Allopurinol in Diabetes Mellitus and Multivessel Coronary Artery Disease

November 20, 2018 updated by: michal roll, Tel-Aviv Sourasky Medical Center

Allopurinol in the Treatment of Patients With Diabetes Mellitus and Multivessel Coronary Artery Disease Treated by Either PCI or CABG: Pilot Study

Atherosclerosis is a progressive disease of the arterial wall, arising from the combination of endothelial dysfunction and inflammation. This link is exacerbated in diabetic patients.

Uric acid is known to generate oxidative stress and it's elevated levels has been shown to be associated with cardiac hypertrophy, inflammation, myocardial fibrosis and diastolic dysfunction. Allopurinol inhibits xanthine oxidase, an enzyme that regulates uric acid production. In observational studies it has been shown to reduce ischemia, inflammation and improve coronary flow. The aim of this study is to see whether treatment with Allopurinol in patients diagnosed with multivessel disease and undergoing treatment with either percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) , will reduce markers of inflammation and improve quality of life and major adverse cardiovascular effects (MACE).

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

This is a pilot study, PROBE design (prospective randomized open label blinded endpoints study), that will include 100 patients.

Patients will be recruited during their hospitalization in the cardiology department of Ichilov- Tel-Aviv Sourasky Medical Center.

It will include patients with known or newly diagnosed diabetes mellitus, hospitalized with diagnosis of acute coronary syndrome and multi-vessel coronary artery disease (CAD) that will be demonstrated by cardiac catheterization that the patients will undergo during their hospitalization in concordance with their diagnosis and practice guidelines.

The decision about intervention with either PCI or CABG will be accepted by a heart team after the initial demonstration of multi-vessel disease.

Study recruitment will take place either in the first 24 hours after PCI or before CABG.

All patients will sign an informed consent and randomized before any intervention is done.

After enrollment, patients will undergo the following baseline procedure (no later than 24 hours from PCI):

  1. Physical examination and medical interview
  2. Quality of life questionnaires (Seattle angina , EQ-5D)
  3. Echocardiogram
  4. Blood tests- see below for description
  5. Endothelial function using the EndoPat®

Blood sampling will be done via IV cannula that will be placed in an antecubital vein. Blood sample analyses will be performed using reagents, calibrators and control materials in the local labs of each participating site. A 40 ml blood sample will be obtained for the following blood tests

  1. Full chemistry including: lipid levels, thyroid function, liver enzymes function, Troponin, BNP, HbA1c, uric acid, creatinine and glucose levels.
  2. Blood count
  3. Inflammatory biomarker (hs-CRP, fibrinogen, IL-6, IL-1B, IL-18, MMP, IL-10, IL-35, TNFa, AchE , PAI-1, MPO, cholinergic status.)
  4. Endothelial function markers: Endothelin-1, I-CAM, V-CAM, superoxide dismutase ADMA, and oxidized LDL
  5. Oxidative Stress- superoxide dismutase ADMA, and oxidized LDL, Plasma protein carbonyls.
  6. Urine samples- microalbuminuria, albumin/creatinine. Uric acid.

Endothelial function will be assessed using EndoPAT 2000 device (Itamar Medical Inc., Caesarea, Israel) that is a device that measures endothelial function using a sensor placed on the fingers. This device has been validated and used previously to assess peripheral arterial tone in other populations. EndoPAT bio-sensors are placed on the index fingers of both arms. EndoPAT quantifies the endothelium-mediated changes in vascular tone, elicited by a 5-minute occlusion of the brachial artery (using a standard blood pressure cuff). When the cuff is released, the surge of blood flow causes an endothelium-dependent Flow Mediated Dilatation (FMD). The dilatation, manifested as reactive hyperemia, is captured by EndoPAT as an increase in the PAT Signal amplitude. A post-occlusion to pre-occlusion ratio is calculated by the EndoPAT software, providing the EndoPAT index. In addition, the EndoPAT system will measure heart rate variability.

After randomization and assessment as described above, the patients will receive treatment according to the study arm they were assigned to which will include either standard medical therapy alone, or standard medical therapy and allopurinol.

Allopurinol will be given initially at 100 mg once daily dose, with dose escalation by 100 mg every 2 weeks till final dose of 300 mg daily will be reached.

After discharge, patients will be assessed several times:

  1. One month after in cardiology clinic. Assessment will include all the tests as in the pre study exam (see above). also, patients will be monitored for the possible side effects of allopurinol treatment.
  2. Three months- in cardiology clinic. Assessment will include all the tests as in the pre study exam (see above).

Study Type

Interventional

Enrollment (Anticipated)

100

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 99 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Acute Coronary Syndrome with positive troponin
  2. Patients with known or newly diagnosed diabetes mellitus with HbA1c above 7% and below 10%
  3. Patients above the age of 40
  4. Stable Hemodynamic state (At least 12 hours from presentation with acute coronary syndrome)
  5. Uric Acid > 6mg/dl or 355 micromol/l (males) and >5mg/dl or 297 Micromol/l (females)

Exclusion Criteria:

  1. HbA1c below 7% or above 10%
  2. Severe valvular insufficiency/Stenosis
  3. Major surgery within 30 days
  4. Any medical condition that would impair participation (e.g. progressive neurological disorders, mental illness)
  5. Known intolerance/ current use of allopurinol/colchicine
  6. Chronic inflammatory diseases: e.g. Lupus, rheumatoid arthritis, etc.
  7. Current treatment with steroids, NSAID, chemotherapy or biologic medications
  8. Extra-cardiac illness that is expected to limit survival to less than 2 years.

  9. Past Cancer within the past 5 years (excluding BCC and SCC).

    -

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: PCI and standard medical treatment
Patients diagnosed with multi vessel disease that after Heart team discussion underwent intervention by PCI and receive standard medical treatment according to practice guidelines.
Active Comparator: PCI, standard treatment and Allopurinol
Patients diagnosed with multi vessel disease that after Heart team discussion underwent intervention by PCI and in addition to standard medical treatment, receive treatment with allopurinol.
Drug: Allopurinol
Allopurinol
Other Names:
  • Alloril
No Intervention: CABG and standard medical treatment
Patients diagnosed with multi vessel disease that after Heart team discussion underwent intervention by CABG and receive standard medical treatment according to practice guidelines.
Active Comparator: CABG standard treatment and Allopurinol
Patients diagnosed with multi vessel disease that after Heart team discussion underwent intervention by CABG and in addition to standard medical treatment, receive treatment with allopurinol.
Drug: Allopurinol
Allopurinol
Other Names:
  • Alloril

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
hs-CRP
Time Frame: 3 months.
Change in inflammatory biomarkers
3 months.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
hs-CRP
Time Frame: one month
Change in inflammatory biomarkers
one month
Endothelial function markers
Time Frame: 3 month
Endothelin-1, I-CAM, V-CAM, superoxide dismutase ADMA, and oxidized LDL, Change of RH-PAT
3 month
Heart rate variability
Time Frame: 3 month
Heart rate variability
3 month
functional status and quality of life: the Seattle angina questionnaire
Time Frame: 3 month
Quality of life evaluation- evaluates functional limitation in different activities due to chest pain and angina
3 month
Uric acid levels
Time Frame: one month and 3 month
Uric acid levels
one month and 3 month
functional status, quality of life: EuroQol EQ-5D questionnaire
Time Frame: 3 month
evaluation of degree of limitation in different daily activities
3 month
Reduction of peri-procedural myocardial infarction
Time Frame: 72 hours
Reduction of peri-procedural myocardial infarction
72 hours
MACE
Time Frame: 3 month
major adverse cardiac events
3 month
Diastolic function
Time Frame: 3 month
Diastolic function per echocardiogram- E/A
3 month
Diastolic function
Time Frame: 3 month
Diastolic function per echocardiogram-E/E' med
3 month
Diastolic function
Time Frame: 3 month
Diastolic function per echocardiogram- E/E' lat
3 month
Diastolic function
Time Frame: 3 month
Diastolic function per echocardiogram- DT time
3 month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tel-Aviv Sourasky Medical Center

Investigators

  • Principal Investigator: Yaron Arbel, M.D, Tel Aviv University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

December 1, 2018

Primary Completion (Anticipated)

December 31, 2019

Study Completion (Anticipated)

January 31, 2020

Study Registration Dates

First Submitted

August 15, 2018

First Submitted That Met QC Criteria

October 5, 2018

First Posted (Actual)

October 9, 2018

Study Record Updates

Last Update Posted (Actual)

November 21, 2018

Last Update Submitted That Met QC Criteria

November 20, 2018

Last Verified

November 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TASMC-18-YA-354-18-CTIL

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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