Low Dose Interleukin-2 in Patients With Stable Ischaemic Heart Disease and Acute Coronary Syndromes

• Status: Completed
• Trial end date: 2019-02-21
• Target enrollment: 0
• Participant gender: All

Summary

The mainstay for treatment for acute coronary syndrome (ACS) focusses on re-establishing and maintaining the patency of vessels following coronary plaque disruption, through the use of anti-platelets and anticoagulants. Despite advances in management ACS still carries a high risk of morbidity and mortality, thus future management is likely to target other pathways.

Recent studies indicate that CD4+ T cells, and more specifically Treg cells, are important for the control of post-ischemic immune responses and the promotion of myocardial healing. The investigators therefore hypothesise that expansion of Treg cells in patients with ACS dampens the activation of the immune response and promotes both plaque and myocardial healing. The investigators hypothesise that this can be achieved through subcutaneous administration of low doses of interleukin-2 (IL-2). IL-2 supplementation appears to be an attractive therapeutic option playing a key role in Treg cell development, expansion, survival and suppressive function.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Collaborator: University of Cambridge
• Treatments: Aldesleukin; Interleukin-2

Criteria

Part A

Inclusion Criteria:

• Age 18-75 years old inclusive

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

• 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

• Written informed consent for participation in the trial

Part A

Exclusion Criteria:

• 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

• Known active bleeding or bleeding diatheses

• Known active infection requiring antibiotic treatment

• Severe hematologic abnormalities (haematocrit <30% AND platelet cell count of <100 × 10^3/μL AND white blood cell count <3.3 × 10^3/μL )

• 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)

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

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

• Uncontrolled hypertension (>160/100 mmHg) at screening

• 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]))

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

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

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

• Respiratory failure

• History of drug induced Stevens Johnson syndrome, Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), toxic epidermal necrolysis, or contrast allergy (requiring steroid treatment)

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

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

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

• Known chronic active hepatitis (B or C)

• Known HIV infection

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

• Known autoimmune disease requiring active immunosuppressive therapy

• History of organ transplantation

• 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.]

• Known pregnancy at screening or visit 2 (where applicable)

• On-going lactation

• Inability to comply with trial procedures

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

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

• Unwillingness or inability to provide written informed consent for participation

• Known hyper- or hypothyroidism

• 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

Inclusion Criteria:

• Age 18-85 years old inclusive

• Current admission (on at least screening visit) with an acute coronary syndrome (non-ST elevation myocardial infarction, i.e., NSTEMI, or unstable angina) with symptoms of myocardial ischemia lasting 10 minutes or more with the patient at rest or with minimal effort plus either elevated levels of TnI on admission or dynamic changes in ECG (new ST-T changes) or T-wave inversion

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

• Written informed consent for participation in the trial

Part B

Exclusion Criteria:

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

• 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

• Known active bleeding or bleeding diatheses

• Known active infection requiring antibiotic treatment

• Severe hematologic abnormalities (haematocrit <30% AND platelet cell count of <100 × 10^3/μL, white blood AND cell count <3.3 × 10^3/μL)

• 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)

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

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

• Uncontrolled hypertension (>160/100 mmHg) at screening

• 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]))

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

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

• Renal impairment at screening (Creatinine clearance [Cockcroft-Gault] <45ml/min)

• Acute respiratory failure

• History of drug induced Stevens Johnson syndrome, Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), toxic epidermal necrolysis, or contrast allergy (requiring steroid treatment)

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

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

• Known chronic active hepatitis (B or C)

• Known HIV infection

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

• Known autoimmune disease requiring active immunosuppressive therapy

• History of organ transplantation

• 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.]

• Known pregnancy at screening (where applicable)

• On-going lactation

• Inability to comply with trial procedures

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

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

• Unwillingness or inability to provide written informed consent for participation

• Known hyper- or hypothyroidism

• 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