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    Clinical Trial Results:
    Investigating Aspirin and Ticagrelor for the prevention of tumour cell-induced platelet aggregation

    Summary
    EudraCT number
    		 2014-004049-29
    Trial protocol
    		 GB  
    Global end of trial date
    29 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2020
    First version publication date
    14 Oct 2020
    Other versions
    Summary report(s)
    		 Published manuscript

    Trial information

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    Trial identification
    Sponsor protocol code
    0456
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 EudraCT: 2014-004049-29
    Sponsors
    Sponsor organisation name
    University of Leicester
    Sponsor organisation address
    Research Governance Office, Academic Department, Leicester General Hospital, Leicester, United Kingdom, LE5 4PW
    Public contact
    Dr D Adlam, University of Leicester, da134@le.ac.uk
    Scientific contact
    Dr D Adlam, University of Leicester, da134@le.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does Ticagrelor effect platelets in ways that are likely to reduce the spread of cancer in the blood of people taking Ticagrelor (i.e. in vivo), and does Ticagrelor seem to have more effect than Aspirin.
    Protection of trial subjects
    Patients and healthy volunteers recruited to the cross-over study were assessed by a study clinician at screening, on commencement of treatment 1 (day 1) and a 2 week intervals until the end of the study (day 54-60). Adverse events were reviewed at each visit. Patients received a telephone follow-up 30-days following the final dose of study drug to check on any additional potentially relevant adverse events. All adverse event information was reviewed by the independent Data and Safety Monitoring Committee. Patients and healthy volunteers recruited to the blood sampling study did not require follow-up.
    Background therapy
    		 Patients were excluded from the cross-over study if, at the time of screening, they were taking antiplatelet therapy, anticoagulation, non-steroidal anti-inflammatory drugs, tamoxifen, cytotoxic chemotherapy, more than 3 lines of chemotherapy or were using strong CYP3A4 inhibitors. Patients were also excluded if they had a history of group, gastrointestinal bleeding or peptic ulceration in the last year. All other prescribed medications were permissible in recruited patients.
    Evidence for comparator
    		 A range of established methods of the assessment of platelet function were used for comparison including: - Platelet spontaneous aggregation - Platelet aggregation in response to agonists - Expression of platelet activation markers on platelets and extracellular vesicles - Quantity of circulating free DNA The affects of drug treatment were then assessed.
    Actual start date of recruitment
    02 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 113
    Worldwide total number of subjects
    113
    EEA total number of subjects
    113
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    74
    From 65 to 84 years
    37
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients and healthy volunteers were recruited from patients attending the University Hospitals Leicester and Healthy Volunteers responding to open advertisement and attending the University of Leicester. Patients and healthy volunteers were recruited between November 2015 and July 2018.

    Pre-assignment
    Screening details
    		 For phase 1 (blood sampling without drug treatment) 62 cancer patients and 17 healthy volunteers. 4 cancer patients were excluded. 1 failed inclusion criteria, 2 declined, 1 unable to bleed. Phase 2 (cross-over) Healthy 24 consented, 1 failed screening (past cancer), 1 withdrew. 22 entered. Cancer 18 consented 2 failed screening bloods

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This study was not designed to assess clinical endpoints but was an exploratory study to investigate in vitro effects. this study was open label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 2 Cross-over treatment study
    Arm description
    		 Note Phase 1 patients were not drug treated and therefore are not include here. Phase 2. Study patients and healthy volunteers were randomly assigned to one of 2 cross-over designs: 1. Ticagrelor 2weeks, washout 2 weeks, aspirin 2 weeks, dual aspirin and ticagrelor 2 weeks 2. Aspirin 2 weeks, washout 2 weeks, ticagrelor 2 weeks, dual aspirin and ticagrelor 2 weesk
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ticagrelor
    Investigational medicinal product code
    Other name
    Brilique
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ticagrelor 180mg loading dose then 90mg twice daily for duration of therapy as per cross-over design above.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Aspirin 300mg loading dose then 75 mg daily for duration of treatment in accordance with cross-over design above.

    Arm title
    		 Phase 1
    Arm description
    		 Blood sampling study. No study drug administration
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Phase 2 Cross-over treatment study Phase 1
    Started
    38
    75
    Completed
    31
    74
    Not completed
    7
    1
         Physician decision
    4
    1
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 This refers to Phase 2 the cross-over drug study. This does not include patients in Phase 1 the blood sampling phase.

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 113 113
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    10 Breast Cancer Patients mean age 57.1 range 56-73 6 Colorectal Cancer Patients mean age 59.8 range 52-74 22 Healthy volunteers mean age 43.4 range 25-60
    Units: years
        arithmetic mean (full range (min-max))
    		 53 (25 to 74) -
    Gender categorical
    Units: Subjects
        Female
    		 68 68
        Male
    		 45 45
    Subject analysis sets

    Subject analysis set title
    Healthy Volunteers
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy volunteers in the cross-over study

    Subject analysis set title
    Metastatic Breast Cancer patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Breast Cancer Patients included in the cross-over study

    Subject analysis set title
    Metastatic Colorectal Cancer Patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Colorectal Cancer Patients included in the cross-over study

    Subject analysis set title
    Phase 1 (blood study)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Phase 1 patients were recruited for blood analysis only. They were not included in the drug study. There were 58 cancer patients and 17 Healthy Volunteers included in this element.

    Subject analysis sets values
    		 Healthy Volunteers Metastatic Breast Cancer patients Metastatic Colorectal Cancer Patients Phase 1 (blood study)
    Number of subjects
    22
    10
    6
    75
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    10 Breast Cancer Patients mean age 57.1 range 56-73 6 Colorectal Cancer Patients mean age 59.8 range 52-74 22 Healthy volunteers mean age 43.4 range 25-60
    Units: years
        arithmetic mean (full range (min-max))
    43.4 (25 to 60)
    57.1 (56 to 73)
    59.8 (52 to 74)
    Gender categorical
    Units: Subjects
        Female
    16
    10
    3
    39
        Male
    6
    0
    3
    36

    End points

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    End points reporting groups
    Reporting group title
    Phase 2 Cross-over treatment study
    Reporting group description
    		 Note Phase 1 patients were not drug treated and therefore are not include here. Phase 2. Study patients and healthy volunteers were randomly assigned to one of 2 cross-over designs: 1. Ticagrelor 2weeks, washout 2 weeks, aspirin 2 weeks, dual aspirin and ticagrelor 2 weeks 2. Aspirin 2 weeks, washout 2 weeks, ticagrelor 2 weeks, dual aspirin and ticagrelor 2 weesk

    Reporting group title
    Phase 1
    Reporting group description
    		 Blood sampling study. No study drug administration

    Subject analysis set title
    Healthy Volunteers
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Healthy volunteers in the cross-over study

    Subject analysis set title
    Metastatic Breast Cancer patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Breast Cancer Patients included in the cross-over study

    Subject analysis set title
    Metastatic Colorectal Cancer Patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Colorectal Cancer Patients included in the cross-over study

    Subject analysis set title
    Phase 1 (blood study)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Phase 1 patients were recruited for blood analysis only. They were not included in the drug study. There were 58 cancer patients and 17 Healthy Volunteers included in this element.

    Primary: Spontaneous Aggregation Comparison

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    End point title
    		 Spontaneous Aggregation Comparison
    End point description
    Measured on Light Transmission Aggregometry There was a significantly higher amount of spontaneous aggregation at baseline in colorectal cancer patient’s platelets (14.8±6.5%), compared to healthy donor platelets (8.11±4.6%) with a p-value of 0.007. Colorectal cancer platelets had a significantly higher amount of spontaneous aggregation at baseline compared to breast cancer platelets (p-value=0.02).
    End point type
    Primary
    End point timeframe
    All crossover participant samples were compared at each treatment point
    End point values
    		 Healthy Volunteers Metastatic Breast Cancer patients Metastatic Colorectal Cancer Patients
    Number of subjects analysed
    18
    10
    6
    Units: Percentage
    8
    9
    15
    Attachments
    		 Untitled (Filename: SPA cross.jpg)
    Statistical analysis title
    		 Spontaneous Aggregation Comparison
    Comparison groups
    Metastatic Breast Cancer patients v Healthy Volunteers v Metastatic Colorectal Cancer Patients
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 t-test, 1-sided
    Confidence interval

    Other pre-specified: Spontaneous Aggregation

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    End point title
    		 Spontaneous Aggregation [1]
    End point description
    Spontaneous platelet Aggregation as measured by light transmission aggregometry The graph shows that there was a significantly increased amount of spontaneous aggregation in the cancer population (9±7.34%) when compared to healthy individuals (4±3.45%). Compared using T-Test Standard Deviations shown
    End point type
    Other pre-specified
    End point timeframe
    Spontaneous platelet Aggregation measured at initial blood sampling of Phase 1
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The trial is designed to have separate data in Phase 1 of the trial (observational data and in vitro data) to Phase 2 which is interventional data
    End point values
    		 Phase 1
    Number of subjects analysed
    59
    Units: Percentage
    9
    Attachments
    		 Spontaneous Aggregation Healthy vs Cancer
    No statistical analyses for this end point

    Other pre-specified: P-Selectin Expression in Phase 1

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    End point title
    		 P-Selectin Expression in Phase 1 [2]
    End point description
    Samples were taken from 15 cancer patients who were not on any medications known to affect platelet function or the coagulation cascade. The platelet activation was measured by flow cytometric analysis of platelet markers. The blood samples were prepared and analysed for P-selectin expression. Controls from healthy volunteers were also prepared. Aspirin, Ticagrelor monotherapies and dual therapies were added in vitro. An unpaired T-Test showed that cancer patients had a significantly higher baseline resting expression of P-selectin compared to healthy volunteers, with a p-value of 0.04
    End point type
    Other pre-specified
    End point timeframe
    P-selectin measured on initial samples from Phase 1 volunteers
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The trial is designed to have separate data in Phase 1 of the trial (observational data and in vitro data) to Phase 2 which is interventional data
    End point values
    		 Phase 1
    Number of subjects analysed
    20
    Units: Percentage
    9
    Attachments
    		 P-Selectin in unstimulated platelets
    No statistical analyses for this end point

    Other pre-specified: Fibrinogen Binding in Phase 1

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    End point title
    		 Fibrinogen Binding in Phase 1 [3]
    End point description
    Samples were taken from 13 cancer patients who were not on any medications known to affect platelet function or the coagulation cascade. The platelet activation was measured by flow cytometric analysis of platelet markers. The blood samples were prepared and analysed for Fibrinogen Binding. Controls from healthy volunteers were also prepared. Aspirin, Ticagrelor monotherapies and dual therapies were added in vitro. There was no significant difference at rest between the amount of fibrinogen bound to cancer patient or healthy donor platelets
    End point type
    Other pre-specified
    End point timeframe
    Fibrinogen Binding was measured on initial samples from Phase 1 volunteers
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The trial is designed to have separate data in Phase 1 of the trial (observational data and in vitro data) to Phase 2 which is interventional data
    End point values
    		 Phase 1
    Number of subjects analysed
    16
    Units: Percentage
    3
    Attachments
    		 Fibrinogen Binding in unstimulated platelets
    No statistical analyses for this end point

    Other pre-specified: Healthy Volunteer Spontaneous Platelet Aggregation

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    End point title
    		 Healthy Volunteer Spontaneous Platelet Aggregation
    End point description
    Measured by Light Transmission Aggregometry. The final aggregation percentage for the healthy volunteers after each antiplatelet treatment were combined to obtain the mean final aggregation in healthy individuals taking that treatment, regardless of the order it was taken in. See graph The mean final spontaneous aggregation at baseline was 8.1±4.2%, and there was no significant difference on two-tailed paired T-Test between this and the 9.2±3.2% aggregation after the washout period. This result shows that in the evaluation of spontaneous aggregation, the washout period was sufficient regardless of randomisation to remove the effect of the first drug given, to return the spontaneous aggregation levels to within that of the baseline level. This is important because if the was
    End point type
    Other pre-specified
    End point timeframe
    Spontaneous aggregation of platelets from healthy donors was measured over 30 minutes
    End point values
    		 Healthy Volunteers
    Number of subjects analysed
    18
    Units: Percentage
    8
    Attachments
    		 Healthy Volunteer Spontaneous Aggregation
    No statistical analyses for this end point

    Other pre-specified: Annexin V Binding Healthy Volunteers

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    End point title
    		 Annexin V Binding Healthy Volunteers
    End point description
    Assessed at rest and in response to CRP-XL stimulation, and results were obtained via flow cytometry There was no difference between the baseline and washout values at rest. There appeared to be a trend to reduced Annexin-V binding with dual therapy, and this supports the in vitro work that our group has completed. In activated platelets stimulated with CRP-XL, there was a trend suggesting that with Ticagrelor and dual antiplatelet therapy there was less Annexin-V binding. However, on two-tailed paired T-tests compared to baseline, there was no significant difference.
    End point type
    Other pre-specified
    End point timeframe
    Annexin-V binding to platelets was assessed at each treatment point
    End point values
    		 Healthy Volunteers
    Number of subjects analysed
    18
    Units: Percentage
    3
    Attachments
    		 Annexin V Binding in unstimulated and stimulated
    No statistical analyses for this end point

    Other pre-specified: P-Selectin Expression in Healthy Volunteers

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    End point title
    		 P-Selectin Expression in Healthy Volunteers
    End point description
    Measured by flow cytometry at rest and on activation with two different concentrations of ADP. No difference between baseline and washout values. In unstimulated resting platelets, there was no statistically significant difference of platelet P-selectin expression between the treatment groups compared to the baseline. There was a significant reduction with Ticagrelor compared to baseline P-selectin expression level when platelets were stimulated by ADP. When dual antiplatelet therapy was taken, P-selectin expression was significantly reduced compared to baseline when stimulated by ADP.
    End point type
    Other pre-specified
    End point timeframe
    P-selectin was measured as an activation marker by flow cytometry on the healthy samples at each treatment point
    End point values
    		 Healthy Volunteers
    Number of subjects analysed
    18
    Units: Percentage
    15
    No statistical analyses for this end point

    Other pre-specified: Fibrinogen Binding in Healthy Volunteers

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    End point title
    		 Fibrinogen Binding in Healthy Volunteers
    End point description
    Measured by flow cytometry at rest and on activation with two different concentrations of ADP. Fibrinogen binding appears to have a high variability at rest. There was a significant reduction in the amount of fibrinogen binding with Ticagrelor treatment compared to baseline, with a p-value of 0.008. When the platelets were activated, Ticagrelor treatment resulted in a significant reduction of fibrinogen binding at both ADP concentrations (p-values are <0.0001). Dual antiplatelet therapy showed a significant reduction in fibrinogen binding on stimulation with ADP. (p-values are <0.0001)
    End point type
    Other pre-specified
    End point timeframe
    Fibrinogen binding was measured as an activation marker by flow cytometry on the healthy samples at each treatment point
    End point values
    		 Healthy Volunteers
    Number of subjects analysed
    18
    Units: Percentage
    32
    Attachments
    		 Fibrinogen Binding in Healthy during treatment
    No statistical analyses for this end point

    Other pre-specified: Spontaneous Aggregation in Breast Cancer

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    End point title
    		 Spontaneous Aggregation in Breast Cancer
    End point description
    Measured by Light Transmission Aggregometry. The final aggregation percentage for the patients after each antiplatelet treatment were combined to obtain the mean final aggregation in healthy individuals taking that treatment, regardless of the order it was taken in. See graph At baseline, platelets from breast cancer patients had 8.7±3.4% final aggregation. This significantly increased after two weeks of aspirin to 12.6±4.6%, when analysed with two-tailed paired T-tests. Ticagrelor and dual therapy had no significant overall effect in changing the amount of aggregation. However, some individual patients were found to have lower levels of aggregation after these treatments.
    End point type
    Other pre-specified
    End point timeframe
    Spontaneous aggregation of platelets from breast cancer patients was measured over 30 minutes
    End point values
    		 Metastatic Breast Cancer patients
    Number of subjects analysed
    10
    Units: Percentage
    9
    Attachments
    		 Spontaneous Aggregation in Breast Cancer Patients
    No statistical analyses for this end point

    Other pre-specified: Spontaneous Aggregation in Colorectal Cancer Patients

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    End point title
    		 Spontaneous Aggregation in Colorectal Cancer Patients
    End point description
    Measured by Light Transmission Aggregometry. The final aggregation percentage for the patients after each antiplatelet treatment were combined to obtain the mean final aggregation in healthy individuals taking that treatment, regardless of the order it was taken in. See graph The baseline final aggregation was varied with a mean of 14.8±6.5%. This was significantly reduced to 7.7±6.5% with Ticagrelor.
    End point type
    Other pre-specified
    End point timeframe
    Spontaneous aggregation of platelets from colorectal cancer patients was measured over 30 minutes
    End point values
    		 Metastatic Colorectal Cancer Patients
    Number of subjects analysed
    6
    Units: Percentage
    15
    Attachments
    		 Spontaneous Aggregation in Colorectal Cancer
    No statistical analyses for this end point

    Other pre-specified: Annexin V Binding in Breast Cancer Patients

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    End point title
    		 Annexin V Binding in Breast Cancer Patients
    End point description
    Assessed at rest and in response to CRP-XL stimulation, and results were obtained via flow cytometry No significant difference in the amount of Annexin-V binding found in unstimulated, resting platelets from breast cancer patients, when they are treated with different antiplatelets. When the platelets were activated with CRP-XL, there was no significant difference between baseline levels of Annexin-V binding compared to treated platelets. At washout, aspirin, Ticagrelor and dual therapy treatments, there was a significantly increased amount of Annexin-V binding when platelets were stimulated
    End point type
    Other pre-specified
    End point timeframe
    Annexin-V binding to platelets was assessed at each treatment point
    End point values
    		 Metastatic Breast Cancer patients
    Number of subjects analysed
    10
    Units: Percentage
    3
    Attachments
    		 Annexin V Binding in Breast Cancer
    No statistical analyses for this end point

    Other pre-specified: Annexin V Binding Colorectal Cancer

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    End point title
    		 Annexin V Binding Colorectal Cancer
    End point description
    Assessed at rest and in response to CRP-XL stimulation, and results were obtained via flow cytometry There was no significant difference in Annexin-V binding to platelets from colorectal cancer patients treated with antiplatelets when compared to baseline, and when the platelets were stimulated no effect of the treatment was seen. At baseline, washout, aspirin, and Ticagrelor treatments, there was a significantly increased amount of Annexin-V binding when platelets were stimulated with CRP-XL compared to unstimulated resting platelets.
    End point type
    Other pre-specified
    End point timeframe
    Annexin-V binding to platelets was assessed at each treatment point
    End point values
    		 Metastatic Colorectal Cancer Patients
    Number of subjects analysed
    6
    Units: Percentage
    3
    Attachments
    		 Annexin V Binding in Colorectal Cancer
    No statistical analyses for this end point

    Other pre-specified: P-Selectin Expression in Breast Cancer Patients

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    End point title
    		 P-Selectin Expression in Breast Cancer Patients
    End point description
    Measured by flow cytometry at rest and on activation with two different concentrations of ADP. P-selectin expression in resting, unstimulated breast cancer platelets did not significantly alter with antiplatelet treatment, and there was no statistically significant difference between all the treatment groups at baseline. When platelets from breast cancer patients were stimulated, Ticagrelor significantly reduced the expression of P-selectin (p-values 0.0011 and <0.0001). Dual therapy also reduced the expression of P-selectin significantly (p-values 0.0029 and <0.0001).
    End point type
    Other pre-specified
    End point timeframe
    P-selectin was measured as an activation marker by flow cytometry on cancer patient samples at each treatment point
    End point values
    		 Metastatic Breast Cancer patients
    Number of subjects analysed
    10
    Units: Percentage
    18
    Attachments
    		 P-Selectin Expression in Breast Cancer
    No statistical analyses for this end point

    Other pre-specified: P-Selectin Expression in Colorectal Patients

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    End point title
    		 P-Selectin Expression in Colorectal Patients
    End point description
    Measured by flow cytometry at rest and on activation with two different concentrations of ADP. No statistically significant difference between all the treatment groups at baseline when unstimulated resting platelets were examined. There was a significant reduction in the expression of P-selectin with Ticagrelor and dual therapy when platelets were stimulated with ADP.
    End point type
    Other pre-specified
    End point timeframe
    P-selectin was measured as an activation marker by flow cytometry on cancer patient samples at each treatment point
    End point values
    		 Metastatic Colorectal Cancer Patients
    Number of subjects analysed
    6
    Units: Percentage
    21
    Attachments
    		 P-Selectin Expression in Colorectal Cancer
    No statistical analyses for this end point

    Other pre-specified: Fibrinogen Binding in Breast Cancer Patients

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    End point title
    		 Fibrinogen Binding in Breast Cancer Patients
    End point description
    Measured by flow cytometry at rest and on activation with two different concentrations of ADP. There were high levels of fibrinogen binding found at baseline in unstimulated and resting platelets (49.5±24.7%), and there was no significant change in this level at the washout. Ticagrelor had a significant effect on paired T-test to reduce the resting unstimulated baseline fibrinogen binding to 26.7±15.6% (p-value 0.04). Dual therapy also significantly reduced fibrinogen binding to 31.4±19.5% from baseline (p-value 0.009).
    End point type
    Other pre-specified
    End point timeframe
    Fibrinogen binding was measured as an activation marker by flow cytometry on the patient samples at each treatment point
    End point values
    		 Metastatic Breast Cancer patients
    Number of subjects analysed
    10
    Units: Percentage
    50
    Attachments
    		 Fibrinogen Binding in Breast Cancer
    No statistical analyses for this end point

    Other pre-specified: Fibrinogen Binding in Colorectal Cancer

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    End point title
    		 Fibrinogen Binding in Colorectal Cancer
    End point description
    Measured by flow cytometry at rest and on activation with two different concentrations of ADP. There was a significant reduction in fibrinogen binding with Ticagrelor when platelets were stimulated with ADP 1x10-5M and 1x10-6M, and with dual therapy upon stimulation with the higher concentration of ADP.
    End point type
    Other pre-specified
    End point timeframe
    Fibrinogen binding was measured as an activation marker by flow cytometry on the patient samples at each treatment point
    End point values
    		 Metastatic Colorectal Cancer Patients
    Number of subjects analysed
    6
    Units: Percentage
    38
    Attachments
    		 Fibrinogen Binding in Colorectal Cancer
    No statistical analyses for this end point

    Other pre-specified: Annexin Binding Comparison

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    End point title
    		 Annexin Binding Comparison
    End point description
    Measure on flow cytometry When the cancer populations were compared to the healthy volunteers there was no significant difference in the amount of Annexin-V binding on resting, unstimulated platelets. When the platelets were activated, there was a significantly lower amount of Annexin-V binding in breast cancer platelets at baseline, washout and with Ticagrelor treatment compared to platelets from healthy donors. There was no significant difference in the amount of Annexin-V binding in colorectal cancer platelets
    End point type
    Other pre-specified
    End point timeframe
    All crossover participant samples were compared at each treatment point
    End point values
    		 Healthy Volunteers Metastatic Breast Cancer patients Metastatic Colorectal Cancer Patients
    Number of subjects analysed
    18
    10
    6
    Units: Percentage
    3
    3
    4
    Attachments
    		 Annexin in all populations unstimulated
    No statistical analyses for this end point

    Other pre-specified: P-Selectin Comparison

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    End point title
    		 P-Selectin Comparison
    End point description
    Measured on flow cytometry When resting, unstimulated platelets from healthy donors were compared to breast cancer platelets using unpaired T-Tests there was no significant difference in the amount of P-selectin expression. There was a significantly higher amount of P-selectin expression in colorectal cancer platelets compared to platelets from healthy donors at baseline. After dual therapy, the amount of P-selectin expression in breast cancer platelets was higher than platelets from healthy donors.
    End point type
    Other pre-specified
    End point timeframe
    All crossover participant samples were compared at each treatment point
    End point values
    		 Healthy Volunteers Metastatic Breast Cancer patients Metastatic Colorectal Cancer Patients
    Number of subjects analysed
    18
    10
    6
    Units: Percentage
    13
    18
    21
    Attachments
    		 P Selectin in all populations (Unstimulated)
    No statistical analyses for this end point

    Other pre-specified: Fibrinogen Binding Comparison

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    End point title
    		 Fibrinogen Binding Comparison
    End point description
    Measured by flow cytometry At baseline, breast cancer platelets that were resting and unstimulated had a significantly higher amount of fibrinogen bound, compared to platelets from healthy donors. Colorectal cancer patients had higher amounts of fibrinogen binding after aspirin treatment compared to platelets from healthy donors at rest. There were no significant differences in fibrinogen binding between platelets from healthy donors or cancer platelets with antiplatelet treatments upon ADP stimulation
    End point type
    Other pre-specified
    End point timeframe
    All crossover participant samples were compared at each treatment point
    End point values
    		 Healthy Volunteers Metastatic Breast Cancer patients Metastatic Colorectal Cancer Patients
    Number of subjects analysed
    18
    10
    6
    Units: Percentage
    30
    50
    38
    Attachments
    		 Fibrinogen Binding all populations (Unstimulated)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From recruitment to 30 days post final administered dose of study drug for phase 2 cross-over study patients only.
    Adverse event reporting additional description
    Adverse events were reviewed at in person by the study physician at 2-week intervals from first administered dose to completion of the cross-over study plus at a phone call made 30-days after the final dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Phase 2 Cross-over treatment study
    Reporting group description
    		 Note Phase 1 patients were not drug treated and therefore are not include here. Phase 2. Study patients and healthy volunteers were randomly assigned to one of 2 cross-over designs: 1. Ticagrelor 2weeks, washout 2 weeks, aspirin 2 weeks, dual aspirin and ticagrelor 2 weeks 2. Aspirin 2 weeks, washout 2 weeks, ticagrelor 2 weeks, dual aspirin and ticagrelor 2 weesk

    Reporting group title
    Phase 1
    Reporting group description
    		 Blood sampling study. No study drug administration

    Serious adverse events
    		 Phase 2 Cross-over treatment study Phase 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 74 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Renal and urinary disorders
    hydronephrosis
    Additional description: Patient found on a routine cancer staging scan to have hydronephrosis due to cancer progression. Not related to study medication.
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
    Additional description: This occurred during dual treatment with Ticagrelor and Aspirin and stopped immediately following cessation of study drugs with no sequelae.
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 74 (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
    Elective hip replacement
    Additional description: Occurred at the end of the follow-up period and had no relationship to the study
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 74 (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: 5%
    Non-serious adverse events
    		 Phase 2 Cross-over treatment study Phase 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 38 (65.79%)
    0 / 74 (0.00%)
    Cardiac disorders
    Palpitations
    Additional description: Patient reported episode of palpitations - not recorded on ECG
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Bruising
    Additional description: 19 Occurrences of bruising of the skin
         subjects affected / exposed
    11 / 38 (28.95%)
    0 / 74 (0.00%)
         occurrences all number
    19
    0
    Bleeding
    Additional description: Non major bleeding occurences reported
         subjects affected / exposed
    5 / 38 (13.16%)
    0 / 74 (0.00%)
         occurrences all number
    6
    0
    Ear and labyrinth disorders
    Dizziness
    Additional description: Episodes of intermittent dizziness described
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Minor abdominal discomfort described
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    Reflux
    Additional description: Non severe reflux
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 74 (0.00%)
         occurrences all number
    5
    0
    Dry mouth
    Additional description: One episode of dry mouth reported
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Nausea
    Additional description: One episode of nausea reported
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 74 (0.00%)
         occurrences all number
    5
    0
    Skin and subcutaneous tissue disorders
    Itchy Skin
    Additional description: Episode of itchy skin on the back, no rash
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Low mood
    Additional description: Patient reported an episode of low mood and feeling 'jittery'
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Oct 2016
    Addition of a healthy volunteer non interventional cohort to the study to allow comparison to the non-interventional cancer population in Phase 1. Addition of new posters and leaflets for all groups to advertise the study for the interventional phases 2 and 3.
    30 Oct 2017
    Personnel and contact detail changes made The ‘2 hour post dose’ blood test made an optional test. There have been numerous protocol deviations made when participants can not commit the time to have this blood test. This will not affect the scientific value, safety or integrity of the study. Additional recruitment strategy changes have been outlined in the protocol, with the sending out of leaflets to suitable Oncology patients. To reflect this, a covering invitation letter has been created and 2 leaflets summarising the study have been made.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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