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

NCT03113773 | Completed Phase 1 DMC

• 1 other identifier: LILACS (A093371)
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Ischemic Heart Disease

Outcome Measures

Primary Outcomes (3)

• Part A - Determination of IL-2 safety and tolerability parameters

  Biochemistry, haematology, ECGs and adverse events will be reviewed throughout the trial

  Through study completion, average of 24 days

• 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.

  Percentage change of CD4+ T regulatory cells will be reviewed following treatment with IL-2.

  Measured Days 1 and 6

• Part B - Determination of IL-2 safety and tolerability parameters

  Biochemistry, haematology, ECGs and adverse events will be reviewed

  Through study completion, average of 24 days

Secondary Outcomes (3)

• Part B - Changes in circulating cardiac biomarkers (including hs-CRP, IL-6, TnI, BNP)

  Measured Days 1, 6 and between days 10-24

• Part B - Change in lymphocyte subsets

  Measured Days 1 and 6

• Part B - Pharmacokinetic analysis of IL-2 levels

  Measured Days 1 and 6

Study Arms (2)

Part A

EXPERIMENTAL

Proleukin/Placebo in patients with stable ischaemic heart disease

Drug: Proleukin; Drug: Placebo Injection

Part B

EXPERIMENTAL

Proleukin/Placebo in patients with cute coronary syndromes

Drug: Proleukin; Drug: Placebo Injection

Interventions

Proleukin DRUG

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.

Part A; Part B

Placebo Injection DRUG

Dextrose 5%

Part A; Part B

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead
• University of Cambridge: collaborator

Study Sites (1)

Addenbrooke's Hospital

Cambridge, Cambridgeshire, CB20QQ, United Kingdom

Location

Related Publications (2)

• Zhao TX, Sriranjan RS, Tuong ZK, Lu Y, Sage AP, Nus M, Hubsch A, Kaloyirou F, Vamvaka E, Helmy J, Kostapanos M, Jalaludeen N, Klatzmann D, Tedgui A, Rudd JHF, Horton SJ, Huntly BJP, Hoole SP, Bond SP, Clatworthy MR, Cheriyan J, Mallat Z. Regulatory T-Cell Response to Low-Dose Interleukin-2 in Ischemic Heart Disease. NEJM Evid. 2022 Jan;1(1):EVIDoa2100009. doi: 10.1056/EVIDoa2100009. Epub 2021 Nov 22.

  PMID: 38319239 DERIVED

• Zhao TX, Kostapanos M, Griffiths C, Arbon EL, Hubsch A, Kaloyirou F, Helmy J, Hoole SP, Rudd JHF, Wood G, Burling K, Bond S, Cheriyan J, Mallat Z. Low-dose interleukin-2 in patients with stable ischaemic heart disease and acute coronary syndromes (LILACS): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase I/II clinical trial. BMJ Open. 2018 Sep 17;8(9):e022452. doi: 10.1136/bmjopen-2018-022452.

  PMID: 30224390 DERIVED

MeSH Terms

Conditions

Myocardial Ischemia

Interventions

aldesleukin

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Vascular Diseases

Study Officials

• Joseph Cheriyan, MBCHB, MA, FRCP

  Cambridge University Hospitals NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr

Study Record Dates

• First Submitted: March 14, 2017
• First Posted: April 14, 2017
• Study Start: May 11, 2017
• Primary Completion: February 21, 2019
• Study Completion: February 21, 2019
• Last Updated: September 14, 2021

Record last verified: 2021-09

Locations

GB (1)