Colchicine in Acutely Decompensated HFREF

NCT06286423 | Recruiting Phase 4 FDA Drug

• 1 other identifier: HSR220446
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (1)

• Difference in the change in high sensitivity C-reactive protein (hsCRP) between colchicine arm and placebo arm in the first 72 hours of treatment

  Change in plasma concentration of hsCRP between baseline and after 72 hours after treatment initiation, comparing colchicine arm vs placebo

  Baseline to 72 hours

Secondary Outcomes (2)

• Difference in hsCRP area under curve between colchicine and placebo arm at 14 days

  Baseline to 14 days

• Difference in change in plasma IL-6 concentration between colchicine arm and placebo arm in the first 72 hours of treatment

  Baseline to 72 hours

Other Outcomes (1)

• Difference in the incidence of a composite of all-cause mortality or hospitalizations for heart failure at 90 days

  Baseline to 90 days

Study Arms (2)

Colchicine 0.6 mg treatment group

EXPERIMENTAL

Treatment group will be given active drug (0.6mg Colchicine) 2x/day (once if subject has kidney disease) for 14 days. Subsequently treatment group subjects will be given active drug (0.6mg Colchicine) 1x/day for 76 +/- days (or once every other day if subject has kidney disease).

Drug: Colchicine 0.6 mg

Control/Placebo group

PLACEBO COMPARATOR

Control/Placebo group will be given placebo that looks identical to study drug with no active ingredients and will take 2x/day (once if subject has kidney disease) for 14 days. Subsequently Control/Placebo group will be given placebo 1x/day for 76 +/- days (or once every other day if subject has kidney disease).

Drug: Control/Placebo group

Interventions

Colchicine 0.6 mg DRUG

Colchicine treated subjects will take 0.6mg of drug 2x per day (1 time if kidney disease is present) for 14 days, then will take 0.6mg of drug 1x per day (or every other day if kidney disease is present) for 76 +/1 days.

Also known as: Colcrys, Gloperba, Lodoco, Mitigare

Colchicine 0.6 mg treatment group

Control/Placebo group DRUG

Placebo treated subjects will take 0.6mg of placebo 2x per day (1 time if kidney disease is present) for 14 days, then will take 0.6mg of placebo1x per day (or every other day if kidney disease is present) for 76 +/1 days.

Control/Placebo group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• LV systolic dysfunction (left ventricular ejection fraction \[LVEF\] \<40%) during the index hospitalization or prior 12 months;
• Expected duration of heart failure at least three months
• Age 18 years or older
• Willing and able to provide written informed consent
• Screening plasma CRP \>0.3 mg/dL (3 mg/L) or high-sensitivity CRP \>2 mg/L

You may not qualify if:

• 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
• Cardiac resynchronization therapy (CRT), coronary artery revascularization procedures, or heart valve surgeries performed within 3 months or planned during the admission
• Previous or planned implantation of left ventricular assist devices or heart transplantation
• Chronic use of intravenous inotropes
• Current or recent (i.e. within 4 half-lives) use of immunosuppressive or anti-inflammatory drugs (not including NSAIDs).
• Current treatment with colchicine or planned initiation of colchicine therapy in the next three months for gout
• Chronic inflammatory disorder, including but not limited to rheumatoid arthritis and systemic lupus erythematosus
• Active infection (of any type)
• Chronic or recurrent infectious disease, including hepatitis B virus, hepatitis C virus, and HIV/AIDS
• Any comorbidity leading to expected survival less than three months or inability to complete the study
• End-stage kidney disease requiring renal replacement therapy
• Neutropenia (\<2,000/mm3) or Thrombocytopenia (\<50,000/mm3)
• Pregnancy
• For all biological females with child bearing potential a pregnancy test will be performed as part of standard of care.
• Presence of specific contraindications to colchicine treatment, which may include

Sponsors & Collaborators

• University of Virginia: lead

Study Sites (1)

UVA Health

Charlottesville, Virginia, 22908, United States

RECRUITING

Related Publications (21)

• Dalbeth N, Lauterio TJ, Wolfe HR. Mechanism of action of colchicine in the treatment of gout. Clin Ther. 2014 Oct 1;36(10):1465-79. doi: 10.1016/j.clinthera.2014.07.017. Epub 2014 Aug 21.

  PMID: 25151572 BACKGROUND

• Leung YY, Yao Hui LL, Kraus VB. Colchicine--Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015 Dec;45(3):341-50. doi: 10.1016/j.semarthrit.2015.06.013. Epub 2015 Jun 26.

  PMID: 26228647 BACKGROUND

• Pascart T, Richette P. Colchicine in Gout: An Update. Curr Pharm Des. 2018;24(6):684-689. doi: 10.2174/1381612824999180115103951.

  PMID: 29336252 BACKGROUND

• Aviel YB, Rawan S, Fahoum S, Wexler I, Berkun Y. Discontinuation of Colchicine Therapy in Children With Familial Mediterranean Fever. J Rheumatol. 2021 Nov;48(11):1732-1735. doi: 10.3899/jrheum.201158. Epub 2021 May 15.

  PMID: 33993110 BACKGROUND

• Bayes-Genis A, Adler Y, de Luna AB, Imazio M. Colchicine in Pericarditis. Eur Heart J. 2017 Jun 7;38(22):1706-1709. doi: 10.1093/eurheartj/ehx246. No abstract available.

  PMID: 30052886 BACKGROUND

• Imazio M, Brucato A, Cemin R, Ferrua S, Maggiolini S, Beqaraj F, Demarie D, Forno D, Ferro S, Maestroni S, Belli R, Trinchero R, Spodick DH, Adler Y; ICAP Investigators. A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2013 Oct 17;369(16):1522-8. doi: 10.1056/NEJMoa1208536. Epub 2013 Aug 31.

  PMID: 23992557 BACKGROUND

• Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, Lopez-Sendon J, Ostadal P, Koenig W, Angoulvant D, Gregoire JC, Lavoie MA, Dube MP, Rhainds D, Provencher M, Blondeau L, Orfanos A, L'Allier PL, Guertin MC, Roubille F. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019 Dec 26;381(26):2497-2505. doi: 10.1056/NEJMoa1912388. Epub 2019 Nov 16.

  PMID: 31733140 BACKGROUND

• Pan Z, Cheng J, Yang W, Chen L, Wang J. Effect of colchicine on inflammatory markers in patients with coronary artery disease: A meta-analysis of clinical trials. Eur J Pharmacol. 2022 Jul 15;927:175068. doi: 10.1016/j.ejphar.2022.175068. Epub 2022 May 27.

  PMID: 35644423 BACKGROUND

• Van Tassell BW, Toldo S, Mezzaroma E, Abbate A. Targeting interleukin-1 in heart disease. Circulation. 2013 Oct 22;128(17):1910-23. doi: 10.1161/CIRCULATIONAHA.113.003199. No abstract available.

  PMID: 24146121 BACKGROUND

• Abbate A, Toldo S, Marchetti C, Kron J, Van Tassell BW, Dinarello CA. Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease. Circ Res. 2020 Apr 24;126(9):1260-1280. doi: 10.1161/CIRCRESAHA.120.315937. Epub 2020 Apr 23.

  PMID: 32324502 BACKGROUND

• Golino M, Moroni F, Abbate A. Connecting the Dots: Inflammatory Burden and Outcomes in Heart Failure. J Am Heart Assoc. 2023 Oct 3;12(19):e031786. doi: 10.1161/JAHA.123.031786. Epub 2023 Sep 30. No abstract available.

  PMID: 37776202 BACKGROUND

• Gracia E, Singh P, Collins S, Chioncel O, Pang P, Butler J. The Vulnerable Phase of Heart Failure. Am J Ther. 2018 Jul/Aug;25(4):e456-e464. doi: 10.1097/MJT.0000000000000794. No abstract available.

  PMID: 29985824 BACKGROUND

• Alonso-Martinez JL, Llorente-Diez B, Echegaray-Agara M, Olaz-Preciado F, Urbieta-Echezarreta M, Gonzalez-Arencibia C. C-reactive protein as a predictor of improvement and readmission in heart failure. Eur J Heart Fail. 2002 Jun;4(3):331-6. doi: 10.1016/s1388-9842(02)00021-1.

  PMID: 12034159 BACKGROUND

• Van Tassell BW, Trankle CR, Canada JM, Carbone S, Buckley L, Kadariya D, Del Buono MG, Billingsley H, Wohlford G, Viscusi M, Oddi-Erdle C, Abouzaki NA, Dixon D, Biondi-Zoccai G, Arena R, Abbate A. IL-1 Blockade in Patients With Heart Failure With Preserved Ejection Fraction. Circ Heart Fail. 2018 Aug;11(8):e005036. doi: 10.1161/CIRCHEARTFAILURE.118.005036.

  PMID: 30354558 BACKGROUND

• Trankle CR, Canada JM, Cei L, Abouzaki N, Oddi-Erdle C, Kadariya D, Christopher S, Viscusi M, Del Buono M, Kontos MC, Arena R, Van Tassell B, Abbate A. Usefulness of Canakinumab to Improve Exercise Capacity in Patients With Long-Term Systolic Heart Failure and Elevated C-Reactive Protein. Am J Cardiol. 2018 Oct 15;122(8):1366-1370. doi: 10.1016/j.amjcard.2018.07.002. Epub 2018 Jul 20.

  PMID: 30244844 BACKGROUND

• Deftereos S, Giannopoulos G, Panagopoulou V, Bouras G, Raisakis K, Kossyvakis C, Karageorgiou S, Papadimitriou C, Vastaki M, Kaoukis A, Angelidis C, Pagoni S, Pyrgakis V, Alexopoulos D, Manolis AS, Stefanadis C, Cleman MW. Anti-inflammatory treatment with colchicine in stable chronic heart failure: a prospective, randomized study. JACC Heart Fail. 2014 Apr;2(2):131-7. doi: 10.1016/j.jchf.2013.11.006.

  PMID: 24720919 BACKGROUND

• Van Tassell BW, Raleigh JM, Abbate A. Targeting interleukin-1 in heart failure and inflammatory heart disease. Curr Heart Fail Rep. 2015 Feb;12(1):33-41. doi: 10.1007/s11897-014-0231-7.

  PMID: 25315037 BACKGROUND

• Van Tassell BW, Canada J, Carbone S, Trankle C, Buckley L, Oddi Erdle C, Abouzaki NA, Dixon D, Kadariya D, Christopher S, Schatz A, Regan J, Viscusi M, Del Buono M, Melchior R, Mankad P, Lu J, Sculthorpe R, Biondi-Zoccai G, Lesnefsky E, Arena R, Abbate A. Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure: Results From REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ Heart Fail. 2017 Nov;10(11):e004373. doi: 10.1161/CIRCHEARTFAILURE.117.004373.

  PMID: 29141858 BACKGROUND

• Roth ME, Chinn ME, Dunn SP, Bilchick KC, Mazimba S. Association of colchicine use for acute gout with clinical outcomes in acute decompensated heart failure. Clin Cardiol. 2022 Jul;45(7):733-741. doi: 10.1002/clc.23830. Epub 2022 Apr 28.

  PMID: 35481608 BACKGROUND

• Van Tassell BW, Abouzaki NA, Oddi Erdle C, Carbone S, Trankle CR, Melchior RD, Turlington JS, Thurber CJ, Christopher S, Dixon DL, Fronk DT, Thomas CS, Rose SW, Buckley LF, Dinarello CA, Biondi-Zoccai G, Abbate A. Interleukin-1 Blockade in Acute Decompensated Heart Failure: A Randomized, Double-Blinded, Placebo-Controlled Pilot Study. J Cardiovasc Pharmacol. 2016 Jun;67(6):544-51. doi: 10.1097/FJC.0000000000000378.

  PMID: 26906034 BACKGROUND

• Kajikawa M, Higashi Y, Tomiyama H, Maruhashi T, Kurisu S, Kihara Y, Mutoh A, Ueda SI. Effect of short-term colchicine treatment on endothelial function in patients with coronary artery disease. Int J Cardiol. 2019 Apr 15;281:35-39. doi: 10.1016/j.ijcard.2019.01.054. Epub 2019 Jan 15.

  PMID: 30683457 BACKGROUND

MeSH Terms

Conditions

Heart Failure

Interventions

Colchicine

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Alkaloids; Heterocyclic Compounds

Study Officials

• Antonio Abbate, MD

  UVA Health

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Austin Hogwood

CONTACT

(804)536-7036; ach2jb@virginia.edu

Francesco Moroni, MD

CONTACT

(804)351-7089; nmf7mm@uvahealth.org

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: February 22, 2024
• First Posted: February 29, 2024
• Study Start: June 1, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2028
• Last Updated: May 8, 2024

Record last verified: 2024-05

Locations

US (1)