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Clinical Trial Results:
A multicentre prospective randomised open-label blinded end-point controlled trial of high-sensitivity cardiac troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent cardiac toxicity in breast cancer and lymphoma patients receiving anthracycline adjuvant therapy

Summary
EudraCT number	2017-000896-99
Trial protocol	GB
Global end of trial date	04 Apr 2022

Results information
Results version number	v1(current)
This version publication date	29 Oct 2023
First version publication date	29 Oct 2023
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

AC16148

ISRCTN number

ISRCTN24439460

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

ACCORD

Sponsor organisation address

QMRI, 47 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ

Public contact

Dr Fiach O'Mahoney, ACCORD, Dr Peter Henriksen, NHS Lothian, +44 131 2429418 , fiach.o'mahony@ed.ac.uk

Scientific contact

Dr Morag MacLean, Edinburgh Clinical Trials Unit; Tel: 0131 651 9914; Email: morag.maclean@ed.ac.uk, Dr Peter Henriksen, NHS Lothian, +44 131 242 3843, phenrik1@exseed.ed.ac.uk

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

31 Jan 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

04 Apr 2022

Global end of trial reached?

Yes

Global end of trial date

04 Apr 2022

Was the trial ended prematurely?

Main objective of the trial

To determine whether known treatments for heart failure can prevent or reduce myocardial injury and the development of left ventricular systolic dysfunction.

Protection of trial subjects

Participants were treated within a standard clinical setting by their NHS clinical care team.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Jun 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 175

Worldwide total number of subjects

175

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)

142

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Cardiac CARE opened for patient recruitment across 9 UK centres. Between 04Oct17 and 30Jun21, 424 patients were approached across 7 of the 9 centres open for recruitment. 191 patients approached were consented. 16 patients from this group were subsequently excluded owing to exclusion criteria. 57 of the remaining 175 patients were randomised.

Screening details

Patients aged ≥18 years commencing anthracycline for adjuvant or neo-adjuvant treatment of breast cancer or non-Hodgkin lymphoma were invited to participate in the study. Patient eligibility was verified by a clinical trial physician after written informed consent was obtained.

Period 1 title

Baseline

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Randomised IMP

Arm description

Arm type

Experimental

Investigational medicinal product name

Candesartan

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Candesartan will be started at 8 mg o.d. and increased at 3-day intervals to 16 mg and 32 mg o.d. First dose will be started as soon as possible after randomisation and will continue until completion/withdrawal from the study.

Investigational medicinal product name

Carvedilol

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Carvedilol will be started at 6.25 mg b.d., and increased to 12.5 mg b.d. and 25 mg b.d. First dose will be started as soon as possible after randomisation and will continue until completion/withdrawal from the study

Randomised Standard Care

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Non randomised

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Randomised IMP	Randomised Standard Care	Non randomised
Started	29	28	118
Completed	29	28	117
Not completed	0	0	1
Consent withdrawn by subject	-	-	1

Period 2 title

2 months

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Randomised IMP

Arm description

Arm type

Experimental

Investigational medicinal product name

Candesartan

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Carvedilol

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Randomised Standard Care

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Non randomised

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	Randomised IMP	Randomised Standard Care	Non randomised
Started	29	28	117
Completed	28	28	111
Not completed	1	0	6
Deceased	-	-	1
Consent withdrawn by subject	1	-	5

Period 3 title

6 months

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Randomised IMP

Arm description

Arm type

Experimental

Investigational medicinal product name

Candesartan

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Carvedilol

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Randomised Standard Care

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Non randomised

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 3	Randomised IMP	Randomised Standard Care	Non randomised
Started	28	28	111
Completed	28	28	106
Not completed	0	0	5
Deceased	-	-	1
Consent withdrawn by subject	-	-	4

Baseline characteristics

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Reporting group title

Randomised IMP

Reporting group description

Reporting group title

Randomised Standard Care

Reporting group description

Reporting group title

Non randomised

Reporting group description

Reporting group values	Randomised IMP	Randomised Standard Care	Non randomised	Total
Number of subjects	29	28	118	175
Age categorical
Units: Subjects
Adults (18-64 years)	21	21	100	142
From 65-84 years	8	7	18	33
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	54.0 ± 14.1	53.5 ± 13.3	52.1 ± 11.0	-
Gender categorical
Units: Subjects
Female	23	22	107	152
Male	6	6	11	23
Disease Type
Units: Subjects
Breast Cancer	17	15	93	125
Non-Hodgkins Lymphoma	12	13	25	50
Smoking
Units: Subjects
Currently	2	5	12	19
Ex (<1 year)	2	0	9	11
Ex (>1 year)	5	5	29	39
Never	20	18	68	106
Pregnancy test
Only recorded for female patients
Units: Subjects
Yes	11	12	51	74
No	12	10	56	78
Not Applicable	6	6	11	23
Reason no pregnancy test
Only recorded for female patients who did not have a pregnancy test
Units: Subjects
Post-menopause	11	9	48	68
Post-sterilisation	1	1	5	7
Not Applicable	17	18	65	100
Diabettes
Units: Subjects
No history	29	28	114	171
Insulin dependent	0	0	3	3
Tablet controlled	0	0	1	1
Diet controlled	0	0	0	0
History of hypertension
Units: Subjects
Yes	2	4	10	16
No	27	24	108	159
History of coronary artery disease
Units: Subjects
Yes	0	2	3	5
No	29	26	115	170
History of heart failure
Units: Subjects
Yes	0	1	1	2
No	29	27	117	173
History of kidney disease
Units: Subjects
Yes	0	2	5	7
No	29	26	113	168
Planned anthracycline cycles
Units: Subjects
4 cycles	2	7	48	57
6 cycles	14	14	35	63
3 cycles	13	7	35	55
Radiotherapy received
Units: Subjects
Yes	16	15	79	110
No	12	13	32	57
Missing	1	0	7	8
Which breast
Only recorded for patient who received radiotherapy.
Units: Subjects
Left	7	5	36	48
Right	6	8	35	49
Both	0	0	3	3
Not in breast	3	2	5	10
Not Applicable	13	13	39	65
Radiotherapy target
Only recorded for patient who received radiotherapy 'Not in breast'.
Units: Subjects
Chest/mediastinum	2	1	1	4
Outside chest/mediastinum region	1	1	4	6
Not Applicable	26	26	113	165
Taken any concomitant medications
Number of patients taking any concomitant medication, patients counted only once, but they could have been taking any number of medications.
Units: Subjects
Yes	16	21	61	98
No	13	7	57	77
Taken any prohibited Concomitant medications
Number of patients taking any concomitant medication, patients counted only once, but they could have been taking any number of medications
Units: Subjects
Yes	0	0	0	0
No	29	28	118	175
Covariate Age Band
Units: Subjects
≥65	8	7	18	33
<65	21	21	100	142
Covariate Baseline LVEF Band
Units: Subjects
≥60	25	27	115	167
<60	4	1	3	8
Covariate Planned Cumulative Dose epirubicin Band
Units: Subjects
=300 mg/m²	14	7	37	58
>300 mg/m²	15	21	81	117
Height
Units: cm
arithmetic mean (standard deviation)	166.5 ± 8.1	167.2 ± 8.4	165.4 ± 7.9	-
Weight
Units: kg
arithmetic mean (standard deviation)	70.73 ± 14.99	82.51 ± 16.74	76.63 ± 16.51	-
Planned epirubicin dose
Planned Cumulative Dose of epirubicin (or epirubicin equivalent).
Units: mg/m²
arithmetic mean (standard deviation)	469.0 ± 229.8	479.3 ± 192.1	424.4 ± 179.7	-

End points

Top of page

Reporting group title

Randomised IMP

Reporting group description

Reporting group title

Randomised Standard Care

Reporting group description

Reporting group title

Non randomised

Reporting group description

Reporting group title

Randomised IMP

Reporting group description

Reporting group title

Randomised Standard Care

Reporting group description

Reporting group title

Non randomised

Reporting group description

Reporting group title

Randomised IMP

Reporting group description

Reporting group title

Randomised Standard Care

Reporting group description

Reporting group title

Non randomised

Reporting group description

Primary: 1.1 Change on LVEF

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End point title

1.1 Change on LVEF

End point description

The primary outcome is the change in LVEF on cardiac MRI scan conducted 6 months after final anthracycline dose compared to baseline cardiac MRI scan conducted before anthracycline therapy starts. Change calculated as LVEF at 6 months minus LVEF at baseline. Both values should be present. Summary statistics are presented in end point "1.1 LVEF".

End point type

Primary

End point timeframe

Change on LVEF on cardiac MRI scan (baseline to 6 months).

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	27	27	97
Units: %
arithmetic mean (standard deviation)	-4.19 ± 7.4	-4.33 ± 4.40	-2.87 ± 6.12

LVEF change-Efficacy-Adjusted-PRIMARY

Statistical analysis description

PRIMARY: Adjusted Change on LVEF on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Standard care plus IMP vs Standard care alone - Efficacy

Comparison groups

Randomised Standard Care v Randomised IMP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

P-value

= 0.817 ^[2]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.373

Confidence interval

level

95%

sides

2-sided

lower limit

-3.593

upper limit

2.846

Notes
[1] - Change calculated as LVEF at 6 months minus LVEF at baseline. Both values should be present. Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years , LVEF at baseline ≥60% or <60% and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m².
[2] - Significance level set at p<0.05.

LVEF change-Efficacy-Non-Adjusted-Sensitivity

Statistical analysis description

Non-Adjusted Change on LVEF on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Standard care plus IMP vs Standard care alone - Efficacy - Sensitivity

Comparison groups

Randomised Standard Care v Randomised IMP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

P-value

= 0.9272 ^[4]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.148

Confidence interval

level

95%

sides

2-sided

lower limit

-3.09

upper limit

3.386

Notes
[3] - Change calculated as LVEF at 6 months minus LVEF at baseline. Both values should be present. Outcome analysed using an non adjusted linear regression model.
[4] - Significance level set at p<0.05.

LVEF change-Exploratory-Adjusted

Statistical analysis description

Change on LVEF on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Low-risk vs High-risk - Exploratory. Estimated mean represents the adjusted mean for the studied parameter by allocated intervention (non-randomised vs standard care alone).

Comparison groups

Non randomised v Randomised Standard Care

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[5]

P-value

= 0.288 ^[6]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-1.298

Confidence interval

level

95%

sides

2-sided

lower limit

-3.708

upper limit

1.112

Notes
[5] - Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years , LVEF at baseline ≥60% or <60%, and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m².
[6] - Significant level set at p<0.05.

LVEF change-Exploratory-Non Adjusted

Statistical analysis description

Change on LVEF on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Low-risk vs High-risk - Exploratory. Estimated mean represents the Non-adjusted mean for the studied parameter by allocated intervention (non-randomised vs standard care alone).

Comparison groups

Non randomised v Randomised Standard Care

Number of subjects included in analysis

124

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[7]

P-value

= 0.2467 ^[8]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-1.4667

Confidence interval

level

95%

sides

2-sided

lower limit

-3.963

upper limit

1.028

Notes
[7] - Sensitivity analysis: Outcome analysed using a non-adjusted linear regression model. Parameter shown normal or near-normal behaviour
[8] - Significance level set at p<0.05.

Secondary: 1.2 Left ventricular ejection fraction (LVEF)

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End point title

1.2 Left ventricular ejection fraction (LVEF)

End point description

These are the observed LVEF at the designated time point.

End point type

Secondary

End point timeframe

First baseline MRI performed 21 Nov 2017 and final follow up MRI performed 01 Apr 2022. The time between baseline and follow up MRI varied between 179 - 463 days.

End point values	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	29	28	118	27	27	97
Units: %
arithmetic mean (standard deviation)	69.38 ± 7.45	69.07 ± 6.11	69.33 ± 5.71	65.74 ± 6.64	64.93 ± 5.90	66.40 ± 6.29

Change LVEF -Non Randomised-Cardiotoxicity-NonAdju

Statistical analysis description

Change on LVEF on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Specificity of hs-cTnI assay for cardiotoxicity. Analysis of the mean of the within-person changes in LVEF between patients’ pre and post-anthracycline MRI scans for the non randomised patients.

Comparison groups

Non randomised v Non randomised

Number of subjects included in analysis

215

Analysis specification

Pre-specified

Analysis type

equivalence ^[9]

P-value

= 0.917 ^[10]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

2.87

Confidence interval

level

95%

sides

2-sided

lower limit

1.452

upper limit

4.28

Notes
[9] - The mean of the within-person changes in LVEF between patients’ pre and post-anthracycline MRI scans for the non randomised patients.
[10] - Outcome analysed using a paired t-test with a two One-Sided Tests (TOST) approach. Parameter shown normal or near-normal behavior. 95% CI Assessment: -2.0 < 1.63 , 4.10 > 2.0 Not equivalent

Secondary: 1.3 Ventricular Dysfunction at 6 months

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End point title

1.3 Ventricular Dysfunction at 6 months

End point description

Ventricular Dysfunction defined as a 10% points fall on LVEF from baseline to 6 months following final dose of anthracycline and a LVEF at 6 months below 50%.

End point type

Secondary

End point timeframe

Cardiac MRI scan conducted at baseline and at 6 months after final anthracycline dose. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: Patients
Yes	0	0	0
No	27	27	97
Missing	1	1	14

No statistical analyses for this end point

Secondary: 1.4 LVEF Fall below 40% at 6 months

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End point title

1.4 LVEF Fall below 40% at 6 months

End point description

End point type

Secondary

End point timeframe

Cardiac MRI scan conducted 6 months after final anthracycline dose. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: Patients
Yes	0	0	0
No	27	27	97
Missing	1	1	14

No statistical analyses for this end point

Secondary: 1.5 LVEF Fall below 50% at 6 months

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End point title

1.5 LVEF Fall below 50% at 6 months

End point description

End point type

Secondary

End point timeframe

Cardiac MRI scan conducted 6 months after final anthracycline dose. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: Patients
Yes	0	0	0
No	27	27	97
Missing	1	1	14

No statistical analyses for this end point

Secondary: 2.1 Global Longitudinal myocardial Strain (GLS)

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End point title

2.1 Global Longitudinal myocardial Strain (GLS)

End point description

These are the observed GLS at the designated time point.

End point type

Secondary

End point timeframe

Cardiac MRI scan conducted at baseline and at 6 months after final anthracycline dose

End point values	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	29	28	117	27	27	94
Units: -%
arithmetic mean (standard deviation)	-16.71 ± 2.73	16.09 ± 2.63	-17.09 ± 1.91	-16.21 ± 2.32	-14.91 ± 1.96	-16.69 ± 1.77

Change GLS-Non Randomised-Cardiotoxicity-NonAdju

Statistical analysis description

Change on GLS on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Specificity of hs-cTnI assay for cardiotoxicity. Analysis of the mean of the within-person changes in GLS between patients’ pre and post-anthracycline MRI scans for the non randomised patients.

Comparison groups

Non randomised v Non randomised

Number of subjects included in analysis

211

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[11]

P-value

= 0.026 ^[12]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

-0.48

Confidence interval

level

95%

sides

2-sided

lower limit

-0.902

upper limit

-0.058

Notes
[11] - The mean of the within-person changes in GLS between patients’ pre and post-anthracycline MRI scans for the non randomised patients.
[12] - Outcome analysed using a paired t-test. Parameter shown normal or near-normal behaviour. Significance level set at p<0.05.

Secondary: 2.2 Change on GLS

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End point title

2.2 Change on GLS

End point description

Change in GLS on cardiac MRI scan conducted 6 months after final anthracycline dose compared to baseline cardiac MRI scan conducted before anthracycline therapy starts

End point type

Secondary

End point timeframe

Change on GLS on cardiac MRI scan (baseline to 6 months).

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	27	27	93
Units: -%
arithmetic mean (standard deviation)	0.58 ± 2.61	1.19 ± 2.20	0.48 ± 2.05

GLS change-Efficacy-Adjusted

Statistical analysis description

Adjusted Change on GLS on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Standard care plus IMP vs Standard care alone – Efficacy

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[13]

P-value

= 0.5923 ^[14]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.371

Confidence interval

level

95%

sides

2-sided

lower limit

-1.753

upper limit

1.012

Notes
[13] - Change calculated as GLS at 6 months minus GLS at baseline. Both values should be present. Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years , LVEF at baseline ≥60% or <60% and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m².
[14] - Significance level set at p<0.05.

GLS change-Efficacy-Non-Adjusted-Sensitivity

Statistical analysis description

Non-Adjusted Change on GLS on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Standard care plus IMP vs Standard care alone - Efficacy - Sensitivity.

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[15]

P-value

= 0.355 ^[16]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.613

Confidence interval

level

95%

sides

2-sided

lower limit

-1.932

upper limit

0.705

Notes
[15] - Change calculated as GLS at 6 months minus GLS at baseline. Both values should be present. Outcome analysed using an Non-adjusted linear regression model.
[16] - Significance level set at p<0.05.

GLS change-Exploratory-Adjusted

Statistical analysis description

Change on GLS on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Low-risk vs High-risk - Exploratory. Estimated mean represents the adjusted mean for the studied parameter by allocated intervention (non-randomised vs standard care alone).

Comparison groups

Randomised Standard Care v Non randomised

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[17]

P-value

= 0.0978 ^[18]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.749

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

1.639

Notes
[17] - Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years, LVEF at baseline ≥60% or <60%, and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m².
[18] - Significant level set at p<0.05.

GLS change-Exploratory-Non-Adjusted

Statistical analysis description

Change on GLS on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Low-risk vs High-risk - Exploratory. Estimated mean represents the Non-adjusted mean for the studied parameter by allocated intervention (non-randomised vs standard care alone).

Comparison groups

Randomised Standard Care v Non randomised

Number of subjects included in analysis

120

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[19]

P-value

= 0.121 ^[20]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.712

Confidence interval

level

95%

sides

2-sided

lower limit

-0.19

upper limit

1.614

Notes
[19] - Sensitivity analysis: Outcome analysed using a non-adjusted linear regression model. Parameter shown normal or near-normal behaviour.
[20] - Significance level set at p<0.05.

Secondary: 2.3 GLS relative fall >15%

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End point title

2.3 GLS relative fall >15%

End point description

Calculated as [(6 month value – baseline value)/baseline value]*100. GLS was measured at the Cardiac MRI scan conducted at baseline and at 6 months after final anthracycline dose.

End point type

Secondary

End point timeframe

>15% (relative) fall in GLS at 6 month post-anthracycline cMRI. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: Patients
Yes	4	1	6
No	23	26	87
Missing	1	1	18

No statistical analyses for this end point

Secondary: 2.4 GLS percent change

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End point title

2.4 GLS percent change

End point description

Calculated as [(6 month value – baseline value)/baseline value]*100.

End point type

Secondary

End point timeframe

Percentage Change on GLS on cardiac MRI scan (baseline to 6 months).

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	27	27	93
Units: %
arithmetic mean (standard deviation)	-1.84 ± 16.64	-5.93 ± 14.70	-2.06 ± 11.81

No statistical analyses for this end point

Secondary: 3.1 Global Circumferential myocardial Strain (GCS)

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End point title

3.1 Global Circumferential myocardial Strain (GCS)

End point description

These are the observed GCS at the designated time point.

End point type

Secondary

End point timeframe

Cardiac MRI scan conducted at baseline and at 6 months after final anthracycline dose

End point values	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	29	28	117	27	27	94
Units: %
arithmetic mean (standard deviation)	-18.87 ± 3.43	-18.03 ± 3.06	-19.56 ± 2.30	-18.83 ± 2.85	-17.73 ± 2.37	-19.07 ± 2.25

Change GCS -Non Randomised-Cardiotoxicity-NonAdju

Statistical analysis description

Change on GCS on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Specificity of hs-cTnI assay for cardiotoxicity. Analysis of the mean of the within-person changes in LVEF between patients’ pre and post-anthracycline MRI scans for the non randomised patients.

Comparison groups

Non randomised v Non randomised

Number of subjects included in analysis

211

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[21]

P-value

= 0.006 ^[22]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

-0.639

Confidence interval

level

95%

sides

2-sided

lower limit

-1.091

upper limit

-0.187

Notes
[21] - The mean of the within-person changes in LVEF between patients’ pre and post-anthracycline MRI scans for the non randomised patients.
[22] - Outcome analysed using a paired t-test. Parameter shown normal or near-normal behaviour. Significance level set at p<0.05.

Secondary: 3.2 Change on GCS

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End point title

3.2 Change on GCS

End point description

Change calculated as GCS at 6 months minus GCS at baseline.

End point type

Secondary

End point timeframe

Change on GLS on cardiac MRI scan (baseline to 6 months).

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	27	27	93
Units: %
arithmetic mean (standard deviation)	0.01 ± 3.69	0.28 ± 2.41	0.64 ± 2.19

GCS change-Efficacy-Adjusted

Statistical analysis description

Adjusted Change on GCS on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Standard care plus IMP vs Standard care alone – Efficacy.

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[23]

P-value

= 0.842 ^[24]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.164

Confidence interval

level

95%

sides

2-sided

lower limit

-1.48

upper limit

1.807

Notes
[23] - Change calculated as GCS at 6 months minus GCS at baseline. Both values should be present. Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years, LVEF at baseline ≥60% or <60% and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m².
[24] - Significance level set at p<0.05.

GCS change-Efficacy-Non-Adjusted-Sensitivity

Statistical analysis description

Non-Adjusted Change on GCS on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Standard care plus IMP vs Standard care alone - Efficacy – Sensitivity

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[25]

P-value

= 0.749 ^[26]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.273

Confidence interval

level

95%

sides

2-sided

lower limit

-1.975

upper limit

1.429

Notes
[25] - Change calculated as GCS at 6 months minus GCS at baseline. Both values should be present. Outcome analysed using an Non-adjusted linear regression model.
[26] - Significance level set at p<0.05.

GCS change-Exploratory-Adjusted

Statistical analysis description

Change on GCS on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Low-risk vs High-risk - Exploratory. Estimated mean represents the adjusted mean for the studied parameter by allocated intervention (non-randomised vs standard care alone).

Comparison groups

Non randomised v Randomised Standard Care

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[27]

P-value

= 0.443 ^[28]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-1.324

upper limit

0.583

Notes
[27] - Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years , LVEF at baseline ≥60% or <60%, and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m².
[28] - Significant level set at p<0.05.

GCS change-Exploratory-Non-Adjusted

Statistical analysis description

Change on GCS on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Low-risk vs High-risk - Exploratory. Estimated mean represents the Non-adjusted mean for the studied parameter by allocated intervention (non-randomised vs standard care alone).

Comparison groups

Randomised Standard Care v Non randomised

Number of subjects included in analysis

120

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[29]

P-value

= 0.47 ^[30]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.355

Confidence interval

level

95%

sides

2-sided

lower limit

-1.326

upper limit

0.616

Notes
[29] - Sensitivity analysis: Outcome analysed using a non-adjusted linear regression model. Parameter shown normal or near-normal behaviour.
[30] - Significance level set at p<0.05.

Secondary: 3.3 GCS relative fall >15%

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End point title

3.3 GCS relative fall >15%

End point description

15% (relative) fall in GCS at 6 month post-anthracycline cMRI.

End point type

Secondary

End point timeframe

Change on GLS on cardiac MRI scan (baseline to 6 months). All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: Patients
Yes	7	3	3
No	20	24	90
Missing	1	1	21

No statistical analyses for this end point

Secondary: 3.4 GCS percent change

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End point title

3.4 GCS percent change

End point description

Calculated as [(6 month value – baseline value)/baseline value]*100.

End point type

Secondary

End point timeframe

Percentage Change on GLS on cardiac MRI scan (baseline to 6 months).

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	27	27	93
Units: %
arithmetic mean (standard deviation)	2.69 ± 20.97	0.03 ± 15.66	-1.81 ± 18.39

No statistical analyses for this end point

Secondary: 4.1 Left Ventricular Mass (LVM)

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End point title

4.1 Left Ventricular Mass (LVM)

End point description

These are the observed LVM at the designated time point.

End point type

Secondary

End point timeframe

Cardiac MRI scan conducted at baseline and at 6 months after final anthracycline dose

End point values	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	29	28	118	27	27	97
Units: g/m²
arithmetic mean (standard deviation)	47.59 ± 12.08	49.54 ± 8.20	46.25 ± 8.43	51.37 ± 11.24	49.70 ± 7.36	48.25 ± 7.96

Change LVM-Non Randomised-Cardiotoxicity-NonAdju

Statistical analysis description

Change on LVEF on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Specificity of hs-cTnI assay for cardiotoxicity. Analysis of the mean of the within-person changes in LVM between patients’ pre and post-anthracycline MRI scans for the non randomised patients.

Comparison groups

Non randomised v Non randomised

Number of subjects included in analysis

215

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[31]

P-value

< 0.001 ^[32]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

-2.103

Confidence interval

level

95%

sides

2-sided

lower limit

-3.283

upper limit

0.923

Notes
[31] - The mean of the within-person changes in LVM between patients’ pre and post-anthracycline MRI scans for the non randomised patients.
[32] - Outcome analysed using a paired t-test. Parameter shown normal or near-normal behaviour. Significance level set at p<0.05.

Secondary: 4.2 Change on LVM

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End point title

4.2 Change on LVM

End point description

Change calculated as LVM at 6 months minus LVM at baseline.

End point type

Secondary

End point timeframe

Change on LVM on cardiac MRI scan (baseline to 6 months)

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	27	27	97
Units: g/m²
arithmetic mean (standard deviation)	3.19 ± 10.88	0.00 ± 8.25	2.10 ± 5.86

LVM change-Efficacy-Adjusted

Statistical analysis description

Adjusted Change on LVM on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Standard care plus IMP vs Standard care alone – Efficacy

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[33]

P-value

= 0.184 ^[34]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

3.787

Confidence interval

level

95%

sides

2-sided

lower limit

-1.861

upper limit

9.435

Notes
[33] - Change calculated as LVM at 6 months minus LVM at baseline. Both values should be present. Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years, LVEF at baseline ≥60% or <60% and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m².
[34] - Significance level set at p<0.05.

LVM change-Efficacy-Non-Adjusted-Sensitivity

Statistical analysis description

Non-Adjusted Change on LVM on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Standard care plus IMP vs Standard care alone - Efficacy – Sensitivity.

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[35]

P-value

= 0.231 ^[36]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

3.185

Confidence interval

level

95%

sides

2-sided

lower limit

-2.086

upper limit

8.456

Notes
[35] - Change calculated as LVM at 6 months minus LVM at baseline. Both values should be present. Outcome analysed using a Non-adjusted linear regression model
[36] - Significance level set at p<0.05

LVM change-Exploratory-Adjusted

Statistical analysis description

Change on LVM on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Low-risk vs High-risk - Exploratory. Estimated mean represents the adjusted mean for the studied parameter by allocated intervention (non-randomised vs standard care alone).

Comparison groups

Randomised Standard Care v Non randomised

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[37]

P-value

= 0.213 ^[38]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-1.725

Confidence interval

level

95%

sides

2-sided

lower limit

-4.456

upper limit

1.006

Notes
[37] - Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years , LVEF at baseline ≥60% or <60%, and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m².
[38] - Significant level set at p<0.05.

LVM change-Exploratory-Non-Adjusted

Statistical analysis description

Change on LVM on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Low-risk vs High-risk - Exploratory. Estimated mean represents the Non-adjusted mean for the studied parameter by allocated intervention (non-randomised vs standard care alone).

Comparison groups

Randomised Standard Care v Non randomised

Number of subjects included in analysis

124

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[39]

P-value

= 0.136 ^[40]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-2.103

Confidence interval

level

95%

sides

2-sided

lower limit

-4.877

upper limit

0.671

Notes
[39] - Sensitivity analysis: Outcome analysed using a non-adjusted linear regression model. Parameter shown normal or near-normal behaviour.
[40] - Significance level set at p<0.05.

Secondary: 5.1 Left Ventricular Volume (LVV)

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End point title

5.1 Left Ventricular Volume (LVV)

End point description

These are the observed LVV at the designated time point.

End point type

Secondary

End point timeframe

Cardiac MRI scan conducted at baseline and at 6 months after final anthracycline dose

End point values	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	29	28	118	27	27	97
Units: ml/m²
arithmetic mean (standard deviation)	63.41 ± 15.36	63.93 ± 9.88	62.52 ± 11.09	69.41 ± 13.85	64.11 ± 11.48	63.62 ± 10.85

Change LVV-Non Randomised-Cardiotoxicity-NonAdju

Statistical analysis description

Change on LVV on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Specificity of hs-cTnI assay for cardiotoxicity. Analysis of the mean of the within-person changes in LVV between patients’ pre and post-anthracycline MRI scans for the non randomised patients.

Comparison groups

Non randomised v Non randomised

Number of subjects included in analysis

215

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[41]

P-value

= 0.256 ^[42]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

-1.155

Confidence interval

level

95%

sides

2-sided

lower limit

-3.162

upper limit

0.852

Notes
[41] - The mean of the within-person changes in LVV between patients’ pre and post-anthracycline MRI scans for the non randomised patients.
[42] - Outcome analysed using a paired t-test. Parameter shown normal or near-normal behaviour. Significance level set at p<0.05

Secondary: 5.2 Change on LVV

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End point title

5.2 Change on LVV

End point description

Change calculated as LVV at 6 months minus LVV at baseline.

End point type

Secondary

End point timeframe

Change on LVV on cardiac MRI scan (baseline to 6 months).

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	27	27	97
Units: ml/m²
arithmetic mean (standard deviation)	5.63 ± 8.91	0.22 ± 9.80	1.15 ± 9.96

LVV change-Efficacy-Adjusted

Statistical analysis description

Adjusted Change on LVV on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Standard care plus IMP vs Standard care alone – Efficacy

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[43]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

6.014

Confidence interval

level

95%

sides

2-sided

lower limit

0.591

upper limit

11.438

Notes
[43] - Change calculated as LVV at 6 months minus LVV at baseline. Both values should be present. Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years , LVEF at baseline ≥60% or <60% and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m².

LVV change-Efficacy-Non-Adjusted-Sensitivity

Statistical analysis description

Non-Adjusted Change on LVV on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Standard care plus IMP vs Standard care alone - Efficacy – Sensitivity

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[44]

P-value

= 0.039 ^[45]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

5.407

Confidence interval

level

95%

sides

2-sided

lower limit

0.293

upper limit

10.522

Notes
[44] - Change calculated as LVV at 6 months minus LVV at baseline. Both values should be present. Outcome analysed using a Non-adjusted linear regression model
[45] - Significance level set at p<0.05.

LVV change-Exploratory-Adjusted

Statistical analysis description

Change on LVV on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Low-risk vs High-risk - Exploratory. Estimated mean represents the adjusted mean for the studied parameter by allocated intervention (non-randomised vs standard care alone).

Comparison groups

Randomised Standard Care v Non randomised

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[46]

P-value

= 0.708 ^[47]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-5.022

upper limit

3.423

Notes
[46] - Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years , LVEF at baseline ≥60% or <60%, and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m².
[47] - Significant level set at p<0.05.

LVV change-Exploratory-Non-Adjusted

Statistical analysis description

Change on LVV on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Low-risk vs High-risk - Exploratory. Estimated mean represents the Non-adjusted mean for the studied parameter by allocated intervention (non-randomised vs standard care alone).

Comparison groups

Randomised Standard Care v Non randomised

Number of subjects included in analysis

124

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[48]

P-value

= 0.667 ^[49]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.932

Confidence interval

level

95%

sides

2-sided

lower limit

-5.208

upper limit

3.343

Notes
[48] - Sensitivity analysis: Outcome analysed using a non-adjusted linear regression model. Parameter shown normal or near-normal behaviour.
[49] - Significance level set at p<0.05.

Secondary: 6.1 Left Ventricular Area (LAA)

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End point title

6.1 Left Ventricular Area (LAA)

End point description

These are the observed LAA at the designated time point.

End point type

Secondary

End point timeframe

Cardiac MRI scan conducted at baseline and at 6 months after final anthracycline dose.

End point values	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	29	28	118	27	27	91
Units: cm²/m²
arithmetic mean (standard deviation)	11.93 ± 2.48	11.36 ± 2.39	11.57 ± 2.61	11.93 ± 1.82	10.85 ± 2.03	11.70 ± 2.50

Change LAA -Non Randomised-Cardiotoxicity-NonAdju

Statistical analysis description

Change on LAA on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Specificity of hs-cTnI assay for cardiotoxicity. Analysis of the mean of the within-person changes in LAA between patients’ pre and post-anthracycline MRI scans for the non randomised patients.

Comparison groups

Non randomised v Non randomised

Number of subjects included in analysis

209

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[50]

P-value

= 0.3185 ^[51]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

-0.286

Confidence interval

level

95%

sides

2-sided

lower limit

-0.852

upper limit

0.28

Notes
[50] - The mean of the within-person changes in LAA between patients’ pre and post-anthracycline MRI scans for the non randomised patients.
[51] - Outcome analysed using a paired t-test. Parameter shown normal or near-normal behaviour. Significance level set at p<0.05.

Secondary: 6.2 Change on LAA

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End point title

6.2 Change on LAA

End point description

Change calculated as LAA at 6 months minus LAA at baseline.

End point type

Secondary

End point timeframe

Change on LAA on cardiac MRI scan (baseline to 6 months).

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	27	27	91
Units: cm²/m²
arithmetic mean (standard deviation)	-0.04 ± 2.43	-0.52 ± 2.15	0.29 ± 2.72

LAA change-Efficacy-Adjusted

Statistical analysis description

Adjusted Change on LAA on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Standard care plus IMP vs Standard care alone – Efficacy

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[52]

P-value

= 0.646 ^[53]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.305

Confidence interval

level

95%

sides

2-sided

lower limit

-1.021

upper limit

1.631

Notes
[52] - Change calculated as LAA at 6 months minus LAA at baseline. Both values should be present. Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years , LVEF at baseline ≥60% or <60% and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m².
[53] - Significance level set at p<0.05.

LAA change-Efficacy-Non-Adjusted-Sensitivity

Statistical analysis description

Non-Adjusted Change on LAA on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Standard care plus IMP vs Standard care alone - Efficacy – Sensitivity.

Comparison groups

Randomised Standard Care v Randomised IMP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[54]

P-value

= 0.444 ^[55]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

0.481

Confidence interval

level

95%

sides

2-sided

lower limit

-0.771

upper limit

1.734

Notes
[54] - Change calculated as LAA at 6 months minus LAA at baseline. Both values should be present. Outcome analysed using a Non-adjusted linear regression model.
[55] - Significance level set at p<0.05.

LAA change-Exploratory-Adjusted

Statistical analysis description

Change on LAA on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Low-risk vs High-risk - Exploratory. Estimated mean represents the adjusted mean for the studied parameter by allocated intervention (non-randomised vs standard care alone).

Comparison groups

Randomised Standard Care v Non randomised

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[56]

P-value

= 0.126 ^[57]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.856

Confidence interval

level

95%

sides

2-sided

lower limit

-1.956

upper limit

0.243

Notes
[56] - Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years, LVEF at baseline ≥60% or <60%, and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m².
[57] - Significant level set at p<0.05.

LAA change-Exploratory-Non-Adjusted

Statistical analysis description

Change on LAA on cardiac MRI scan (baseline to 6 months) - Statistical analysis - Low-risk vs High-risk - Exploratory. Estimated mean represents the Non-adjusted mean for the studied parameter by allocated intervention (non-randomised vs standard care alone).

Comparison groups

Randomised Standard Care v Non randomised

Number of subjects included in analysis

118

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[58]

P-value

= 0.161 ^[59]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-0.804

Confidence interval

level

95%

sides

2-sided

lower limit

-1.934

upper limit

0.325

Notes
[58] - Sensitivity analysis: Outcome analysed using a non-adjusted linear regression model. Parameter shown normal or near-normal behaviour.
[59] - Significance level set at p<0.05.

Secondary: 7.1 Hs-cTnI

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End point title

7.1 Hs-cTnI

End point description

Note: When Hs-cTnI (high sensitivity cardiac troponin I) values were given as ‘<x ng/L’, it was assumed that they were equal to x/2 ng/L.

End point type

Secondary

End point timeframe

Hs-cTnI (high sensitivity cardiac troponin I) assay at Cycle 1 (Baseline) and at 2 months. If the Hs-cTnI value at 2 months was missing, the value taken closest in time prior to this was used, until a non-missing value was found up to Cycle 2.

End point values	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	27	28	111	28	28	114
Units: ng/L
arithmetic mean (standard deviation)	2.09 ± 1.73	4.89 ± 10.92	1.17 ± 1.02	27.39 ± 24.31	36.25 ± 31.78	17.36 ± 14.72

No statistical analyses for this end point

Secondary: 7.2 Change in Hs-cTnI

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End point title

7.2 Change in Hs-cTnI

End point description

Note: When Hs-cTnI (high sensitivity cardiac troponin I) values were given as ‘<x ng/L’, it was assumed that they were equal to x/2 ng/L.

End point type

Secondary

End point timeframe

Change between Hs-cTnI (high sensitivity cardiac troponin I) at baseline (cycle 1) and at 2 months. If the Hs-cTnI value at 2 months was missing, the value taken closest in time prior to this was used, until a non-missing value was found up to Cycle 2.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	26	28	109
Units: ng/L
arithmetic mean (standard deviation)	26.48 ± 24.41	31.36 ± 32.47	16.33 ± 14.90

Change on Hs-cTnI - Efficacy - Adjusted

Statistical analysis description

Change on Hs-cTnI (high sensitivity cardiac troponin I) (baseline to 2 months) - Statistical analysis - Standard care plus IMP vs Standard care alone - Efficacy

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[60]

P-value

= 0.8464 ^[61]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-1.551

Confidence interval

level

95%

sides

2-sided

lower limit

-17.556

upper limit

14.454

Notes
[60] - Change calculated as Hs-cTnI at baseline (cycle 1) minus Hs-cTnI at 2 months. Both values should be present. If the value at 2 months was missing, the value taken closest in time prior to this was used. Analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years , LVEF at baseline ≥60% or <60% and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m². Parameter shown normal or near-normal behaviour.
[61] - Significance level set at p<0.05.

Change on Hs-cTnI - Efficacy - Sensitivity - NonAd

Statistical analysis description

Change on Hs-cTnI (high sensitivity cardiac troponin I) (baseline to 2 months) - Statistical analysis - Standard care plus IMP vs Standard care alone - Efficacy - Sensitivity

Comparison groups

Randomised Standard Care v Randomised IMP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[62]

P-value

= 0.538 ^[63]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-4.876

Confidence interval

level

95%

sides

2-sided

lower limit

-20.658

upper limit

10.906

Notes
[62] - Change calculated as Hs-cTnI at baseline (cycle 1) minus Hs-cTnI at 2 months. Both values should be present. If the value at 2 months was missing, the value taken closest in time prior to this was used. Analysed using a non adjusted linear regression model. Parameter shown normal or near-normal behaviour.
[63] - Significance level set at p<0.05.

Change on Hs-cTnI - Exploratory - adjusted

Statistical analysis description

Change on Hs-cTnI (high sensitivity cardiac troponin I) (baseline to 2 months) - Statistical analysis - Low-risk vs High-risk - Exploratory

Comparison groups

Randomised Standard Care v Non randomised

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[64]

P-value

< 0.001 ^[65]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

14.298

Confidence interval

level

95%

sides

2-sided

lower limit

6.182

upper limit

22.414

Notes
[64] - Change calculated as Hs-cTnI at baseline (cycle 1) minus Hs-cTnI at 2 months. Both values should be present. If the value at 2 months was missing, the value taken closest in time prior to this was used. Analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years , LVEF at baseline ≥60% or <60% and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m². Parameter shown normal or near-normal behaviour.
[65] - Significance level set at p<0.05.

Change on Hs-cTnI - Exploratory - Non adjusted

Statistical analysis description

Change on Hs-cTnI (high sensitivity cardiac troponin I) (baseline to 2 months) - Statistical analysis - Low-risk vs High-risk - Exploratory

Comparison groups

Randomised Standard Care v Non randomised

Number of subjects included in analysis

137

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[66]

P-value

< 0.001 ^[67]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

15.031

Confidence interval

level

95%

sides

2-sided

lower limit

6.774

upper limit

23.289

Notes
[66] - Change calculated as Hs-cTnI at baseline (cycle 1) minus Hs-cTnI at 2 months. Both values should be present. If the value at 2 months was missing, the value taken closest in time prior to this was used. Analysed using an adjusted linear regression model.
[67] - Significance level set at p<0.05.

Secondary: 7.3.1 Hs-cTnI AUC - 3 Cycles

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End point title

7.3.1 Hs-cTnI AUC - 3 Cycles

End point description

For patients with 3 Planned cycles of Anthracycline. Note: When Hs-cTnI (high sensitivity cardiac troponin I) values were given as ‘<x ng/L’, it was assumed that they were equal to x/2 ng/L.

End point type

Secondary

End point timeframe

Area under the curve (AUC) Calculated using the trapezium rule. AUC can only be calculated if there are more than four troponin values in the profile and one of the values has to be at baseline (i.e. cycle 1).

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	11	7	32
Units: (ng/L)*days
arithmetic mean (standard deviation)	1588 ± 520	3109 ± 4927	1225 ± 893

Hs-cTnI AUC 3 Cycles - Specificity

Statistical analysis description

Hs-cTnI AUC 3 Cycles - Statistical analysis - Specificity of hs-cTnI assay for cardiotoxicity

Comparison groups

Non randomised v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[68]

P-value

= 0.37 ^[69]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

-0.1414

Confidence interval

level

95%

sides

2-sided

lower limit

-0.97

upper limit

0.143

Notes
[68] - Outcome analysed using an independent samples t-test, Unequal variances. Parameter has been log transformed and it shown normal or near-normal behaviour. The estimated mean difference represents the natural log mean difference of the AUC.
[69] - Significance level set at p<0.05.

Secondary: 7.3.2 Hs-cTnI AUC - 4 Cycles

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End point title

7.3.2 Hs-cTnI AUC - 4 Cycles

End point description

For patients with 3 Planned cycles of Anthracycline. Note: When Hs-cTnI (high sensitivity cardiac troponin I) values were given as ‘<x ng/L’, it was assumed that they were equal to x/2 ng/L.

End point type

Secondary

End point timeframe

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	2	7	46
Units: (ng/L)*days
arithmetic mean (standard deviation)	1420 ± 98	3174 ± 1580	1605 ± 1150

Hs-cTnI AUC 4 Cycles - Specificity

Statistical analysis description

Hs-cTnI AUC 4 Cycles - Statistical analysis - Specificity of hs-cTnI assay for cardiotoxicity

Comparison groups

Non randomised v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[70]

P-value

= 0.008 ^[71]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

-0.828

Confidence interval

level

95%

sides

2-sided

lower limit

-1.438

upper limit

-0.218

Notes
[70] - Outcome analysed using an independent samples t-test, equal variances. Parameter has been log transformed and it shown normal or near-normal behaviour. The estimated mean difference represents the natural log mean difference of the AUC.
[71] - Significance level set at p<0.05.

Secondary: 7.3.3 Hs-cTnI AUC - 6 Cycles

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End point title

7.3.3 Hs-cTnI AUC - 6 Cycles

End point description

For patients with 3 Planned cycles of Anthracycline. Note: When Hs-cTnI (high sensitivity cardiac troponin I) values were given as ‘<x ng/L’, it was assumed that they were equal to x/2 ng/L.

End point type

Secondary

End point timeframe

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	13	14	32
Units: (ng/L)*days
arithmetic mean (standard deviation)	6590 ± 3528	6052 ± 4188	2516 ± 1559

Hs-cTnI AUC 6 Cycles - Specificity

Statistical analysis description

Hs-cTnI AUC 6 Cycles - Statistical analysis - Specificity of hs-cTnI assay for cardiotoxicity

Comparison groups

Randomised Standard Care v Non randomised

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[72]

P-value

= 0.003 ^[73]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

-0.787

Confidence interval

level

95%

sides

2-sided

lower limit

-1.305

upper limit

-0.27

Notes
[72] - Outcome analysed using an independent samples t-test, equal variances. Parameter has been log transformed and it shown normal or near-normal behaviour. The estimated mean difference represents the natural log mean difference of the AUC.
[73] - Significance level set at p<0.05.

Secondary: 7.4 Chronic myocardial injury (MI) at 2 months or after

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End point title

7.4 Chronic myocardial injury (MI) at 2 months or after

End point description

Defined as a persistent elevations of Hs-cTnI above the gender-specific 99th centile at 2 month follow up. If the 2-month follow up sample was not available then Hs-cTnI elevation above this threshold at any point beyond this was counted. Note 1: Gender specific thresholds (99% upper reference limit) for the Abbott ARCHITECHT assay are <16 ng/L (female) and <34 ng/L (male). Note 2: When Hs-cTnI (high sensitivity cardiac troponin I) values were given as ‘<x ng/L’, it was assumed that they were equal to x/2 ng/L.

End point type

Secondary

End point timeframe

at 2 months or after randomisation. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	29	28	117
Units: Patients
yes	10	15	34
no	18	10	72
missing	1	3	11

No statistical analyses for this end point

Secondary: 7.5 Risk of severe and early on-treatment cardiotoxixity

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End point title

7.5 Risk of severe and early on-treatment cardiotoxixity

End point description

Defined as any hs-cTnI measurement of >80 ng/L during or after treatment (from cycle 1 to 6 months follow up). Note: When Hs-cTnI (high sensitivity cardiac troponin I) values were given as ‘<x ng/L’, it was assumed that they were equal to x/2 ng/L.

End point type

Secondary

End point timeframe

From cycle 1 to 6 months follow up. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: patients
yes	3	5	0
no	26	23	116
missing	0	0	0

No statistical analyses for this end point

Secondary: 8.1 Death and cardiovascular death since consent

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End point title

8.1 Death and cardiovascular death since consent

End point description

At last observed point in the study for each patient, calculated from consent.

End point type

Secondary

End point timeframe

Since consent. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: patients
Alive	29	28	116
Dead - Cardiovascular	0	0	0
Dead - Other reason	20	0	2

Any Death

Statistical analysis description

Note: There are not enough patients with events to perform any adjusted or unadjusted survival analysis

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 9999999 ^[74]

Method

Logrank

Confidence interval

Notes
[74] - Log-rang P-value : Not estimable

Secondary: 8.2 Any new diagnosis of heart failure

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End point title

8.2 Any new diagnosis of heart failure

End point description

End point type

Secondary

End point timeframe

Counted from date of consent to date of last available observation for each patient. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: patients
yes	0	1	0
no	29	27	118

New diagnosis of heart failure (HF) since consent

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[75]

P-value

= 9999999 ^[76]

Method

Logrank

Confidence interval

Notes
[75] - There are not enough patients with events to perform any adjusted or unadjusted survival analysis
[76] - Log-rank P-value : Not estimable

Secondary: 9.1 Pulse

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End point title

9.1 Pulse

End point description

Baseline measured before any dose of anthracycline is given (Cycle 1).

End point type

Secondary

End point timeframe

Pulse at baseline, 2 months and 6 months

End point values	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	114	23	25	92	25	21	87
Units: bpm
arithmetic mean (standard deviation)	77.43 ± 11.63	81.82 ± 13.23	78.59 ± 11.02	80.13 ± 11.57	83.80 ± 13.68	85.11 ± 12.75	73.56 ± 9.20	84.76 ± 12.62	77.22 ± 12.61

Pulse at 6 months - Post Hoc - Adjusted

Statistical analysis description

Outcome analysed using an adjusted linear regression model. Covariates: age at consent ≥65 or <65 years, LVEF at baseline ≥60% or <60%, and planned cumulative epirubicin equivalent dose as =300 mg/m² or >300 mg/m²

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[77]

P-value

= 0.003 ^[78]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-10.755

Confidence interval

level

95%

sides

2-sided

lower limit

-17.627

upper limit

-3.882

Notes
[77] - Parameter shown normal or near-normal behaviour.
[78] - Significance level set at p<0.05

Pulse at 6 months - Post Hoc - Non Adjusted

Statistical analysis description

Outcome analysed using an adjusted linear regression model.

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[79]

P-value

= 0.001 ^[80]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-11.202

Confidence interval

level

95%

sides

2-sided

lower limit

-17.698

upper limit

-4.705

Notes
[79] - Parameter shown normal or near-normal behaviour.
[80] - Significance level set at p<0.05

Secondary: 9.2 Systolic Blood Pressure

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End point title

9.2 Systolic Blood Pressure

End point description

Baseline was measured before any dose of anthracycline is given (Cycle 1).

End point type

Secondary

End point timeframe

Systolic Blood Pressure at baseline, 2 months and 6 months

End point values	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	114	24	25	92	25	22	86
Units: mmHg
arithmetic mean (standard deviation)	130.79 ± 16.57	132.43 ± 18.42	128.24 ± 16.34	119.75 ± 21.65	131.92 ± 16.86	123.21 ± 14.28	117.92 ± 16.71	127.68 ± 14.70	124.80 ± 14.71

SBP at 6 months - Post Hoc - Adjusted

Statistical analysis description

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[81]

P-value

= 0.121 ^[82]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-7.387

Confidence interval

level

95%

sides

2-sided

lower limit

-16.817

upper limit

2.043

Notes
[81] - Parameter shown normal or near-normal behaviour.
[82] - Significance level set at p<0.05.

SBP at 6 months - Post Hoc - Non Adjusted

Statistical analysis description

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[83]

P-value

= 0.064 ^[84]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-8.762

Confidence interval

level

95%

sides

2-sided

lower limit

-18.066

upper limit

0.542

Notes
[83] - Parameter shown normal or near-normal behaviour.
[84] - Significance level set at p<0.05.

Secondary: 9.3 Diastolic Blood Pressure

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End point title

9.3 Diastolic Blood Pressure

End point description

Baseline was measured before any dose of anthracycline is given (Cycle 1).

End point type

Secondary

End point timeframe

Diastolic Blood Pressure at baseline, 2 months and 6 months

End point values	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	114	24	25	92	25	22	86
Units: mmHg
arithmetic mean (standard deviation)	79.71 ± 12.43	79.79 ± 11.27	78.15 ± 9.69	68.38 ± 11.22	81.0 ± 9.07	76.37 ± 8.37	72.60 ± 11.09	79.32 ± 9.19	78.12 ± 10.02

DBP at 6 months - Post Hoc - Adjusted

Statistical analysis description

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[85]

P-value

= 0.055 ^[86]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-6.173

Confidence interval

level

95%

sides

2-sided

lower limit

-12.498

upper limit

0.152

Notes
[85] - Parameter shown normal or near-normal behaviour.
[86] - Significance level set at p<0.05.

DBP at 6 months - Post Hoc - Non Adjusted

Statistical analysis description

Outcome analysed using an adjusted linear regression model.

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

non-inferiority ^[87]

P-value

= 0.03 ^[88]

Method

Regression, Linear

Parameter type

Mean difference (final values)

Point estimate

-6.718

Confidence interval

level

95%

sides

2-sided

lower limit

-12.752

upper limit

0.684

Notes
[87] - Parameter shown normal or near-normal behaviour.
[88] - Significance level set at p<0.05.

Secondary: 9.4 Hypotension at 2 months

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End point title

9.4 Hypotension at 2 months

End point description

Hypotension is present if a systolic blood pressure strictly below(<) 90 mmHg occurred. If the value at 2 months is missing, the value taken closest in time prior to this was used until a non-missing value was found up to Cycle 2. Statistical analysis was planned but not feasible for this outcome.

End point type

Secondary

End point timeframe

at 2 months. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	29	28	117
Units: patients
yes	0	0	0
no	29	28	113
missing	0	0	5

No statistical analyses for this end point

Secondary: 9.5 Bradycardia at 2 months

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End point title

9.5 Bradycardia at 2 months

End point description

Bradycardia is present if a heart rate of fewer than 50 beats per minute (bpm) at 2 months occurred. If the value at 2 months is missing, the value taken closest in time prior to this was used until a non-missing value was found up to Cycle 2. Statistical analysis was planned but not feasible for this outcome.

End point type

Secondary

End point timeframe

at 2 months. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	29	28	117
Units: patients
yes	0	0	0
no	29	28	113
missing	0	0	5

No statistical analyses for this end point

Secondary: 10.1 Any hyperkalaemia

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End point title

10.1 Any hyperkalaemia

End point description

Hyperkalemia is an elevated level of potassium (K+) in the blood, (K+≥ 5.0 mmol/L).

End point type

Secondary

End point timeframe

Measured at any point after randomisation. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: patients
yes	6	5	12
no	23	23	104
missing	0	0	2

Incidence of hyperkalaemia - Adjusted

Statistical analysis description

Outcome analysed using logistic regression. The main studied effect is: Standard care plus candesartan and carvedilol vs standard care alone and the covariates were the binary fixed effects: age at consent ≥65 or <65 years, planned cumulative epirubicin equivalent dose 300 mg/m² or >300 mg/m² and baseline LVEF ≥60% or <60%.

Comparison groups

Randomised Standard Care v Randomised IMP

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.539 ^[89]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.378

upper limit

6.446

Notes
[89] - Significance level set at p<0.05.

Incidence of hyperkalaemia - Non Adjusted

Statistical analysis description

Outcome analysed using logistic regression. The main studied effect is: Standard care plus candesartan and carvedilol vs standard care alone

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.539 ^[90]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.321

upper limit

4.492

Notes
[90] - Significance level set at p<0.05.

Secondary: 10.2 Any worsening renal function

Top of page

End point title

10.2 Any worsening renal function

End point description

Worsening renal function: Decrease in eGFR of > 25% from baseline or an increase in creatinine of > 30% from baseline. Baseline was measured before any dose of anthracycline is given (Cycle 1). Change calculated as (value at timepoint - value at baseline)/(value at baseline).

End point type

Secondary

End point timeframe

Measured at any point after baseline. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: patients
yes	2	2	3
no	27	26	110
missing	0	0	5

Incidence of worsening renal function - Adjusted

Statistical analysis description

The main studied effect is: Standard care plus candesartan and carvedilol vs standard care alone and the covariates were the binary fixed effects: age at consent ≥65 or <65 years, planned cumulative epirubicin equivalent dose 300 mg/m² or >300 mg/m² and baseline LVEF ≥60% or <60%.

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[91]

P-value

= 0.918 ^[92]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.118

Confidence interval

level

95%

sides

2-sided

lower limit

0.135

upper limit

9.265

Notes
[91] - Outcome analysed using logistic regression
[92] - Significance level set at p<0.05.

Incidence of worsening renal function-NonAdjusted

Statistical analysis description

The main studied effect is: Standard care plus candesartan and carvedilol vs standard care alone.

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[93]

P-value

= 0.971 ^[94]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.963

Confidence interval

level

95%

sides

2-sided

lower limit

0.126

upper limit

7.35

Notes
[93] - Outcome analysed using logistic regression
[94] - Significance level set at p<0.05.

Secondary: 10.3 Any acute kidney injury

Top of page

End point title

10.3 Any acute kidney injury

End point description

Acute kidney injury: An eGFR drop to <45 ml/min/1.73m². Where eGRF = estimated glomerular filtration rate. Statistical analysis was planned but it is not feasible for this outcome

End point type

Secondary

End point timeframe

Measured at any point after randomisation. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: patients
yes	0	0	0
no	29	28	116
missing	0	0	2

No statistical analyses for this end point

Secondary: 10.4 Any fatigue

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End point title

10.4 Any fatigue

End point description

Fatigue grade ≥ 2 by Common terminology criteria for adverse events (CTCAE) classification.

End point type

Secondary

End point timeframe

Measured at any point after randomisation. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: patients
yes	1	7	14
no	28	21	102
missing	0	0	2

Incidence of Fatigue - Adjusted

Statistical analysis description

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[95]

P-value

= 0.057 ^[96]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.116

Confidence interval

level

95%

sides

2-sided

lower limit

0.013

upper limit

1.065

Notes
[95] - Outcome analysed using logistic regression
[96] - Significance level set at p<0.05.

Incidence of Fatigue - Non Adjusted

Statistical analysis description

Outcome analysed using logistic regression. The main studied effect is: Standard care plus candesartan and carvedilol vs standard care alone.

Comparison groups

Randomised IMP v Randomised Standard Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[97]

P-value

= 0.0437 ^[98]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.107

Confidence interval

level

95%

sides

2-sided

lower limit

0.012

upper limit

0.939

Notes
[97] - Outcome analysed using logistic regression
[98] - Significance level set at p<0.05.

Secondary: 10.5 New diagnosis of atrial fibrillation

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End point title

10.5 New diagnosis of atrial fibrillation

End point description

Statistical analysis was planned but it is not feasible for this outcome.

End point type

Secondary

End point timeframe

Measured at any point after randomisation. All available data used.

End point values	Randomised IMP	Randomised Standard Care	Non randomised
Number of subjects analysed	28	28	111
Units: patients
yes	0	0	0
no	29	28	116
missing	0	0	2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From consent to last study visit for each participant

Adverse event reporting additional description

The sites will only record symptoms of interest that could be considered an AR to the study intervention.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Received intervention

Reporting group description

Participants who received at least one dose of Carvedilol or Candesartan

Reporting group title

Not received Intervention

Reporting group description

Participants who did not receive any Carvedilol or Candesartan

Serious adverse events	Received intervention	Not received Intervention
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 28 (21.43%)	17 / 147 (11.56%)
number of deaths (all causes)	0	2
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic carcinoma metastatic
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Investigations
Liver function test abnormal
Additional description: blood and lymphatic system disorders - deranged LFTs
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fracture
Additional description: 1 participant had T12 fracture 1 participant had a hip fracture
subjects affected / exposed	0 / 28 (0.00%)	2 / 147 (1.36%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
Additional description: Deliberate overdose
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Thrombosis
Additional description: Right internal jugular vein thrombosis
subjects affected / exposed	1 / 28 (3.57%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Thrombosis
Additional description: Right atrial thrombosis
subjects affected / exposed	1 / 28 (3.57%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
Additional description: Dizziness and syncope
subjects affected / exposed	3 / 28 (10.71%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
Additional description: 1 participant had Atypical chest pain 1 participant had pleuritic chest pain
subjects affected / exposed	1 / 28 (3.57%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
Additional description: Worsening left leg rash and pyrexial
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Proptosis
Additional description: right eye proptosis
subjects affected / exposed	1 / 28 (3.57%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 28 (3.57%)	0 / 147 (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
Dyspnoea
Additional description: Dyspnoea (not meeting criteria for new or worsening heart failure)
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Obstruction
Additional description: Lower airway obstruction
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
COVID-19 pneumonia
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 28 (3.57%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Pain in extremity
Additional description: Admitted to hospital wit sudden onset of leg pain
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Breast abscess
subjects affected / exposed	1 / 28 (3.57%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 28 (3.57%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	1 / 28 (3.57%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Received intervention	Not received Intervention
Total subjects affected by non serious adverse events
subjects affected / exposed	17 / 28 (60.71%)	7 / 147 (4.76%)
Vascular disorders
Mass
Additional description: Right atrial mass
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences all number	0	1
Hypotension
Additional description: 1 participant Hypotension secondary to neutropenic sepsis 1 participant hypotension grade 2
subjects affected / exposed	1 / 28 (3.57%)	1 / 147 (0.68%)
occurrences all number	1	1
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences all number	0	1
Nervous system disorders
Dizziness
Additional description: Dizziness and syncope
subjects affected / exposed	16 / 28 (57.14%)	3 / 147 (2.04%)
occurrences all number	18	3
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences all number	0	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea
Additional description: Dyspnoea (not meeting criteria for new or worsening heart failure)
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences all number	0	1
Skin and subcutaneous tissue disorders
Rash
Additional description: Rash on hand at infusion site
subjects affected / exposed	0 / 28 (0.00%)	1 / 147 (0.68%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

28 Aug 2017

Protocol v2.0 was the initial approved protocol. SA01 - notified REC that co-enrolment with Add-Aspirin study would be permitted. Did various corrections, clarifications and defined visit windows in the protocol and updated to v3.0 The REC requested to include website details in the protocol and it was updated to v4.0

31 Jan 2018

SA02 Updated protocol inclusion criteria to allow recruitment of participants scheduled to receive 300 mg/m2 epirubicin dose, and 3 cycles of chemo. Updated co-enrolment section in protocol to clarify how co-enrolment would be recorded, and protocol version updated to v5.0

14 Mar 2018

SA03 Updated protocol inclusion criteria to include enrolment of non-Hodgkin Lymphoma patients scheduled for CHOP or R-CHOP. Update to randomisation minimisation section and protocol updated to v6.0

18 Jun 2018

SA05 Various sections in protocol updated including - can withdraw patients who didn't receive full anthracycline dose, clarify CHOP regimes permitted, expand to allow randomisation at any of cycles 2-6 if the cTnI threshold is reached, and clarification about SAE recording and reporting. Protocol updated to v7.0

27 May 2019

SA07 - Updated protocol to clarify timing of treatment allocation after randomisation and that IMP dose changes can be done at clinician discretion. Protocol updated to v8.0

04 Sep 2019

SA08 - updated protocol to permit IMP to be provided by post, and that cTnI could also be done using the Alinity assay. The protocol was updated to v9.0 Recruitment was temporarily halted due to the global pandemic.

14 Jun 2021

SA09 Update to the wording of secondary endpoints and they were split into groupings. Protocol updated to v10.0. A minor amendment followed to correct typos and the protocol was updated to v11.0

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
16 Mar 2020	Covid19 pandemic: the sponsor put a temporary halt to recruitment on 17 March 2020. Participants already enrolled continued their study visits as these coincided with cancer treatment. From 06 Jul 2020 the temporary halt was lifted. Sites were required to complete a risk assessment and following sponsor approval they were permitted to restart recruitment. Recruitment restarted, albeit at a slower rate.	06 Jul 2020

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

None reported

http://www.ncbi.nlm.nih.gov/pubmed/29217634
http://www.ncbi.nlm.nih.gov/pubmed/35766037

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 1.1 Change on LVEF

Primary: 1.1 Change on LVEF

Secondary: 1.2 Left ventricular ejection fraction (LVEF)

Secondary: 1.2 Left ventricular ejection fraction (LVEF)

Secondary: 1.3 Ventricular Dysfunction at 6 months

Secondary: 1.3 Ventricular Dysfunction at 6 months

Secondary: 1.4 LVEF Fall below 40% at 6 months

Secondary: 1.4 LVEF Fall below 40% at 6 months

Secondary: 1.5 LVEF Fall below 50% at 6 months

Secondary: 1.5 LVEF Fall below 50% at 6 months

Secondary: 2.1 Global Longitudinal myocardial Strain (GLS)

Secondary: 2.1 Global Longitudinal myocardial Strain (GLS)

Secondary: 2.2 Change on GLS

Secondary: 2.2 Change on GLS

Secondary: 2.3 GLS relative fall >15%

Secondary: 2.3 GLS relative fall >15%

Secondary: 2.4 GLS percent change

Secondary: 2.4 GLS percent change

Secondary: 3.1 Global Circumferential myocardial Strain (GCS)

Secondary: 3.1 Global Circumferential myocardial Strain (GCS)

Secondary: 3.2 Change on GCS

Secondary: 3.2 Change on GCS

Secondary: 3.3 GCS relative fall >15%

Secondary: 3.3 GCS relative fall >15%

Secondary: 3.4 GCS percent change

Secondary: 3.4 GCS percent change

Secondary: 4.1 Left Ventricular Mass (LVM)

Secondary: 4.1 Left Ventricular Mass (LVM)

Secondary: 4.2 Change on LVM

Secondary: 4.2 Change on LVM

Secondary: 5.1 Left Ventricular Volume (LVV)

Secondary: 5.1 Left Ventricular Volume (LVV)

Secondary: 5.2 Change on LVV

Secondary: 5.2 Change on LVV

Secondary: 6.1 Left Ventricular Area (LAA)

Secondary: 6.1 Left Ventricular Area (LAA)

Secondary: 6.2 Change on LAA

Secondary: 6.2 Change on LAA

Secondary: 7.1 Hs-cTnI

Secondary: 7.1 Hs-cTnI

Secondary: 7.2 Change in Hs-cTnI

Secondary: 7.2 Change in Hs-cTnI

Secondary: 7.3.1 Hs-cTnI AUC - 3 Cycles

Secondary: 7.3.1 Hs-cTnI AUC - 3 Cycles

Secondary: 7.3.2 Hs-cTnI AUC - 4 Cycles

Secondary: 7.3.2 Hs-cTnI AUC - 4 Cycles

Secondary: 7.3.3 Hs-cTnI AUC - 6 Cycles

Secondary: 7.3.3 Hs-cTnI AUC - 6 Cycles

Secondary: 7.4 Chronic myocardial injury (MI) at 2 months or after

Secondary: 7.4 Chronic myocardial injury (MI) at 2 months or after

Secondary: 7.5 Risk of severe and early on-treatment cardiotoxixity

Secondary: 7.5 Risk of severe and early on-treatment cardiotoxixity

Secondary: 8.1 Death and cardiovascular death since consent

Secondary: 8.1 Death and cardiovascular death since consent

Secondary: 8.2 Any new diagnosis of heart failure

Secondary: 8.2 Any new diagnosis of heart failure

Secondary: 9.1 Pulse

Secondary: 9.1 Pulse

Secondary: 9.2 Systolic Blood Pressure

Secondary: 9.2 Systolic Blood Pressure

Secondary: 9.3 Diastolic Blood Pressure

Secondary: 9.3 Diastolic Blood Pressure

Secondary: 9.4 Hypotension at 2 months

Secondary: 9.4 Hypotension at 2 months

Secondary: 9.5 Bradycardia at 2 months

Secondary: 9.5 Bradycardia at 2 months

Secondary: 10.1 Any hyperkalaemia

Secondary: 10.1 Any hyperkalaemia

Secondary: 10.2 Any worsening renal function

Secondary: 10.2 Any worsening renal function

Secondary: 10.3 Any acute kidney injury