Chronic Kidney Disease, Heart Failure
Conditions
Keywords
Heart Failure, Type 2 diabetes mellitus, Diabetic kidney disease, Chronic kidney disease, Mineralocorticoid receptor modulator, Sodium-glucose co-transporter-2 inhibitor, AZD9977, Dapagliflozin, Urinary albumin creatinine ratio
Brief summary
The purpose of the study is to evaluate the efficacy and safety of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone and to assess the dose-response relationship, dapagliflozin alone and 3 doses of AZD9977 combined with dapagliflozin on urinary albumin to creatinine ratio (UACR). The study will be conducted in participants with heart failure (HF) with left ventricular ejection fraction (LVEF \[below 60%\]) and chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR \[between ≥ 20 and ≤ 60 mL/min/1.73 m\^2, with at least 20% of participants with eGFR ≥ 20 to \<30 mL/min/1.73\^2 and a maximum of 35% of participants with eGFR ≥ 45 mL/min/1.73 m\^2\]).
Detailed description
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.
Interventions
DRUGAZD9977
Participants will receive AZD9977 as per the arms they are randomized.
DRUGDapagliflozin
Participants will receive dapagliflozin as per the arms they are randomized.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Participants who meet the eligibility criteria will be randomized to one of the following treatment group: 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
Eligibility
Sex/Gender
ALL
Age
21 Years to 130 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 |
| 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. |
Countries
Belgium, Bulgaria, Canada, Czechia, Denmark, Germany, Hungary, India, Italy, Japan, Lithuania, Poland, Russia, Slovakia, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
The study was conducted between 26-January-2021 (first subject first visit) to 22-September-2023 (last subject last visit).
Pre-assignment details
Participants who signed the Informed Consent Form (ICF) were enrolled into study. The study included an optional pre-screening visit.
Participants by arm
| Arm | Count |
|---|---|
| AZD9977 15 mg + Dapagliflozin 10 mg Participants received AZD9977 15 mg and dapagliflozin 10 mg orally once daily for 12 weeks. | 34 |
| AZD9977 50 mg + Dapagliflozin 10 mg Participants received AZD9977 50 mg and dapagliflozin 10 mg orally once daily for 12 weeks. | 31 |
| AZD9977 150 mg + Dapagliflozin 10 mg Participants received AZD9977 150 mg and dapagliflozin 10 mg orally once daily for 12 weeks. | 35 |
| AZD9977 150 mg Participants received AZD9977 150 mg and placebo matching to dapagliflozin orally once daily for 12 weeks. | 6 |
| Dapagliflozin 10 mg Participants received dapagliflozin 10 mg and placebo matching to AZD9977 orally once daily for 12 weeks. | 33 |
| Placebo Placebo participants received placebo matching to AZD9977 and dapagliflozin orally once daily for 12 weeks. | 5 |
| Total | 144 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 4 | 3 | 1 | 1 | 1 |
| Overall Study | Death | 0 | 1 | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Participants discontinued study treatment due to other reasons | 0 | 2 | 2 | 0 | 1 | 0 |
| Overall Study | Protocol-Specified Withdrawal Criterion Met | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Subjects randomised, not treated, Protocol Deviation | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Subjects randomised, not treated, Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 2 | 0 |
| Overall Study | Withdrawal of Consent | 1 | 1 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | AZD9977 15 mg + Dapagliflozin 10 mg | AZD9977 50 mg + Dapagliflozin 10 mg | AZD9977 150 mg + Dapagliflozin 10 mg | AZD9977 150 mg | Dapagliflozin 10 mg | Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 70.9 Years STANDARD_DEVIATION 7.1 | 72.4 Years STANDARD_DEVIATION 8.4 | 73.7 Years STANDARD_DEVIATION 8.1 | 77.0 Years STANDARD_DEVIATION 8.7 | 72.2 Years STANDARD_DEVIATION 9.4 | 77.2 Years STANDARD_DEVIATION 5.8 | 72.7 Years STANDARD_DEVIATION 8.2 |
| Race/Ethnicity, Customized Asian | 4 Participants | 3 Participants | 7 Participants | 0 Participants | 3 Participants | 0 Participants | 17 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 30 Participants | 27 Participants | 27 Participants | 6 Participants | 28 Participants | 4 Participants | 122 Participants |
| Sex: Female, Male Female | 11 Participants | 5 Participants | 8 Participants | 1 Participants | 10 Participants | 1 Participants | 36 Participants |
| Sex: Female, Male Male | 23 Participants | 26 Participants | 27 Participants | 5 Participants | 23 Participants | 4 Participants | 108 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 2 / 31 | 0 / 34 | 0 / 6 | 1 / 33 | 0 / 5 |
| other Total, other adverse events | 1 / 33 | 4 / 31 | 13 / 34 | 5 / 6 | 7 / 33 | 2 / 5 |
| serious Total, serious adverse events | 1 / 33 | 3 / 31 | 2 / 34 | 0 / 6 | 4 / 33 | 2 / 5 |
Outcome results
Primary
Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 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.
Time frame: Baseline (Day 1) to Week 12
Population: Full analysis set included all participants who were randomized and either received or did not receive any study intervention. Here, 'number of participants analyzed' specifies all participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AZD9977 15 mg + Dapagliflozin 10 mg | Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at Week 12 | -56.391 Percent change from baseline |
| AZD9977 50 mg + Dapagliflozin 10 mg | Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at Week 12 | -42.085 Percent change from baseline |
| AZD9977 150 mg + Dapagliflozin 10 mg | Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at Week 12 | -58.047 Percent change from baseline |
| AZD9977 150 mg | Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at Week 12 | -45.01 Percent change from baseline |
| Dapagliflozin 10 mg | Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at Week 12 | -34.318 Percent change from baseline |
| Placebo | Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at Week 12 | 230.32 Percent change from baseline |
p-value: 0.3645F-Test
Secondary
Absolute Value of eGFR Over Time
Effect of all doses of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo on eGFR was assessed
Time frame: Baseline (Day 1) to Week 12
Population: Safety analysis set included all participants who were randomized and received any study intervention. Here, 'number of participants analyzed' specifies all participants who were evaluated for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD9977 15 mg + Dapagliflozin 10 mg | Absolute Value of eGFR Over Time | Baseline | 41.341 mL/min/1.73 m^2 | Standard Deviation 12.902 |
| AZD9977 15 mg + Dapagliflozin 10 mg | Absolute Value of eGFR Over Time | Week 12 | 41.219 mL/min/1.73 m^2 | Standard Deviation 15.112 |
| AZD9977 50 mg + Dapagliflozin 10 mg | Absolute Value of eGFR Over Time | Baseline | 38.586 mL/min/1.73 m^2 | Standard Deviation 10.155 |
| AZD9977 50 mg + Dapagliflozin 10 mg | Absolute Value of eGFR Over Time | Week 12 | 39.429 mL/min/1.73 m^2 | Standard Deviation 8.998 |
| AZD9977 150 mg + Dapagliflozin 10 mg | Absolute Value of eGFR Over Time | Baseline | 43.663 mL/min/1.73 m^2 | Standard Deviation 16.168 |
| AZD9977 150 mg + Dapagliflozin 10 mg | Absolute Value of eGFR Over Time | Week 12 | 39.063 mL/min/1.73 m^2 | Standard Deviation 13.819 |
| AZD9977 150 mg | Absolute Value of eGFR Over Time | Baseline | 36.874 mL/min/1.73 m^2 | Standard Deviation 12.626 |
| AZD9977 150 mg | Absolute Value of eGFR Over Time | Week 12 | 34.075 mL/min/1.73 m^2 | Standard Deviation 21.071 |
| Dapagliflozin 10 mg | Absolute Value of eGFR Over Time | Baseline | 41.895 mL/min/1.73 m^2 | Standard Deviation 12.791 |
| Dapagliflozin 10 mg | Absolute Value of eGFR Over Time | Week 12 | 37.973 mL/min/1.73 m^2 | Standard Deviation 11.571 |
| Placebo | Absolute Value of eGFR Over Time | Baseline | 40.288 mL/min/1.73 m^2 | Standard Deviation 15.176 |
| Placebo | Absolute Value of eGFR Over Time | Week 12 | 48.920 mL/min/1.73 m^2 | Standard Deviation 21.111 |
Secondary
Absolute Value of Serum Potassium Over Time
Effect of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo on serum K+ was assessed.
Time frame: Baseline (Day 1) and Week 12
Population: Safety analysis set included all participants who were randomized and received any study intervention. Here, 'number of participants analyzed' specifies all participants who were evaluated for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD9977 15 mg + Dapagliflozin 10 mg | Absolute Value of Serum Potassium Over Time | Baseline | 4.60 mmol/L | Standard Deviation 0.38 |
| AZD9977 15 mg + Dapagliflozin 10 mg | Absolute Value of Serum Potassium Over Time | Week 12 | 4.62 mmol/L | Standard Deviation 0.5 |
| AZD9977 50 mg + Dapagliflozin 10 mg | Absolute Value of Serum Potassium Over Time | Baseline | 4.44 mmol/L | Standard Deviation 0.61 |
| AZD9977 50 mg + Dapagliflozin 10 mg | Absolute Value of Serum Potassium Over Time | Week 12 | 4.53 mmol/L | Standard Deviation 0.43 |
| AZD9977 150 mg + Dapagliflozin 10 mg | Absolute Value of Serum Potassium Over Time | Baseline | 4.46 mmol/L | Standard Deviation 0.44 |
| AZD9977 150 mg + Dapagliflozin 10 mg | Absolute Value of Serum Potassium Over Time | Week 12 | 4.63 mmol/L | Standard Deviation 0.43 |
| AZD9977 150 mg | Absolute Value of Serum Potassium Over Time | Baseline | 4.50 mmol/L | Standard Deviation 0.38 |
| AZD9977 150 mg | Absolute Value of Serum Potassium Over Time | Week 12 | 5.00 mmol/L | Standard Deviation 0.61 |
| Dapagliflozin 10 mg | Absolute Value of Serum Potassium Over Time | Baseline | 4.60 mmol/L | Standard Deviation 0.66 |
| Dapagliflozin 10 mg | Absolute Value of Serum Potassium Over Time | Week 12 | 4.64 mmol/L | Standard Deviation 0.4 |
| Placebo | Absolute Value of Serum Potassium Over Time | Baseline | 4.50 mmol/L | Standard Deviation 0.28 |
| Placebo | Absolute Value of Serum Potassium Over Time | Week 12 | 4.33 mmol/L | Standard Deviation 0.32 |
Secondary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
Effect of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo on eGFR was assessed.
Time frame: Baseline (Day 1) and Week 12
Population: Safety analysis set included all participants who were randomized and received any study intervention. Here, 'number of participants analyzed' specifies all participants who were evaluated for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD9977 15 mg + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | -1.432 mL/min/1.73 m^2 |
| AZD9977 50 mg + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | -1.160 mL/min/1.73 m^2 |
| AZD9977 150 mg + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | -5.307 mL/min/1.73 m^2 |
| AZD9977 150 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | -0.923 mL/min/1.73 m^2 |
| Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | -3.498 mL/min/1.73 m^2 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | 6.880 mL/min/1.73 m^2 |
Secondary
Change From Baseline in Serum Potassium (K+)
Effect of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo on serum K+ was assessed.
Time frame: Baseline (Day 1) and Week 12
Population: Safety analysis set included all participants who were randomized and received any study intervention. Here, 'number of participants analyzed' specifies all participants who were evaluated for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD9977 15 mg + Dapagliflozin 10 mg | Change From Baseline in Serum Potassium (K+) | 0.056 millimoles per liter (mmol/L) |
| AZD9977 50 mg + Dapagliflozin 10 mg | Change From Baseline in Serum Potassium (K+) | 0.003 millimoles per liter (mmol/L) |
| AZD9977 150 mg + Dapagliflozin 10 mg | Change From Baseline in Serum Potassium (K+) | 0.109 millimoles per liter (mmol/L) |
| AZD9977 150 mg | Change From Baseline in Serum Potassium (K+) | 0.55 millimoles per liter (mmol/L) |
| Dapagliflozin 10 mg | Change From Baseline in Serum Potassium (K+) | 0.040 millimoles per liter (mmol/L) |
| Placebo | Change From Baseline in Serum Potassium (K+) | 0.03 millimoles per liter (mmol/L) |
Secondary
Number of Participants With Adverse Events (AEs)
The safety and tolerability of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo was assessed.
Time frame: From baseline (Day 1) until Day 113
Population: Safety analysis set included all participants who were randomized and received any study intervention. Here, 'number of participants analyzed' specifies all participants who were evaluated for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD9977 15 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE | 9 Participants |
| AZD9977 15 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any SAE | 1 Participants |
| AZD9977 15 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to discontinuation of IP | 0 Participants |
| AZD9977 15 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to dose interruption | 1 Participants |
| AZD9977 15 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to withdrawal from study | 0 Participants |
| AZD9977 15 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any SAE with outcome death | 0 Participants |
| AZD9977 50 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE | 12 Participants |
| AZD9977 50 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to discontinuation of IP | 4 Participants |
| AZD9977 50 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any SAE | 3 Participants |
| AZD9977 50 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to withdrawal from study | 5 Participants |
| AZD9977 50 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any SAE with outcome death | 2 Participants |
| AZD9977 50 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to dose interruption | 1 Participants |
| AZD9977 150 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to withdrawal from study | 2 Participants |
| AZD9977 150 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE | 18 Participants |
| AZD9977 150 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any SAE with outcome death | 0 Participants |
| AZD9977 150 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any SAE | 2 Participants |
| AZD9977 150 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to dose interruption | 1 Participants |
| AZD9977 150 mg + Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to discontinuation of IP | 3 Participants |
| AZD9977 150 mg | Number of Participants With Adverse Events (AEs) | Any AE | 5 Participants |
| AZD9977 150 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to dose interruption | 0 Participants |
| AZD9977 150 mg | Number of Participants With Adverse Events (AEs) | Any SAE | 0 Participants |
| AZD9977 150 mg | Number of Participants With Adverse Events (AEs) | Any SAE with outcome death | 0 Participants |
| AZD9977 150 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to discontinuation of IP | 1 Participants |
| AZD9977 150 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to withdrawal from study | 0 Participants |
| Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any SAE with outcome death | 1 Participants |
| Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any SAE | 4 Participants |
| Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE | 14 Participants |
| Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to dose interruption | 3 Participants |
| Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to withdrawal from study | 1 Participants |
| Dapagliflozin 10 mg | Number of Participants With Adverse Events (AEs) | Any AE leading to discontinuation of IP | 1 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any AE leading to dose interruption | 1 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any AE | 3 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any SAE with outcome death | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any AE leading to discontinuation of IP | 1 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any AE leading to withdrawal from study | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any SAE | 2 Participants |
Secondary
Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 12 Weeks to Assess Dose-Response Relationship
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.
Time frame: Baseline (Day 1) to Week 12
Population: Full analysis set included all participants who were randomized and either received or did not receive any study intervention. Here, 'number of participants analyzed' specifies all participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AZD9977 15 mg + Dapagliflozin 10 mg | Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 12 Weeks to Assess Dose-Response Relationship | -56.391 Percent change from baseline |
| AZD9977 50 mg + Dapagliflozin 10 mg | Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 12 Weeks to Assess Dose-Response Relationship | -42.085 Percent change from baseline |
| AZD9977 150 mg + Dapagliflozin 10 mg | Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 12 Weeks to Assess Dose-Response Relationship | -58.047 Percent change from baseline |
| AZD9977 150 mg | Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 12 Weeks to Assess Dose-Response Relationship | -45.01 Percent change from baseline |
| Dapagliflozin 10 mg | Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 12 Weeks to Assess Dose-Response Relationship | -34.318 Percent change from baseline |
| Placebo | Percent Change From Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 12 Weeks to Assess Dose-Response Relationship | 230.32 Percent change from baseline |
p-value: 0.158895% CI: [-62.53, 17.644]Mixed Models Analysis
p-value: 0.684695% CI: [-52.195, 62.634]Mixed Models Analysis
p-value: 0.139895% CI: [-64.85, 16.066]Mixed Models Analysis