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

Primary Purpose

Colchicine, Diabetes Mellitus, Type 2, Coronary Artery Disease

Status
Completed
Phase
Phase 2
Locations
Japan
Study Type
Interventional
Intervention
Colchicine 0.5 mg
Colchicine 0.25 mg
Placebo
Sponsored by
University of the Ryukyus
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colchicine

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 7000 /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.

Sites / Locations

  • Hiroshima University Hospital
  • Kitasato University Hospital
  • Urasoe Sogo Hospital
  • Dokkyo Medical University Nikko Medical Center
  • Showa University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Colchicine 0.5 mg

Colchicine 0.25 mg

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Change in serum high-sensitivity CRP (mg/dl)

Secondary Outcome Measures

Change in serum high-sensitivity CRP (mg/dl)
Change in Flow Mediated Dilatation (%)
Change in adhesive ability of white blood cell (number/field of view)
Change in time through the microchannel of white blood cell (sec)
Change in plasma myeloperoxidase level (ng/ml)

Full Information

First Posted
October 23, 2017
Last Updated
May 10, 2022
Sponsor
University of the Ryukyus
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1. Study Identification

Unique Protocol Identification Number
NCT03376698
Brief Title
Dose-finding Study of Colchicine in Type 2 Diabetic Patients With Coronary Artery Disease
Acronym
DRC-04
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Completed
Study Start Date
June 15, 2017 (Actual)
Primary Completion Date
March 4, 2022 (Actual)
Study Completion Date
April 1, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of the Ryukyus

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colchicine, Diabetes Mellitus, Type 2, Coronary Artery Disease, White Blood Cell, Inflammation, Diarrhea

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
54 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Colchicine 0.5 mg
Arm Type
Active Comparator
Arm Title
Colchicine 0.25 mg
Arm Type
Active Comparator
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Colchicine 0.5 mg
Intervention Description
oral administration of Colchicine 0.5 mg once daily for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Colchicine 0.25 mg
Intervention Description
oral administration of Colchicine 0.25 mg once daily for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
oral administration of Placebo once daily for 12 weeks
Primary Outcome Measure Information:
Title
Change in serum high-sensitivity CRP (mg/dl)
Time Frame
4 weeks
Secondary Outcome Measure Information:
Title
Change in serum high-sensitivity CRP (mg/dl)
Time Frame
12 weeks
Title
Change in Flow Mediated Dilatation (%)
Time Frame
12 weeks
Title
Change in adhesive ability of white blood cell (number/field of view)
Time Frame
4 weeks
Title
Change in time through the microchannel of white blood cell (sec)
Time Frame
4 weeks
Title
Change in plasma myeloperoxidase level (ng/ml)
Time Frame
4 and 12 weeks
Other Pre-specified Outcome Measures:
Title
Cardiovascular events
Description
death, myocardial infarction, stroke, hospitalization due to worsening heart failure, unstable angina
Time Frame
12 weeks
Title
Adverse events
Time Frame
12 weeks
Title
Side effect
Time Frame
12 weeks
Title
Diarrhea
Description
especially notable adverse event
Time Frame
12 weeks
Title
Concentration of colhicine in plasma (ng/ml)
Description
feasible facility only
Time Frame
12 weeks
Title
Concentration of colhicine in white blood cell (ng/1*10^9 cells)
Description
feasible facility only
Time Frame
12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The subjects in this trial must have all of the following criteria. 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 7000 /μL. Patients aged 20 years and older 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. 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. Patients with prior hypersensitivity to Colchicine. Patients with taking Colhicine presently or to 30 days before confirmation tests of eligibility. Patients with liver cirrhosis Patients with clinical cholestasis. Patients with decreasing renal function (eGFR < 30 mL/min/1.73m2) at confirmation tests of eligibility. Patients with active malignancy. 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 Strong Inhibitor Atazanavir, Clarithromycin, Indinavir, Itraconazole, Nelfinavir, Ritonavir, Saquinavir, Darunavir, Telithromycin, Telaprevir, Preparation including Cobicistat Moderate Inhibitor Amprenavir, Aprepitant, Diltiazem, Erythromycin, Fluconazole, Fosamprenavir, Verapamil 2. P-glycoprotein inhibitor Ciclosporin Patients taking Amiodarone or Quinidine. Patients with infectious or inflammatory disease at confirmation tests of eligibility. Current smoker 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.) Patients registered in other clinical trials presently or within 30 days before acquisition consent of this trial. Patients whom physician in charge considered inappropriate for the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Shinichiro Ueda, PhD
Organizational Affiliation
blessyou@med.u-ryukyu.ac.jp
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hiroshima University Hospital
City
Hiroshima
Country
Japan
Facility Name
Kitasato University Hospital
City
Kanagawa
Country
Japan
Facility Name
Urasoe Sogo Hospital
City
Okinawa
Country
Japan
Facility Name
Dokkyo Medical University Nikko Medical Center
City
Tochigi
Country
Japan
Facility Name
Showa University Hospital
City
Tokyo
Country
Japan

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

Dose-finding Study of Colchicine in Type 2 Diabetic Patients With Coronary Artery Disease

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