Efficacy, Safety and Tolerability of AZD9977 and Dapagliflozin in Participants With Heart Failure and Chronic Kidney Disease

After screening, eligible participants will undergo a run-in period where all participants receive dapagliflozin for up to 7 weeks depending on pre-study use of SGLT2i or not. At the end of the run-in period, eligible participants will be randomly assigned with a 1:1:1:1 ratio to receive once daily administration of one of the following 4 study treatments group for 12 weeks. To ensure blinding, the study treatment will be administered in the form of 3 oral capsules of AZD9977 or placebo and 1 oral tablet or dapagliflozin.

1. AZD9977 Dose A + dapagliflozin 10 mg
2. AZD9977 Dose B + dapagliflozin 10 mg
3. AZD9977 Dose C + dapagliflozin 10 mg
4. Dapagliflozin 10 mg

Participants will be randomized to one of the above treatment group, according to type 2 diabetes mellitus \[T2DM (yes/no)\] and eGFR (≥ 20 to <30 mL/min/1.73\^2; or ≥ 30 to < 45 mL/min/1.73\^2; or ≥45 mL/min/1.73\^2).

The total duration of participation will be approximately 22 to 24weeks.

• AZD9977 (Drug): Participants will receive AZD9977 as per the arms they are randomized.
• Dapagliflozin (Drug): Participants will receive dapagliflozin as per the arms they are randomized.

Primary outcomes

• Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at Week 12 [Baseline (Day 1) to Week 12]: The effect of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone on UACR assessed. Urine samples were collected for the analysis of UACR. UACR (milligrams per gram \[mg/g\]) was calculated as 10 x urine albumin (mg per deciliter \[mg/dL\])/urine creatinine (g/dL). Change from baseline in UACR at the end of 12 weeks of study treatment was calculated as the average of the UACR values at Week 12 and was analyzed by a mixed-effects model for repeated measures (MMRM). Due to early removal of arms (AZD9977 150 mg monotherapy and Placebo), the study objectives were revised and the MMRM analysis included the 4 remaining arms (AZD9977 15 mg + Dapagliflozin, AZD9977 50 mg + Dapagliflozin, AZD9977 150 mg + Dapagliflozin, and Dapagliflozin 10 mg). Since 2 arms were removed from the study resulting in fewer participants only descriptive statistics are shown for those two arms without formal comparison.

Secondary outcomes

• Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 12 Weeks to Assess Dose-Response Relationship [Baseline (Day 1) to Week 12]: The dose-response relationship of dapagliflozin alone and 3 doses of AZD9977 combined with dapagliflozin on UACR was assessed. Urine samples were collected for the analysis of UACR. UACR (mg/g) was calculated as 10 x urine albumin (mg/dL)/urine creatinine (g/dL). Change from baseline in UACR at the end of 12 weeks of study treatment was calculated as the average of the UACR values at Week 12 and was analyzed by a mixed-effects model for repeated measures (MMRM). Due to early removal of arms (AZD9977 150 mg monotherapy and Placebo), the study objectives were revised and the MMRM analysis included the 4 remaining arms (AZD9977 15 mg + Dapagliflozin, AZD9977 50 mg + Dapagliflozin, AZD9977 150 mg + Dapagliflozin, and Dapagliflozin 10 mg). Since 2 arms were removed from the study resulting in fewer participants, only descriptive statistics was shown for those two arms without formal comparison.
• Number of Participants With Adverse Events (AEs) [From baseline (Day 1) until Day 113]: The safety and tolerability of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo was assessed.
• Change From Baseline in Serum Potassium (K+) [Baseline (Day 1) and Week 12]: Effect of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo on serum K+ was assessed.
• Absolute Value of Serum Potassium Over Time [Baseline (Day 1) and Week 12]: Effect of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo on serum K+ was assessed.
• Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) [Baseline (Day 1) and Week 12]: Effect of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo on eGFR was assessed.
• Absolute Value of eGFR Over Time [Baseline (Day 1) to Week 12]: Effect of all doses of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo on eGFR was assessed

Sex: All, ages: 21 Years to 130 Years

Inclusion Criteria:

Participants are included in the study if any of the following criteria apply:

* Documented diagnosis of stable symptomatic HF (New York Heart Association class II-III) at screening, and a medical history of typical symptoms and signs of HF in those who are currently receiving loop diuretic treatment
* Left ventricular ejection fraction <60% documented by the most recent echocardiogram or cardiac magnetic resonance imaging within the last 12 months prior to screening
* Stable background treatment for HF, hypertension, diabetes mellitus or renal disease according to guidelines
* N-terminal-pro-brain natriuretic peptide (NT proBNP) ≥300 pg/mL for participants with sinus rhythm at screening; and NT proBNP ≥600 pg/mL for participants with atrial fibrillation/flutter at screening
* The eGFR ≥30 and ≤60 mL/min/1.73\^2 (by CKD- EPI formula) and UACR ≥30 mg/g (3 mg/mmol) and <3000 mg/g (300 mg/mmol)
* Body mass index less than 40 kg/m\^2
* Serum/plasma K+ level ≥ 3.5 and < 5.0 mmol/L within 10 days prior to randomization
* Serum/ plasma Na+ level within normal reference values within 10 days prior to randomization
* Systolic blood pressure should be at protocol defined range at randomization (Visit 3), with no change to antihypertensive treatments in previous 3 weeks
* Male or female of non-childbearing potential
* All participants must follow protocol defined contraceptives procedures

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

* Primary glomerulopathy, vasculitic renal disease, prior dialysis or unstable rapidly progressing renal disease, autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or anti-neutrophil cytoplasm antibody-associated vasculitis
* Participants with currently decompensated HF requiring hospitalization for optimization of HF treatment and are not on stable HF therapy at the time of enrollment
* HF due to cardiomyopathies
* High output HF (e.g., due to hyperthyroidism or Paget's disease)
* HF due to pericardial disease, congenital heart disease or clinically significant uncorrected primary cardiac valvular disease or planned cardiac valve repair/replacement
* Participants with uncontrolled diabetes mellitus (Glycated hemoglobin >10%)
* Participants with Type 1 diabetes mellitus
* Intermittent or persistent 2nd or 3rd degree atrioventricular block, sinus node dysfunction with clinically significant bradycardia or sinus pauses, not treated with a pacemaker
* History of any life-threatening cardiac dysrhythmia or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter
* Acute coronary syndrome and/or elective/non-elective percutaneous cardiac interventions (within 3 months) prior to randomisation or is planned to undergo any of these procedures during the study
* Any major cardiovascular (eg, open chest, coronary artery bypass grafting or valvular repair/replacement) or major non-cardiovascular surgery within 3 months prior to randomisation or is planned to undergo any cardiovascular surgery during the study
* Heart transplantation or left ventricular assist device at any time or if these are planned
* Kidney or any organ transplantation or if these are planned
* Medical conditions associated with development of hyperkalaemia (Addison's disease )
* History or ongoing allergy/hypersensitivity, to sodium-glucose co-transporter-2 inhibitor (SGLT2i e.g., dapagliflozin, empagliflozin)
* Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within previous 3 months prior to randomisation
* Hepatic disease, including hepatitis and/or hepatic impairment (Child-Pugh class A-C), and aspartate aminotransferase or alanine transaminase or total bilirubin should be in protocol defined range at time of screening and/ or within 7 days prior to randomization
* Participants with newly detected pathological laboratory values or an ongoing disease condition
* If the participants clinical signs and symptoms consistent with COVID-19, and has been previously hospitalized with COVID-19 infection and did not fully recover their previous health status
* Previous randomization in the present study
* Prior medical treatment with an mineralocorticoid receptor antagonist where the medication was taken within 90 days prior to screening
* Current or prior treatment within 6 months prior to screening with cytotoxic therapy, immunosuppressive therapy, or other immunotherapy

Participant flow

Outcome results

• Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at Week 12 (Primary), Mean, Percent change from baseline: AZD9977 15 mg + Dapagliflozin 10 mg -56.391 (-71.528 to -33.207); AZD9977 50 mg + Dapagliflozin 10 mg -42.085 (-64.174 to -6.376); AZD9977 150 mg + Dapagliflozin 10 mg -58.047 (-73.560 to -33.430); AZD9977 150 mg -45.01 (NA to NA); Dapagliflozin 10 mg -34.318 (-58.204 to 3.220); Placebo 230.32 (NA to NA) (p 0.3645)
• Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 12 Weeks to Assess Dose-Response Relationship (Secondary), Mean, Percent change from baseline: AZD9977 15 mg + Dapagliflozin 10 mg -56.391 (-71.528 to -33.207); AZD9977 50 mg + Dapagliflozin 10 mg -42.085 (-64.174 to -6.376); AZD9977 150 mg + Dapagliflozin 10 mg -58.047 (-73.560 to -33.430); AZD9977 150 mg -45.01 (NA to NA); Dapagliflozin 10 mg -34.318 (-58.204 to 3.220); Placebo 230.32 (NA to NA) (p 0.1588)
• Number of Participants With Adverse Events (AEs) (Secondary), Count of participants, Participants: AZD9977 15 mg + Dapagliflozin 10 mg 9; AZD9977 50 mg + Dapagliflozin 10 mg 12; AZD9977 150 mg + Dapagliflozin 10 mg 18; AZD9977 150 mg 5; Dapagliflozin 10 mg 14; Placebo 3
• Change From Baseline in Serum Potassium (K+) (Secondary), Least squares mean, millimoles per liter (mmol/L): AZD9977 15 mg + Dapagliflozin 10 mg 0.056 (-0.106 to 0.219); AZD9977 50 mg + Dapagliflozin 10 mg 0.003 (-0.184 to 0.190); AZD9977 150 mg + Dapagliflozin 10 mg 0.109 (-0.061 to 0.279); AZD9977 150 mg 0.55 (NA to NA); Dapagliflozin 10 mg 0.040 (-0.129 to 0.209); Placebo 0.03 (NA to NA)
• Absolute Value of Serum Potassium Over Time (Secondary), Mean, mmol/L: AZD9977 15 mg + Dapagliflozin 10 mg 4.60 +/- 0.38; AZD9977 50 mg + Dapagliflozin 10 mg 4.44 +/- 0.61; AZD9977 150 mg + Dapagliflozin 10 mg 4.46 +/- 0.44; AZD9977 150 mg 4.50 +/- 0.38; Dapagliflozin 10 mg 4.60 +/- 0.66; Placebo 4.50 +/- 0.28
• Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) (Secondary), Least squares mean, mL/min/1.73 m^2: AZD9977 15 mg + Dapagliflozin 10 mg -1.432 (-4.305 to 1.441); AZD9977 50 mg + Dapagliflozin 10 mg -1.160 (-4.351 to 2.030); AZD9977 150 mg + Dapagliflozin 10 mg -5.307 (-8.295 to -2.320); AZD9977 150 mg -0.923 (NA to NA); Dapagliflozin 10 mg -3.498 (-6.528 to -0.469); Placebo 6.880 (NA to NA)
• Absolute Value of eGFR Over Time (Secondary), Mean, mL/min/1.73 m^2: AZD9977 15 mg + Dapagliflozin 10 mg 41.341 +/- 12.902; AZD9977 50 mg + Dapagliflozin 10 mg 38.586 +/- 10.155; AZD9977 150 mg + Dapagliflozin 10 mg 43.663 +/- 16.168; AZD9977 150 mg 36.874 +/- 12.626; Dapagliflozin 10 mg 41.895 +/- 12.791; Placebo 40.288 +/- 15.176

Adverse events

Time frame: From baseline (Day 1) until Day 113

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Enrolment stopped early because of slow recruitment. Therefore, pre-specified sample size of 500 and planned statistical power were not achieved. Nine subjects were excluded from analysis due to site misconduct and GCP non-compliance.

56 more sites not listed.

• Study Protocol (PDF, 2022-02-02)
• Statistical Analysis Plan (PDF, 2019-11-26)

• John McMurray, Principal investigator, University of Glasgow, United Kingdom