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Clinical Trial Results:
BMC2012, Cell based therapy by implanted bone marrow-derived mononuclear cells (BMC) for bone augmentation of plate-stabilized proximal humeral fractures - a randomized, open, multicentric study - phase IIa

Summary
EudraCT number	2015-001820-51
Trial protocol	DE
Global end of trial date	07 Jan 2020

Results information
Results version number	v1(current)
This version publication date	08 Sep 2021
First version publication date	08 Sep 2021
Other versions
Summary report(s)	Synopsis BMC2012 phase II

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

BMC2012-PhaseII

ISRCTN number

US NCT number

NCT02803177

WHO universal trial number (UTN)

Sponsor organisation name

Klinik für Unfall-, Hand- und Wiederherstellungschirurgie, Universitätsklinikum Frankfurt

Sponsor organisation address

Theodor-Stern-Kai 7, Frankfurt/Main, Germany, 60590

Public contact

Prof. Dr. Ingo Marzi, Klinik für Unfall-, Hand- und Wiederherstellungschirurgie, Universitätsklinikum Frankfurt, Goethe-Un, +49 6963016123, marzi@trauma.uni-frankfurt.de

Scientific contact

Prof. Dirk Henrich, Klinik für Unfall-, Hand- und Wiederherstellungschirurgie, Universitätsklinikum Frankfurt, +49 6963017110, d.henrich@trauma.uni-frankfurt.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

17 Aug 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

07 Jan 2020

Global end of trial reached?

Yes

Global end of trial date

07 Jan 2020

Was the trial ended prematurely?

Main objective of the trial

Osseous healing of fracture after 12 weeks by radiological evaluation: • Frequency of secondary dislocation of result of reposition (varus dislocation of ≥ 20° of head/shaft angle α, Δα)

Protection of trial subjects

Novalgin 500 mg p.o. Paracetamol 1g/ 100 ml i.v. Enoxaparin 20 mg s.c.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Jun 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 57

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

date of first enrolment, date of last completed: 02.07.2016 - 06.06.2019 Frankfurt, Germany

Screening details

Main criteria for inclusion: - patients between the ages of ≥50 and ≤90 with a proximal humerus fracture - Indication for an open reduction and internal stabilization with a proximal fixed-angle plate of the humerus (PHILOS®, Synthes, Oberdorf, Switzerland) - 2, 3 or 4 fragment Neer fracture Dislocation of ≥10 mm between the fragments and/or

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Main Inclusion criteria: - patients between the ages of ≥50 and ≤90 with a proximal humerus fracture - Indication for an open reduction and internal stabilization with a proximal fixed-angle plate of the humerus (PHILOS®, Synthes, Oberdorf, Switzerland) - 2, 3 or 4 fragment Neer fracture - Dislocation of ≥10 mm between the fragments and/or - angle of ≥45° between the fragments and/or - Dislocation of the tubercle majus from ≥5 mm

Are arms mutually exclusive

Yes

Verum

Arm description

verum group should have received the cell-based therapy with implantation of BMC2012 in the surgical treatment of subcapital humerus fractures

Arm type

Experimental

Investigational medicinal product name

BMC2012- bone marrow-derived mononuclear cells

Investigational medicinal product code

Other name

BMC2012- bone marrow-derived mononuclear cells

Pharmaceutical forms

Matrix for implantation matrix

Routes of administration

Not mentioned

Dosage and administration details

Local Implantation of ex-vivo concentrated, washed and filtrated human bone marrow-derived mononiclear cells (BMC) seeded onto ß-tricalciumphosphate(TCP) 1.3 x 106 autologous BMC/ml/ml ß-TCP

Control

Arm description

patients in the control group should have received only the cell-free bone graft substitute ß-TCP

Arm type

only the cell-free bone graft substitute ß-TCP

Investigational medicinal product name

only the cell-free bone graft substitute ß-TCP

Investigational medicinal product code

Other name

only the cell-free bone graft substitute ß-TCP

Pharmaceutical forms

Matrix for implantation matrix

Routes of administration

Not mentioned

Dosage and administration details

Local Implantation of ß-tricalciumphosphate (TCP)

Investigational medicinal product name

BMC2012- bone marrow-derived mononuclear cells

Investigational medicinal product code

Other name

BMC2012- bone marrow-derived mononuclear cells

Pharmaceutical forms

Matrix for implantation matrix

Routes of administration

Not mentioned

Dosage and administration details

Local Implantation of ex-vivo concentrated, washed and filtrated human bone marrow-derived mononiclear cells (BMC) seeded onto ß-tricalciumphosphate(TCP) 1.3 x 106 autologous BMC/ml/ml ß-TCP

Number of subjects in period 1	Verum	Control
Started	29	28
Completed	29	28

Baseline characteristics

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Reporting group title

Verum

Reporting group description

verum group should have received the cell-based therapy with implantation of BMC2012 in the surgical treatment of subcapital humerus fractures

Reporting group title

Control

Reporting group description

patients in the control group should have received only the cell-free bone graft substitute ß-TCP

Reporting group values	Verum	Control	Total
Number of subjects	29	28	57
Age categorical
42 subjects are in the age categorie between 65-84. 15 subjects are in the age categories between 18-64.
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	11	12	23
From 65-84 years	18	16	34
85 years and over	0	0	0
Gender categorical
Units: Subjects
Female	21	20	41
Male	8	8	16

End points

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Reporting group title

Verum

Reporting group description

verum group should have received the cell-based therapy with implantation of BMC2012 in the surgical treatment of subcapital humerus fractures

Reporting group title

Control

Reporting group description

patients in the control group should have received only the cell-free bone graft substitute ß-TCP

Primary: Osseous healing of fracture

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End point title

Osseous healing of fracture

End point description

Osseous healing of fracture after 12 weeks by radiological evaluation: Frequency of secondary dislocation of result of reposition (varus dislocation of ≥ 20° of head/shaft angle α, ∆α)

End point type

Primary

End point timeframe

12 weeks

End point values	Verum	Control
Number of subjects analysed	29	28
Units: grad
number (not applicable)	29	28

Attachments

Data BMCII

primary test statistic

Statistical analysis description

The primary outcome parameter is the incidence of secondary loss of reduction result at 12 weeks, which is defined as varus dislocation of ≥ 20° of head-shaft angle in the true a.p. radiograph compared with the primary reduction result. For the statistical evaluation of the primary dichotomous study variable, the chi-square test is applied. The frequency of occurrence of secondary dislocations (> 20°) in the treatment groups (BMC2012+ß-TCP, ß-TCP only) is compared.

Comparison groups

Verum v Control

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Chi-squared

Parameter type

Frequency distribution

Confidence interval

Adverse events

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Timeframe for reporting adverse events

12 weeks

Assessment type

Non-systematic

Dictionary name

no dictionary used

Dictionary version

Reporting group title

Verum

Reporting group description

patients of the verum group received the cell-based therapy with implantation of BMC2012 in the surgical treatment of subcapital humerus fractures.

Reporting group title

control

Reporting group description

patients in the control group received only the cell-free bone graft substitute ß-TCP

Serious adverse events	Verum	control
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 29 (20.69%)	5 / 28 (17.86%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Vascular disorders
Aortic insufficiency
subjects affected / exposed	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
hypertensive derailment
subjects affected / exposed	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
NSTEMI, cardiac decompensation
subjects affected / exposed	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tachyarrethmia with know atrial fibrillation
subjects affected / exposed	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
acute renale insufficiency
subjects affected / exposed	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Inlay erosion hip
subjects affected / exposed	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 29 (3.45%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
intraarticular screw perforation
subjects affected / exposed	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Infection triggered COPD
subjects affected / exposed	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 29 (3.45%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	Verum	control
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 29 (24.14%)	4 / 28 (14.29%)
Gastrointestinal disorders
stomach problems
subjects affected / exposed	1 / 29 (3.45%)	1 / 28 (3.57%)
occurrences all number	1	1
Skin and subcutaneous tissue disorders
Exanthema subitum
subjects affected / exposed	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	1	0
Melanoma recurrent
subjects affected / exposed	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	1	0
Renal and urinary disorders
blood in urine
subjects affected / exposed	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
lumbago
subjects affected / exposed	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	1	0
Pain
subjects affected / exposed	0 / 29 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1
Infections and infestations
cold
subjects affected / exposed	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	1	0
chills
subjects affected / exposed	1 / 29 (3.45%)	0 / 28 (0.00%)
occurrences all number	1	0
circulatory problems
subjects affected / exposed	1 / 29 (3.45%)	1 / 28 (3.57%)
occurrences all number	1	1

More information

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Were there any global substantial amendments to the protocol? Yes

25 May 2016

Test plan version 3 from 18.02.2016 conditioned by PEI deficiency letter from 21.12.2015

04 Oct 2016

SV Change Schmidt-Horlohé -> Wincheringer; incl. CTA for changes Non Subst.02 (address FhG; protocol V3.1)

17 Jul 2017

Protocol V4.0 from 04.05.2017 (AEs and UAEs and administrative changes)

23 Aug 2017

Message PZ Prof. Hansen (HT Kliniken)

26 Feb 2018

PP V5.0 from 22.01.2018, ICF V3.0 from 23.01.2018

02 Jul 2018

ICF V3.1 (DSGVO)

16 Apr 2019

SV Wechsel Wincheringer → Albrecht-Schoeck;

24 Jun 2019

Fisher test is replaced by the chi-square test. Originally, the evaluation was planned with the Fisher exact test. However, this test does not fully exploit the significance level and is therefore considered unnecessarily conservative. > Interim analysis to be performed after 56 patients or 60% of patients have reached study visit 5.

20 Aug 2019

IB V3 (neue Lit.), DSUR No. 3

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results:
BMC2012, Cell based therapy by implanted bone marrow-derived mononuclear cells (BMC) for bone augmentation of plate-stabilized proximal humeral fractures - a randomized, open, multicentric study - phase IIa

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Osseous healing of fracture

Primary: Osseous healing of fracture

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: BMC2012, Cell based therapy by implanted bone marrow-derived mononuclear cells (BMC) for bone augmentation of plate-stabilized proximal humeral fractures - a randomized, open, multicentric study - phase IIa

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Osseous healing of fracture

Primary: Osseous healing of fracture

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
BMC2012, Cell based therapy by implanted bone marrow-derived mononuclear cells (BMC) for bone augmentation of plate-stabilized proximal humeral fractures - a randomized, open, multicentric study - phase IIa