Atherosclerotic Cardiovascular Disease, Chronic Kidney Disease
Conditions
Keywords
Cardiorenal disease, Estimated glomerular filtration rate, Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) cryopyrin, inflammatory cytokines
Brief summary
The purpose of this study is to evaluate the safety, tolerability and the pharmacodynamics (PD) of AZD4144 following oral administration in participants with atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease (CKD).
Detailed description
This is a Phase 1b, randomized, double blind, placebo-controlled study and will be conducted in participants with established ASCVD and CKD with persistent inflammation (High-sensitivity C-reactive protein \[hsCRP\] \> 2 mg/L and eGlomerular filtration rate \[eGFR\] ≥ 30 to \< 60 mL/min/1.73m2). The participants will be randomized in the 1:1 ratio to either receive treatment with AZD4144 or placebo. The study will be comprised of: * A screening period of 28 days * Treatment period where each participant will either receive oral dose of AZD4144 or placebo for 28 days. * A follow-up visit (Day 35 ±1) and a Final Follow-up (on Day 56±1) post first dose administration. The total duration of the study will be approximately 12 weeks.
Interventions
DRUGAZD4144
Oral solution of AZD4144 will be given to randomised participants as per the arm they have been assigned.
OTHERPlacebo
Placebo will be given orally to randomized participants as per the arm they are assigned.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Participants with established ASCVD history of one or more of the following 1. Prior Myocardial infarction (MI) (\>60 days from index event) or coronary revascularization procedure like coronary stenting or Coronary artery bypass graft (CABG) 2. Prior ischemic stroke (\>60 days from index event) 3. Symptomatic Peripheral Arterial Disease * Chronic kidney disease defined as eGlomular filtration rate (eGFR) ≥ 30 to \< 60 mL/min/1.73 m2 * Serum hsCRP \> 2 mg/L * Body mass index ≥ 18 to ≤ 45 kg/m2 * All females must have a negative pregnancy test at the Screening Visit and at the randomization visit 1. Sexually active male participants with partner of childbearing potential must adhere to the contraception methods 2. Females of childbearing potential must not be lactating and if heterosexually active must agree to use an approved method of highly effective contraception 3. Females of non-childbearing potential must be confirmed at the Screening visit Key
Exclusion criteria
* History of malignancy within the last 5 years * History of MI, coronary revascularization, stroke or revascularization for peripheral arterial disease in the 60 days prior to Screening * Active systemic infection within 30 days * Clinically significant active and chronic infections within 60 days prior to randomization * Clinically significant recurrent infection (≥ 2× during the last 12-month period). * Renal transplant participants, participants on dialysis, and those with a history of acute kidney injury in the past 12 month
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative change from baseline to 4 weeks in systemic Interleukin-6 (IL-6) levels | Day 1 to Day 28 | The effect of AZD4144 on circulating inflammatory biomarker IL-6 compared with placebo will be evaluated. |
| Number of participants with adverse events | From first dose (Day 1) until Follow-up (Day 56±1) | The safety and the tolerability of AZD4144 compared with placebo will be evaluated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative change from baseline to 4 weeks in systemic IL-18 and High-sensitivity C-reactive protein (hsCRP) levels | Day 1 to Day 28 | The effect of AZD4144 on circulating inflammatory biomarkers IL-18 and hsCRP compared with placebo will be evaluated. |
| Maximum plasma drug concentration (Cmax) | Day 1 to Day 28 (pre-dose), Day 1 and Day 22±1 (post-dose) | The Cmax after administration of AZD4144 in participants with ASCVD and CKD will be evaluated. |
| Time to reach maximum observed concentration (tmax) | Day 1 to Day 28 (pre-dose), Day 1 and Day 22±1 (post-dose) | The tmax after administration of AZD4144 in participants with ASCVD and CKD will be evaluated. |
| Observed lowest concentration before the next dose is administered (Ctrough) | Day 1 to Day 28 (pre-dose), Day 1 and Day 22±1 (post-dose) | The Ctrough after administration of AZD4144 in participants with ASCVD and CKD will be evaluated. |
Countries
Bulgaria, Hungary, Romania, United States
Outcome results
None listed