comparison groups

Full Analysis Set (FAS) - [Visit 2 to Visit 3 (excl.)] v Full Analysis Set (FAS) - [Visit 3 (incl.) to Visit 4]

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[105]

Method

Parameter type

Change from baseline

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.313

upper limit

0.293

Notes
[105] - N=13

SEP2 - Change between periods | PPS

Statistical analysis description

Change in proportion of positive responses to SEP Q2 from [V2-V3 (excl.)] to [V3 (incl.)-V4] for PPS.

Comparison groups

Per Protocol Set (PPS) - [Visit 2 to Visit 3 (excl.)] v Per Protocol Set (PPS) - [Visit 3 (incl.) to Visit 4]

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[106]

Method

Parameter type

Change from baseline

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.313

upper limit

0.293

Notes
[106] - N=13

Secondary: SE | Erectile function | Event time per session

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End point title

SE | Erectile function | Event time per session

End point description

As only parameters that were independent from the duration of measurement were analyzed, 'event time per session' instead of 'number of nocturnal erections' was analyzed.

End point type

Secondary

End point timeframe

Measured at visit 2 (basleline) and visit 4 (day 53-59).

End point values	RigiScan Analysis Set - Visit 2	RigiScan Analysis Set - Visit 4
Number of subjects analysed	4	4
Units: Event time per session [%]
Patient 020	39	9
Patient 045	21	21
Patient 050	57	18
Patient 057	42	37

No statistical analyses for this end point

Secondary: SE | Erectile function | Average event rigidity penis base

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End point title

SE | Erectile function | Average event rigidity penis base

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	RigiScan Analysis Set - Visit 2	RigiScan Analysis Set - Visit 4
Number of subjects analysed	4	4
Units: RIgidity base [%]
Patient 020	39	36
Patient 045	27	29
Patient 050	27	38
Patient 057	24	39

No statistical analyses for this end point

Secondary: SE | Erectile function |Average event rigidity penis tip

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End point title

SE | Erectile function |Average event rigidity penis tip

End point description

Analysis was waived due to insufficient data (measurements from the penis tip are missing in at least one of the visits).

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	RigiScan Analysis Set - Visit 2	RigiScan Analysis Set - Visit 4
Number of subjects analysed	0 ^[107]	0 ^[108]
Units: Rigidity tip [%]
Patient 020
Patient 045
Patient 050
Patient 057

Notes
[107] - For all patients measurements from the penis tip are missing in at least one of the visits.
[108] - For all patients measurements from the penis tip are missing in at least one of the visits.

No statistical analyses for this end point

Secondary: SE | Erectile function | Average tumescence increase penis base

Top of page

End point title

SE | Erectile function | Average tumescence increase penis base

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	RigiScan Analysis Set - Visit 2	RigiScan Analysis Set - Visit 4
Number of subjects analysed	4	4
Units: Tumescence increase [%]
Patient 020	30	45
Patient 045	25	25
Patient 050	26	28
Patient 057	28	29

No statistical analyses for this end point

Secondary: SE | Erectile function | Average tumescence increase penis tip

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End point title

SE | Erectile function | Average tumescence increase penis tip

End point description

Analysis was waived due to insufficient data (measurements from the penis tip are missing in at least one of the visits).

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	RigiScan Analysis Set - Visit 2	RigiScan Analysis Set - Visit 4
Number of subjects analysed	0 ^[109]	0 ^[110]
Units: Tumescence increase [%]
Patient 020
Patient 045
Patient 050
Patient 057

Notes
[109] - For all patients measurements from the penis tip are missing in at least one of the visits.
[110] - For all patients measurements from the penis tip are missing in at least one of the visits.

No statistical analyses for this end point

Secondary: SE | Erectile function | AUC for rigidity penis base

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End point title

SE | Erectile function | AUC for rigidity penis base

End point description

Analysis was waived due to insufficient data.

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	RigiScan Analysis Set - Visit 2	RigiScan Analysis Set - Visit 4
Number of subjects analysed	0 ^[111]	0 ^[112]
Units: AUC
arithmetic mean (standard deviation)	±	±

Notes
[111] - Analysis was waived due to insufficient data.
[112] - Analysis was waived due to insufficient data.

No statistical analyses for this end point

Secondary: SE | Erectile function | AUC for rigidity penis tip

Top of page

End point title

SE | Erectile function | AUC for rigidity penis tip

End point description

Analysis was waived due to insufficient data.

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	RigiScan Analysis Set - Visit 2	RigiScan Analysis Set - Visit 4
Number of subjects analysed	0 ^[113]	0 ^[114]
Units: AUC
arithmetic mean (standard deviation)	±	±

Notes
[113] - Analysis was waived due to insufficient data.
[114] - Analysis was waived due to insufficient data.

No statistical analyses for this end point

Secondary: SE | Erectile function | AUC for tumescence penis base

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End point title

SE | Erectile function | AUC for tumescence penis base

End point description

Analysis was waived due to insufficient data.

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	RigiScan Analysis Set - Visit 2	RigiScan Analysis Set - Visit 4
Number of subjects analysed	0 ^[115]	0 ^[116]
Units: AUC
arithmetic mean (standard deviation)	±	±

Notes
[115] - Analysis was waived due to insufficient data.
[116] - Analysis was waived due to insufficient data.

No statistical analyses for this end point

Secondary: SE | Erectile function | AUC for tumescence penis tip

Top of page

End point title

SE | Erectile function | AUC for tumescence penis tip

End point description

Analysis was waived due to insufficient data.

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	RigiScan Analysis Set - Visit 2	RigiScan Analysis Set - Visit 4
Number of subjects analysed	0 ^[117]	0 ^[118]
Units: AUC
arithmetic mean (standard deviation)	±	±

Notes
[117] - Analysis was waived due to insufficient data.
[118] - Analysis was waived due to insufficient data.

No statistical analyses for this end point

Secondary: SE | Laboratory Parameters | NT-proBNP at rest

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End point title

SE | Laboratory Parameters | NT-proBNP at rest

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	25 ^[119]	23 ^[120]	28 ^[121]	27 ^[122]
Units: ng/l
arithmetic mean (standard deviation)	158.6 ± 256.26	127.4 ± 197.58	149.6 ± 187.56	133.3 ± 169.69

Notes
[119] - Data of five patients missing.
[120] - Data of five patients missing.
[121] - Data of two patients missing.
[122] - Data of one patient missing.

Change from BL to V4 in NT-ProBNP at rest (FAS)

Statistical analysis description

Change in S-NT-ProBNP at rest from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[123]

Method

Parameter type

Change from baseline

Point estimate

-23.4

Confidence interval

level

95%

sides

2-sided

lower limit

-68.4

upper limit

21.5

Notes
[123] - N=24

Change from BL to V4 in NT-ProBNP at rest (PPS)

Statistical analysis description

Change in S-NT-ProBNP at rest from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[124]

Method

Parameter type

Change from baseline

Point estimate

-7.3

Confidence interval

level

95%

sides

2-sided

lower limit

-38.7

upper limit

24.2

Notes
[124] - N=23

Secondary: SE | Laboratory Parameters | NT-proBNP increase after spiroergometry

Top of page

End point title

SE | Laboratory Parameters | NT-proBNP increase after spiroergometry

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	22 ^[125]	21 ^[126]	25 ^[127]	25 ^[128]
Units: ng/l
arithmetic mean (standard deviation)	23.7 ± 40.16	24.6 ± 40.95	23.5 ± 32.35	23.5 ± 32.35

Notes
[125] - Data of eight patients missing.
[126] - Data of seven patients missing.
[127] - Data of five patients missing.
[128] - Data of three patients missing.

Change in increase from BL to V4 | NT-ProBNP (FAS)

Statistical analysis description

Change in increase of S-NT-ProBNP from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[129]

Method

Parameter type

Change from baseline

Point estimate

-3.7

Confidence interval

level

95%

sides

2-sided

lower limit

-10.8

upper limit

3.5

Notes
[129] - N=20

Change in increase from BL to V4 | NT-ProBNP (PPS)

Statistical analysis description

Change in increase of S-NT-ProBNP from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[130]

Method

Parameter type

Change from baseline

Point estimate

-3.7

Confidence interval

level

95%

sides

2-sided

lower limit

-10.8

upper limit

3.5

Notes
[130] - N=20

Secondary: SE | Laboratory Parameters | ADMA at rest

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End point title

SE | Laboratory Parameters | ADMA at rest

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	29 ^[131]	27 ^[132]	28 ^[133]	27 ^[134]
Units: umol/L
arithmetic mean (standard deviation)	0.509 ± 0.0890	0.511 ± 0.0913	0.511 ± 0.0829	0.513 ± 0.0840

Notes
[131] - Data of one patient missing.
[132] - Data of one patient missing.
[133] - Data of two patients missing.
[134] - Data of one patient missing.

Change from BL to V4 in ADMA at rest (FAS)

Statistical analysis description

Change in ADMA at rest from baseline until visit 4 (week 8) for PPS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[135]

Method

Parameter type

Change from baseline

Point estimate

0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.025

upper limit

0.04

Notes
[135] - N=27

Change from BL to V4 in ADMA at rest (PPS)

Statistical analysis description

Change in ADMA at rest from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[136]

Method

Parameter type

Change from baseline

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.024

upper limit

0.043

Notes
[136] - N=26

Secondary: SE | Laboratory Parameters | BH4/BH2 at rest

Top of page

End point title

SE | Laboratory Parameters | BH4/BH2 at rest

End point description

Not analysed as none of the two analytes BH2 and BH4 could be detected in the blood samples.

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	0 ^[137]	0 ^[138]	0 ^[139]	0 ^[140]
Units: Ratio BH4/BH2
arithmetic mean (standard deviation)	±	±	±	±

Notes
[137] - Not analysed as none of the two analytes BH2 and BH4 could be detected in the blood samples.
[138] - Not analysed as none of the two analytes BH2 and BH4 could be detected in the blood samples.
[139] - Not analysed as none of the two analytes BH2 and BH4 could be detected in the blood samples.
[140] - Not analysed as none of the two analytes BH2 and BH4 could be detected in the blood samples.

No statistical analyses for this end point

Secondary: SE | Laboratory Parameters | oxLDL/LDL at rest

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End point title

SE | Laboratory Parameters | oxLDL/LDL at rest

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	22 ^[141]	21 ^[142]	26 ^[143]	25 ^[144]
Units: oxLDL/LDL ratio
arithmetic mean (standard deviation)	18.43 ± 7.391	18.51 ± 7.565	19.61 ± 10.436	19.75 ± 10.626

Notes
[141] - Data of eight patients missing.
[142] - Data of seven patients missing.
[143] - Data of four patients missing.
[144] - Data of three patients missing.

Change from BL to V4 in oxLDL/LDL at rest (FAS)

Statistical analysis description

Change in oxLDL/LDL ratio from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[145]

Method

Parameter type

Change from baseline

Point estimate

1.29

Confidence interval

level

95%

sides

2-sided

lower limit

-1.13

upper limit

3.7

Notes
[145] - N=20

Change from BL to V4 oxLDL/LDL at rest (PPS)

Statistical analysis description

Change in oxLDL/LDL ratio from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[146]

Method

Parameter type

Change from baseline

Point estimate

1.39

Confidence interval

level

95%

sides

2-sided

lower limit

-1.15

upper limit

3.94

Notes
[146] - N=19

Secondary: SE | Laboratory Parameters | MDA at rest

Top of page

End point title

SE | Laboratory Parameters | MDA at rest

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	29 ^[147]	27 ^[148]	28 ^[149]	27 ^[150]
Units: umol/L
arithmetic mean (standard deviation)	0.580 ± 0.2251	0.587 ± 0.2307	0.543 ± 0.3864	0.553 ± 0.3901

Notes
[147] - Data of one patient missing.
[148] - Data of one patient missing.
[149] - Data of two patients missing.
[150] - Data of one patient missing.

Change from BL to V4 in MDA at rest (FAS)

Statistical analysis description

Change in MDA at rest from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[151]

Method

Parameter type

Change from baseline

Point estimate

-0.084

Confidence interval

level

95%

sides

2-sided

lower limit

-0.237

upper limit

0.068

Notes
[151] - N=27

Change from BL to V4 in MDA at rest (PPS)

Statistical analysis description

Change in MDA at rest from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[152]

Method

Parameter type

Change from baseline

Point estimate

-0.076

Confidence interval

level

95%

sides

2-sided

lower limit

-0.233

upper limit

0.082

Notes
[152] - N=26

Secondary: SE | Laboratory Parameters | MDA increase after spiroergometry

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End point title

SE | Laboratory Parameters | MDA increase after spiroergometry

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	25 ^[153]	24 ^[154]	23 ^[155]	23 ^[156]
Units: umol/L
arithmetic mean (standard deviation)	0.006 ± 0.3402	-0.032 ± 0.2884	-0.060 ± 0.3699	-0.060 ± 0.3699

Notes
[153] - Data of five patients missing.
[154] - Data of four patients missing.
[155] - Data of seven patients missing.
[156] - Data of five patients missing.

Change in increase from BL to V4 | MDA (FAS)

Statistical analysis description

Change in increase of MDA after spiroergometry from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[157]

Method

Parameter type

Change from baseline

Point estimate

0.004

Confidence interval

level

95%

sides

2-sided

lower limit

-0.162

upper limit

0.17

Notes
[157] - N=22

Change in increase from BL to V4 | MDA (PPS)

Statistical analysis description

Change in increase of MDA after spiroergometry from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[158]

Method

Parameter type

Change from baseline

Point estimate

0.004

Confidence interval

level

95%

sides

2-sided

lower limit

-0.162

upper limit

0.17

Notes
[158] - N=22

Secondary: SE | Laboratory Parameters | Nitrate/Nitrite at rest

Top of page

End point title

SE | Laboratory Parameters | Nitrate/Nitrite at rest

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	29 ^[159]	27 ^[160]	28 ^[161]	27 ^[162]
Units: Nitrate/Nitrite ratio
arithmetic mean (standard deviation)	43.54 ± 25.732	43.54 ± 26.538	37.36 ± 16.612	37.89 ± 16.689

Notes
[159] - Data of one patient missing.
[160] - Data of one patient missing.
[161] - Data of two patients missing.
[162] - Data of one patient missing.

Change (BL to V4) in Nitrate/Nitrite at rest (FAS)

Statistical analysis description

Change in Nitrate/Nitrite ratio at rest from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[163]

Method

Parameter type

Change from baseline

Point estimate

-7.09

Confidence interval

level

95%

sides

2-sided

lower limit

-18.07

upper limit

3.88

Notes
[163] - N=27

Change (BL to V4) in Nitrate/Nitrite at rest (PPS)

Statistical analysis description

Change in Nitrate/Nitrite ratio at rest from baseline until visit 4 (week 8) for FAS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[164]

Method

Parameter type

Change from baseline

Point estimate

-7

Confidence interval

level

95%

sides

2-sided

lower limit

-18.42

upper limit

4.43

Notes
[164] - N=26

Secondary: SE | Laboratory Parameters | Nitrate/Nitrite increase after spiroergometry

Top of page

End point title

SE | Laboratory Parameters | Nitrate/Nitrite increase after spiroergometry

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	25 ^[165]	24 ^[166]	23 ^[167]	23 ^[168]
Units: Nitrate/Nitrite ratio
arithmetic mean (standard deviation)	2.83 ± 5.434	2.54 ± 5.362	4.55 ± 8.550	4.55 ± 8.550

Notes
[165] - Data of five patients missing.
[166] - Data of four patients missing.
[167] - Data of seven patients missing.
[168] - Data of five patients missing.

Change in increase from BL to V4 | NO3-/NO2- (FAS)

Statistical analysis description

Change of increase in Nitrate/Nitrite ratio from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[169]

Method

Parameter type

Change from baseline

Point estimate

1.47

Confidence interval

level

95%

sides

2-sided

lower limit

-2.71

upper limit

5.65

Notes
[169] - N=22

Change in increase from BL to V4 | NO3-/NO2- (PPS)

Statistical analysis description

Change of increase in Nitrate/Nitrite ratio from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[170]

Method

Parameter type

Change from baseline

Point estimate

1.47

Confidence interval

level

95%

sides

2-sided

lower limit

-2.71

upper limit

5.65

Notes
[170] - N=22

Secondary: SE | Laboratory Parameters | Plasma-F2-Isoprostane at rest

Top of page

End point title

SE | Laboratory Parameters | Plasma-F2-Isoprostane at rest

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	29 ^[171]	27 ^[172]	28 ^[173]	27 ^[174]
Units: nmol/L
arithmetic mean (standard deviation)	0.607 ± 0.3825	0.607 ± 0.3968	0.776 ± 0.5027	0.785 ± 0.5099

Notes
[171] - Data of one patient missing.
[172] - Data of one patient missing.
[173] - Data of two patients missing.
[174] - Data of one patient missing.

Change (BL to V4) in F2-Isoprostane at rest (FAS)

Statistical analysis description

Change in plasma F2-Isoprostane at rest from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[175]

Method

Parameter type

Change from baseline

Point estimate

0.147

Confidence interval

level

95%

sides

2-sided

lower limit

-0.057

upper limit

0.351

Notes
[175] - N=27

Change (BL to V4) in F2-Isoprostane at rest (PPS)

Statistical analysis description

Change in plasma F2-Isoprostane at rest from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[176]

Method

Parameter type

Change from baseline

Point estimate

0.155

Confidence interval

level

95%

sides

2-sided

lower limit

-0.057

upper limit

0.366

Notes
[176] - N=26

Secondary: SE | Laboratory Parameters | Plasma-F2-Isoprostane increase after spiroergometry

Top of page

End point title

SE | Laboratory Parameters | Plasma-F2-Isoprostane increase after spiroergometry

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	25 ^[177]	24 ^[178]	23 ^[179]	23 ^[180]
Units: nmol/L
arithmetic mean (standard deviation)	0.122 ± 0.6947	0.125 ± 0.7095	0.162 ± 0.7229	0.162 ± 0.7229

Notes
[177] - Data of five patients missing.
[178] - Data of four patients missing.
[179] - Data of seven patients missing.
[180] - Data of five patients missing.

Change in increase from BL to V4 | F2-Isopro (FAS)

Statistical analysis description

Change in increase of plasma F2 Isoprostane after spiroergometry from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 4 v Full Analysis Set (FAS) - Visit 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[181]

Method

Parameter type

Change from baseline

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.49

upper limit

0.45

Notes
[181] - N=22

Change in increase from BL to V4 | F2-Isopro (PPS)

Statistical analysis description

Change in increase of plasma F2 Isoprostane after spiroergometry from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 4 v Per Protocol Set (PPS) - Visit 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[182]

Method

Parameter type

Change from baseline

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.49

upper limit

0.45

Notes
[182] - N=22

Secondary: SE | Laboratory Parameters | hs-CRP at rest

Top of page

End point title

SE | Laboratory Parameters | hs-CRP at rest

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	25 ^[183]	23 ^[184]	28 ^[185]	27 ^[186]
Units: mg/L
arithmetic mean (standard deviation)	2.56 ± 3.214	2.49 ± 3.335	2.30 ± 3.503	2.30 ± 3.570

Notes
[183] - Data of five patients missing.
[184] - Data of five patients missing.
[185] - Data of two patients missing.
[186] - Data of one patient missing.

Change from BL to V4 in hs-CRP at rest (FAS)

Statistical analysis description

Change in S-CRP from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[187]

Method

Parameter type

Change from baseline

Point estimate

0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

0.89

Notes
[187] - N=24

Change from BL to V4 in hs-CRP at rest (PPS)

Statistical analysis description

Change in S-CRP from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[188]

Method

Parameter type

Change from baseline

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.73

upper limit

0.95

Notes
[188] - N=23

Secondary: SE | Laboratory Parameters | hs-CRP increase after spiroergometry

Top of page

End point title

SE | Laboratory Parameters | hs-CRP increase after spiroergometry

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	22 ^[189]	21 ^[190]	25 ^[191]	25 ^[192]
Units: mg/L
arithmetic mean (standard deviation)	0.35 ± 0.705	0.36 ± 0.721	0.36 ± 0.819	0.36 ± 0.819

Notes
[189] - Data of eight patients missing.
[190] - Data of seven patients missing.
[191] - Data of five patients missing.
[192] - Data of three patients missing.

Change in increase from BL to V4 | hs-CRP (FAS)

Statistical analysis description

Change in increase of S-CRP after spiroergometry from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[193]

Method

Parameter type

Change from baseline

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.32

upper limit

0.45

Notes
[193] - N=20

Change in increase from BL to V4 | hs-CRP (PPS)

Statistical analysis description

Change in increase of S-CRP after spiroergometry from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[194]

Method

Parameter type

Change from baseline

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.32

upper limit

0.45

Notes
[194] - N=20

Secondary: SE | Laboratory Parameters | IL-6 at rest

Top of page

End point title

SE | Laboratory Parameters | IL-6 at rest

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	23 ^[195]	22 ^[196]	23 ^[197]	22 ^[198]
Units: ng/L
arithmetic mean (standard deviation)	4.2 ± 3.73	4.1 ± 3.80	4.0 ± 2.79	3.9 ± 2.84

Notes
[195] - Data of seven patients missing.
[196] - Data of six patients missing.
[197] - Data of seven patients missing.
[198] - Data of six patients missing.

Change from BL to V4 in IL-6 at rest (FAS)

Statistical analysis description

Change in S-Interleukin-6 at rest from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 4 v Full Analysis Set (FAS) - Visit 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[199]

Method

Parameter type

Change from baseline

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

Notes
[199] - N=18

Change from BL to V4 in IL-6 at rest (PPS)

Statistical analysis description

Change in S-Interleukin-6 at rest from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[200]

Method

Parameter type

Change from baseline

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-2.6

upper limit

1.2

Notes
[200] - N=17

Secondary: SE | Laboratory Parameters | IL-6 increase after spiroergometry

Top of page

End point title

SE | Laboratory Parameters | IL-6 increase after spiroergometry

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	19 ^[201]	19 ^[202]	20 ^[203]	20 ^[204]
Units: ng/L
arithmetic mean (standard deviation)	0.9 ± 1.65	0.9 ± 1.65	0.7 ± 1.26	0.7 ± 1.26

Notes
[201] - Data of eleven patients missing.
[202] - Data of nine patients missing.
[203] - Data of ten patients missing.
[204] - Data of eight patients missing.

Change in increase from BL to V4 | IL-6 (FAS)

Statistical analysis description

Change in increase of S-Interleukin-6 after spiroergometry from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[205]

Method

Parameter type

Change from baseline

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

0.2

Notes
[205] - N=14

Change in increase from BL to V4 | IL-6 (PPS)

Statistical analysis description

Change in increase of S-Interleukin-6 after spiroergometry from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[206]

Method

Parameter type

Change from baseline

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

0.2

Notes
[206] - N=14

Secondary: SE | Laboratory Parameters | Plasma-Microparticles at rest

Top of page

End point title

SE | Laboratory Parameters | Plasma-Microparticles at rest

End point description

End point type

Secondary

End point timeframe

Measured at visit 2 (baseline) and visit 4 (day 53-59).

End point values	Full Analysis Set (FAS) - Visit 2	Per Protocol Set (PPS) - Visit 2	Full Analysis Set (FAS) - Visit 4	Per Protocol Set (PPS) - Visit 4
Number of subjects analysed	28 ^[207]	26 ^[208]	28 ^[209]	27 ^[210]
Units: per uL
arithmetic mean (standard deviation)
AV+	7.00 ± 2.397	7.04 ± 2.405	6.41 ± 1.773	6.49 ± 1.757
CD105+	0.55 ± 0.243	0.51 ± 0.193	0.55 ± 0.203	0.53 ± 0.194
GP1b+	3.61 ± 2.152	3.70 ± 2.212	3.79 ± 1.985	3.81 ± 2.019
Glyco.A+	1.68 ± 0.985	1.60 ± 0.906	1.49 ± 0.898	1.49 ± 0.915
CD11a+	3.35 ± 0.669	3.28 ± 0.641	3.40 ± 0.827	3.37 ± 0.819
CD31+	0.06 ± 0.084	0.06 ± 0.085	0.06 ± 0.088	0.06 ± 0.089

Notes
[207] - Data of two patients missing.
[208] - Data of two patients missing.
[209] - Data of two patients missing.
[210] - Data of one patient missing.

Change from BL to V4 in AV+ (FAS)

Statistical analysis description

Change in AV+ from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[211]

Method

Parameter type

Change from baseline

Point estimate

-0.55

Confidence interval

level

95%

sides

2-sided

lower limit

-1.65

upper limit

0.55

Notes
[211] - N=26

Change from BL to V4 in AV+ (PPS)

Statistical analysis description

Change in AV+ from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[212]

Method

Parameter type

Change from baseline

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

0.71

Notes
[212] - N=25

Change from BL to V4 in CD105+ (FAS)

Statistical analysis description

Change in CD105+ from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 4 v Full Analysis Set (FAS) - Visit 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[213]

Method

Parameter type

Change from baseline

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.09

upper limit

0.07

Notes
[213] - N=26

Change from BL to V4 in CD105+ (PPS)

Statistical analysis description

Change in CD105+ from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[214]

Method

Parameter type

Change from baseline

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.07

upper limit

0.08

Notes
[214] - N=25

Change from BL to V4 in GP1b+ (FAS)

Statistical analysis description

Change in Gp1b+ from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[215]

Method

Parameter type

Change from baseline

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.67

upper limit

1.06

Notes
[215] - N=26

Change from BL to V4 in GP1b+ (PPS)

Statistical analysis description

Change in Gp1b+ from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[216]

Method

Parameter type

Change from baseline

Point estimate

0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

1.08

Notes
[216] - N=25

Change from BL to V4 in Glyco.A+ (FAS)

Statistical analysis description

Change in Glyco.A+ from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[217]

Method

Parameter type

Change from baseline

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

0.11

Notes
[217] - N=26

Change from BL to V4 in Glyco.A+ (PPS)

Statistical analysis description

Change in Glyco.A+ from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[218]

Method

Parameter type

Change from baseline

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.35

upper limit

0.14

Notes
[218] - N=25

Change from BL to V4 in CD11a+ (FAS)

Statistical analysis description

Change in CD11a+ from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[219]

Method

Parameter type

Change from baseline

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.19

upper limit

0.2

Notes
[219] - N=26

Change from BL to V4 in CD11a+ (PPS)

Statistical analysis description

Change in CD11a+ from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[220]

Method

Parameter type

Change from baseline

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.21

Notes
[220] - N=25

Change from BL to V4 in CD31+ (FAS)

Statistical analysis description

Change in CD31+ from baseline until visit 4 (week 8) for FAS.

Comparison groups

Full Analysis Set (FAS) - Visit 2 v Full Analysis Set (FAS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[221]

Method

Parameter type

Change from baseline

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.05

upper limit

0.05

Notes
[221] - N=26

Change from BL to V4 in CD31+ (PPS)

Statistical analysis description

Change in CD31+ from baseline until visit 4 (week 8) for PPS.

Comparison groups

Per Protocol Set (PPS) - Visit 2 v Per Protocol Set (PPS) - Visit 4

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[222]

Method

Parameter type

Change from baseline

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.05

upper limit

0.05

Notes
[222] - N=25

Adverse events

Top of page

Timeframe for reporting adverse events

From first intake of study medication until last visit.

Adverse event reporting additional description

Adverse events (AE) were defined as any undesirable event occuring between first intake of study medication and last visit. Events occuring between study enrollment and first intake of study medication are classified as health related events (HRE) and were not reported as AEs.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Safety Analysis Set

Reporting group description

The Safety Analysis Set (SAF) consists of all patients who received at least one dose of study medication.

Serious adverse events	Safety Analysis Set
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 35 (5.71%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Gastrointestinal disorders
Inguinal hernia
subjects affected / exposed	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Umbilical hernia
subjects affected / exposed	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

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

Non-serious adverse events	Safety Analysis Set
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 35 (31.43%)
Vascular disorders
Haematoma
subjects affected / exposed	1 / 35 (2.86%)
occurrences all number	1
Hypertension
subjects affected / exposed	1 / 35 (2.86%)
occurrences all number	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 35 (2.86%)
occurrences all number	1
Gastrointestinal disorders
Dyspepsia
subjects affected / exposed	1 / 35 (2.86%)
occurrences all number	1
Frequent bowel movements
subjects affected / exposed	1 / 35 (2.86%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 35 (2.86%)
occurrences all number	1
Skin and subcutaneous tissue disorders
Rash pruritic
subjects affected / exposed	1 / 35 (2.86%)
occurrences all number	1
Psychiatric disorders
Restlessness
subjects affected / exposed	1 / 35 (2.86%)
occurrences all number	1
Sleep disorder
subjects affected / exposed	1 / 35 (2.86%)
occurrences all number	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 35 (2.86%)
occurrences all number	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	4 / 35 (11.43%)
occurrences all number	4
Gastroenteritis
subjects affected / exposed	1 / 35 (2.86%)
occurrences all number	1

More information

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Were there any global substantial amendments to the protocol? Yes

02 Nov 2015

Non-substantial protocol amendment: change in the responsibility for suspected unexpected serious adverse reactions (SUSAR) reporting from CRO to sponsor; clarification of wording.

24 May 2016

Non-substantial protocol amendment: change in responsibilities of resonsible Biometrician; adjustment of study duration, changed number of measurements for arterial stiffness, determination of erectile function by determining the average (instead of maximum) rigidity and tumescence at the base and tip of the penis.

28 Jun 2017

Substantial protocol amendment: modification of inclusion and exclusion criteria based on results of screening failure analyses: too low values in the IIEF and MLHF with regard to heart failure symptoms: inclusion criterion 3 omitted; inclusion criterion 7 adjusted: IIEF changed from 11-21 points to less than 22 points; quality assurance measures adapted to ICH E6 (R2); change of responsible biometrician.

16 May 2018

Substantial protocol amendment: change of approval status and application of the active substance by the competent authority: Active substance is now registered as a traditional herbal medicinal product for support of cardiovascular function: Change of title and inclusion criteria.

25 Jun 2018

Substantial amendment of Patient information and Informed Consent Form: adaption of Patient information and Informed Consent form due to data protection regulation that came in to force in May 2018.

19 Nov 2019

Substantial protocol amendment: change of the contracted CRO and resulting responsibilities in monitoring, data management, statistical analysis and medical writing; adaption of the absolute and relative discontinuation criteria of bicycle spiroergometry; adjustment of the recruitment and study duration; introduction of a questionnaire for improved interpretation of the measurement results; new information on side effects of the IMP (hypersensitivity reactions).

02 Mar 2020

Non-substantial amendment of Patient information and Informed Consent Form: adaption of the privacy statement in patient information due to Data Protection Amendment and Implementation 2019, adaption of IB (version Oct. 2019)

02 Apr 2020

Substantial amendment trial level: suspension of the clinical trial as an urgent safety measure to protect participants, as the population under study is one of the groups most at risk from COVID-19 due to several factors.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
01 Mar 2020	The start of the study was in Q3/2016 with the inclusion of the first patient. The last visit of the last patient and thus the end of the study was expected by the end of 2020. Due to COVID-19 pandemic the study was interrupted in March-2020. Due to delayed patient recruitment, which was also adversely affected by the COVID 19 pandemic, the study was not restarted. The decision to terminate the entire study prematurely was made in compliance with the protocol by the sponsor in consultation with the investigator on 09-Sep-2020, representing the official end of study. Thus, the total duration of the study was 49 months.	-

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

The significance of the study and results is limited by the reduced number of recruited and analyzed patients.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Primary Endpoint - Change in AVR (Retinal arteriolar to venous ratio)

Primary: Primary Endpoint - Change in AVR (Retinal arteriolar to venous ratio)

Secondary: SE | Microvascular structure| Central retinal arterial equivalent (CRAE)

Secondary: SE | Microvascular structure| Central retinal arterial equivalent (CRAE)

Secondary: SE | Microvascular structure| Central retinal venous equivalent (CRVE)

Secondary: SE | Microvascular structure| Central retinal venous equivalent (CRVE)

Secondary: SE | Macrovascular function | Cardio-ankle pulse wave velocity

Secondary: SE | Macrovascular function | Cardio-ankle pulse wave velocity

Secondary: SE | Macrovascular function | Cardio-ankle vascular index (CAVI)

Secondary: SE | Macrovascular function | Cardio-ankle vascular index (CAVI)

Secondary: SE | Macrovascular function | Amplitude of the forward pulse wave (Pf)

Secondary: SE | Macrovascular function | Amplitude of the forward pulse wave (Pf)

Secondary: SE | Macrovascular function | Amplitude of the backward pulse wave (Pb)

Secondary: SE | Macrovascular function | Amplitude of the backward pulse wave (Pb)

Secondary: SE | Macrovascular function | Central arterial blood pressure (systolic, diastolic, mean)

Secondary: SE | Macrovascular function | Central arterial blood pressure (systolic, diastolic, mean)

Secondary: SE | Macrovascular function | Aortic pulse wave velocity (aoPWV)

Secondary: SE | Macrovascular function | Aortic pulse wave velocity (aoPWV)

Secondary: SE | Macrovascular function | Aortic pulse pressure (aoPP)

Secondary: SE | Macrovascular function | Aortic pulse pressure (aoPP)

Secondary: SE | Macrovascular function | Augmentation pressure (AP)

Secondary: SE | Macrovascular function | Augmentation pressure (AP)

Secondary: SE | Macrovascular function | Peripheral arterial blood pressure (systolic and diastolic)

Secondary: SE | Macrovascular function | Peripheral arterial blood pressure (systolic and diastolic)

Secondary: SE | Macrovascular function | Cardiac ejection time

Secondary: SE | Macrovascular function | Cardiac ejection time

Secondary: SE | Endurance performance in bicycle spiroergometry | Oxygen uptake at maximum burden (VO2 peak [ml/min])

Secondary: SE | Endurance performance in bicycle spiroergometry | Oxygen uptake at maximum burden (VO2 peak [ml/min])

Secondary: SE | Endurance performance in bicycle spiroergometry | Power at maximum burden [watts]

Secondary: SE | Endurance performance in bicycle spiroergometry | Power at maximum burden [watts]

Secondary: SE | Endurance performance in bicycle spiroergometry | Increase of the product of systolic arterial blood pressure and heart rate between rest and 50 watts load

Secondary: SE | Endurance performance in bicycle spiroergometry | Increase of the product of systolic arterial blood pressure and heart rate between rest and 50 watts load

Secondary: SE | Endurance performance in bicycle spiroergometry | Increase in blood lactate between rest and 50 watts load

Secondary: SE | Endurance performance in bicycle spiroergometry | Increase in blood lactate between rest and 50 watts load

Secondary: SE | Clinical Symptomatology | Sum Score in MLHFQ

Secondary: SE | Clinical Symptomatology | Sum Score in MLHFQ

Secondary: SE | Erectile function | Total Score in IIEF

Secondary: SE | Erectile function | Total Score in IIEF

Secondary: SE | Erectile function | Value for erectile function in IIEF

Secondary: SE | Erectile function | Value for erectile function in IIEF

Secondary: SE | Erectile function | Question 1 in the SEP – proportion of positive responses to any responses for question 1

Secondary: SE | Erectile function | Question 1 in the SEP – proportion of positive responses to any responses for question 1

Secondary: SE | Erectile function | Question 2 in the SEP – proportion of positive responses for question 2 to any responses for question 1

Secondary: SE | Erectile function | Question 2 in the SEP – proportion of positive responses for question 2 to any responses for question 1

Secondary: SE | Erectile function | Event time per session

Secondary: SE | Erectile function | Event time per session

Secondary: SE | Erectile function | Average event rigidity penis base

Secondary: SE | Erectile function | Average event rigidity penis base

Secondary: SE | Erectile function |Average event rigidity penis tip

Secondary: SE | Erectile function |Average event rigidity penis tip

Secondary: SE | Erectile function | Average tumescence increase penis base

Secondary: SE | Erectile function | Average tumescence increase penis base

Secondary: SE | Erectile function | Average tumescence increase penis tip

Secondary: SE | Erectile function | Average tumescence increase penis tip

Secondary: SE | Erectile function | AUC for rigidity penis base

Secondary: SE | Erectile function | AUC for rigidity penis base

Secondary: SE | Erectile function | AUC for rigidity penis tip

Secondary: SE | Erectile function | AUC for rigidity penis tip

Secondary: SE | Erectile function | AUC for tumescence penis base

Secondary: SE | Erectile function | AUC for tumescence penis base

Secondary: SE | Erectile function | AUC for tumescence penis tip

Secondary: SE | Erectile function | AUC for tumescence penis tip

Secondary: SE | Laboratory Parameters | NT-proBNP at rest

Secondary: SE | Laboratory Parameters | NT-proBNP at rest

Secondary: SE | Laboratory Parameters | NT-proBNP increase after spiroergometry

Secondary: SE | Laboratory Parameters | NT-proBNP increase after spiroergometry

Secondary: SE | Laboratory Parameters | ADMA at rest

Secondary: SE | Laboratory Parameters | ADMA at rest

Secondary: SE | Laboratory Parameters | BH4/BH2 at rest

Secondary: SE | Laboratory Parameters | BH4/BH2 at rest

Secondary: SE | Laboratory Parameters | oxLDL/LDL at rest