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The Impact of Aspirin Dose Modification on the Innate Immune Response - Will Lower Dose Aspirin Therapy Reduce the Response to Endotoxin (WILLOW TREE)

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ClinicalTrials.gov Identifier: NCT03869268
Recruitment Status : Recruiting
First Posted : March 11, 2019
Last Update Posted : June 25, 2019
Sponsor:
Information provided by (Responsible Party):
Sheffield Teaching Hospitals NHS Foundation Trust

Brief Summary:

Heart attacks are usually caused by clots in a coronary artery, depriving the heart muscle of blood. Platelets are the main type of blood cell causing clots to form and physicians typically give a combination of two anti-platelet drugs, aspirin and ticagrelor, to treat this. However, aspirin and ticagrelor have effects not just on the platelets but also on the immune system. The investigator has been investigating the effects of different doses of aspirin in heart attack participants when taken alongside ticagrelor, and have found that a new, lower dose of aspirin given twice daily, rather than the usual standard dose once daily, reduces the tendency to bleed whilst on treatment. The investigators are hoping to study the wider effects of different aspirin doses, with and without ticagrelor, and have therefore developed this study.

During the two periods of the study, the investigator will give healthy volunteers a combinations of these medications and then stimulate their immune system, in order to see if the medications affect the immune response. The study will involve a period of medication for 10-14 days followed by a day in hospital stimulating the immune system with an injection into the bloodstream of a substance known as endotoxin, which causes temporary flu-like symptoms, followed by blood and urine tests. The investigator will then repeat the process, after a minimum of five weeks, taking a different medication combination and having a further endotoxin injection. The investigator will also keep in contact by telephone until 2 weeks after the end of the medication to ensure participant remain well.


Condition or disease Intervention/treatment Phase
Acute Coronary Syndrome Drug: Aspirin Drug: Ticagrelor Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This trial is a randomised controlled hybrid parallel-group and crossover study.
Masking: None (Open Label)
Masking Description: Masking is not applicable for this trial as this is an open label study.
Primary Purpose: Prevention
Official Title: The Impact of Aspirin Dose Modification on the Innate Immune Response - Will Lower Dose Aspirin Therapy Reduce the Response to Endotoxin
Actual Study Start Date : April 24, 2019
Estimated Primary Completion Date : August 31, 2020
Estimated Study Completion Date : April 30, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: No Drug

Patients will be randomised to receive no drug for the first medication period (10 days).

Patient will then be allocated to receive ticagrelor 90mg twice daily for the second medication period (10 days)

Drug: Ticagrelor
Ticagrelor will be allocated as a single loading dose of 180 mg (2 x 90 mg orodispersible tablets) and will be used in conjunction with aspirin depending on the arm of the trial the participant is randomised to.

Active Comparator: Ticagrelor 180 mg

Participants will be randomised to receive loading dose of ticagrelor 180 mg on the last day of the first medication period (10-14 days).

Participants will then be allocated to receive no aspirin but a loading dose of ticagrelor 180 mg on the last day of treatment for the second medication period (10-14 days).

Drug: Ticagrelor
Ticagrelor will be allocated as a single loading dose of 180 mg (2 x 90 mg orodispersible tablets) and will be used in conjunction with aspirin depending on the arm of the trial the participant is randomised to.

Active Comparator: Aspirin 20mg

Participants will be randomised to receive aspirin 20 mg twice daily for the first medication period (10 days).

Participants will then be allocated to receive aspirin 20 mg twice daily for the second medication period (10-14 days), plus a loading dose of ticagrelor 180 mg on the last day of the period.

Drug: Aspirin
Aspirin will be allocated in different doses and will be used in conjunction with ticagrelor depending on the arm of the trial the participant is randomised to. The different doses are as follows: 20 mg, 75 mg and 300 mg.

Drug: Ticagrelor
Ticagrelor will be allocated as a single loading dose of 180 mg (2 x 90 mg orodispersible tablets) and will be used in conjunction with aspirin depending on the arm of the trial the participant is randomised to.

Active Comparator: Aspirin 20 mg & Ticagrelor 180 mg

Participants will be randomised to receive aspirin 20 mg twice daily for the first medication period (10-14 days).

Participants will then be allocated to receive aspirin 20 mg twice daily for the second medication period (10-14 days), plus a loading dose of ticagrelor 180 mg on the last day of the period.

Drug: Aspirin
Aspirin will be allocated in different doses and will be used in conjunction with ticagrelor depending on the arm of the trial the participant is randomised to. The different doses are as follows: 20 mg, 75 mg and 300 mg.

Drug: Ticagrelor
Ticagrelor will be allocated as a single loading dose of 180 mg (2 x 90 mg orodispersible tablets) and will be used in conjunction with aspirin depending on the arm of the trial the participant is randomised to.

Active Comparator: Aspirin 75 mg

Participants will be randomised to receive aspirin 75 mg once daily for the first medication period (10-14 days).

Participants will then be allocated to receive aspirin 75 mg once daily for the second medication period (10-14 days), plus a loading dose of ticagrelor 180 mg on the last day of the period.

Drug: Aspirin
Aspirin will be allocated in different doses and will be used in conjunction with ticagrelor depending on the arm of the trial the participant is randomised to. The different doses are as follows: 20 mg, 75 mg and 300 mg.

Drug: Ticagrelor
Ticagrelor will be allocated as a single loading dose of 180 mg (2 x 90 mg orodispersible tablets) and will be used in conjunction with aspirin depending on the arm of the trial the participant is randomised to.

Active Comparator: Aspirin 75 mg & Ticagrelor 180 mg

Participants will be randomised to receive aspirin 75 mg once daily for the first medication period (10-14 days), plus a loading dose of ticagrelor 180 mg on the last day of the period.

Participants will then be allocated to receive aspirin 75 mg once daily for the second medication period (10-14 days).

Drug: Aspirin
Aspirin will be allocated in different doses and will be used in conjunction with ticagrelor depending on the arm of the trial the participant is randomised to. The different doses are as follows: 20 mg, 75 mg and 300 mg.

Drug: Ticagrelor
Ticagrelor will be allocated as a single loading dose of 180 mg (2 x 90 mg orodispersible tablets) and will be used in conjunction with aspirin depending on the arm of the trial the participant is randomised to.

Active Comparator: Aspirin 300 mg

Participants will be randomised to receive aspirin 300 mg once daily for the first medication period (10 days).

Participants will then be allocated to receive aspirin 300 mg once daily for the second medication period (10-14 days), plus a loading dose of ticagrelor 180 mg on the last day of the period.

Drug: Aspirin
Aspirin will be allocated in different doses and will be used in conjunction with ticagrelor depending on the arm of the trial the participant is randomised to. The different doses are as follows: 20 mg, 75 mg and 300 mg.

Drug: Ticagrelor
Ticagrelor will be allocated as a single loading dose of 180 mg (2 x 90 mg orodispersible tablets) and will be used in conjunction with aspirin depending on the arm of the trial the participant is randomised to.

Active Comparator: Aspirin 300 mg & Ticagrelor 180 mg

Participants will be randomised to receive aspirin 300 mg once daily for the first medication period (10-14 days) plus a loading dose of ticagrelor 180 mg on the last day of the period.

Participants will then be allocated to receive aspirin 300 mg once daily for the second medicaion period (10-14 days).

Drug: Aspirin
Aspirin will be allocated in different doses and will be used in conjunction with ticagrelor depending on the arm of the trial the participant is randomised to. The different doses are as follows: 20 mg, 75 mg and 300 mg.

Drug: Ticagrelor
Ticagrelor will be allocated as a single loading dose of 180 mg (2 x 90 mg orodispersible tablets) and will be used in conjunction with aspirin depending on the arm of the trial the participant is randomised to.




Primary Outcome Measures :
  1. Medication comparison [ Time Frame: Through study completion - 07/12/2020 (each participant assessed over ~24 weeks) ]
    plasma TNF-α at 2 hours post-injection of 2 ng/kg endotoxin compared between participants receiving no IMP, aspirin (Aspirin lysine) 20 mg BD, aspirin (Aspirin lysine) 75 mg OD and aspirin (Aspirin lysine) 300 mg OD.


Secondary Outcome Measures :
  1. Plasma Levels [ Time Frame: Through study completion - 07/12/2020 (each participant assessed over ~24 weeks) ]
    Plasma levels from 0 to 6 hours after endotoxin administration, of TNF-α

  2. Plasma TNF Levels [ Time Frame: Through study completion - 07/12/2020 (each participant assessed over ~24 weeks) ]
    Plasma levels from 0 to 6 hours after endotoxin administration, of plasma TNF-α

  3. Serum CRP Changes [ Time Frame: Through study completion - 07/12/2020 (each participant assessed over ~24 weeks) ]
    Change in serum CRP from 0 to 6 hours after endotoxin administration

  4. Leukocyte count [ Time Frame: Through study completion - 07/12/2020 (each participant assessed over ~24 weeks) ]
    Leukocyte count, from 0 to 6 hours after endotoxin administration

  5. Serum TXB2 [ Time Frame: Through study completion - 07/12/2020 (each participant assessed over ~24 weeks) ]
    Serum TXB2 from 0 to 6 hours after endotoxin administration



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male subjects, or female subjects not of childbearing potential (either surgically sterile or post-menopausal)]
  • Age between 18 and 65 years inclusive
  • Non-smokers
  • Body mass index (BMI) between 18 and 28 kg/m2 inclusive, with a body weight between 60-100 kg
  • In good health as determined by a medical history, physical examination, vital signs and clinical laboratory test results, including renal and liver function, and full blood count
  • Provision of informed consent before any trial-related activity

Exclusion Criteria:

  • Any history of cancer, diabetes or, in the opinion of the investigator, clinically-significant cardiovascular, respiratory, metabolic, renal, hepatic, gastrointestinal, haematological, dermatological, neurological, psychiatric or other major disorders
  • Any history of either significant multiple drug allergies or known allergy to the study drugs or any medicine chemically related to the study drugs
  • A clinically-significant illness within 4 weeks of randomisation
  • Any clinically-significant abnormal laboratory test results at screening in the opinion of the investigator
  • A supine blood pressure at screening, after resting for 5 minutes, higher than 150/90 mmHg or lower than 105/65 mmHg
  • A supine heart rate at screening, after resting for 5 minutes, outside the range of 50-100 beats/min
  • Receipt of any prescribed or over-the-counter systemic or topical medication within 48 hours prior to the start of dosing
  • Planned or expected requirement, during the next 3 months (at randomisation, or 3 weeks at the start of period 2), for any systemic or topical prescribed drug, or for systemic or topical over-the-counter NSAID, corticosteroid, anthihistamine or any other drug that could affect inflammation, thrombosis or haemostasis in the opinion of the investigator.
  • Receipt of an investigational medicinal product within the previous four months (new chemical entity) or three months (licensed product) or subjects who have received a vaccine within three months preceding the start of dosing. When reconfirming eligibility at the start of period 2, receipt of aspirin, ticagrelor or endotoxin during period 1 of this study will not be counted for this purpose.
  • Any donation of blood or plasma in the month preceding the start of dosing.
  • A history of alcohol or drug abuse
  • Mental incapacity or language barriers that preclude adequate understanding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03869268


Contacts
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Contact: Robert Storey 0114 2266159 ext 66159 R.F.Storey@sheffield.ac.uk
Contact: William Parker 0114 226159 ext 66159 W.Parker@sheffield.ac.uk

Locations
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United Kingdom
Sheffield Teaching Hospitals NHS Foundation Trust Recruiting
Sheffield, South Yorkshire, United Kingdom, S5 7AU
Contact: Robert Storey    0114 2159554 ext 59554    R.F.Storey@sheffield.ac.uk   
Sponsors and Collaborators
Sheffield Teaching Hospitals NHS Foundation Trust

Publications:

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Responsible Party: Sheffield Teaching Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT03869268     History of Changes
Other Study ID Numbers: STH20370
First Posted: March 11, 2019    Key Record Dates
Last Update Posted: June 25, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Acute Coronary Syndrome
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Aspirin
Ticagrelor
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents