A Study to Evaluate the Safety and Efficacy of AZD5718 in Participants With Proteinuric Chronic Kidney Disease
Condition: Chronic Kidney Disease
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic
Intervention: AZD5718; Dapagliflozin 10 mg; Placebo
Intervention description: Participants will receive once daily oral dose of AZD5718 as per the arms they are randomised, and will continue until Week 20.; Participants will receive once daily oral dose of 10 mg dapagliflozin for 8 weeks as an add-on therapy.; Participants will receive once daily oral dose of placebo matched to AZD5718, and will continue until Week 20.
Intervention MeSH terms: Dapagliflozin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: 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.
Enrollment: 613.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: Nephrology; Chronic kidney disease; Proteinuria; Diabetic kidney disease; Diabetes mellitus

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.
    

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^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.