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Low-dose Interleukin-2 for the Reduction of Vascular Inflammation in Acute Coronary Syndromes - IVORY (IVORY)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04241601
Recruitment Status : Not yet recruiting
First Posted : January 27, 2020
Last Update Posted : July 9, 2020
Sponsor:
Information provided by (Responsible Party):
Joseph Cheriyan, MD, Cambridge University Hospitals NHS Foundation Trust

Tracking Information
First Submitted Date  ICMJE December 9, 2019
First Posted Date  ICMJE January 27, 2020
Last Update Posted Date July 9, 2020
Estimated Study Start Date  ICMJE August 31, 2020
Estimated Primary Completion Date January 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 22, 2020)
Change in vascular inflammation [ Time Frame: Baseline: Visit 2, day -6-0, and Follow Up: Visit 15, day 61 ]
Vascular inflammation (as measured by mean TBR max in the index vessel) is measured by mean TBR max in the index 18F-FDG PET/CT
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 22, 2020)
  • Change in mean TBR max in each arterial region [ Time Frame: Baseline: Visit 2, day -6-0, and Follow Up: Visit 15, day 61 ]
    Change in mean max TBR in each arterial region individually restricted to those slices with TBR>1.6
  • Change in lymphocyte subsets, Natural Killer (NK) cells, and B lymphocytes between low dose IL-2 and Placebo [ Time Frame: Throughout treatment period: Visit 3, day 1; Visit 7, day 5; Visit 8, day 12; Visit 10, day 26; Visit 14, day 54, Visit 15, day 61; Visit 16, day 82 ]
    Lymphocyte subsets:T effector [Teffs] cells defined as central memory and effector memory T cells in the non-Treg gated T cells; Natural Killer (NK) cells: CD3−CD56+CD16+CD19; and B lymphocytes: CD19+CD4−. Evaluated by flow cytometry
  • Change in percentage of Treg cells between low dose IL-2 and placebo [ Time Frame: Throughout treatment period: Visit 3, day 1; Visit 7, day 5; Visit 8, day 12; Visit 10, day 26; Visit 14, day 54, Visit 15, day 61; Visit 16, day 82 ]
    Treg cells are defined as CD3+CD4+CD25highCD127low cells within the CD3+CD4+ T cell gate. Evaluated by flow cytometry
  • Change in serum cardiac biomarkers: hsCRP [ Time Frame: Throughout treatment period: Visit 3, day 1; Visit 7, day 5; Visit 8, day 12; Visit 10, day 26; Visit 14, day 54, Visit 15, day 61; Visit 16, day 82 ]
    High-sensitivity C-reactive protein (hsCRP), in mg/L
  • Change in serum cardiac biomarkers: IL-6 [ Time Frame: Throughout treatment period: Visit 3, day 1; Visit 7, day 5; Visit 8, day 12; Visit 10, day 26; Visit 14, day 54, Visit 15, day 61; Visit 16, day 82 ]
    Interleukin 6 (IL-6), in pg/ml
  • Change in serum cardiac biomarkers: BNP [ Time Frame: Throughout treatment period: Visit 3, day 1; Visit 7, day 5; Visit 8, day 12; Visit 10, day 26; Visit 14, day 54, Visit 15, day 61; Visit 16, day 82 ]
    B-type Natriuretic peptide (BNP), in pg/mL
  • Change in serum cardiac biomarkers: Troponin I [ Time Frame: Throughout treatment period: Visit 3, day 1; Visit 7, day 5; Visit 8, day 12; Visit 10, day 26; Visit 14, day 54, Visit 15, day 61; Visit 16, day 82 ]
    Troponin I, in ng/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Incidence of Adverse Events [ Time Frame: Visit 1 (day -7-0) through to Visit 16 (day 82) ]
    Number of incidences of adverse events is assessed via adverse change in routine test results and patient consultation. Events will be catalogued using MedDRA coding.
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Incidence of injection site reaction [ Time Frame: All dosing visit: Visit 3 (day 1) through to Visit 14 (day 54) ]
    Location of injection site will be recorded as will incidences of induration, redness and swelling at the injection site
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Full Blood Count: total white cell count [ Time Frame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82) ]
    Haematology tests - full blood count: Total white cell count (WBC), in 10^9/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Full Blood Count: Red cell count [ Time Frame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82) ]
    Haematology tests - full blood count: Red cell count (RBC), in 10^12/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Full Blood Count: Haemoglobin [ Time Frame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82) ]
    Haematology tests - full blood count: Haemoglobin (Hb), in g/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Full Blood Count: Platelets [ Time Frame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82) ]
    Haematology tests - full blood count: Platelet Count, in 10^9/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Neutrophils [ Time Frame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82) ]
    Haematology tests - differential blood count: Neutrophils, in 10^9/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Lymphocytes [ Time Frame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82) ]
    Haematology tests - differential blood count: Lymphocytes, in 10^9/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Monocytes [ Time Frame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82) ]
    Haematology tests - differential blood count: Monocytes, in 10^9/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Eosinophils [ Time Frame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82) ]
    Haematology tests - differential blood count: Eosinophils, in 10^9/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Basophils [ Time Frame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82) ]
    Haematology tests - differential blood count: Basophils, in 10^9/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry - Urea [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82) ]
    Clinical biochemistry test: level of urea, in mmol/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry - Creatinine [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82) ]
    Clinical biochemistry test: level of creatinine, in µmol/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry test for liver function - ALT [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82) ]
    Clinical biochemistry blood test for liver function: Alanine Aminotransferase (ALT), in µ/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry test for liver function - ALP [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82) ]
    Clinical biochemistry blood test for liver function: Alkaline Phosphatase (ALP), in µ/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry test for liver function - Albumin [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82) ]
    Clinical biochemistry blood test for liver function: Albumin, in g/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry test for liver function - Bilirubin [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82) ]
    Clinical biochemistry blood test for liver function: Bilirubin, in µmol/L
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Thyroid function [ Time Frame: Visit 1 (day -7-0) and Visit 16 (day 82) ]
    A thyroid function blood test of level of TSH (thyroid-stimulating hormone) in the blood will be performed. T4 (Thyroxine) will be performed if TSH is abnormal.
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Electrical activity of the heart recorded using a 21-lead electrocardiogram [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82) ]
    12-lead ECG recording - QTcB (Corrected QT using Bazett's formula) intervals, in ms
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Blood pressure assessment [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82) ]
    Blood pressure will be assessed using systolic and diastolic pressure measured in mmHg.
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Heart rate assessment [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82) ]
    Heart rate assessed using bpm
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Respiratory rate assessment [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82) ]
    Measured using breaths per minute
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Oxygen saturation assessment [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82) ]
    Assessment of oxygen saturation and measured in percentage
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Physical examination evaluation - Gastrointestinal [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82) ]
    Incidences of a abdominal distention, palpations and/or patient self-report of physical discomfort or pain
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Physical examination evaluation - Skin [ Time Frame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82) ]
    Incidences of ISR lesions, nodules and/or bruising
  • Extended dosing of IL-2 in ACS patients safety and tolerability: Incidence of cardiovascular events [ Time Frame: Visit 2 (day -6-0) and Visit 15 (day 61) ]
    Occurrence of another important cardiovascular event(s) such a miocardial infarction. These will be captured through AEs and SAEs
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Low-dose Interleukin-2 for the Reduction of Vascular Inflammation in Acute Coronary Syndromes - IVORY
Official Title  ICMJE Low-dose Interleukin-2 for the Reduction of Vascular Inflammation in Acute Coronary Syndromes
Brief 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 focused 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 have been limited by increased risk of haemorrhagic events. Future breakthroughs in management are most likely to arise from targeting other relevant pathophysiological pathways. Particularly, the immune response which is an important process that has been neglected in the management of patients with ACS.

In this trial the investigators investigate the efficacy of low dose IL-2 compared with placebo in patients with ACS.

Detailed Description

A heart attack occurs when there is reduced blood flow to heart muscle cells which results from narrowings or blockages in walls of blood vessels supplying the heart, due to fatty deposits and inflammatory cells that build up over time. This build-up leads to heart muscle damage called a heart attack. The immune system plays an important role in both the development of the narrowings and the damage to the heart muscle during a heart attack. Studies have shown that there is a lower level of protective immune cells called regulatory T-cells (Tregs) in heart attack patients. Increasing the number of circulating Tregs may have a direct effect in reducing the inflammation in arteries, preventing further narrowings in blood vessels and improving heart muscle function.

Aldesleukin, also known as interleukin-2 (IL-2), is a medicine that stimulates the production of Treg cells when given at low doses and is the drug being tested in this trial. IL-2 is licensed for the treatment of kidney cancer where it is given at much higher doses than planned in this trial. It appears to be safe and well tolerated at low doses while increasing Treg cells.

IVORY will be conducted in patients presenting with a heart attack (Acute Coronary Syndrome (ACS)). Approximately, 60 patients will be randomized to receive either low dose IL-2 or placebo. It is a Phase 2, randomised, double- blinded, placebo-controlled experimental trial. Total study duration for each participant will be approximately 13 weeks.

Participants will undergo two PET/CT (Positron emission tomography-computed tomography) scans to observe change of inflammation in the blood vessels from baseline between the two trial groups (Primary Endpoint).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
a randomised, double-blind, placebo controlled, parallel group experimental medicine trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

The trial will be double-blind, with active and placebo doses appearing identical at point of issue and administration. The CUH central pharmacy will be unblinded and provided with a copy of the concealment list. Data analysis for the trial will be performed by a statistician who will be unblinded after the database lock.

The statistician, or delegate, may be unblinded for individual patients after their treatment period has concluded, to facilitate rapid reporting of safety events.

Primary Purpose: Treatment
Condition  ICMJE Acute Coronary Syndromes
Intervention  ICMJE
  • Drug: Interleukin-2 [IL-2]
    Active Comparator: IL-2 plays a key role in Treg cell development, expansion, survival and suppressive function
    Other Name: Aldesleukin
  • Other: Placebo Dextrose 5% solution
    Placebo Comparator: Dextrose 5% solution
Study Arms  ICMJE
  • Active Comparator: low dose interleukin-2
    Commercially available aldesleukin with a UK marketing authorisation will be used and will be initially prepared as per SmPC. Active and Placebo doses appearing identical at point of issue and administration.
    Intervention: Drug: Interleukin-2 [IL-2]
  • Placebo Comparator: Placebo
    Commercially available dextrose 5% injection with a UK marketing authorisation at equivalent dose volume will be used for the placebo formulation. Placebo and Active doses appearing identical at point of issue and administration.
    Intervention: Other: Placebo Dextrose 5% solution
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: January 22, 2020)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2024
Estimated Primary Completion Date January 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Able to provide written informed consent to participate.
  • Current admission (on the screening visit) with an acute coronary syndrome - ST elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), or unstable angina (UA) with symptoms suggestive of myocardial ischaemia lasting 10 minutes or longer with the patient at rest or with minimal effort AND EITHER i. elevated levels of TnI on admission OR ii. dynamic changes in ECG (new ST-T changes or T-wave inversion).
  • Where applicable, to be included in the trial women must be:

    i) Postmenopausal (for the purposes of this trial, postmenopausal is defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms) OR ii) Have had a documented hysterectomy and/or bilateral oophorectomy or sterilised OR iii) Peri-menopausal with a negative pregnancy test at screening (for the purposes of inclusion in this trial. Peri-menopausal is defined as women with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms, irregular periods). They will also have to comply with the use of contraception for the duration of the trial and undergo additional pregnancy tests during and after treatment.

  • High sensitivity C-reactive protein of >2 mg/L at screening.
  • Willingness and possibility to start dosing within 8 days from initial date of admission to the primary hospital for ACS.
  • Able to comply with all trial mandated visits.

Exclusion Criteria:

  • Current presentation (at screening) with cardiogenic shock (systolic blood pressure <80 mm Hg, unresponsive to fluids, or necessitating catecholamines).
  • Current presentation with cardiac arrest.
  • Signs or symptoms of active infection requiring intravenous antibiotic treatment at screening.
  • History of malignancies requiring active treatment (However, patients with a history of treated localised basal or squamous cell skin cancer are not excluded from participation in this trial).
  • History of solid organ transplantation or other bone marrow transplantation.
  • History of recurrent epileptic seizures in the previous 4 years; repetitive or difficult to control seizures, coma or toxic psychosis lasting >48 hours.
  • Uncontrolled hypotension (Systolic BP (SBP)<80mmHg or DBP<50mmHg) OR uncontrolled hypertension (SBP>180 or DBP>120 mmHg) at screening.
  • Average corrected QT interval (QTc) > 450 msecs using Bazett's formula from average of triplicate ECGs (or > 480 msecs if bundle branch block).
  • Renal impairment defined as Creatinine clearance [Cockcroft-Gault] <45ml/min at screening.
  • Liver dysfunction (defined as ALT > 2xULN) at screening.
  • Evidence of cholestasis defined as elevated Total Bilirubin Levels, (TBL > 1.5 x ULN) and Alkaline Phosphatase, ALP (ALP > 1.5 x ULN), at screening.
  • Known hypothyroidism or hyperthyroidism.
  • Known autoimmune disease requiring active immunosuppressive treatment.
  • Any oral or intravenous immunosuppressive treatment including regular prednisolone, hydrocortisone or disease modifying drugs. [Inhaled or topical steroids are permissible].
  • Patients on cytotoxic drugs and interferon-alpha.
  • Known Type 1 or Type 2 diabetes mellitus.
  • Contraindication to IL-2 treatment or hypersensitivity to IL-2 or to any of its excipients.
  • Participation in a previous research trial in the last 3 years which involved exposure to significant ionising radiation (i.e. cumulative research radiation dose >5 mSv)
  • Participation in a clinical trial where the patient has received a drug or new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of the drug (whichever is longer) prior to the first dose of trial medication, Visit 3 (Day 1).
  • Any medical history or clinically relevant abnormality that is deemed by the principal investigator/delegate to make the patient ineligible for inclusion because of a safety concern.
  • Pregnant women or breast feeding women.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Heike Templin +44(0)1223 250874 heike.templin@addenbrookes.nhs.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04241601
Other Study ID Numbers  ICMJE IVORY
2017-005130-27 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Joseph Cheriyan, MD, Cambridge University Hospitals NHS Foundation Trust
Study Sponsor  ICMJE Cambridge University Hospitals NHS Foundation Trust
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Joseph Cheriyan, MBChB,FRCP Cambridge Unversity Hospitals NHS Foundation Trust; Unversity of Cambridge
PRS Account Cambridge University Hospitals NHS Foundation Trust
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP