Repurposing Colchicine to Improve Vascular Function in Hypertension

Study Overview
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Brief Summary
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In this project the potential beneficial effect of the drug colchicine on vascular reactivity and blood pressure will be assessed. Colchicine is a commonly used anti-inflammatory medication approved for the treatment of gout, Familial Mediterranean Fever and pericarditis in Denmark. The current project idea is based on accumulating evidence in the literature for a beneficial role of colchicine treatment in the prevention of cardiovascular disease in parallel with novel mechanistic insight from our own research. Recently, colchicine was associated with a lower risk of cardiovascular disease, including reduced myocardial infarctions, strokes and acute coronary syndrome . However, none of these trials have investigated the effect of colchicine on arterial tone or stiffness, changes to which may underlie the reduced risk of cardiovascular disease associated with colchicine. In support of the hypothesis that colchicine will improve vascular reactivity, a study in 1985 by Lagrue et al. found that daily, low-dose colchicine improved arterial stiffness in a small cohort of hypertensive patients. More recently, colchicine was shown to improve arterial stiffness in patients with Familial Mediterranean fever supporting a cardiovascular protective role of colchicine. Finally, colchicine is also proposed to have anti-inflammatory effects in the vascular system.

Detailed Description
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In this project w the potential beneficial effect of the drug colchicine on vascular reactivity and blood pressure is evaluated. Colchicine is a commonly used anti-inflammatory medication approved for the treatment of gout, Familial Mediterranean Fever and pericarditis in Denmark. The current project idea is based on accumulating evidence in the literature for a beneficial role of colchicine treatment in the prevention of cardiovascular disease in parallel with novel mechanistic insight from research of the investigators. Recently, colchicine was associated with a lower risk of cardiovascular disease, including reduced myocardial infarctions, strokes and acute coronary syndrome. However, none of these trials have investigated the effect of colchicine on arterial tone or stiffness, changes to which may underlie the reduced risk of cardiovascular disease associated with colchicine. In support of thehypothesis that colchicine will improve vascular reactivity, a study in 1985 by Lagrue et al. found that daily, low-dose colchicine improved arterial stiffness in a small cohort of hypertensive patients. More recently, colchicine was shown to improve arterial stiffness in patients with Familial Mediterranean fever supporting a cardiovascular protective role of colchicine. Finally, colchicine is also proposed to have anti-inflammatory effects in the vascular system.

Official Title
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Repurposing Colchicine to Improve Vascular Function in Hypertension

Conditions
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Essential Hypertension

Intervention / Treatment
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* Drug: Colchicine Tablets
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with essential hypertension BMI<30 blood pressure (sys/dia) ≥120 mmhg and/or ≥80 mmhg while on hypertensive medication OR blood pressure (sys/dia) ≥130 mmhg and/or ≥85 mmhg without hypertensive medication Exclusion Criteria: smoking excessive alcohol use chronic diseases (beside essential hypertension)

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single blinded randomized placebo-controlled intervention
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Colchicine<br>3 weeks of treatment with colchicine | Drug: Colchicine Tablets<br>* patients with essential hypertension are randomized to receive either 3 weeks of colchicine<br>* Other names: Colchicine;|
| Placebo Comparator: Placebo<br>3 weeks of placebo-treatment | Drug: Placebo<br>* patients with essential hypertension are randomized to receive either 3 weeks of placebo-treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in vascular function with treatment measured as flowchanges with ultrasound doppler in response to infusions of isoprenaline | Infusions of isoprenalin in the brachial artery, measurement of blood flow with ultrasound doppler and intraarterial blood pressure with an intraarterial transducer for the calculation of leg vascular conductance | Change in vascular conductance in response to infusions is assessed after acute treatment and before and within 72 hours after the 3 weeks of colchicine or placebo treatment | 
| Changes in vascular function with training measured as flowchanges with ultrasound doppler divided by changes in blood pressure measured with intraarterial canula, in response to infusions of acetylcholine | Infusions of acetylcholine in the brachial artery, measurement of blood flow with ultrasound doppler and intraarterial blood pressure with an intraarterial transducer for the calculation of leg vascular conductance | Change in vascular conductance in response to infusions is assessed after acute treatment before and within 72 hours after the 3 weeks of colchicine or placebo treatment | 
| Changes in vascular function with training measured as flowchanges with ultrasound doppler divided by changes in blood pressure measured with intraarterial canula, in response to infusions of sodium nitroprusside | Infusions of sodium nitroprusside in the brachial artery, measurement of blood flow with ultrasound doppler and intraarterial blood pressure with an intraarterial transducer for the calculation of leg vascular conductance | Change in vascular conductance in response to infusions is assessed after acute treatment and before and within 72 hours after the 3 weeks of colchicine or placebo treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure | Blood pressure measured at home with an automated blood pressure device | Measurements are made before and after 3 weeks of treatment with colchicine or placebo. | 
| Vascular compliance | measured by intraarterial blood pressure and changes in arterial diameter by ultrasound doppler | Measurements are made before and after 3 weeks of treatment with colchicine or placebo. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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essential hypertension, colchicine, vascular function, vascular compliance, blood pressure