The Sponsor decided to terminate the study early due to lack of efficacy. There were no safety concerns related to the study.

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.

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.

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^2.

• 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 1.
  • 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 2.
  • 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®).

• Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional exploratory genetic research.

• Participants should have: a) stable blood pressure (BP [BP <= 150/100 mmHg at Visit 1, and 3]); b)stable dose of angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARB) for at least 4 weeks prior to Screening Visit 1; c) participants who have been unable to tolerate ACEi or ARB therapy may be enrolled.

• Participants must have been on a stable dose for at least 4 weeks prior to Screening Visit 1, who have been on additional antihypertensives (including diuretics); on treatment with drugs with potential to influence albuminuria eg., non-steroidal anti-inflammatory drug; on renin inhibitor or an aldosterone antagonist in combination with an ACEi or an ARB.

• Participants on Sodium-glucose co-transporter-2 inhibitors (SGLT2i) or Glucagon-like peptide-1 receptor agonist (GLP1-RA) treatment, the participants must have been on a stable dose for at least 4 weeks prior to randomization visit.

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 1.

• Any of the following concomitant conditions or diseases at Screening Visit 1:

  1. History of QT prolongation associated with other medications that required discontinuation of that medication, and congenital long QT syndrome.
  2. Acute coronary syndrome, percutaneous coronary intervention, coronary artery bypass grafting within 6 months.
  3. High degree atrioventricular block II-III, sinus node dysfunction.
  4. Stroke within 3 months, heart failure, and anticipated dialysis or renal transplantation within 1 year.
  5. Any other condition or clinically relevant abnormal findings in physical examination, laboratory results or ECG during screening period.
  6. History of substance dependence or a positive screen for drugs or alcohol abuse. Alcohol and drug screening to be completed for all participants locally with laboratory kits provided by the central laboratory.

• Participant who had severe course of COVID-19 (extracorporeal membrane oxygenation, mechanically ventilated), and/or had a confirmed case of COVID-19 within 4 weeks of Screening Visit 1.

• Ongoing use of any biologic drug and/or small molecule targeting the immune system.

• Any serum creatinine-altering drugs within 1 month prior to Screening Visit 1.

• Treatment with any concomitant medications known to be associated with Torsades de Pointes or potent inducers/inhibitors of cytochrome P450 3A4 within 4 weeks of Visit 3 (Randomization).

• Treatment with zileuton, cilastatin (dipeptidase-1 [DPEP1] inhibitor), or leukotriene receptor antagonists (eg, montelukast) within 4 weeks of Screening Visit 1.

• Treatment with simvastatin, lovastatin, and atorvastatin at doses > 40 mg per day within 1 month prior to Screening Visit 1.

• Concurrent enrollment in another clinical study involving an investigational treatment or drug or participation in a device study within 3 months prior to Screening Visit 1.

• Participants with a known hypersensitivity to AZD5718 or any of the excipients of the product. Participants with a known hypersensitivity to dapagliflozin or any of the excipients of the product.

• Donation of blood or significant blood loss in excess of 500 mL within 3 months prior to Day 1 (or > 1200 mL in the year prior to Day 1).

• Plasma donation within 60 days prior to Day 1.

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study center).

• Judgement by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

• For women only - currently pregnant (a negative serum pregnancy test is required at Screening Visit 1 and urine pregnancy test at Day 1 [Visit 3]) or breast-feeding.

• An employee, or close relative of an employee, of AstraZeneca, the Contract Research Organisation, or the study site, regardless of the employee's role.

• Participants who are legally institutionalized.

• Participants working night shifts, and who cannot avoid strenuous manual labour during the study.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

No member of the study team at AstraZeneca, or representative, personnel at study centres, or any CRO handling data will have access to the randomization scheme prior to unblinding for the primary analysis.

No unpublished information contained herein may be disclosed without prior written approval from AstraZeneca. Access to this document must be restricted to relevant parties.