Overview
The goal of this clinical trial is to learn if treatment with ticagrelor tablets can decrease inflammation in patients with Chronic Kidney Disease (CKD). Inflammation is thought to contribute to the risk of heart disease which is the leading cause of death in patients with CKD. Decreasing inflammation may decrease the risk of heart disease.
The main questions it aims to answer are:
- Why are patients with CKD at increased risk for heart disease and how to reduce that risk in the future.
- If there could be new treatment options for managing inflammation in blood of patients with CKD.
Researchers will compare Ticagrelor to a Placebo (a look-alike substance that contains no drug) to see if ticagrelor decreases inflammation in adult patients with CKD. A comparator (control) group not receiving the drug/placebo will consist of adults without CKD.
Participants with CKD will:
- Take ticagrelor 90 mg or placebo orally twice daily for 42 days
- Visit the clinic once every 2 weeks for checkups, tests, and bloodwork
- Participation will last approximately 12 weeks
Participants without CKD (control group) will visit the clinic twice (7 weeks apart) to provide information and bloodwork. Participation will last approximately 7 weeks with additional optional visits.
Description
This randomized, double-blind, placebo-controlled trial tests the hypothesis that platelet inhibition with ticagrelor, a P2Y12 receptor antagonist, will reduce serum inflammatory cytokine levels and improve surrogate cardiovascular (CV) markers in adult patients with chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) \<45 ml/min/1.73m² who do not have a CV indication for antiplatelet therapy. The primary endpoint is serum IL-1β at Day 42 vs. baseline.
A parallel mechanistic arm will characterize leukocyte gene expression changes induced by P2Y12 antagonism using bulk RNA sequencing and will elucidate the molecular mechanisms by which CKD platelets alter leukocyte secretory function via P2Y12 receptors through in vitro co-culture studies.
The primary objective is to determine whether ticagrelor monotherapy decreases serum IL-1β and other inflammatory cytokines in patients with CKD (eGFR \<45 ml/min/1.73m²) who do not have a CV indication for antiplatelet therapy, and to evaluate the clinical relevance of this cytokine reduction on surrogate markers of CV risk.
The secondary objectives focus on genomics and mechanistic work on samples obtained from patients with CKD. Samples from a comparator group of controls without CKD will be used for better interpretation of the results.
Aim 1 (CKD Participants): N = 180 adults with CKD; eGFR \<45 ml/min/1.73m² (CKD-EPI equation); age 21-75 years; both sexes; all racial/ethnic backgrounds; receiving maximally tolerated or labeled dose of renin-angiotensin-aldosterone system inhibitors (RAASi) as guideline-directed medical therapy (GDMT); not receiving dialysis. Randomized 1:1 to ticagrelor (N=90) or placebo (N=90).
Aim 2 (Control Participants): N = 50 adults without CKD; eGFR \>60 ml/min/1.73m²; UACR \<30 mg/g; age 21-75 years; frequency-matched to CKD participants by decade of age, sex, and race. No study intervention administered.
Ticagrelor (P2Y12 receptor antagonist), 90 mg orally twice daily (BID), administered as encapsulated tablets for 42 days; or matching placebo, identically encapsulated, orally twice daily for 42 days. Study drug is added on top of maximally tolerated RAASi therapy (guideline-directed medical therapy/GDMT). Baseline use of aspirin is captured as a stratification variable for randomization. No changes to GDMT dose are permitted during the intervention period unless required for participant safety. Control participants receive no study intervention.
Eligibility
INCLUSION CRITERIA
Population 1: CKD Participants
- Provision of signed and dated written informed consent.
- Age 21 to 75 years at the time of screening, inclusive.
- Diagnosis of chronic kidney disease with estimated glomerular filtration rate (eGFR) \<45 ml/min/1.73m² as calculated by the CKD-EPI equation, confirmed from medical records or laboratory results.
- Currently receiving the maximally tolerated or labeled dose of a renin-angiotensin-aldosterone system inhibitor (RAASi) as guideline-directed medical therapy (GDMT), or documentation of the reason for not receiving RAASi (e.g., intolerance, contraindication).
Population 2: Control Participants
- Provision of signed and dated written informed consent.
- Age 21 to 75 years at the time of screening, inclusive.
- Normal kidney function, defined as eGFR \>60 ml/min/1.73m² (CKD-EPI equation) and urinary albumin-to-creatinine ratio (UACR) \<30 mg/g, confirmed from medical records or laboratory results.
EXCLUSION CRITERIA
Population 1: CKD Participants
- Unwilling or unable to participate in the protocol or comply with its components.
- End-stage renal disease (defined as receiving peritoneal dialysis or hemodialysis) or any prior solid organ or bone marrow transplant. Rationale: dialysis directly affects platelet function and would confound the primary endpoint.
- Acute kidney injury superimposed on CKD at the time of screening.
- Acute coronary syndrome, acute myocardial infarction, or acute cerebrovascular event within 6 months prior to screening. Rationale: these participants are likely receiving P2Y12 inhibitor therapy, and their enrollment would confound the primary endpoint.
- Hospitalization, major surgery, or use of systemic antibiotics within 1 month prior to screening. Rationale: these events are potentially associated with acute inflammatory changes that would confound baseline cytokine measurements.
- Blood dyscrasias, active bleeding of any site, or a known bleeding diathesis.
- History of gastrointestinal bleeding within 6 months prior to screening.
- Concomitant use of any antiplatelet agent other than aspirin (e.g., clopidogrel, prasugrel, dipyridamole) or any antithrombotic or anticoagulant medication (e.g., warfarin, direct oral anticoagulants) at the time of screening or anticipated need during the study period.
- Hemoglobin \<8 g/dL, white blood cell count \>20,000/μL, or platelet count \<50,000/μL at the time of screening.
- Any active malignancy requiring systemic treatment, or chronic liver disease (including cirrhosis or hepatitis with active inflammation).
- Current use of immunosuppressive medications (e.g., corticosteroids, calcineurin inhibitors, mycophenolate). Rationale: these medications independently alter cytokine profiles and leukocyte gene expression, confounding the primary and mechanistic endpoints.
- Age older than 75 years. Rationale: individuals older than 75 years carry a substantially higher risk of bleeding on antiplatelet therapy and are excluded for participant safety.
- Pregnancy or breastfeeding at the time of screening or plans to become pregnant during the study period. Women of reproductive potential will undergo a urine pregnancy test at screening (Visit 1); a positive result excludes from participation.
- Known severe hypersensitivity or allergy to ticagrelor or any component of the study drug formulation.
- Treatment with another investigational drug or other intervention ongoing, or within a month of randomization.
- Ongoing treatment for infection.
Population 2: Control Participants
- Any known diagnosis of chronic kidney disease, eGFR ≤60 ml/min/1.73m², or UACR ≥30 mg/g.
- Inability to sign consent and HIPAA form. Legal Authorized Representatives are not allowed to sign the consent form.
- Unwillingness or inability to participate in the protocol or comply with any of its components.
- Any current use of aspirin or NSAIDs and not willing to hold.
- Current use of antibiotics or ongoing infection.
