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Clinical Trial Results:
Stamcellebehandling af patienter med kronisk kranspulsåresygdom MesenchYmal STROMAL CELL therapy in patients with chronic myocardial ischemia (MyStromalCell Trial)

Summary
EudraCT number	2009-017752-28
Trial protocol	DK
Global end of trial date	23 Jun 2017

Results information
Results version number	v1(current)
This version publication date	29 Jul 2019
First version publication date	29 Jul 2019
Other versions
Summary report(s)	Article

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

MSCII

ISRCTN number

US NCT number

NCT01449032

WHO universal trial number (UTN)

Sponsor organisation name

Rigshospitalet

Sponsor organisation address

Blegdamsvej 9, Copenhagen, Denmark, 2100

Public contact

Jens Kastrup, Department of Cardiology, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark, jens.kastrup@regionh.dk

Scientific contact

Jens Kastrup, Department of Cardiology, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark, jens.kastrup@regionh.dk

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 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

23 Jun 2017

Global end of trial reached?

Yes

Global end of trial date

23 Jun 2017

Was the trial ended prematurely?

Main objective of the trial

To improve myocardial perfusion and exercise capacity in patients with chronic ischemic heart disease

Protection of trial subjects

The patients were protected according to the Declaration of Helsinki and the protocol was approved by the Danish National Ethical Committee (02-268856) and Danish Medicines Agency (2612-2867). The Good Clinical Practice Unit of the Capital Region monitored the study. All patients provided written informed consent prior entering the study.

Background therapy

There were no test or products used in the groups beside intramyocardial injections of autologous adipose derived stromal cells stimulated with VEGF_A165 in the active arm and intramyocardial injections of saline in the placebo group. Liposuction was performed in all patients.

Evidence for comparator

Adipose derived stromal cells (ASCs) are reported to be more angiogeneic than mesenchymal stromal cells, which potentially favors myocardial perfusion and regeneration in patients with chronic ischemic heart disease (CIHD). Preclinical studies have previously demonstrated the benefit of intramyocardial injection of ASCs. In mice with CIHD, ASC improved left ventricle ejection fraction (LVEF) assessed by echocardiography and 18F-FDG microPET imaging. Moreover, intramyocardially injected ASCs have demonstrated increased LVEF, wall thickness, and reduction of infarct size in rats. A small study using an intramyocardial injection of freshly harvested adipose-derived stromal vascular fraction (SVF) cells in patients with refractory angina showed that exercise capacity in the active group remained stable during the follow-up period while there was a decrease in the placebo group. Another small study delivering freshly harvested adipose-derived SVF cells intracoronary in patients with ST-elevation myocardial infarction showed a trend towards improved LVEF. Another trial used intramyocardial injection of adipose-derived SVF cells in patients with ischemic heart failure and showed that maximum oxygen consumption on exercise treadmill testing was increased in the therapy group but not significantly different from the placebo group. SVF consists of only 2 % ASCs. So, this study was established to investigate the effect of culture expanded ASCs in patients with CIHD.

Actual start date of recruitment

01 Apr 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Denmark: 61

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

This trial was initiated in 2010 and the enrolment was completed in 2014. The patients were included from Denmark.

Screening details

In total 110 patient signed the informed consent. However, 37 patients did not meet the inclusion criteria, 10 withdrew their consent, 1 dead before randomization and 1 had limited amount of abdominal adipose tissue.

Number of subjects started

Number of subjects completed

Period 1 title

Baseline period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

The patients were randomized 2 : 1 to ASC or placebo, in blocks of six with a computer-generated list by an unrelated study person.

Are arms mutually exclusive

Yes

Placebo

Arm description

Intramyocardial injections of saline

Arm type

Placebo

Investigational medicinal product name

Saline

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intracardiac use

Dosage and administration details

Intramyocardial injections of 3 cc saline

Active arm

Arm description

Intramyocardial injections of autologous adipose derived stromal cells

Arm type

Active comparator

Investigational medicinal product name

Adipose derived stromal cells

Investigational medicinal product code

Other name

ASCs

Pharmaceutical forms

Solution for injection

Routes of administration

Intracardiac use

Dosage and administration details

The number of adipose derived stromal cells reached after culture expansion were delivered intramyocardially in 10-15 injections of 2mL .

Number of subjects in period 1	Placebo	Active arm
Started	20	41
Completed	19	37
Not completed	1	4
Consent withdrawn by subject	-	1
Myocardial infarction during follow-up	-	1
Myocardial infarction during follow-up period	1	-
Adverse event, non-fatal	-	1
Dead	-	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Intramyocardial injections of saline

Reporting group title

Active arm

Reporting group description

Intramyocardial injections of autologous adipose derived stromal cells

Reporting group values	Placebo	Active arm	Total
Number of subjects	20	41	61
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
63.5 ± 8.7 years in the placebo arm 65.5 ± 9.7 years in the active arm
Units: years
median (standard deviation)	63.5 ± 8.7	65.5 ± 9.7	-
Gender categorical
Male gender placebo:20 (100); active Group: 35 (87.5)
Units: Subjects
Female	0	6	6
Male	20	35	55
Left ventricular ejection fraction (LVEF)
LVEF in the placebo Group: 54 ± 8 and in the active Group: 52 ± 8
Units: procent
median (standard deviation)	54 ± 8	52 ± 8	-
Bicycle exercise time
Theplacebo Group: 437 ± 53 s and the active group: 383 ± 30 s
Units: second
median (standard deviation)	437 ± 53	383 ± 30	-

End points

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Reporting group title

Placebo

Reporting group description

Intramyocardial injections of saline

Reporting group title

Active arm

Reporting group description

Intramyocardial injections of autologous adipose derived stromal cells

Primary: Bicycle exercise time

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End point title

Bicycle exercise time

End point description

The mean duration of bicycle exercise test at baseline was 437 ± 53 s and 383 ± 30 s for the placebo and active groups, respectively. At 6 months follow-up, the exercise test duration of time increased to 446 ± 64 s and 407 ± 36 s in placebo group and active group, respectively. The primary endpoint, changes in exercise test from baseline to follow-up, was increased in the placebo group by 9 s (95% CI –203 to 221 s) and in the active Group by 22 s (95% CI –164 to 208 s). However, there was no statistical significant difference between the two groups. The increase in time duration, from baseline to follow-up, was only significant in the ASC group.

End point type

Primary

End point timeframe

6 months follow-up after intramyocardial injections of either saline or adipose derived stromal cells

End point values	Placebo	Active arm
Number of subjects analysed	20 ^[1]	40 ^[2]
Units: seconds	19	37

Notes
[1] - 19 were available for the primary endpoint
[2] - 37 were available at the time of primary endpoint

repeated measures analysis

Statistical analysis description

Repeated measure with autoregressive covariance structure is used for follow-up data due to more than two time-points.

Comparison groups

Active arm v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

< 0.05 ^[4]

Method

Reapeated measures analysis

Parameter type

Mean difference (net)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Dispersion value

Notes
[3] - The primary end point is exercise tolerance testing 6 months after the treatment. With an estimated enrollment of 60 patients, the statistic power was estimated to be more than 90% for the detection of an improvement in exercise tolerance testing of 60 s in the active group compared with the placebo group, with an expected standard deviation of 35 s and a 5% α-value.
[4] - P<0.05 was considered of significance

Adverse events

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Timeframe for reporting adverse events

From baseline to 6 months follow-up

Adverse event reporting additional description

Adverse events were obtained through patient files and at the follow-up consultations

Assessment type

Systematic

Dictionary name

GCP unit

Dictionary version

Reporting group title

Placebo

Reporting group description

The group recieved saline injections Subjects in the active group, affected by serious and non-serious adverse events were 4 and 4, respectively.

Reporting group title

Active group

Reporting group description

The group recieved adipose derived stromal cells Subjects in the active group, affected by serious and non-serious adverse events were 9 and 4, respectively.

Serious adverse events	Placebo	Active group
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 20 (20.00%)	9 / 40 (22.50%)
number of deaths (all causes)	0	1
number of deaths resulting from adverse events	0	0
Vascular disorders
hematoma
Additional description: Hematoma at insertion site for NOGA procedure
subjects affected / exposed	1 / 20 (5.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
Additional description: Myocardial infarction observed in the follow-up period
subjects affected / exposed	1 / 20 (5.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
Additional description: Due to side effects of medicin
subjects affected / exposed	1 / 20 (5.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
Additional description: Angina worsening
subjects affected / exposed	3 / 20 (15.00%)	6 / 40 (15.00%)
occurrences causally related to treatment / all	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
Additional description: Procedure related pericardial effusion
subjects affected / exposed	0 / 20 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ECG changes
Additional description: After saline and stem cell therapy probably related to the procedure
subjects affected / exposed	2 / 20 (10.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 20 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anemia
subjects affected / exposed	1 / 20 (5.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Discomfort
Additional description: Generel discomfort
subjects affected / exposed	0 / 20 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumonia
subjects affected / exposed	1 / 20 (5.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
Additional description: Rash and fever - Allergic reaction
subjects affected / exposed	0 / 20 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Placebo	Active group
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 20 (0.00%)	3 / 40 (7.50%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea
Additional description: A short period with feeling of breathlessness
subjects affected / exposed	0 / 20 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Pneumonia
subjects affected / exposed	0 / 20 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Oedema peripheral
Additional description: one-sided leg/knee oedema
subjects affected / exposed	0 / 20 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

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

Limitations of the study are that at the baseline; the exercise time duration is seemingly better in the placebo group compared to the ASC group and the changes seem like they are increasing constantly.

http://www.ncbi.nlm.nih.gov/pubmed/29333165

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Clinical trials

Clinical Trial Results:
Stamcellebehandling af patienter med kronisk kranspulsåresygdom MesenchYmal STROMAL CELL therapy in patients with chronic myocardial ischemia (MyStromalCell Trial)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Bicycle exercise time

Primary: Bicycle exercise time

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

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Clinical trials

Clinical Trial Results: Stamcellebehandling af patienter med kronisk kranspulsåresygdom MesenchYmal STROMAL CELL therapy in patients with chronic myocardial ischemia (MyStromalCell Trial)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Bicycle exercise time

Primary: Bicycle exercise time

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Stamcellebehandling af patienter med kronisk kranspulsåresygdom MesenchYmal STROMAL CELL therapy in patients with chronic myocardial ischemia (MyStromalCell Trial)