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Clinical Trial Results:
COAST - Cisplatin Ototoxicity attenuated by Aspirin Trial A randomised, Phase II, double-blind, placebo-controlled, two arm Trial to establish whether Aspirin can reduce hearing loss/ototoxicity for patients receiving Cisplatin chemotherapy.

Summary
EudraCT number	2012-001509-25
Trial protocol	GB
Global end of trial date	01 Feb 2016

Results information
Results version number	v1(current)
This version publication date	19 Jul 2017
First version publication date	19 Jul 2017
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

RHMCAN0860

ISRCTN number

ISRCTN83689269

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

University Hospital Southampton NHS Foundation Trust

Sponsor organisation address

Southampton General Hospital, Tremona Road, Southampton, United Kingdom, SO16 6YD

Public contact

Karen Martin, Senior Trials Manager, Southampton Clinical Trials Unit, 0044 2381205154, K.S.Martin@soton.ac.uk

Scientific contact

Karen Martin, Senior Trials Manager, Southampton Clinical Trials Unit, 0044 2381205154, K.S.Martin@soton.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

15 Sep 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Feb 2016

Was the trial ended prematurely?

Main objective of the trial

To establish whether aspirin can reduce hearing loss/ototoxicity for patients receiving cisplatin based chemotherapy. Secondary objectives: 1. To determine whether it is feasible to conduct a Phase III randomised controlled Trial of aspirin for the same patient population. 2. To quantify the extent of hearing loss in patients receiving cisplatin via the use of otoacoustic emissions (OAE). 3. To determine whether patients are able to tolerate short-term, large doses of enteric-coated aspirin taken with omeprazole without significant side-effects and with no loss of cisplatin dose-intensity

Protection of trial subjects

The protocol stated: It may be necessary to prescribe a gastro protectant as a supportive measure during the course of the Trial. In this situation the patient should be instructed not to take the omeprazole or omeprazole-placebo from the Trial medication patient pack and should continue with the alternative gastro-protectant at the discretion of the PI or delegated responsible clinician. There was also provision for dose modification due to toxicity: Gastrointestinal bleeding:  Grade 1 toxicity: No intervention required.  Grade 2 toxicity at first occurrence: Stop Trial drug until toxicity resolved to grade 1 or 0.  Grade 2 toxicity at second occurrence: Stop Trial drug permanently.  Grade 3 and 4 toxicity at first occurrence: Stop Trial drug permanently. No dose reductions of the Trial drug are allowed. Appropriate management of any bleeding event should be carried out. Non bleeding toxicities (thought by the PI or designee to be related to the Trial drug)  Grade 1 toxicity: No intervention required, continue Trial drug  Grade 2 toxicity at first occurrence: Stop Trial drug until toxicity resolved to grade 1 or 0.  Grade 2 toxicity at second occurrence: Stop Trial drug permanently.  Grade 3 and 4 toxicity at first occurrence: Stop Trial drug permanently. Interaction with other drugs: A wash out period is not required for any aspirin containing medications taken prior to randomisation. Patients will be advised that additional aspirin and NSAIDs should not be taken during the treatment phase of the Trial. Patients on oral anti-coagulants such as warfarin are excluded from the trial. Details of any aspirin containing medications taken in the three weeks before randomisation should be recorded in the concomitant medication section of the CRF. Patients on therapeutic aspirin at baseline (dose of <75mg) will be eligible for Trial entry at the discretion of the PI providing the dose will not increase during the trial.

Background therapy

Patients will receive up to 6 cycles of cisplatin chemotherapy according to tumour site, response and toxicity.

Evidence for comparator

This is a randomised, Phase II, double-blind, placebo-controlled, two arm feasibility Trial*. Patients will be randomised into either Arm 1 or Arm 2 of the Trial. Arm 1 patients will receive cisplatin with aspirin and omeprazole. Arm 2 patients will receive cisplatin with aspirin placebo and omeprazole placebo. This Trial design, as specified by Rubinstein et al. is not intended to replace a subsequent Phase III Trial but rather indicate if there is a reasonable probability of efficacy and to give a clearer idea of the magnitude of effect in order to better estimate the sample size for a Phase III Trial*. *Rubinstein LV., Korn EL., Freidlin B., Hunsberger S., Ivy SP and Smith MA. Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol. 2005 Oct 1;23 (28):7199-206

Actual start date of recruitment

01 Oct 2012

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: 94

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

94 patients were recruited from Mar 2013 to Jul 2015 from 8 UK cancer centers. Patients were stratified at randomisation by planned cisplatin-dose using these categories: (i)≥200mg/m2 but <300mg/m2; (ii) ≥300mg/m2 but <400mg/m2; (iii) ≥400mg/m2. Patients were eligible if they were 18 yrs or over and deemed suitable for cisplatin chemotherapy dose

Screening details

The SCTU will be contacted in order to register a patient and obtain a screening identification number for the trial. Once eligibility for the study is confirmed randomisation will be via an independent web-based system (TENALEA) and will be stratified by planned cisplatin-dose.

Number of subjects started

439 ^[1]

Number of subjects completed

Reason: Number of subjects

Physician decision: 42

Reason: Number of subjects

Not eligible - Patient to have split dose regimen: 6

Reason: Number of subjects

Not eligible - Patient has Aspirin contradictions: 9

Reason: Number of subjects

Not eligible - Has Nasopharyngeal Carcinoma: 9

Reason: Number of subjects

Not eligible - Pre-existing hearing loss: 8

Reason: Number of subjects

Not eligible - Patient not fit for chemotherapy: 28

Reason: Number of subjects

Not eligible - Due on NSAIDs during treatment: 1

Reason: Number of subjects

Not eligible - Patient receiving Aspirin >75mg/day: 3

Reason: Number of subjects

Patient choice - didn't want to take part in study: 50

Reason: Number of subjects

Other reason - not specified: 46

Reason: Number of subjects

Not eligible - Other reason: 61

Reason: Number of subjects

Patient choice - Other reason: 82

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 345 subjects were actively screened and for the reasons presented in the table below, 251 did not complete the pre-assignment period.

Period 1 title

Overall (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Assessor

Blinding implementation details

Patients are randomised via the ALEA system to a treatment arm by means of a unique three-digit patient pack number. For subsequent cycles, a new patient pack number is requested via the ALEA system, which corresponds to the patient’s randomised treatment arm. Only CTU statisticians were unblinded during the trial. Emergency unblinding for AEs were through an unblinding service at ESMS.

Are arms mutually exclusive

Yes

Arm 1: Aspirin and Omeprazole

Arm description

Arm 1- Patients will be administered 975mg aspirin (enteric coated) three times daily, orally and 20mg omeprazole once daily, orally, for 4 days commencing the day before cisplatin administration. For patients receiving cisplatin chemotherapy on Days 1 and 2 of each cycle the treatment will be administered for a total of 5 days (commencing the day before each cisplatin treatment, and continuing for 4 days after). Aspirin (A) and Omeprazole (O) Group Each Cycle* Day 1 – A + O Day 2 – A + O + cisplatin Day 3 – A+ O Day 4 – A + O The total number of cisplatin cycles varies with cancer site from up to 6 cycles * Eligible Patients receiving cisplatin chemotherapy over a 2 day consecutive regimen will receive a total of 5 days IMP, commencing the day before starting treatment.

Arm type

Experimental

Investigational medicinal product name

aspirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

A single batch of aspirin tablets will be manufactured into aspirin 975mg tablets. The aspirin tablet cores will be enteric coated. The aspirin-matched placebo will be of the same appearance and size as aspirin tablets. The placebo tablets will also have the same enteric coating product as the active tablet. The patient should take one tablet three times a day for the 4 or 5 day treatment period. Patients on a 4 day regime should be instructed not to take IMP on day 5 and to return day 5 drug to the research nurse at their next visit (if applicable).

Investigational medicinal product name

omeprazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NuPharm will source omeprazole from a supplier and each 20mg dose will be removed from the packaging and over-encapsulated in one opaque gelatine capsule (size 0). The omeprazole-matched placebo will be of the same size and shape as the omeprazole tablet. Each placebo tablet will be over-encapsulated in one opaque gelatine capsule (size 0).The patient should take 1 capsule a day for the 4 or 5 day treatment period. Patients on a 4 day regime should be instructed not to take IMP on day 5 and to return day 5 drug to the research nurse at their next visit (if applicable).

Arm 2: Placebo

Arm description

Arm 2- Patients will be administered aspirin matched placebo three times daily, orally, for 4 days and omeprazole matched placebo once daily, orally, for 4 days commencing the day before cisplatin administration. For patients receiving cisplatin chemotherapy on Days 1 and 2 of each cycle the aspirin and omeprazole matched placebos will be administered for a total of 5 days (commencing the day before each cisplatin treatment, and continuing for 4 days after). Aspirin-placebo (AP) and Omeprazole-placebo (OP) Group Each Cycle* Day 1 – AP + OP Day 2 – AP + OP + cisplatin Day 3 – AP + OP Day 4 – AP + OP The total number of cisplatin cycles varies with cancer site from up to 6 cycles * Eligible Patients receiving cisplatin chemotherapy over a 2 day consecutive regimen will receive a total of 5 days IMP, commencing the day before starting treatment.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Matching aspirin placebo will be administered at a dose of 975mg three times daily orally for 4 days (commencing the day before each cisplatin treatment). Patients receiving cisplatin chemotherapy on days 1 and 2 of each cycle, matching aspirin placebo will be administered at a dose of 975mg three times daily orally for a total of 5 days (commencing the day before each cisplatin treatment) Matching omeprazole placebo will be administered at a dose of 20mg, taken orally once daily for 4 or 5 days depending on the number of days of cisplatin chemotherapy per cycle.

Number of subjects in period 1	Arm 1: Aspirin and Omeprazole	Arm 2: Placebo
Started	45	49
Followed-up to Day 7 post-chemotherapy	42	42
Completed	32	34
Not completed	13	15
Adverse event, serious fatal	1	2
Consent withdrawn by subject	4	4
Physician decision	1	1
Adverse event, non-fatal	1	1
Incorrect randomisation	1	-
Lost to follow-up	4	6
Changed treatment post cycle 1	1	-
Developed recurrence disease, needed further trt	-	1

Baseline characteristics

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Reporting group title

Arm 1: Aspirin and Omeprazole

Reporting group description

Reporting group title

Arm 2: Placebo

Reporting group description

Reporting group values	Arm 1: Aspirin and Omeprazole	Arm 2: Placebo	Total
Number of subjects	45	49	94
Age categorical
Units: Subjects
Adults (18-64 years)	33	28	61
From 65-84 years	12	21	33
85 years and over	0	0	0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	56 (52 to 65)	62 (55 to 66)	-
Gender categorical
Units: Subjects
Female	9	13	22
Male	36	36	72
Tumour group
Units: Subjects
Bladder-carcinoma	9	15	24
Germ Cell	7	5	12
Head & Neck	21	14	35
Thoracic	8	14	22
Left Lung	0	1	1
PTA hearing test values in both ears - sum of 6kHz and 8kHz
Pure tone audiogram (PTA) test at frequencies of 6 and 8kHz in both ears at baseline.
Units: kHz
arithmetic mean (standard deviation)	166.1 ( 71.25 )	161.6 ( 76.71 )	-

Subject analysis set title

ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

This population includes all patients that were randomised regardless of treatment.

Subject analysis set title

Per-protocol population

Subject analysis set type

Per protocol

Subject analysis set description

This population includes patients in the ITT population who have an IMP (aspirin or placebo) compliance of greater than to equal to 80% for each cycle of cisplatin chemotherapy. Also, the patient should not have any major protocol violations.

Subject analysis sets values	ITT population	Per-protocol population
Number of subjects	94	53
Age categorical
Units: Subjects
Adults (18-64 years)	61	36
From 65-84 years	33	17
85 years and over	0	0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	60 (52 to 66)	60 (54 to 66)
Gender categorical
Units: Subjects
Female
Male
Tumour group
Units: Subjects
Bladder-carcinoma
Germ Cell
Head & Neck
Thoracic
Left Lung
PTA hearing test values in both ears - sum of 6kHz and 8kHz
Pure tone audiogram (PTA) test at frequencies of 6 and 8kHz in both ears at baseline.
Units: kHz
arithmetic mean (standard deviation)	( )	( )

End points

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Reporting group title

Arm 1: Aspirin and Omeprazole

Reporting group description

Reporting group title

Arm 2: Placebo

Reporting group description

Subject analysis set title

ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

This population includes all patients that were randomised regardless of treatment.

Subject analysis set title

Per-protocol population

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Total post-treatment hearing loss (first post-chemotherapy PTA test)

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End point title

Total post-treatment hearing loss (first post-chemotherapy PTA test)

End point description

Total post treatment hearing loss = total post treatment hearing – total baseline hearing. Where, 1 Total baseline hearing is the sum of PTA measurements at 6kHz and 8kHz in both ears prior to their first cisplatin dose. 2 Total post treatment hearing is the sum of PTA measurements at 6kHz and 8kHz in both ears from the first PTA test after their last cisplatin dose, where the first PTA test is due 7 days after last cisplatin dose.

End point type

Primary

End point timeframe

Difference is calculated using the first post-chemotherapy PTA hearing test (scheduled to be 7 days (+/- 3) after last cisplatin dose) and the corresponding baseline value.

End point values	Arm 1: Aspirin and Omeprazole	Arm 2: Placebo
Number of subjects analysed	39 ^[1]	40 ^[2]
Units: kHz	39	40

Attachments

Assessment of normality

Notes
[1] - The number of patients in arm 1 with both a baseline and one post-chemo PTA measurements.
[2] - The number of patients in arm 1 with both a baseline and one post-chemo PTA measurements.

Analysis of covariance

Statistical analysis description

ANCOVA model: Total post treatment hearing post-chemotherapy (the sum of PTA measurements at 6kHz and 8kHz in both ears at the first time point after their last cisplatin dose) = intercept + treatment arm + total hearing at baseline (the sum of PTA measurements at 6kHz and 8kHz in both ears prior to their first cisplatin dose) + randomisation stratification factor dose of cisplatin.

Comparison groups

Arm 2: Placebo v Arm 1: Aspirin and Omeprazole

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.233 ^[3]

Method

ANCOVA

Parameter type

LSM difference

Point estimate

9.38

Confidence interval

level

60%

sides

2-sided

lower limit

-1.45

upper limit

20.22

Notes
[3] - One-sided p-value

Primary: Total post-treatment hearing loss (first post-chemotherapy PTA test)

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End point title

Total post-treatment hearing loss (first post-chemotherapy PTA test) ^[4]

End point description

End point type

Primary

End point timeframe

Difference is calculated using the first post-chemotherapy PTA hearing test (scheduled to be 7 days (+/- 3) after last cisplatin dose) and the corresponding baseline value.

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses have been specified for this primary end point. The Primary analysis was the ANCOVA model with post treatment hearing as the outcome, adjusted for the baseline hearing measure.

End point values	Arm 1: Aspirin and Omeprazole	Arm 2: Placebo
Number of subjects analysed	39 ^[5]	40 ^[6]
Units: kHz
arithmetic mean (standard deviation)	49 ( 61.41 )	36 ( 50.85 )

Notes
[5] - Number in arm 1 with both PTA measurements - baseline and one post-chemo
[6] - Number in arm 1 with both PTA measurements - baseline and one post-chemo

No statistical analyses for this end point

Secondary: Total post-treatment hearing loss (second post-chemotherapy PTA test)

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End point title

Total post-treatment hearing loss (second post-chemotherapy PTA test)

End point description

Total post treatment hearing loss = total post treatment hearing – total baseline hearing. Where, 1 Total baseline hearing is the sum of PTA measurements at 6kHz and 8kHz in both ears prior to their first cisplatin dose. 2 Total post treatment hearing is the sum of PTA measurements at 6kHz and 8kHz in both ears from the secondPTA test after their last cisplatin dose, where the first PTA test is due 90 days after last cisplatin dose.

End point type

Secondary

End point timeframe

Difference is calculated using the first post-chemotherapy PTA hearing test (scheduled to be 90 days (+/- 7 days) after last cisplatin dose) and the corresponding baseline value.

End point values	Arm 1: Aspirin and Omeprazole	Arm 2: Placebo
Number of subjects analysed	27 ^[7]	30 ^[8]
Units: kHz	27	30

Notes
[7] - Number in arm 1 with both PTA measures - at baseline and second post-chemo
[8] - Number in arm 2 with both PTA measurements - baseline and second post-chemo

Analysis of covariance

Statistical analysis description

ANCOVA model: Total post treatment hearing post-chemotherapy (the sum of PTA measurements at 6kHz and 8kHz in both ears at the second time point after their last cisplatin dose) = intercept + treatment arm + total hearing at baseline (the sum of PTA measurements at 6kHz and 8kHz in both ears prior to their first cisplatin dose) + randomisation stratification factor dose of cisplatin.

Comparison groups

Arm 1: Aspirin and Omeprazole v Arm 2: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.044 ^[9]

Method

ANCOVA

Parameter type

LSM difference

Point estimate

24.18

Confidence interval

level

60%

sides

2-sided

lower limit

12.36

upper limit

36.01

Notes
[9] - One-sided p-value

Secondary: Total post-treatment hearing loss (second post-chemotherapy PTA test)

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End point title

Total post-treatment hearing loss (second post-chemotherapy PTA test)

End point description

Total post treatment hearing loss = total post treatment hearing – total baseline hearing. Where, 1 Total baseline hearing is the sum of PTA measurements at 6kHz and 8kHz in both ears prior to their first cisplatin dose. 2 Total post treatment hearing is the sum of PTA measurements at 6kHz and 8kHz in both ears from the second PTA test after their last cisplatin dose, where the second PTA test is due 90 days after last cisplatin dose.

End point type

Secondary

End point timeframe

Difference is calculated using the second post-chemotherapy PTA hearing test (scheduled to be 90 days (+/- 7) after last cisplatin dose) and the corresponding baseline value.

End point values	Arm 1: Aspirin and Omeprazole	Arm 2: Placebo
Number of subjects analysed	27 ^[10]	30 ^[11]
Units: kHz
arithmetic mean (standard deviation)	63.9 ( 52.59 )	37.3 ( 49.94 )

Notes
[10] - Number in arm 1 with the two PTA tests - one at baseline and second after chemo
[11] - Number in arm 2 with the two PTA tests - one at baseline and second after chemo

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

The reporting requirement for SAEs affecting patients applies for all events occurring from date of informed consent up to 4 weeks after the last administration of trial drugs.

Adverse event reporting additional description

At each contact with the patient, the investigator sought information on adverse events by specific questioning and, as appropriate, by examination. The clinical course of each event should be followed until resolution, stabilisation, or until it has been determined that the study treatment or participation is not the cause.

Assessment type

Systematic

Dictionary name

CTCAE

Dictionary version

Reporting group title

Arm 1: Aspirin group

Reporting group description

Reporting group title

Arm 2: Placebo group

Reporting group description

Serious adverse events	Arm 1: Aspirin group	Arm 2: Placebo group
Total subjects affected by serious adverse events
subjects affected / exposed	20 / 45 (44.44%)	19 / 49 (38.78%)
number of deaths (all causes)	1	2
number of deaths resulting from adverse events	0	0
Investigations
Neutrophil count decreased
subjects affected / exposed	0 / 45 (0.00%)	2 / 49 (4.08%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Weight loss
subjects affected / exposed	1 / 45 (2.22%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 45 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thromboembolic event
subjects affected / exposed	0 / 45 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Stroke
subjects affected / exposed	0 / 45 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Blood and lymphatic system disorders, other
subjects affected / exposed	1 / 45 (2.22%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Febrile neutropenia
subjects affected / exposed	3 / 45 (6.67%)	4 / 49 (8.16%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Fever
subjects affected / exposed	2 / 45 (4.44%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 45 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 45 (2.22%)	0 / 49 (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 / 45 (2.22%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 45 (0.00%)	2 / 49 (4.08%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	2 / 45 (4.44%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mucositis oral
subjects affected / exposed	2 / 45 (4.44%)	5 / 49 (10.20%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 45 (2.22%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oral pain
subjects affected / exposed	0 / 45 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 45 (4.44%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Urinary retention
subjects affected / exposed	1 / 45 (2.22%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Lung infection
subjects affected / exposed	0 / 45 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 45 (2.22%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 45 (2.22%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 45 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	2 / 45 (4.44%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Arm 1: Aspirin group	Arm 2: Placebo group
Total subjects affected by non serious adverse events
subjects affected / exposed	40 / 45 (88.89%)	47 / 49 (95.92%)
Vascular disorders
Thromboembolic event
subjects affected / exposed	1 / 45 (2.22%)	6 / 49 (12.24%)
occurrences all number	1	7
General disorders and administration site conditions
Fatigue
subjects affected / exposed	14 / 45 (31.11%)	18 / 49 (36.73%)
occurrences all number	21	44
Fever
subjects affected / exposed	3 / 45 (6.67%)	3 / 49 (6.12%)
occurrences all number	3	4
Pain
subjects affected / exposed	4 / 45 (8.89%)	5 / 49 (10.20%)
occurrences all number	5	5
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 45 (8.89%)	6 / 49 (12.24%)
occurrences all number	5	7
Dyspnoea
subjects affected / exposed	2 / 45 (4.44%)	5 / 49 (10.20%)
occurrences all number	2	5
Epistaxis
subjects affected / exposed	3 / 45 (6.67%)	2 / 49 (4.08%)
occurrences all number	5	2
Respiratory, thoracic and mediastinal disorders, other
subjects affected / exposed	4 / 45 (8.89%)	3 / 49 (6.12%)
occurrences all number	4	3
Psychiatric disorders
Anxiety
subjects affected / exposed	3 / 45 (6.67%)	1 / 49 (2.04%)
occurrences all number	3	1
Insomnia
subjects affected / exposed	3 / 45 (6.67%)	4 / 49 (8.16%)
occurrences all number	3	5
Investigations
Neutrophil count decreased
subjects affected / exposed	8 / 45 (17.78%)	8 / 49 (16.33%)
occurrences all number	12	14
Platelet count decreased
subjects affected / exposed	1 / 45 (2.22%)	4 / 49 (8.16%)
occurrences all number	4	4
Weight loss
subjects affected / exposed	2 / 45 (4.44%)	4 / 49 (8.16%)
occurrences all number	2	4
White blood cell decreased
subjects affected / exposed	3 / 45 (6.67%)	5 / 49 (10.20%)
occurrences all number	6	9
Injury, poisoning and procedural complications
Dermatitis radiation
subjects affected / exposed	3 / 45 (6.67%)	0 / 49 (0.00%)
occurrences all number	3	0
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 45 (2.22%)	6 / 49 (12.24%)
occurrences all number	1	8
Dysgeusia
subjects affected / exposed	4 / 45 (8.89%)	7 / 49 (14.29%)
occurrences all number	8	8
Headache
subjects affected / exposed	4 / 45 (8.89%)	4 / 49 (8.16%)
occurrences all number	4	8
Lethargy
subjects affected / exposed	11 / 45 (24.44%)	15 / 49 (30.61%)
occurrences all number	15	28
Paresthesia
subjects affected / exposed	3 / 45 (6.67%)	4 / 49 (8.16%)
occurrences all number	3	4
Peripheral motor neuropathy
subjects affected / exposed	4 / 45 (8.89%)	8 / 49 (16.33%)
occurrences all number	5	9
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	7 / 45 (15.56%)	4 / 49 (8.16%)
occurrences all number	15	11
Ear and labyrinth disorders
Hearing impaired
subjects affected / exposed	2 / 45 (4.44%)	3 / 49 (6.12%)
occurrences all number	2	7
Tinnitus
subjects affected / exposed	12 / 45 (26.67%)	20 / 49 (40.82%)
occurrences all number	24	32
Vertigo
subjects affected / exposed	5 / 45 (11.11%)	2 / 49 (4.08%)
occurrences all number	5	2
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 45 (2.22%)	4 / 49 (8.16%)
occurrences all number	1	6
Constipation
subjects affected / exposed	16 / 45 (35.56%)	19 / 49 (38.78%)
occurrences all number	24	30
Diarrhoea
subjects affected / exposed	10 / 45 (22.22%)	10 / 49 (20.41%)
occurrences all number	12	14
Dry mouth
subjects affected / exposed	4 / 45 (8.89%)	3 / 49 (6.12%)
occurrences all number	5	3
Dyspepsia
subjects affected / exposed	4 / 45 (8.89%)	12 / 49 (24.49%)
occurrences all number	4	18
Mucositis oral
subjects affected / exposed	14 / 45 (31.11%)	12 / 49 (24.49%)
occurrences all number	21	13
Nausea
subjects affected / exposed	22 / 45 (48.89%)	28 / 49 (57.14%)
occurrences all number	34	55
Oral pain
subjects affected / exposed	8 / 45 (17.78%)	4 / 49 (8.16%)
occurrences all number	12	6
Vomiting
subjects affected / exposed	11 / 45 (24.44%)	16 / 49 (32.65%)
occurrences all number	13	20
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	5 / 45 (11.11%)	11 / 49 (22.45%)
occurrences all number	5	13
Skin and subcutaneous tissue disorders, other
subjects affected / exposed	4 / 45 (8.89%)	7 / 49 (14.29%)
occurrences all number	6	8
Musculoskeletal and connective tissue disorders
Chest wall pain
subjects affected / exposed	3 / 45 (6.67%)	1 / 49 (2.04%)
occurrences all number	4	1
Infections and infestations
Mucosal infection
subjects affected / exposed	5 / 45 (11.11%)	3 / 49 (6.12%)
occurrences all number	6	6
Urinary tract infection
subjects affected / exposed	5 / 45 (11.11%)	3 / 49 (6.12%)
occurrences all number	6	3
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	7 / 45 (15.56%)	17 / 49 (34.69%)
occurrences all number	9	25
Dehydration
subjects affected / exposed	4 / 45 (8.89%)	3 / 49 (6.12%)
occurrences all number	4	3
Hypoalbuminemia
subjects affected / exposed	3 / 45 (6.67%)	4 / 49 (8.16%)
occurrences all number	5	5

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Were there any global substantial amendments to the protocol? Yes

25 Jun 2013

Protocol updated (v6) • Clarification to exclusion criteria number 2 regarding Head & Neck patients being treated with Radiotherapy, • Change to exclusion criteria number 10 to read ‘Patients with symptomatically overt hearing loss which the Principal Investigator (PI) considers should exclude the use of cisplatin’. • Change to secondary trial endpoint number 6 (PTA test frequencies) to remove tests at 10 and 12kHz as equipment cannot be calibrated at these frequencies. • GFR can now be calculated within 2 weeks prior to starting chemotherapy. • Added wording 'if the patient is too unwell to travel for the hearing assessment at 4-7 days post final Cisplatin treatment, they should be re-assessed on a weekly basis by telephone until they are well enough to re-schedule the appointment' Addition of information regarding NG or PEG tube. Information on wash out prior to randomisation. Appendix II, additional information on Adverse Events for Hearing, Gastrointestinal and Renal disorders. Addition of one extra column in the schedule of observations to clarify extra pre-treatment visit

24 Sep 2013

Protocol updated (v7) • Change in exclusion criteria from previous transient ischaemic attacks or cerebral vascular disease to previous haemorrhagic stroke • Removal of exclusion criteria severe ischaemic heart disease or myocardial infarction • Addition information on omeprazole - 'We are co-prescribing omeprazole to reduce both of these problems. Omeprazole is a proton pump inhibitor used for the treatment of gastric ulcers, duodenal ulcers, gastro-oesophageal reflux disease, acid-related dyspepsia, Zollinger-Ellison syndrome and for the eradication of Helicobacter pylori. It is also used to treat or prevent ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDs) and to reduce gastric acid before surgery. We do not expect Omeprazole to affect trial outcome.'

09 Jan 2014

Protocol updated (v8) • The wording related to the OAE testing has been made more generic to cover the opening of additional sites to the trial. • The OAE test cannot be performed at all hospital trusts participating in this trial. In some cases there may be the option for patients to travel outside of their region to have both their PTA and OAE tests at an alternative location. Patients who are not able to travel, or do not have the OAE testing service available to them, are still able to participate in the trial and will therefore only have the PTA assessment. • Changing the packaging of the IMP in two ways. • For all new shipments the bottles containing aspirin/placebo and omeprazole/placebo will be provided directly to the patient and not within a carton or outer pack. • The IMP labels have been updated to include patient pack number as this was previously on the outer carton label which will not be supplied with future shipments to existing and new sites.

03 Jun 2015

Protocol updated (v9) • Increase in number of patients to be recruited has required amendments to Section 3 - Trial Design; Section 8.1 - Sample size. • Amendment to the exclusion criteria – clarification regarding oral-anticoagulants • Update to section 5.3.2 – Chemotherapy delay/discontinuation • Update to section 7.1 Definition of End of Trial

28 Oct 2015

Protocol updated (v10) The main purpose of this amendment is a change to the primary endpoint definition in the protocol. This change has been necessary as many patients are too ill from the side effects of the cisplatin chemotherapy to return for their second PTA hearing test assessment within the protocol defined window. The following was therefore recommended by the IDMC and agreed by the TMG committee:- • The first available PTA assessment will be used for the primary endpoint (regardless of time frame). • Wherever possible PTA assessments will be scheduled within the protocol defined time window unless the patient is too ill to attend in which case a PTA assessment will be scheduled as soon as the patient feels well enough.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
02 Feb 2015	Drug supply issue: A decision was made to suspend recruitment, and all sites were notified of this on 2-Feb-2015. Drug supply issue resolved: Sites were reopened to recruitment on 12 Feb 2015	12 Feb 2015

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

None

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Clinical trials

Clinical Trial Results:
COAST - Cisplatin Ototoxicity attenuated by Aspirin Trial A randomised, Phase II, double-blind, placebo-controlled, two arm Trial to establish whether Aspirin can reduce hearing loss/ototoxicity for patients receiving Cisplatin chemotherapy.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Total post-treatment hearing loss (first post-chemotherapy PTA test)

Primary: Total post-treatment hearing loss (first post-chemotherapy PTA test)

Primary: Total post-treatment hearing loss (first post-chemotherapy PTA test)

Primary: Total post-treatment hearing loss (first post-chemotherapy PTA test)

Secondary: Total post-treatment hearing loss (second post-chemotherapy PTA test)

Secondary: Total post-treatment hearing loss (second post-chemotherapy PTA test)

Secondary: Total post-treatment hearing loss (second post-chemotherapy PTA test)

Secondary: Total post-treatment hearing loss (second post-chemotherapy PTA test)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Outside EU/EEA

Clinical trials

Clinical Trial Results: COAST - Cisplatin Ototoxicity attenuated by Aspirin Trial A randomised, Phase II, double-blind, placebo-controlled, two arm Trial to establish whether Aspirin can reduce hearing loss/ototoxicity for patients receiving Cisplatin chemotherapy.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Total post-treatment hearing loss (first post-chemotherapy PTA test)

Primary: Total post-treatment hearing loss (first post-chemotherapy PTA test)

Primary: Total post-treatment hearing loss (first post-chemotherapy PTA test)

Primary: Total post-treatment hearing loss (first post-chemotherapy PTA test)

Secondary: Total post-treatment hearing loss (second post-chemotherapy PTA test)

Secondary: Total post-treatment hearing loss (second post-chemotherapy PTA test)

Secondary: Total post-treatment hearing loss (second post-chemotherapy PTA test)

Secondary: Total post-treatment hearing loss (second post-chemotherapy PTA test)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
COAST - Cisplatin Ototoxicity attenuated by Aspirin Trial A randomised, Phase II, double-blind, placebo-controlled, two arm Trial to establish whether Aspirin can reduce hearing loss/ototoxicity for patients receiving Cisplatin chemotherapy.