Clinical trial NCT06286423: Colchicine in Acutely Decompensated HFREF
Official title: Colchicine in Acutely Decompensated Heart Failure With Reduced Ejection Fraction: a Pilot Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Heart Failure
Decompensated Heart Failure
Heart Failure With Reduced Ejection Fraction
Keywords: Colchicine
Heart Failure
Decompensated Heart Failure
Heart Failure with Reduced Ejection Fraction
HFrEF
Lead sponsor: University of Virginia
Sponsor class: OTHER
First posted: 2024-02-29
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study team is planning to use controls in the present study. Controls will be patients from the target population, i.e. acutely decompensated heart failure with reduced ejection fraction.
Primary purpose: TREATMENT

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 1:1 to receive either the experimental drug (Colchicine) or matching placebo. The regimen in the active arm will consist of 14 days of Colchicine 0.6 mg bid followed by 76±14 days of Colchicine 0.6 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, 24±6h, 48±6h and 72±6h after treatment initiation, and subsequently at 14±7 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 14±7 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 90±14; 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) ≥3.0 mg/l and for treatment duration over 7 days, and was higher for doses of 1.0 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 (N=237) who were chronically on Colchicine for other, non-cardiac reasons, i.e. crystal arthropathy, had significantly better in-hospital outcomes when compared to HF patient who did not chronically receive colchicine (N=810). 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, i.e. hsCRP, in patients with acutely decompensated HF with reduced left ventricular ejection fraction.

Eligibility criteria: Inclusion Criteria:

1. Primary admission diagnosis of acute decompensated heart failure as evidenced by:

   * Heart failure symptoms and at least one of the following:
   * Pulmonary congestion/edema at physical exam (or chest radiography)
   * E/e' \> 13 on transthoracic echocardiography
   * Left heart catheterization showing elevated left ventricular (LV) end-diastolic pressure \>18 mmHg or right heart catheterization showing pulmonary artery occluding pressure (wedge) \>16 mmHg
   * Elevated plasma B-type natriuretic peptide (\>100 pg/ml) or N-terminal B-type natriuretic peptide (\>300 pg/ml)
2. LV systolic dysfunction (left ventricular ejection fraction \[LVEF\] \<40%) during the index hospitalization or prior 12 months;
3. Expected duration of heart failure at least three months
4. Age 18 years or older
5. Willing and able to provide written informed consent
6. Screening plasma CRP \>0.3 mg/dL (3 mg/L) or high-sensitivity CRP \>2 mg/L

Exclusion Criteria:

1. Concomitant clinically significant comorbidities that would interfere with the execution or interpretation of the study, including but not limited to acute coronary syndromes, uncontrolled hypertension or orthostatic hypotension, tachy- or brady-arrhythmias, acute or chronic pulmonary disease or neuromuscular disorders affecting respiration
2. Cardiac resynchronization therapy (CRT), coronary artery revascularization procedures, or heart valve surgeries performed within 3 months or planned during the admission
3. Previous or planned implantation of left ventricular assist devices or heart transplantation
4. Chronic use of intravenous inotropes
5. Current or recent (i.e. within 4 half-lives) use of immunosuppressive or anti-inflammatory drugs (not including NSAIDs).
6. Current treatment with colchicine or planned initiation of colchicine therapy in the next three months for gout
7. Chronic inflammatory disorder, including but not limited to rheumatoid arthritis and systemic lupus erythematosus
8. Active infection (of any type)
9. Chronic or recurrent infectious disease, including hepatitis B virus, hepatitis C virus, and HIV/AIDS
10. Prior (within the past 5 years) or current malignancy, with the exclusion of in situ lesion with low potential for progression
11. Any comorbidity leading to expected survival less than three months or inability to complete the study
12. End-stage kidney disease requiring renal replacement therapy
13. Neutropenia (\<2,000/mm3) or Thrombocytopenia (\<50,000/mm3)
14. Pregnancy

    * For all biological females with child bearing potential a pregnancy test will be performed as part of standard of care.
15. Presence of specific contraindications to colchicine treatment, which may include

    * Previous adverse reaction to colchicine
    * Biliary obstruction
    * Renal impairment with estimated glomerular filtration rate (eGFR) \<30 ml/min
    * Liver cirrhosis from stage Child-Pugh A to more advanced
16. Prisoners
17. Treatment with medication contraindicated for concomitant use with colchicine per

Food and Drugs Administration labeling, including:

* Protease inhibitors
* Macrolides antibiotic
* Ketoconazole, Fluconazole and Itraconazole
* Nefazodone
* Non-dihydropiridine calcium channel blockers
* Aprepitant
* Ranolazine
* Cyclosporine

Primary outcomes:
measure: Difference in the change in high sensitivity C-reactive protein (hsCRP) between colchicine arm and placebo arm in the first 72 hours of treatment
timeFrame: Baseline to 72 hours
Secondary outcomes:
measure: Difference in hsCRP area under curve between colchicine and placebo arm at 14 days
timeFrame: Baseline to 14 days
measure: Difference in change in plasma IL-6 concentration between colchicine arm and placebo arm in the first 72 hours of treatment
timeFrame: Baseline to 72 hours
Other outcomes:
measure: Difference in the incidence of a composite of all-cause mortality or hospitalizations for heart failure at 90 days
timeFrame: Baseline to 90 days
Locations:
city: Charlottesville
country: United States
facility: UVA Health
state: Virginia
Study officials:
affiliation: UVA Health
name: Antonio Abbate, MD
role: PRINCIPAL_INVESTIGATOR
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