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Dose-finding Study of Colchicine in Type 2 Diabetic Patients With Coronary Artery Disease (DRC-04)

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ClinicalTrials.gov Identifier: NCT03376698
Recruitment Status : Recruiting
First Posted : December 18, 2017
Last Update Posted : April 19, 2019
Sponsor:
Information provided by (Responsible Party):
Shinichiro Ueda, University of the Ryukyus

Brief Summary:
This study is designed to investigate dose-dependent effects of low dose colchicine on inflammatory responses, endothelial function in type 2 diabetic patients with coronary artery disease and leukocyte activation. This study also tested the relationship between doses and safety issue such as incidence of diarrhea. Eligible patients will be randomly allocated to three treatment group: colchicine at 0.5mg per day, 0.25mg per day or placebo for 12 weeks in a double blind , parallel group design. High sensitive-CRP at 4 weeks as primary end point and flow mediated vasodilatation at 12 weeks as the secondary end point will be measured.

Condition or disease Intervention/treatment Phase
Colchicine Diabetes Mellitus, Type 2 Coronary Artery Disease White Blood Cell Inflammation Diarrhea Drug: Colchicine 0.5 mg Drug: Colchicine 0.25 mg Drug: Placebo Phase 2

Detailed Description:
Mortality rate in Japanese coronary artery disease (CAD) patients has been deemed the lowest among developed countries for the long time. However, cohort study of the investigators based on the registry of 8000 patients with CAD and type 2 diabetes has shown that cardiovascular mortality of such patients even under the optimized standard therapy and relatively intensive control of risk factors was higher than the investigators thought. Given substantial experimental evidence suggesting roles of inflammation as a key player in the development of atherosclerosis and significant association of enhanced inflammatory reaction and cardiovascular events in registry-based cohort of the investigators, the investigators are planning of phase 3 trial of colchicine, which is an ancient anti-inflammatory drug, for the regulatory approval as a drug preventing of cardiovascular events in diabetic CAD patients with enhanced inflammatory reaction. To develop appropriate study protocol of phase 3 trial, a dose-finding study is apparently warranted since our pharmacokinetics study and pharmacokinetics /pharmacodynamics study showed that colchicine stays in leukocytes with a long half life being more than 40 hours and showed consistent inhibition of leukocyte activation for more than 48 hours. In terms of safety issue, 0.5mg of colchicine, which has been frequently used in several cardiovascular trials, is associated with high incidence of diarrhea. As dose-dependency is assumed regarding diarrhea, a dose finding study for safety issue is also needed. The investigators, thus, conduct a double-blind randomized controlled trial to investigate dose-dependent effects on inflammatory responses using highly sensitive-CRP as an indicator, endothelial function using FMD, and incidence of diarrhea comparing once daily oral administration of 0.5 mg, 0.25 mg of colchicine and placebo for 12 weeks in CAD patients with type 2 diabetes mellitus and leukocyte activation. The investigators focus on patients with type 2 diabetes and leukocyte activation among CAD patients for regulatory approval because it is likely that such patients are at highest risk and respond well to colchicine.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 69 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Placebo-controlled Phase II Trial to Evaluate the Dose-dependent Effect of Colchicine on Inflammatory Response and Endothelial Function in Type 2 Diabetic Patients With Coronary Artery Disease and Leukocyte Activation
Actual Study Start Date : June 15, 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Colchicine

Arm Intervention/treatment
Active Comparator: Colchicine 0.5 mg Drug: Colchicine 0.5 mg
oral administration of Colchicine 0.5 mg once daily for 12 weeks

Active Comparator: Colchicine 0.25 mg Drug: Colchicine 0.25 mg
oral administration of Colchicine 0.25 mg once daily for 12 weeks

Placebo Comparator: Placebo Drug: Placebo
oral administration of Placebo once daily for 12 weeks




Primary Outcome Measures :
  1. Change in serum high-sensitivity CRP (mg/dl) [ Time Frame: 4 weeks ]

Secondary Outcome Measures :
  1. Change in serum high-sensitivity CRP (mg/dl) [ Time Frame: 12 weeks ]
  2. Change in Flow Mediated Dilatation (%) [ Time Frame: 12 weeks ]
  3. Change in adhesive ability of white blood cell (number/field of view) [ Time Frame: 4 weeks ]
  4. Change in time through the microchannel of white blood cell (sec) [ Time Frame: 4 weeks ]
  5. Change in plasma myeloperoxidase level (ng/ml) [ Time Frame: 4 and 12 weeks ]

Other Outcome Measures:
  1. Cardiovascular events [ Time Frame: 12 weeks ]
    death, myocardial infarction, stroke, hospitalization due to worsening heart failure, unstable angina

  2. Adverse events [ Time Frame: 12 weeks ]
  3. Side effect [ Time Frame: 12 weeks ]
  4. Diarrhea [ Time Frame: 12 weeks ]
    especially notable adverse event

  5. Concentration of colhicine in plasma (ng/ml) [ Time Frame: 12 weeks ]
    feasible facility only

  6. Concentration of colhicine in white blood cell (ng/1*10^9 cells) [ Time Frame: 12 weeks ]
    feasible facility only



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The subjects in this trial must have all of the following criteria.

    1. Patients with type 2 diabetes mellitus with coronary artery disease(*1) with increased inflammatory response(*2).

      • 1:"Type 2 diabetes" mellitus is diagnosed by criteria according to The Japan Diabetes Society. "Coronary artery disease" is defined as having equal to or greater than 75% stenosis in coronary angiography, history of acute coronary syndrome, and history of coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).
      • 2:"Increased inflammatory response" is defined as follow; White blood cell levels at confirmation tests of eligibility is equal to or greater than 7500 /μL.
    2. Patients aged 20 years and older
    3. In female subjects who had possibility of pregnancy and male subjects who had female partner who had possibility of pregnancy and not undergone a contraceptive surgery(*3), patients with consent of performing optimal contraception from starting study drug to 90 days from final taking.

      • 3: Male subjects who had undergone a contraceptive surgery are defined as elapsing for at least one year after vasectomy and having a certification of no sperm at ejaculation.
    4. After receiving sufficient explanation for the participation of this study, patients who wrote document of informed consent by the patient's free will with sufficient understanding.

Exclusion Criteria:

  • The subjects who conflict with at least one of the following criteria are exclude from this trial.

    1. Patients with prior hypersensitivity to Colchicine.
    2. Patients with taking Colhicine presently or to 30 days before confirmation tests of eligibility.
    3. Patients with liver cirrhosis
    4. Patients with clinical cholestasis.
    5. Patients with decreasing renal function (eGFR < 30 mL/min/1.73m2) at confirmation tests of eligibility.
    6. Patients with active malignancy.
    7. Patients taking drugs that are indicated as "combined caution" in the package insert of Colchicine as a drug which may interact with Colchicine. 1. Drugs inhibiting cytochrome P450 drug-metabolizing enzyme

      1. Strong Inhibitor Atazanavir, Clarithromycin, Indinavir, Itraconazole, Nelfinavir, Ritonavir, Saquinavir, Darunavir, Telithromycin, Telaprevir, Preparation including Cobicistat
      2. Moderate Inhibitor Amprenavir, Aprepitant, Diltiazem, Erythromycin, Fluconazole, Fosamprenavir, Verapamil 2. P-glycoprotein inhibitor Ciclosporin
    8. Patients taking Amiodarone or Quinidine.
    9. Patients with infectious or inflammatory disease at confirmation tests of eligibility.
    10. Current smoker
    11. Patients with pregnancy, possible pregnancy, on breast-feeding or who wish to become pregnant during trial. (The female subjects who had possibility of pregnancy receive a pregnancy test.)
    12. Patients registered in other clinical trials presently or within 30 days before acquisition consent of this trial.
    13. Patients whom physician in charge considered inappropriate for the study.

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): NCT03376698


Contacts
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Contact: Akihiro Tokushige, PhD +81-98-895-1195 akihiro@med.u-ryukyu.ac.jp
Contact: Yumi Ikehara +81-98-895-1195 yikehara@med.u-ryukyu.ac.jp

Locations
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Japan
Hiroshima University Hospital Recruiting
Hiroshima, Japan
Contact: Yukihito Higashi, PhD         
Kitasato University Hospital Recruiting
Kanagawa, Japan
Contact: Junya Ako, PhD         
Urasoe Sogo Hospital Recruiting
Okinawa, Japan
Contact: Hiroki Uehara         
Dokkyo Medical University Nikko Medical Center Recruiting
Tochigi, Japan
Contact: Takanori Yasu, PhD         
Showa University Hospital Recruiting
Tokyo, Japan
Contact: Shinji Koba, PhD         
Sponsors and Collaborators
University of the Ryukyus
Investigators
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Principal Investigator: Shinichiro Ueda, PhD blessyou@med.u-ryukyu.ac.jp
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Responsible Party: Shinichiro Ueda, Professor, University of the Ryukyus
ClinicalTrials.gov Identifier: NCT03376698    
Other Study ID Numbers: 1195
First Posted: December 18, 2017    Key Record Dates
Last Update Posted: April 19, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Diabetes Mellitus, Type 2
Inflammation
Diarrhea
Pathologic Processes
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Signs and Symptoms, Digestive
Signs and Symptoms
Colchicine
Gout Suppressants
Antirheumatic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents