LILACS

Low dose interleukin-2 in patients with stable ischaemic heart disease and acute coronary syndromes (LILACS)

Research summary

Acute coronary syndromes (ACS) result from coronary plaque(s) disruption, which initiates a thrombotic process leading to partial or complete obstruction of the vessel lumen with subsequent myocardial ischaemia and necrosis. The mainstay of treatment is currently focussed on the re-establishment and maintenance of coronary artery patency using anti-platelets and anticoagulants with or without mechanical dilatation and stenting of the culprit artery. Despite important advances in management, ACS still carries a risk of substantial morbidity and mortality. The improved efficacy of novel anti-platelet and anticoagulant agents has been mitigated by increased risk of haemorrhagic events. Thus, future breakthroughs in management are most likely to arise from targeting other relevant pathophysiological pathways. Particularly, we believe that the immune response is an important process that has been neglected in the management of patients with ACS.

This Phase I/II trial will carefully examine the safety of low-dose IL-2 in cardiovascular patients where it is currently contraindicated. The planned doses will be given to the trial patients once a day, over five days as subcutaneous injections [Part A patients: Repeated doses will be given in the range of 0.3x106 IU up to a maximum of 3.0x106 IU (total of 25 completed patients across 5 groups: 3:2 randomisation IL-2:placebo) / Part B patients: Repeated doses will be given at doses not exceeding the maximum dose used in Part A (total of 32 completed patients across 4 groups: 6:2 randomisation IL-2:placebo)]. These doses have been chosen on the basis of safety and tolerability data from published clinical studies. In the low dose IL-2 studies evaluated, there were a low rate of adverse events (AEs) in all of the studies with the most commonly reported AEs being injection site reactions, fatigue, fever, nausea and vomiting. A low percentage of serious adverse events (SAEs) were recorded in a GVHD-risk study and these SAEs included haemorrhage (CNS), anorexia, and infection (colitis).

The experimental and clinical background in low-dose IL-2 therapy suggests a potential clinical utility of Treg cell expansion in patients with ACS. Administration of low doses of IL-2 in various clinical settings appears to be safe and remarkably efficacious at promoting selective expansion of Treg cells with preserved suppressive function. This is the first trial to assess the mechanism of action of IL-2 therapy in cardiovascular patients. The aim of Part A of this clinical trial is to assess the safety of low-dose IL-2 as well as the proof of mechanism in patients with stable ischaemic heart disease, on an outpatient basis. Part B aims to assess the safety and efficacy of, and increase in Treg as a result of this drug supplementation, in the setting of ACS. Our future perspective is to follow-up this trial by looking at a larger group of patients to determine the efficacy of the treatment (effect of low dose IL-2 on vascular inflammation as assessed by FDG-PET/CT in patients with ACS).

clinicaltrials.gov

Main inclusion criteria

Part A

  1. Age 18-75 years old inclusive

  2. Previous history (≥ 6 months from planned first day of dosing) of coronary artery disease

  3. No history of recent (< 6 months from planned first day of dosing) admissions for an unstable cardiovascular event e.g. MI (Myocardial Infarction), unstable angina, ACS

  4. Written informed consent for participation in the trial

Part B

  1. Age 18-85 years old inclusive

  2. Current admission (on at least screening visit) with NSTEMI/ACS

  3. Willingness to be dosed within 8 days from initial date of current admission for ACS

  4. Written informed consent for participation in the trial

Main exclusion criteria

Part A

  1. Current presentation with cardiogenic shock (systolic blood pressure <80 mm Hg, unresponsive to fluids, or necessitating catecholamines), severe congestive heart failure and/or pulmonary oedema

  2. Known active bleeding or bleeding diatheses

  3. Known active infection requiring antibiotic treatment

  4. Severe hematologic abnormalities (haematocrit <30% AND platelet cell count of <100 × 103/μL AND white blood cell count <3.3 × 103/μL)

  5. Known malignancies requiring active treatment or follow up (However, patients with current/a history of localised basal or squamous cell skin cancer are not excluded from participation in this trial)

  6. Known heart failure with impaired LV function: echocardiographic findings of LV EF < 45%

  7. Hypotension (Systolic BP<100mm Hg, DBP<50mmHg) at screening

  8. Uncontrolled hypertension (>160/100 mmHg) at screening

  9. History of recurrent syncope (Electrocardiographic history suggestive of arrhythmia syncope (e.g. bifascicular block, sinus bradycardia < 40 beats per minute in absence of sinoatrial block or medications, pre-excited QRS complex, abnormal QT interval, ST segment elevation leads V1 through V3 [Brugada syndrome], negative T wave in right precordial leads and epsilon wave [arrhythmogenic right ventricular dysplasia/cardiomyopathy]))

  10. Known hepatic failure or abnormal LFTs at baseline (ALT > 2 x ULN).

  11. Elevated Total Bilirubin Levels, (TBL > 1.5 x ULN) and Alkaline Phosphatase, ALP (ALP > 1.5 x ULN), at baseline

  12. Acute kidney injury or chronic kidney disease at Stage > 3B (eGFR < 45)

  13. Respiratory failure

  14. History of drug induced Stevens Johnson syndrome, Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) or toxic epidermal necrolysis

  15. History of recurrent epileptic seizures in the previous 4 years; repetitive or difficult to control seizures, coma or toxic psychosis lasting >48 hours

  16. If known diabetic, uncontrolled diabetes defined as HbA1c > 64 mmol/mol

  17. Average corrected QT interval (QTc) > 450 msecs using Bazett's formula using triplicate ECGs (or > 480 msecs if bundle branch block)

  18. Known chronic active hepatitis (B or C)

  19. Known HIV infection

  20. Current infection possibly related to recent or on-going immunosuppressive treatment

  21. Known autoimmune disease requiring active immunosuppressive therapy

  22. History of organ transplantation

  23. Any oral or intravenous Immunosuppressive treatment including Prednisolone, hydrocortisone or disease modifying drugs such as Azathioprine, interferon-alpha, Cyclophosphamide or Mycophenolate. [Other immunosuppressive therapies should be discussed with PI. Inhaled or topical steroids are permissible.]

  24. Known pregnancy at screening or visit 2 (where applicable)

  25. On-going lactation

  26. Inability to comply with trial procedures

  27. Current participation in the active dosing phase of other interventional clinical trials

  28. Contra indication to IL-2 treatment or hypersensitivity to IL-2 or to any of its excipients

  29. Unwillingness or inability to provide written informed consent for participation

  30. Known hyper- or hypothyroidism

  31. Any medical history or clinically relevant abnormality that is deemed by the principal investigator/delegate and/or medical monitor to make the patient ineligible for inclusion because of a safety concern

Part B

  1. ST elevation myocardial infarction (heart attack) on this admission.

  2. Current presentation with cardiogenic shock (systolic blood pressure <80 mm Hg, unresponsive to fluids, or necessitating catecholamines), electrical instability, severe congestive heart failure and/or pulmonary oedema.

  3. Known active bleeding or bleeding diatheses.

  4. Known active infection requiring antibiotic treatment.

  5. Severe hematologic abnormalities (haematocrit <30% AND platelet cell count of <100 × 103/μL, white blood AND cell count <3.3 × 103/μL).

  6. Known malignancies requiring active treatment or follow up (However, patients with current/a history of localised basal or squamous cell skin cancer are not excluded from participation in this trial).

  7. Known heart failure with impaired LV function: echocardiographic findings of LV EF < 35%.

  8. Hypotension (Systolic BP (SBP)<100mm Hg, DBP<50mmHg) at screening.

  9. Uncontrolled hypertension (>160/100 mmHg) at screening.

  10. History of recurrent syncope (Electrocardiographic history suggestive of arrhythmia syncope (e.g., bifascicular block, sinus bradycardia < 40 beats per minute in absence of sinoatrial block or medications, pre-excited QRS complex, abnormal QT interval, ST segment elevation leads V1 through.

  11. V3 [Brugada syndrome], negative T wave in right precordial leads and epsilon wave [arrhythmogenic right ventricular dysplasia/cardiomyopathy].

  12. Known hepatic failure or abnormal LFTs at baseline (ALT > 2 x ULN).

  13. Elevated Total Bilirubin Levels, (TBL > 1.5 x ULN) and Alkaline Phosphatase, ALP (ALP > 1.5 x ULN), at baseline.

  14. Acute kidney injury or chronic kidney disease at Stage > 3B (eGFR < 45)

  15. Acute respiratory failure

  16. History of drug induced Stevens Johnson syndrome, Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) or toxic epidermal necrolysis.

  17. History of recurrent epileptic seizures in the previous 4 years; repetitive or difficult to control seizures, coma or toxic psychosis lasting >48 hours.

  18. Average corrected QT interval (QTc) > 450 msecs using Bazett's formula using triplicate ECGs (or > 480 msecs if bundle branch block)

  19. Known chronic active hepatitis (B or C).

  20. Known HIV infection.

  21. Current infection possibly related to recent or on-going immunosuppressive treatment.

  22. Known autoimmune disease requiring active immunosuppressive therapy

  23. History of organ transplantation

  24. Any oral or intravenous immunosuppressive treatment including Prednisolone, hydrocortisone or disease modifying drugs such as Azathioprine, interferon-alpha, Cyclophosphamide or Mycophenolate. [Other immunosuppressive therapies should be discussed with PI. Inhaled or topical steroids are permissible.]

  25. Known pregnancy at screening (where applicable).

  26. On-going lactation.

  27. Inability to comply with trial procedures.

  28. Current participation in the active dosing phase of other interventional clinical trials.

  29. Contraindication to IL-2 treatment or hypersensitivity to IL-2 or to any of its excipients.

  30. Unwillingness or inability to provide written informed consent for participation.

  31. Known hyper- or hypothyroidism.

  32. Any medical history or clinically relevant abnormality that is deemed by the principal investigator/delegate and/or medical monitor to make the patient ineligible for inclusion because of a safety concern.

Chief investigator

Dr Joseph Cheriyan

Contact details

Senior Clinical Trials Coordinator: Heike Templin

Telephone: 01223 250874 | Email:[email protected]