A Phase 2b Randomised, Double-Blind, Placebo-Controlled, Multi-Centre, Dose-Ranging Study of AZD5718 in Participants With Proteinuric Chronic Kidney Disease
Overview
- Phase
- Phase 2
- Intervention
- AZD5718
- Conditions
- Chronic Kidney Disease
- Sponsor
- AstraZeneca
- Enrollment
- 613
- Locations
- 1
- Primary Endpoint
- Change From Baseline in Reduction of Urine Albumin to Creatinine Ratio (ACR) to Week 20
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
The purpose of the study is to evaluate the dose-response efficacy, safety, and pharmacokinetics (PK) of AZD5718 in participants with proteinuric chronic kidney disease.
Detailed Description
The study will be conducted in approximately 118 study centers across 12 countries. The overall study period will be around 28 weeks. Approximately 632 participants comprising of 67% diabetic kidney disease (DKD) and 33% non-DKD participants will be enrolled. After a screening period of up to 4 weeks, the participants will be randomised in a 1:1:1:1 ratio to receive one of the doses of AZD5718 and/or placebo for the first 12 weeks (Day 85 \[treatment period 1\]), with an add-on therapy of 8 weeks of dapagliflozin for all participants from Week 12 to 20 (Day 85 to 141 \[treatment period 2\]). Only participants still taking their assigned treatment from treatment period 1 will progress to treatment period 2. Any participant with urine albumin to creatinine ratio (ACR) \< 30 mg/g at Week 12 will be excluded from treatment period 2. The eligibility check to enter treatment period 2 will be done at Visit 7 (Week 12) using the last available urine ACR result. The final analysis will be done after all participants have completed follow-up period of up to 4 weeks. The expected total study duration, including the Screening Period, for each participant will be at least 28 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Capable of giving signed informed consent form.
- •Male or female adults, \>= 18 years of age at study entry.
- •For participants who haven't reached the age of maturity according to local regulations in their country, a written informed consent should be obtained from the participant and participants legally acceptable representative.
- •Body weight within 50-150 kg and body mass index within the range 18 to 45 kg/m\^
- •Participants with proteinuric CKD defined as:
- •eGFR 20 - 75 mL/min/1.73m\^2 based on Chronic Kidney Disease Epidemiology Collaboration equation at Screening Visit
- •Albuminuria defined as 200 -5000 mg albumin/g creatinine based on the geometric mean of the replicated measurements using 3 sequential first morning void urine at Visit
- •Participants with diagnosis of Type 2 Diabetes Mellitus (DM) \[for DKD sub-group only\].
- •Females of non-childbearing potential must have been surgically sterilized or be postmenopausal, and all female participants must have a negative pregnancy test at screening and prior to study drug administration.
- •Male participants must be surgically sterile or agree to use highly effective contraceptives. Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a male condom with spermicide from Day 1 to 3 months after the last dose of the study drug. Approved/Certified measurements in Japan are as Vasectomy, tubal occlusion, intrauterine device (provided coils are copper banded), levonorgestrel intrauterine system (eg, Mirena®). These measurements are acceptable forms of highly effective birth control in Japan. Not Approved/Certified measurements in Japan are as: Cerazette® (desogestrel) pills, medroxyprogesterone injections (eg, Depo-Provera®), etonogestrel implants (eg, Implanon®, Norplan®), normal and low dose combined oral pills, norelgestromin/ethinylestradiol transdermal system (eg, Evra® Patch), intravaginal device (eg, NuvaRing®).
Exclusion Criteria
- •Participants with recent positive hepatitis B or hepatitis C.
- •Diagnosis of polycystic kidney disease or anatomical causes of CKD.
- •Diagnosis of Type 1 DM.
- •Participants with severe hepatic impairment (Child-Pugh class C).
- •Abnormal laboratory findings at Screening Visit
- •Any of the following concomitant conditions or diseases at Screening Visit 1:
- •History of QT prolongation associated with other medications that required discontinuation of that medication, and congenital long QT syndrome.
- •Acute coronary syndrome, percutaneous coronary intervention, coronary artery bypass grafting within 6 months.
- •High degree atrioventricular block II-III, sinus node dysfunction.
- •Stroke within 3 months, heart failure, and anticipated dialysis or renal transplantation within 1 year.
Arms & Interventions
AZD5718 Dose 1 + Dapagliflozin 10 mg
Participants will receive once daily oral dose 1 of AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.
Intervention: AZD5718
AZD5718 Dose 1 + Dapagliflozin 10 mg
Participants will receive once daily oral dose 1 of AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.
Intervention: Dapagliflozin 10 mg
AZD5718 Dose 2 + Dapagliflozin 10 mg
Participants will receive once daily oral dose 2 of AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.
Intervention: AZD5718
AZD5718 Dose 2 + Dapagliflozin 10 mg
Participants will receive once daily oral dose 2 of AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.
Intervention: Dapagliflozin 10 mg
AZD5718 Dose 3 + Dapagliflozin 10 mg
Participants will receive once daily oral dose 3 of AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.
Intervention: AZD5718
AZD5718 Dose 3 + Dapagliflozin 10 mg
Participants will receive once daily oral dose 3 of AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.
Intervention: Dapagliflozin 10 mg
Placebo + Dapagliflozin 10 mg
Participants will receive once daily oral dose of placebo matched to AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.
Intervention: Dapagliflozin 10 mg
Placebo + Dapagliflozin 10 mg
Participants will receive once daily oral dose of placebo matched to AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.
Intervention: Placebo
Outcomes
Primary Outcomes
Change From Baseline in Reduction of Urine Albumin to Creatinine Ratio (ACR) to Week 20
Time Frame: Week 1 (Baseline) to Week 20
The dose response effect of AZD5718 on urine ACR at 20 weeks was evaluated. Values less than 1 indicate improvement from baseline.
Secondary Outcomes
- Change From Baseline in 24-hours Mean Systolic Blood Pressure to Week 12(Week 1 (Baseline) to Week 12)
- Plasma Concentrations of AZD5718(From Week 2 to Week 20)
- Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12(Week 1 (Baseline), Week 2, Week 4, Week 8, and Week 12)
- Number of Participants With Adverse Events and Serious Adverse Events(From Screening (Week -4 to 0) to Week 24)
- Change From Baseline in Reduction of Urine ACR to Week 12(Week 1 (Baseline) to Week 12)