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

This study is currently recruiting participants.
See Contacts and Locations
Verified June 2017 by Joseph Cheriyan, MD, Cambridge University Hospitals NHS Foundation Trust
Sponsor:
Collaborator:
University of Cambridge
Information provided by (Responsible Party):
Joseph Cheriyan, MD, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier:
NCT03113773
First received: March 14, 2017
Last updated: June 7, 2017
Last verified: June 2017
  Purpose

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.


Condition Intervention Phase
Ischemic Heart Disease Drug: Proleukin Drug: Placebo Injection Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Low Dose Interleukin-2 in Patients With Stable Ischaemic Heart Disease and Acute Coronary Syndromes

Resource links provided by NLM:


Further study details as provided by Joseph Cheriyan, MD, Cambridge University Hospitals NHS Foundation Trust:

Primary Outcome Measures:
  • Part A - Determination of IL-2 safety and tolerability parameters [ Time Frame: Through study completion, average of 28 days ]
    Biochemistry, haematology, ECGs and adverse events will be reviewed throughout the trial

  • Part B - Change in the mean circulating Treg levels (percentage of CD4+ T regulatory defined as CD3+, CD4+, CD25high, CD127low cells within the CD3+, CD4+ T cell gate) following treatment with IL-2. [ Time Frame: Measured Days 1 and 6 ]
    Percentage change of CD4+ T regulatory cells will be reviewed following treatment with IL-2.

  • Part B - Determination of IL-2 safety and tolerability parameters [ Time Frame: Through study completion, average of 28 days ]
    Biochemistry, haematology, ECGs and adverse events will be reviewed


Secondary Outcome Measures:
  • Part B - Changes in circulating cardiac biomarkers (including hs-CRP, IL-6, TnI, BNP) [ Time Frame: Measured Days 1, 6 and 28 ]
    Circulating cardiac biomarkers (including hs-CRP, IL-6, TnI, BNP)

  • Part B - Change in lymphocyte subsets [ Time Frame: Measured Days 1 and 6 ]
    Change in lymphocyte subsets

  • Part B - Pharmacokinetic analysis of IL-2 levels [ Time Frame: Measured Days 1 and 6 ]
    PK analysis of IL-2


Estimated Enrollment: 57
Actual Study Start Date: June 7, 2017
Estimated Study Completion Date: August 2018
Estimated Primary Completion Date: May 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A
Proleukin/Placebo in patients with stable ischaemic heart disease
Drug: Proleukin
Patients will be treated with subcutaneous injections of IL-2 (range 0.3 X 10^6 - 3.0 X 10^6 IU) or placebo once daily for five consecutive days during the trial.A maximum dose of 3.0 X 10^6 IU will be allowed per day.
Drug: Placebo Injection
Dextrose 5%
Experimental: Part B
Proleukin/Placebo in patients with cute coronary syndromes
Drug: Proleukin
Patients will be treated with subcutaneous injections of IL-2 (range 0.3 X 10^6 - 3.0 X 10^6 IU) or placebo once daily for five consecutive days during the trial.A maximum dose of 3.0 X 10^6 IU will be allowed per day.
Drug: Placebo Injection
Dextrose 5%

Detailed Description:

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 [ i) Part A : Repeated doses will be given in the range of 0.3x10^6 IU up to a maximum of 3.0x10^6 IU (total of 25 completed patients across 5 groups: 3:2 randomisation IL-2:placebo) ii) Part B : 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 (graft-versus-host disease)-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. 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.

The investigators hypothesize that low doses of IL-2 in patients with ACS can increase Treg number and function, and ultimately promote plaque stabilisation and myocardial healing (this will be further addressed in future studies). In this context, it may improve patient recovery and limit the occurrence/recurrence of major clinical events.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Part A

Inclusion Criteria:

  • Age 18-75 years old inclusive
  • Previous history (> 6 months) of coronary artery disease
  • No history of recent (< 6 months) 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%, platelet cell count of <100 × 103/μL, white blood cell count <4 × 103/μL)
  • Known malignancies
  • Known heart failure with impaired LV (Left Ventricular) function: echocardiographic findings of LV EF (Left Ventricular Ejection Fraction) < 45%
  • Hypotension (Systolic BP<100mm Hg, Diastolic BP <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 (Liver Function Test) 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 skin hypersensitivity reactions
  • History of 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
  • 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 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 18-75 years old inclusive
  • Current admission (on at least screening visit) with NSTEMI/ACS
  • 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%, platelet cell count of <100 × 103/μL, white blood cell count <4 × 103/μL)
  • Known malignancies
  • Known heart failure with impaired LV function: echocardiographic findings of LV EF < 45%
  • 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
  • Acute kidney injury or chronic kidney disease at Stage > 3B (eGFR < 45)
  • Acute respiratory failure
  • History of skin hypersensitivity reactions
  • History of 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
  • 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 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03113773

Contacts
Contact: Charmaine Griffiths, BN, MPH 01223 348963 charmaine.griffiths@addenbrookes.nhs.uk
Contact: Emma Day, BSc, MSc, PhD 01223 349132 emma.day@addenbrookes.nhs.uk

Locations
United Kingdom
Addenbrooke's Hospital Recruiting
Cambridge, Cambridgeshire, United Kingdom, CB20QQ
Contact: Joseph Cheriyan, MBChB, MA, FRCP       jc403@medschl.cam.ac.uk   
Principal Investigator: Joseph Cheriyan, MBChB, MA, FRCP         
Sponsors and Collaborators
Cambridge University Hospitals NHS Foundation Trust
University of Cambridge
Investigators
Principal Investigator: Joseph Cheriyan, MBCHB, MA, FRCP Cambridge University Hospitals NHS Foundation Trust
  More Information

Responsible Party: Joseph Cheriyan, MD, Dr, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT03113773     History of Changes
Other Study ID Numbers: LILACS (A093371)
Study First Received: March 14, 2017
Last Updated: June 7, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Ischemia
Heart Diseases
Acute Coronary Syndrome
Myocardial Ischemia
Coronary Artery Disease
Pathologic Processes
Cardiovascular Diseases
Vascular Diseases
Coronary Disease
Arteriosclerosis
Arterial Occlusive Diseases
Aldesleukin
Interleukin-2
Antineoplastic Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on September 21, 2017