Ignite Creation Date:
2024-05-06 @ 8:11 PM
Last Modification Date:
2024-10-26 @ 3:22 PM
Study NCT ID:
NCT06286423
Status:
RECRUITING
Last Update Posted:
2024-05-08
First Post:
2024-02-22
Brief Title:
Colchicine in Acutely Decompensated HFREF
Sponsor:
University of Virginia
Organization:
University of Virginia
Study Overview
Official Title:
Colchicine in Acutely Decompensated Heart Failure With Reduced Ejection Fraction a Pilot Study
Status:
RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a double blind placebo-controlled pilot trial randomizing patients admitted to the hospital with acutely decompensated heart failure ADHF and inflammation to receive either colchicine or matching placebo
Upon enrollment patients will be randomized 11 to receive either the experimental drug Colchicine or matching placebo The regimen in the active arm will consist of 14 days of Colchicine 06 mg bid followed by 7614 days of Colchicine 06 mg once per day Placebo regimen will be analogous with one pill bid for 14 days followed by one pill once per day for 76 days Dose reduction for patients with Stage III chronic kidney disease is allowed as detailed in the protocol At the same time dose reduction can also be elected in case of GI symptoms The study team will transiently stop the experimental medication in case of acute kidney injury AKI defined per Kidney Disease Improving Global Outcomes KDIGO Stage I as specified in the protocol
These patients will continue with their standard of care for the management of heart failure which consists of a combination of medications that relieve congestion normalize blood pressure and heart rate and block the effects of hormones on the heart The proposed treatment will be in addition to standard of care No standard of care medications will be withheld While inflammation is a known risk factor in heart failure there are no standard anti-inflammatory drugs used in patients with heart failure as the benefit is not established The study team will study colchicine an anti-inflammatory drug as compares with placebo
Blood will be obtained from the patients in order to measure hsCRP and IL-6 Blood samples will be collected at baseline 246h 486h and 726h after treatment initiation and subsequently at 147 days and at study closure The first four blood samples will be obtained while the subject is still admitted to the hospital The blood sample at 147 days will be obtained during an outpatient encounter A study closure visit with clinical assessment and experimental drug collection for capsule counting to assess compliance will be conducted at 9014 the final blood sample will be collected at that time
Upon enrollment patients will be randomized 11 to receive either the experimental drug Colchicine or matching placebo The regimen in the active arm will consist of 14 days of Colchicine 06 mg bid followed by 7614 days of Colchicine 06 mg once per day Placebo regimen will be analogous with one pill bid for 14 days followed by one pill once per day for 76 days Dose reduction for patients with Stage III chronic kidney disease is allowed as detailed in the protocol At the same time dose reduction can also be elected in case of GI symptoms The study team will transiently stop the experimental medication in case of acute kidney injury AKI defined per Kidney Disease Improving Global Outcomes KDIGO Stage I as specified in the protocol
These patients will continue with their standard of care for the management of heart failure which consists of a combination of medications that relieve congestion normalize blood pressure and heart rate and block the effects of hormones on the heart The proposed treatment will be in addition to standard of care No standard of care medications will be withheld While inflammation is a known risk factor in heart failure there are no standard anti-inflammatory drugs used in patients with heart failure as the benefit is not established The study team will study colchicine an anti-inflammatory drug as compares with placebo
Blood will be obtained from the patients in order to measure hsCRP and IL-6 Blood samples will be collected at baseline 246h 486h and 726h after treatment initiation and subsequently at 147 days and at study closure The first four blood samples will be obtained while the subject is still admitted to the hospital The blood sample at 147 days will be obtained during an outpatient encounter A study closure visit with clinical assessment and experimental drug collection for capsule counting to assess compliance will be conducted at 9014 the final blood sample will be collected at that time
Detailed Description:
Colchicine - a pleotropic anti-inflammatory drug Colchicine is a natural alcaloid extract from plants of the genus Colchium autumn crocus From a pharmacological point of view colchicine binds in a poorly reversible manner to tubulin and prevents microtubule formation therefore interfering with organelle trafficking intercellular adhesion and cellular migration Interestingly colchicine at therapeutic concentration was shown to inhibit nucleotide-binding oligomerization domain leucine-rich repeat-containing protein NLRP 3 inflammasome hence inhibit the release of interleukin-1 IL-1 to reduce the surface expression and downstream signaling of tumor necrosis factor TNF and alter leukocyte and endothelial expression of L-selectin and E-selecting respectively potentially interfering with leukocytes homing and extravasation The net effect is a potently anti-inflammatory which lead to successful use of colchicine in the treatment of primarily inflammatory condition in particular acute arthritis such as gout or pseudogout and serositis
Colchicine in cardiovascular disease The positive effects of colchicine in cardiovascular conditions have long been appreciated In particular colchicine has been successfully used to resolve pericardial inflammation and eventually symptoms in pericarditis and to effectively prevent recurrences in those individuals who develop recurrent pericarditis More recent data have shown a significant reduction of recurrent myocardial infarction MI and stroke with low dose colchicine among patient with recent MI possibly due to resolution of vulnerable plaque phenotype or prevention of plaque activation in the setting of an acute inflammatory condition Interestingly a recent meta-analysis showed that low dose colchicine was in fact able to significantly abate systemic inflammation among patients with chronic coronary artery disease Of note the effect was most pronounced among patients with baseline high-sensitivity C-reactive protein hs-CRP 30 mgl and for treatment duration over 7 days and was higher for doses of 10 mg daily than lower colchicine doses
Heart failure is an inflammatory condition Inflammation promotes and aggravates heart failure HF Of note master inflammatory cytokines in particular interleukin-1 IL-1 was shown to cause direct cardio-depression and induce myocyte contractile dysfunction in both humans and pre-clinical models of cardiovascular diseases Of note elevated levels of inflammation and sustained subclinical inflammation over time is associated with worse HF outcomes After a HF exacerbation patients are at higher risk of further decompensation Such time window lasts approximately 30 to 90 days and has been defined the vulnerable period of HF Given that elevated inflammatory burden has been associated with early HF adverse events it is possible although yet unproven that inflammation could play a role in the vulnerable period
Targeted inhibition of inflammatory pathways was shown to abate systemic inflammation in HF patients and to improve cardiovascular performance in terms of exercise capacity and peak VO2 on cardiopulmonary exercise tests A single-center randomized controlled trial randomizing 267 patients with HF with reduced ejection fraction who were clinically stable to receive either placebo or colchicine showed a significant reduction of inflammatory biomarkers namely high sensitivity C-reactive protein hsCRP and interleukin 6 IL-6 No reduction in mortality or HF-related hospitalization was observed but a trend towards improved subjective symptoms was observed Of note the study did not include patients with recently decompensated HF which are the ones who show signs of greater systemic inflammation are at increased risk for adverse outcomes and are most likely to significantly benefit from additional treatments In the prior study patients were indeed not selected according to baseline levels of inflammation In particular epidemiological studies have shown how higher baseline levels of inflammation are associated with worse HF prognosis and our group has shown that HFrEF patients with high inflammatory burden at baseline are likely to benefit from modulation of inflammation More recently a retrospective single-center study performed at University of Virginia showed that among 1047 patients admitted for acutely decompensated HF ADHF those N237 who were chronically on Colchicine for other non-cardiac reasons ie crystal arthropathy had significantly better in-hospital outcomes when compared to HF patient who did not chronically receive colchicine N810 Of note this appears to be the largest study to assess the effects of colchicine in this population and suggesting a promising therapeutic role for colchicine in ADHF
Because elevated levels of clinical and subclinical inflammation are associated with worse outcomes and since patients are at higher risk of further decompensation within 30 to 90 days after an episode of HF a 90 day dosing window was chosen Unfortunately no data on the effect of colchicine on the vulnerable period first 90 days after the acute episode was available in the prior study
The investigators hypothesize that treatment with colchicine is safe to start in patients with acutely decompensated HF and it will significantly inhibit systemic inflammation as shown by a reduction of biomarkers of systemic inflammation ie hsCRP in patients with acutely decompensated HF with reduced left ventricular ejection fraction
Colchicine in cardiovascular disease The positive effects of colchicine in cardiovascular conditions have long been appreciated In particular colchicine has been successfully used to resolve pericardial inflammation and eventually symptoms in pericarditis and to effectively prevent recurrences in those individuals who develop recurrent pericarditis More recent data have shown a significant reduction of recurrent myocardial infarction MI and stroke with low dose colchicine among patient with recent MI possibly due to resolution of vulnerable plaque phenotype or prevention of plaque activation in the setting of an acute inflammatory condition Interestingly a recent meta-analysis showed that low dose colchicine was in fact able to significantly abate systemic inflammation among patients with chronic coronary artery disease Of note the effect was most pronounced among patients with baseline high-sensitivity C-reactive protein hs-CRP 30 mgl and for treatment duration over 7 days and was higher for doses of 10 mg daily than lower colchicine doses
Heart failure is an inflammatory condition Inflammation promotes and aggravates heart failure HF Of note master inflammatory cytokines in particular interleukin-1 IL-1 was shown to cause direct cardio-depression and induce myocyte contractile dysfunction in both humans and pre-clinical models of cardiovascular diseases Of note elevated levels of inflammation and sustained subclinical inflammation over time is associated with worse HF outcomes After a HF exacerbation patients are at higher risk of further decompensation Such time window lasts approximately 30 to 90 days and has been defined the vulnerable period of HF Given that elevated inflammatory burden has been associated with early HF adverse events it is possible although yet unproven that inflammation could play a role in the vulnerable period
Targeted inhibition of inflammatory pathways was shown to abate systemic inflammation in HF patients and to improve cardiovascular performance in terms of exercise capacity and peak VO2 on cardiopulmonary exercise tests A single-center randomized controlled trial randomizing 267 patients with HF with reduced ejection fraction who were clinically stable to receive either placebo or colchicine showed a significant reduction of inflammatory biomarkers namely high sensitivity C-reactive protein hsCRP and interleukin 6 IL-6 No reduction in mortality or HF-related hospitalization was observed but a trend towards improved subjective symptoms was observed Of note the study did not include patients with recently decompensated HF which are the ones who show signs of greater systemic inflammation are at increased risk for adverse outcomes and are most likely to significantly benefit from additional treatments In the prior study patients were indeed not selected according to baseline levels of inflammation In particular epidemiological studies have shown how higher baseline levels of inflammation are associated with worse HF prognosis and our group has shown that HFrEF patients with high inflammatory burden at baseline are likely to benefit from modulation of inflammation More recently a retrospective single-center study performed at University of Virginia showed that among 1047 patients admitted for acutely decompensated HF ADHF those N237 who were chronically on Colchicine for other non-cardiac reasons ie crystal arthropathy had significantly better in-hospital outcomes when compared to HF patient who did not chronically receive colchicine N810 Of note this appears to be the largest study to assess the effects of colchicine in this population and suggesting a promising therapeutic role for colchicine in ADHF
Because elevated levels of clinical and subclinical inflammation are associated with worse outcomes and since patients are at higher risk of further decompensation within 30 to 90 days after an episode of HF a 90 day dosing window was chosen Unfortunately no data on the effect of colchicine on the vulnerable period first 90 days after the acute episode was available in the prior study
The investigators hypothesize that treatment with colchicine is safe to start in patients with acutely decompensated HF and it will significantly inhibit systemic inflammation as shown by a reduction of biomarkers of systemic inflammation ie hsCRP in patients with acutely decompensated HF with reduced left ventricular ejection fraction
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None