Clinical trial NCT06824987: Dose-Ranging Safety, Tolerability, and Efficacy Study of AZD2373 in Participants With APOL1-Mediated Kidney Disease
Official title: Phase 2b Multicentre, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Dose-Ranging Study to Assess the Efficacy, Safety, and Tolerability of AZD2373 in Participants With APOL1-Mediated Kidney Disease (APPRECIATE)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: APOL1-Mediated Kidney Disease
Keywords: APOL1-Mediated Kidney Disease
AZD2373
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2025-02-13
Enrollment: 96
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomized at a 1:1:1 ratio to 3 study treatment arms:

* Placebo group
* AZD2373 - Arm 1
* AZD2373 - Arm 2
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the efficacy and safety of AZD2373 in participants diagnosed with APOL1-Mediated Kidney Disease (AMKD) who are homozygotes or compound heterozygotes for APOL1 high-risk genotypes (G1 and G2). The primary hypothesis to be evaluated is that AZD2373, compared with placebo, will result in a greater reduction in UACR as assessed by the relative change from Baseline in UACR at Week 30.

Detailed description: This is a Phase 2b study to assess efficacy and safety of AZD2373 involving 3 study treatment arms where participants and study personnel including study investigators are blinded to the assigned treatment.

Participants with 300 mg/g or greater UACR and eGFR ≥ 25mL/min/1.73m2 will be recruited into the study. Participants on kidney replacement therapy (dialysis or kidney transplant) or any other organ transplant will be excluded.

All participants will remain in the study on treatment until the last participant has completed 30 weeks of treatment. The treatment duration will be up to minimum of 30 weeks of study treatment.

Approximately 96 participants will be randomized to study intervention (approximately 32 participants in each treatment group).

Eligibility criteria: Inclusion Criteria:

* Age: Male and female participants aged 18 to 65 years, inclusive at the time of informed consent.
* Participants who have high-risk APOL1 genotype (G1/G1; G1/G2; G2/G2). The screening period can be extended if there are delays related to the shipment, handling, or processing of genotype results.
* A geometric mean UACR ≥ 300 mg/g calculated based on the mean of readings taken from 3 FMV urine samples collected on 3 consecutive days. Since the mean will be assessed for eligibility, any of the 3 readings may fall below 300 mg/g.
* eGFR ≥ 25 mL/min/1.73m2.
* Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria:

* Participants with diagnosis of Type 1 diabetes mellitus.
* Body Mass Index \> 45 kg/m2.
* SBP \> 180 mmHg/DBP \> 110 mmHg (measured when the participant is considered to be at steady state, and preferably when they have taken their BP medications that same day).
* QTcF \> 470 ms.
* Acute coronary syndrome/Acute myocardial infraction +/- coronary intervention with Percutaneous coronary intervention or Coronary artery bypass grafting within 6 months.
* Transient ischaemic attack/ stroke within 3 months.
* High second to third degree AV block or clinically significant sinus node dysfunction untreated with pacemaker.
* A history of ventricular arrhythmias requiring treatment.
* Participants with Type 2 diabetes mellitus must be excluded if ANY of the following conditions are present:

  1. Current or any past use of insulin
  2. Screening Haemoglobin A1c \> 8.0%
  3. Receiving more than one oral anti-hyperglycaemic agent (excluding SGLT inhibitors which can be taken in addition to one other oral anti-hyperglycaemic agent).
* Participant on kidney replacement therapy (dialysis or kidney transplant) or any other organ transplant.
* History or serologic evidence of autoimmune-mediated glomerular disease including but not limited to: lupus nephritis (positive lupus serology), ANCA associated vasculitis (antineutrophil cytoplasmic antibody), membranous nephropathy (anti-phospholipase A2 receptor antibody or other autoantibody associated with membranous nephropathy), anti-GBM disease (anti-GBM antibody), or IgA nephropathy.
* Another underlying cause of kidney disease that is not associated with APOL1, including but not limited to polycystic kidney disease or, congenital anomalies of the kidney and urinary tract.
* History of a diagnosed coagulopathy, a major unexplained bleeding event, or other high-risk bleeding diathesis.

Primary outcomes:
measure: Relative change in Urine Albumin-Creatinine Ratio (UACR)
timeFrame: From Baseline at Week 30
Secondary outcomes:
measure: Relative change in Urine Albumin-Creatinine Ratio (UACR)
timeFrame: From Baseline at the End of Treatment (Until the last participant completes Week 30)
measure: Relative change in Urine Protein-Creatinine Ratio (UPCR)
timeFrame: From Baseline at Week 30
measure: Relative change in Urine Protein-Creatinine Ratio (UPCR)
timeFrame: From Baseline at the End of Treatment (Until the last participant completes Week 30)
measure: Proportion of participants achieving a 45% or greater reduction in Urine Albumin-Creatinine Ratio (UACR)
timeFrame: From Baseline at Week 30
measure: Proportion of participants achieving a 45% or greater reduction in Urine Albumin-Creatinine Ratio (UACR)
timeFrame: From Baseline at the End of Treatment (Until the last participant completes Week 30)
measure: Relative change in eGFR
timeFrame: From Baseline at the End of Treatment (Until the last participant completes Week 30)
measure: Incidence of development of ADA and ADA titer (if participants are ADA-positive)
timeFrame: During treatment (up to Week 30) and follow-up (up to 12 weeks)
measure: Plasma concentration
timeFrame: From Baseline at the End of Treatment (Until the last participant completes Week 30)
measure: Adverse Events (AEs), Serious Adverse Events (SAEs), and Drug Adverse Events (DAEs).
timeFrame: From baseline at the End of Treatment (Until the last participant completes Week 30)
Other outcomes:
Locations:
city: Alabaster
country: United States
facility: Research Site
state: Alabama
city: Birmingham
country: United States
facility: Research Site
state: Alabama
city: Irondale
country: United States
facility: Research Site
state: Alabama
city: Gardena
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Northridge
country: United States
facility: Research Site
state: California
city: Valencia
country: United States
facility: Research Site
state: California
city: Brandon
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Orlando
country: United States
facility: Research Site
state: Florida
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Lawrenceville
country: United States
facility: Research Site
state: Georgia
city: Macon
country: United States
facility: Research Site
state: Georgia
city: Hinsdale
country: United States
facility: Research Site
state: Illinois
city: Lafayette
country: United States
facility: Research Site
state: Louisiana
city: Bethesda
country: United States
facility: Research Site
state: Maryland
city: Potomac
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Roseville
country: United States
facility: Research Site
state: Michigan
city: Tupelo
country: United States
facility: Research Site
state: Mississippi
city: Brooklyn
country: United States
facility: Research Site
state: New York
city: Laurelton
country: United States
facility: Research Site
state: New York
city: Fayetteville
country: United States
facility: Research Site
state: North Carolina
city: Greenville
country: United States
facility: Research Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Research Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Research Site
state: North Carolina
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Anderson
country: United States
facility: Research Site
state: South Carolina
city: Columbia
country: United States
facility: Research Site
state: South Carolina
city: Orangeburg
country: United States
facility: Research Site
state: South Carolina
city: Spartanburg
country: United States
facility: Research Site
state: South Carolina
city: Chattanooga
country: United States
facility: Research Site
state: Tennessee
city: Dallas
country: United States
facility: Research Site
state: Texas
city: Dallas
country: United States
facility: Research Site
state: Texas
city: Mesquite
country: United States
facility: Research Site
state: Texas
city: Pearland
country: United States
facility: Research Site
state: Texas
city: San Antonio
country: United States
facility: Research Site
state: Texas
city: Alexandria
country: United States
facility: Research Site
state: Virginia
city: Norfolk
country: United States
facility: Research Site
state: Virginia
city: Leicester
country: United Kingdom
facility: Research Site
city: Liverpool
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
Study officials:
References: