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The Effect of ENZAlutamide on the Anti-Xa Levels of Patients Receiving DOACs (ENZA-D)

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ClinicalTrials.gov Identifier: NCT03920566
Recruitment Status : Not yet recruiting
First Posted : April 19, 2019
Last Update Posted : April 22, 2019
Sponsor:
Collaborators:
Pharmacy Research UK
University of Brighton
Information provided by (Responsible Party):
Royal Marsden NHS Foundation Trust

Brief Summary:
This study aims to determine the nature and significance of the theoretical drug interaction between enzalutamide (a drug used to treat prostate cancer) and the direct-acting oral anticoagulant drugs (DOACs). This will be done in two ways: a laboratory study which will take place at the University of Brighton, and a clinical study in which patients will be identified who are currently taking DOACs and are due to start treatment with enzalutamide. The activity of the DOAC will be monitored using anti-Xa levels before and after commencing treatment with enzalutamide.

Condition or disease Intervention/treatment
Drug Interaction Other: Anti-Xa level

Detailed Description:

Enzalutamide is an effective and well-tolerated treatment for advanced prostate cancer. Unfortunately however, enzalutamide can sometimes interact with other medicines that the patient is taking, altering their concentration in the blood-stream. Enzalutamide can do this in two ways: either by increasing the breakdown of a medicine, or by blocking a special protein, called p-glycoprotein, that pumps it out of the body. An example of a medicine whose breakdown is increased by enzalutamide is warfarin. Warfarin is used to prevent, and treat blood clots that have formed in the deep veins of the legs (deep vein thrombosis or DVT) or have become lodged in blood vessels in the lungs (pulmonary embolism or PE). As enzalutamide is known to reduce the effect of warfarin, the manufacturer advises avoiding using the two medicines together. Instead,we can use a new class of medicines called the direct oral anticoagulants, or DOACs.

DOACs have an additional advantage over warfarin in that they do not require regular monitoring with blood tests. We, and other experts in the field believe that there may be a problem using DOACs and enzalutamide together, however scientific evidence suggests that enzalutamide may stop the p-glycoprotein pump from working properly, and alter its ability to pump out a range of medicines. Other evidence suggests that under certain conditions, enzalutamide may actually increase the activity of P-glycoprotein, and reduce the concentration of other medicines in the bloodstream. However, there is no scientific evidence, or evidence from patients, that has looked directly at thecombination of enzalutamide and DOACs together. Because no routine monitoring is carried out with DOACs, we are not sure of the extent of this problem, but the consequences of over or underdosing could be serious.

We have recently generated some preliminary data in our laboratory which has the measured the extent of this interaction, but we need to repeat these experiments before we can draw any firm conclusions from them. In this pilot study, we will explore the potential interaction between enzalutamide and DOACs. First, we will measure the activity of DOACs in patients who are due to start treatment with enzalutamide using a simple, well established blood test. We will then repeat this blood test after the first month of treatment, along with regular blood tests, to determine if there has been a change in the effectiveness of the DOAC. Second, we aim to build uponour laboratory data, and examine whether brief, or prolonged exposure to enzalutamide affects the ability of p-glycoproteinto pump out DOACs.

Our aims are to

  1. determine if enzalutamide interacts with DOACs in patients recruited from an advanced prostatecancer clinic
  2. understand in greater detail the nature of any interaction between enzalutamide and DOACs in the laboratory
  3. assess the feasibility of expanding this study to generate sufficient evidence to make recommendations for clinical practice.

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Study Type : Observational
Estimated Enrollment : 15 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: A Pilot Study To Investigate the Effect of ENZAlutamide on the Anti-Xa Levels of Patients Receiving Direct-acting Anticoagulants (DOACS) (ENZA-D)
Estimated Study Start Date : May 2019
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2020

Resource links provided by the National Library of Medicine



Intervention Details:
  • Other: Anti-Xa level
    Anti-Xa level taken before commencing enzalutamide and repeated after 4 weeks of treatment


Primary Outcome Measures :
  1. Anti-Xa level [ Time Frame: time 0 and time 4 weeks ]
    Difference between anti-Xa levels taken at two time points (baseline and 4-weeks after commencing enzalutamide)

  2. Efflux ratio (with enzalutamide) [ Time Frame: Each experiment will be conducted over a period of <1 day ]
    Difference in efflux ratio for edoxaban/ rivaroxaban / apixaban in the absence/presence of enzalutamide over a range of concentrations

  3. Efflux ratio (with enzalutamide and positive control) [ Time Frame: Each experiment will be conducted over a period of <1 day ]
    Difference in efflux ratio for edoxaban/ rivaroxaban / apixaban in the presence of enzalutamide and a positive control (e.g. verapamil, whilst ensuring appropriate statistical power)


Secondary Outcome Measures :
  1. Bleeding [ Time Frame: 4 weeks ]

    Common Terminology Criteria for Adverse Events (various types of bleeding or hemorrhage are listed. The most appropriate will be selected and graded 1-5 where Grade 1=Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.

    Grade 2=Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living.

    Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living.

    Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event


  2. Bruising [ Time Frame: 4 weeks ]
    A finding of injury of the soft tissues or bone characterized by leakage of blood into surrounding tissues. Graded according to Common Terminology Criteria for Adverse Events grades 1-2 where grade 1=localized or in a dependent area and grade 2 = generalize bruising

  3. Venous Thromboembolism [ Time Frame: 4 weeks ]

    Common Terminology Criteria for Adverse Events (various different thromboembolic events are listed. The most appropriate will be selected and graded 1-5 where Grade 1=Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.

    Grade 2=Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living.

    Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living.

    Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients who are currently taking direct-acting oral anticoagulant drugs who are due to start treatment with enzalutamide for the treatment of prostate cancer.
Criteria

Inclusion Criteria:

  • Male patients aged > 18 years old
  • Diagnosis of castrate resistant metastatic prostate cancer
  • Due to commence treatment with enzalutamide
  • Currently prescribed edoxaban, rivaroxaban or apixaban
  • Calculated CrCl (Cockroft & Gault) > 30ml/min

Exclusion Criteria:

  • Patients <18 years old
  • Due to stop edoxaban/ rivaroxaban / apixaban during study period (i.e. within 4 weeks of recruitment)
  • Currently taking other medicines which induce or inhibit P-gp or increase/reduce the effect of apixaban or rivaroxaban (e.g. verapamil, ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, erythromycin (refer to appendix 1 for complete list)
  • Currently taking any herbal/complimentary medicines (other than homeopathic products)
  • Calculated CrCl (Cockroft & Gault) <30ml/min
  • Severe hepatic impairment (Childs-Pugh class C)
  • Lacks capacity, including patients with documented dementia (or psychometric marker e.g. Abbreviated Mental Test Score (AMTS) <7/10) or inability to give informed consent for study participation.

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): NCT03920566


Contacts
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Contact: Emma Foreman 0208 6426011 ext 1067 Emma.Foreman@rmh.nhs.uk

Sponsors and Collaborators
Royal Marsden NHS Foundation Trust
Pharmacy Research UK
University of Brighton
Investigators
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Principal Investigator: Emma Foreman Royal Marsden NHS Foundation Trust
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Responsible Party: Royal Marsden NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT03920566    
Other Study ID Numbers: CCR 5039
First Posted: April 19, 2019    Key Record Dates
Last Update Posted: April 22, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Royal Marsden NHS Foundation Trust:
Enzalutamide
Anticoagulant Drugs
P-glycoprotein
Additional relevant MeSH terms:
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Heparin, Low-Molecular-Weight
Dalteparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action