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Clinical Trial Results:
TOFFEE Trial Toxicity OF Fluoropyrimidines: A comparative study of the cardiotoxicity of capEcitabine and tEysuno

Summary
EudraCT number	2012-005282-12
Trial protocol	GB
Global end of trial date	08 Oct 2020

Results information
Results version number	v1(current)
This version publication date	24 Jun 2023
First version publication date	24 Jun 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

V 7.0, 10 May 2020

ISRCTN number

US NCT number

NCT01845337

WHO universal trial number (UTN)

Sponsor organisation name

ACCORD (University of Edinburgh and NHS Lothian)

Sponsor organisation address

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

Public contact

Annya Smyth, University of Edinburgh, +44 01312423325, Annya.Smyth@ed.ac.uk

Scientific contact

Annya Smyth, University of Edinburgh, +44 01312423325, Annya.Smyth@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

08 Oct 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

08 Oct 2020

Global end of trial reached?

Yes

Global end of trial date

08 Oct 2020

Was the trial ended prematurely?

Yes

Main objective of the trial

To investigate the effect of capecitabine and teysuno on cardiovascular parameters (continuous ECG recording, high sensitivity troponin and BNP) to determine whether there is a difference in the cardiotoxicity of teysuno compared to the current standard of care cancer medicine, capecitabine.

Protection of trial subjects

All patients were aged >18 and had capacity to understand the information and make an informed decision. After detailed discussion, all patients were provided with written patient information and given time for questions before signing consent. Given opportunity to withdraw at any time. Provided with contact details for trials team.

Background therapy

Supportive medicines such as anti-emetics and anti-diarrhoeals that are provided as standard along with chemotherapy treatment.

Evidence for comparator

Fluoropyrimidines (FPs) are widely used chemotherapy agents for the management of patients with colorectal, breast, upper gastrointestinal, head and neck cancers. Capecitabine is an oral prodrug of 5-fluorouracil (5FU) which is used extensively in the UK and Europe but is associated with clinically overt cardiotoxicity in up to 9% of patients. Teysuno is an alternative oral fluoropyrimidine, used widely in Asia, with a marketing authorisation in Europe for use in combination with cisplatin for the treatment of gastric cancer. Teysuno is not described as having cardiotoxicity, but studies have never been performed.

Actual start date of recruitment

02 Jun 2014

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: 59

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Patients starting chemotherapy with either Capecitabine or CapOx were recruited from South East Scotland between June 2014 and March 2020.

Screening details

The trial was discussed with patients at their oncology clinic appointment and they were provided with verbal and written information. They were invited to attend a trials clinic some days thereafter. If not interested then patients proceeded to chemotherapy without participating in the trial and their rights were not affected. At least 50% of pati

Period 1 title

Consented to treatment

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind ^[1]

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer

Blinding implementation details

The patient and treating oncology team knew which treatment the patient had been randomised to. The study was blinded to the trial team and to the cardiovascular research team analysing the endpoints of the study. All cardiovascular endpoint data was analysed/investigated in batches, identified only by trial number, by technicians and the cardiovascular research team, often at a time significantly removed from the patient’s participation in the study. The cardiovascular research team was blinded

Are arms mutually exclusive

Yes

Capecitabine

Arm description

Capecitabine or Capecitabine + oxaliplatin (CapOx)

Arm type

Active comparator

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

L01BC06

Other name

Xeloda

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine 1250mg/m2 BD for 14 days out of 21 days (or capecitabine 1000mg/m2 BD for 14 days every 21 days for patients aged >70 or with eGFR 30-50ml/min). Capecitabine 1000mg/m2 BD for 14 days out of 21 days (or capecitabine 750mg/m2 BD for 14 days every 21 days for patients aged >70 or with eGFR 30-50ml/min) with Oxaliplatin 130mg/m2 IV Day 1 every 21 days

Teysuno (also known as S-1)

Arm description

Teysuno is a combination of (i) the 5-FU pro-drug, tegafur, (ii) a dihydropyrimidine dehydrogenase (DPD) inhibitor, gimeracil, and (iii) a phosphorylation inhibitor, oteracil.

Arm type

Experimental

Investigational medicinal product name

Tegafur / Gimeracil / Oteracil tablets

Investigational medicinal product code

L01BC53

Other name

S-1 or Teysuno

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Teysuno 30 mg/m2 twice daily, for 14 days every 21 days (or 25mg/m2 for patients aged >70 or with eGFR 30-50) Teysuno 25mg/m2 twice daily, for 14 days every 21 days with Oxaliplatin 130mg/m2 IV Day 1 every 21 days

Notes
[1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
Justification: The cardiovascular research team who performed the primary and secondary endpoint analyses were blinded to treatment allocation. The clinical study team responsible for day to day care were unblinded.

Number of subjects in period 1	Capecitabine	Teysuno (also known as S-1)
Started	30	29
Completed	28	28
Not completed	2	1
Clinical deterioration before starting	1	-
Infection and Covid pandemic before starting	1	-
family bereavement before starting	-	1

Period 2 title

Started treatment

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Single blind ^[2]

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer

Blinding implementation details

Are arms mutually exclusive

Yes

Capecitabine

Arm description

Randomised to capecitabine containing treatment and took at least one tablet

Arm type

Active comparator

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

L01BC06

Other name

Xeloda

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Teysuno S-1

Arm description

Randomised to receive Teysuno S-1 containing chemo and took at least one tablet

Arm type

Experimental

Investigational medicinal product name

Tegafur / Gimeracil / Oteracil tablets

Investigational medicinal product code

L01BC53

Other name

S-1 or Teysuno

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Notes
[2] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
Justification: The cardiovascular research team who performed the primary and secondary endpoint analyses were blinded to treatment allocation. The clinical study team responsible for day to day care were unblinded.

Number of subjects in period 2	Capecitabine	Teysuno S-1
Started	28	28
Completed	28	27
Not completed	0	1
family bereavement before starting	-	1

Baseline characteristics

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Reporting group title

Consented to treatment

Reporting group description

59 patients consented to treatment, and were randomised and are therefore the baseline group

Reporting group values	Consented to treatment	Total
Number of subjects	59	59
Age categorical
All patients randomised
Units: Subjects
Adults (18-64 years)	27	27
From 65-84 years	32	32
Age continuous
Arithmetic mean and range of ages for both groups of patients
Units: years
arithmetic mean (full range (min-max))	64 (39 to 83)	-
Gender categorical
Gender of all patients consented and randomised
Units: Subjects
female capecitabine	8	8
female teysuno S1	11	11
male capecitabine	22	22
male teysuno S1	18	18
Baseline CTCA
CT coronary angiography done at baseline for as many patients as possible
Units: Subjects
capecitabine	30	30
teysuno S1	29	29

Subject analysis set title

Capecitabine on treatment

Subject analysis set type

Per protocol

Subject analysis set description

Patients who were randomised to Cap or CapOx, and started some oral chemotherapy

Subject analysis set title

Teysuno on treatment

Subject analysis set type

Per protocol

Subject analysis set description

Patients who were randomised to Teysuno or TeyOx, and who started some oral chemotherapy

Subject analysis sets values	Capecitabine on treatment	Teysuno on treatment
Number of subjects	28	28
Age categorical
All patients randomised
Units: Subjects
Adults (18-64 years)	14	10
From 65-84 years	14	18
Age continuous
Arithmetic mean and range of ages for both groups of patients
Units: years
arithmetic mean (full range (min-max))	63 (42 to 83)	66 (39 to 82)
Gender categorical
Gender of all patients consented and randomised
Units: Subjects
female capecitabine	8	0
female teysuno S1	0	10
male capecitabine	20	0
male teysuno S1	0	18
Baseline CTCA
CT coronary angiography done at baseline for as many patients as possible
Units: Subjects
capecitabine	26	0
teysuno S1	0	27

End points

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Reporting group title

Capecitabine

Reporting group description

Capecitabine or Capecitabine + oxaliplatin (CapOx)

Reporting group title

Teysuno (also known as S-1)

Reporting group description

Teysuno is a combination of (i) the 5-FU pro-drug, tegafur, (ii) a dihydropyrimidine dehydrogenase (DPD) inhibitor, gimeracil, and (iii) a phosphorylation inhibitor, oteracil.

Reporting group title

Capecitabine

Reporting group description

Randomised to capecitabine containing treatment and took at least one tablet

Reporting group title

Teysuno S-1

Reporting group description

Randomised to receive Teysuno S-1 containing chemo and took at least one tablet

Subject analysis set title

Capecitabine on treatment

Subject analysis set type

Per protocol

Subject analysis set description

Patients who were randomised to Cap or CapOx, and started some oral chemotherapy

Subject analysis set title

Teysuno on treatment

Subject analysis set type

Per protocol

Subject analysis set description

Patients who were randomised to Teysuno or TeyOx, and who started some oral chemotherapy

Primary: Duration of ST change baseline to max (100uV)

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End point title

Duration of ST change baseline to max (100uV)

End point description

The primary endpoint of the study is the difference in the duration of ST deviation pre-treatment and during treatment

End point type

Primary

End point timeframe

Baseline before treatment Mean duration of ST change during 3 days of continuous ECG monitoring

End point values	Capecitabine	Teysuno (also known as S-1)
Number of subjects analysed	28 ^[1]	27 ^[2]
Units: hours
geometric mean (standard deviation)	1.08 ± 6.10	1.35 ± 5.34

Notes
[1] - capecitabine patients with >1 day 24 hour ECG recordings
[2] - teysuno S1 patients with >1 day 24 hour ECG recordings

Comparison between cap and S1

Comparison groups

Capecitabine v Teysuno (also known as S-1)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

≤ 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Confidence interval

Variability estimate

Standard deviation

Notes
[3] - difference between the two groups

Secondary: Ischaemic burden baseline to max (100 uv threshold)

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End point title

Ischaemic burden baseline to max (100 uv threshold)

End point description

Before treatment and during treatment with means of 24 hour continuous ECG recordings

End point type

Secondary

End point timeframe

Baseline and on treatment

End point values	Capecitabine	Teysuno (also known as S-1)
Number of subjects analysed	28 ^[4]	27 ^[5]
Units: mV
arithmetic mean (standard deviation)	20131 ± 55495	1591 ± 20188

Notes
[4] - > 1 24 hour ECG recording cap treated
[5] - > 1 24 hour ECG recording S1 treated

Wilcoxon rank sum test

Statistical analysis description

a non-parametric equivalent to the two-sample t-test since the data is not Normally distributed.

Comparison groups

Capecitabine v Teysuno (also known as S-1)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

< 0.05 ^[7]

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Confidence interval

Variability estimate

Standard deviation

Notes
[6] - comparing treatment groups for change in ischaemic burden (baseline to max at 100uV)
[7] - p=0.0479 which is statistically significant

Secondary: Ischaemic burden Baseline to max (200 uv threshold)

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End point title

Ischaemic burden Baseline to max (200 uv threshold)

End point description

Compare ischaemic burden in both treatment groups from baseline test to max ischaemic burden for each group

End point type

Secondary

End point timeframe

Before and during ECG monitoring

End point values	Capecitabine	Teysuno (also known as S-1)
Number of subjects analysed	28 ^[8]	27 ^[9]
Units: mV
arithmetic mean (standard deviation)	18045 ± 51604	-1360 ± 12145

Notes
[8] - capecitabine for whom > 1 24 ECG available
[9] - S1 teysuno for whom > 1 24 ECG available

Comparison between cap and S1 IB baseline max 200

Statistical analysis description

Baseline for each group to max IB for each group. Comparison between treatment groups

Comparison groups

Capecitabine v Teysuno (also known as S-1)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[10]

P-value

≤ 0.05 ^[11]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[10] - comparison
[11] - p=0.0532 not statistically significant

Secondary: Ischaemic Burden Baseline to mean of all on treatment ECG days (100 uv threshold)

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End point title

Ischaemic Burden Baseline to mean of all on treatment ECG days (100 uv threshold)

End point description

Mean daily IB baseline to max for both cap and S1 treated patients for whom >1 x 24 ECG recording available

End point type

Secondary

End point timeframe

Baseline and up to 3 days monitoring on treatment

End point values	Capecitabine	Teysuno (also known as S-1)
Number of subjects analysed	28 ^[12]	27 ^[13]
Units: mv
arithmetic mean (standard deviation)	20569 ± 56128	1072 ± 22123

Notes
[12] - cap patients
[13] - teysuno patients for whom >1 x 24 ECG recording

Comparison of mean daily IB baseline to max at 100

Statistical analysis description

Comparison between mean daily IB from baseline to max values for patients treated with capecitabine or teysuno , for whom >1 x 24 ECG recording available, at the 100uV threshold for detection

Comparison groups

Capecitabine v Teysuno (also known as S-1)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[14]

P-value

≤ 0.05 ^[15]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[14] - comparison to look for differences
[15] - p=0.0442 which is statistically significant

Secondary: Ischaemic burden baseline to mean of all on treatment ECG days (200 uv threshold)

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End point title

Ischaemic burden baseline to mean of all on treatment ECG days (200 uv threshold)

End point description

comparison between cap and S1 groups, when measured at 200uV threshold and using the mean daily IB from baseline to max

End point type

Secondary

End point timeframe

baseline and during 1-3 days of continuous ECG monitoring

End point values	Capecitabine	Teysuno (also known as S-1)
Number of subjects analysed	28 ^[16]	27 ^[17]
Units: mv
arithmetic mean (standard deviation)	18413 ± 52665	-1410 ± 12283

Notes
[16] - cap treated patients for whom > 1 x 24 ECG recording available
[17] - S1 treated patients for whom > 1 x 24 ECG recording available

Comparison cap and S1 mean daily IB 200uV b

Statistical analysis description

Comparison between cap and S1 treated groups, when ECGs analysed at 200uV threshold, looking at mean daily ischaemic burden measuring it from baseline to maximum over 3 days

Comparison groups

Capecitabine v Teysuno (also known as S-1)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

≤ 0.05 ^[19]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[18] - comparison to evaluate differences
[19] - P= 0.0532 which is not statistically significant

Adverse events

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Timeframe for reporting adverse events

First cycle of each treatment (21 days) Ongoing collection of SAEs for teysuno treated patients only, beyond C1, as part of safety monitoring for an off label drug. This could falsely elevate the number of SAEs when compared to capecitabine

Adverse event reporting additional description

Both capecitabine and S1 are cytotoxic drugs with expected and anticipated adverse effects, according to the SPC. AEs were recorded. Cycles are 3 weekly AEs and SAEs were evaluated for cycle 1 only for both groups SAEs were evaluated for teysuno S1 for all cycles, including beyond cycle 1 trial period

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

14.0

Reporting group title

Teysuno S1

Reporting group description

Patients treated with teysuno either as single agent or in combination with oxaliplatin. Only AEs of Grade 2,3 or 4 are included. All AEs and SAEs collected for teysuno patients, even beyond C1

Reporting group title

Capecitabine

Reporting group description

Patients treated with capecitabine, either as a single agent or in combination with oxaliplatin during the first cycle of treatment (the trial period) Only AEs of grade 2,3 or 4 are counted

Serious adverse events	Teysuno S1	Capecitabine
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 28 (32.14%)	6 / 28 (21.43%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Vascular disorders
Arterial thrombosis
subjects affected / exposed	0 / 28 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Paroxysmal arrhythmia
Additional description: AF
subjects affected / exposed	0 / 28 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain - cardiac
Additional description: Diagnosis of cardiac cause not definitively made
subjects affected / exposed	1 / 28 (3.57%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Transient ischaemic attack
subjects affected / exposed	2 / 28 (7.14%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 28 (3.57%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	2 / 28 (7.14%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 28 (7.14%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 28 (3.57%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
Additional description: Subacute (SABO)
subjects affected / exposed	0 / 28 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Urinary tract disorder
Additional description: Catheter related infection
subjects affected / exposed	1 / 28 (3.57%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 28 (3.57%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypercalcaemia of malignancy
subjects affected / exposed	0 / 28 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Teysuno S1	Capecitabine
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 28 (14.29%)	4 / 28 (14.29%)
General disorders and administration site conditions
Fatigue
subjects affected / exposed	4 / 28 (14.29%)	2 / 28 (7.14%)
occurrences all number	5	2
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 28 (3.57%)	2 / 28 (7.14%)
occurrences all number	1	2
Nausea
subjects affected / exposed	2 / 28 (7.14%)	4 / 28 (14.29%)
occurrences all number	2	4
Vomiting
subjects affected / exposed	0 / 28 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	2
Dyspepsia
subjects affected / exposed	1 / 28 (3.57%)	1 / 28 (3.57%)
occurrences all number	1	1

More information

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Were there any global substantial amendments to the protocol? Yes

20 Feb 2015

Included patients with CUP, modified cap dose if reduced eGFR as per SPC, statement that venous plethysmography and Badimon chamber are optional substudies, platelet aggregation studies removed, unblinding section updated, new patient information booklet.

19 Feb 2016

Added the option of slight alteration to timing of CTCA

15 Jun 2018

Description of co-enrolment strategy, new RSI for capecitabine, description of details of trial steering group and data monitoring committee, added the option of reducing doses in frail/elderly in keeping with standard practice, updated the RSI for capecitabine and teysuno and added a GDPR statement and GDPR patient information.

22 May 2020

Update to SPC and RSI for capecitabine, removal of vascular substudy and tPA and PAI-1 and update to statistical analysis plan.

Were there any global interruptions to the trial? No

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

The trial temporarily stopped recruiting during the Covid-19 pandemic and later that year, when it was clear the impact of the pandemic continued, a decision was made to stop recruitment into the trial and close the study, without fully recruiting.

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Clinical trials

Clinical Trial Results:
TOFFEE Trial Toxicity OF Fluoropyrimidines: A comparative study of the cardiotoxicity of capEcitabine and tEysuno

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Duration of ST change baseline to max (100uV)

Primary: Duration of ST change baseline to max (100uV)

Secondary: Ischaemic burden baseline to max (100 uv threshold)

Secondary: Ischaemic burden baseline to max (100 uv threshold)

Secondary: Ischaemic burden Baseline to max (200 uv threshold)

Secondary: Ischaemic burden Baseline to max (200 uv threshold)

Secondary: Ischaemic Burden Baseline to mean of all on treatment ECG days (100 uv threshold)

Secondary: Ischaemic Burden Baseline to mean of all on treatment ECG days (100 uv threshold)

Secondary: Ischaemic burden baseline to mean of all on treatment ECG days (200 uv threshold)

Secondary: Ischaemic burden baseline to mean of all on treatment ECG days (200 uv threshold)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: TOFFEE Trial Toxicity OF Fluoropyrimidines: A comparative study of the cardiotoxicity of capEcitabine and tEysuno

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Duration of ST change baseline to max (100uV)

Primary: Duration of ST change baseline to max (100uV)

Secondary: Ischaemic burden baseline to max (100 uv threshold)

Secondary: Ischaemic burden baseline to max (100 uv threshold)

Secondary: Ischaemic burden Baseline to max (200 uv threshold)

Secondary: Ischaemic burden Baseline to max (200 uv threshold)

Secondary: Ischaemic Burden Baseline to mean of all on treatment ECG days (100 uv threshold)

Secondary: Ischaemic Burden Baseline to mean of all on treatment ECG days (100 uv threshold)

Secondary: Ischaemic burden baseline to mean of all on treatment ECG days (200 uv threshold)

Secondary: Ischaemic burden baseline to mean of all on treatment ECG days (200 uv threshold)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
TOFFEE Trial Toxicity OF Fluoropyrimidines: A comparative study of the cardiotoxicity of capEcitabine and tEysuno