Chronic Kidney Disease
Conditions
Keywords
Nephrology, Chronic kidney disease, Proteinuria, Diabetic kidney disease, Diabetes mellitus
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.
Interventions
DRUGAZD5718
Participants will receive once daily oral dose of AZD5718 as per the arms they are randomised, and will continue until Week 20.
DRUGDapagliflozin 10 mg
Participants will receive once daily oral dose of 10 mg dapagliflozin for 8 weeks as an add-on therapy.
DRUGPlacebo
Participants will receive once daily oral dose of placebo matched to AZD5718, and will continue until Week 20.
Sponsors
Parexel
Emerald Clinical Inc.
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Reduction of Urine Albumin to Creatinine Ratio (ACR) to Week 20 | 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
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Reduction of Urine ACR to Week 12 | Week 1 (Baseline) to Week 12 | The dose response effect of AZD5718 on urine ACR at 12 weeks was evaluated. Values less than 1 indicate improvement from baseline. |
| Number of Participants With Adverse Events and Serious Adverse Events | From Screening (Week -4 to 0) to Week 24 | The safety and tolerability profile of AZD5718 treatment was assessed |
| Change From Baseline in 24-hours Mean Systolic Blood Pressure to Week 12 | Week 1 (Baseline) to Week 12 | The effect of AZD5718 on ambulatory blood pressure was assessed |
| Plasma Concentrations of AZD5718 | From Week 2 to Week 20 | The PK of AZD5718 after repeated oral dosing for 20 weeks was evaluated |
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 1 (Baseline), Week 2, Week 4, Week 8, and Week 12 | The effect of AZD5718 on renal function was evaluated |
Countries
Argentina, Brazil, Germany, Hungary, Israel, Japan, Malaysia, Poland, Taiwan, Ukraine, United States
Participant flow
Recruitment details
Participants were enrolled in this study from 01 October 2020 to 06 September 2022. The study was terminated early on 01 July 2022 due to lack of efficacy.
Pre-assignment details
The screening period was for 4 weeks. Participants who met all the inclusion and none of the exclusion criteria were enrolled to the study. All study assessments were performed as per the schedule of assessment.
Participants by arm
| Arm | Count |
|---|---|
| AZD5718 Dose 1 + Dapagliflozin 10 mg Participants received once daily oral dose of AZD5718 Dose 1 for 12 weeks, and thereafter an add-on therapy of 10 mg dapagliflozin for 8 weeks. | 154 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg Participants received once daily oral dose of AZD5718 Dose 2 for 12 weeks, and thereafter an add-on therapy of 10 mg dapagliflozin for 8 weeks. | 152 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg Participants received once daily oral dose of AZD5718 Dose 3 for 12 weeks, and thereafter an add-on therapy of 10 mg dapagliflozin for 8 weeks. | 149 |
| Placebo + Dapagliflozin 10 mg Participants received once daily oral dose of placebo matched to AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks. | 153 |
| Total | 608 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 2 | 3 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 1 |
| Overall Study | Development of Study Specific Withdrawal Criteria | 3 | 1 | 2 | 2 |
| Overall Study | Due to Covid-19 pandemic | 7 | 3 | 7 | 6 |
| Overall Study | Early termination from the study | 54 | 51 | 50 | 50 |
| Overall Study | Failure to meet randomisation criteria | 2 | 3 | 4 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 1 |
| Overall Study | Missing | 3 | 0 | 0 | 5 |
| Overall Study | Participants who did not receive treatment | 0 | 1 | 4 | 0 |
| Overall Study | Physician Decision | 0 | 3 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 6 | 0 | 3 |
Baseline characteristics
| Characteristic | AZD5718 Dose 1 + Dapagliflozin 10 mg | AZD5718 Dose 2 + Dapagliflozin 10 mg | AZD5718 Dose 3 + Dapagliflozin 10 mg | Placebo + Dapagliflozin 10 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 64.9 Years STANDARD_DEVIATION 10.7 | 63.7 Years STANDARD_DEVIATION 10.63 | 65.1 Years STANDARD_DEVIATION 9.39 | 64.3 Years STANDARD_DEVIATION 10.71 | 64.5 Years STANDARD_DEVIATION 10.37 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 32 Participants | 37 Participants | 28 Participants | 32 Participants | 129 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 122 Participants | 115 Participants | 121 Participants | 121 Participants | 479 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 54 Participants | 55 Participants | 56 Participants | 52 Participants | 217 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants | 16 Participants | 15 Participants | 15 Participants | 66 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 8 Participants | 11 Participants | 9 Participants | 40 Participants |
| Race (NIH/OMB) White | 68 Participants | 73 Participants | 67 Participants | 77 Participants | 285 Participants |
| Sex: Female, Male Female | 57 Participants | 53 Participants | 45 Participants | 53 Participants | 208 Participants |
| Sex: Female, Male Male | 97 Participants | 99 Participants | 104 Participants | 100 Participants | 400 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 154 | 0 / 152 | 0 / 149 | 1 / 153 |
| other Total, other adverse events | 16 / 154 | 8 / 152 | 9 / 149 | 8 / 153 |
| serious Total, serious adverse events | 12 / 154 | 8 / 152 | 11 / 149 | 6 / 153 |
Outcome results
Primary
Change From Baseline in Reduction of Urine Albumin to Creatinine Ratio (ACR) 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.
Time frame: Week 1 (Baseline) to Week 20
Population: Per-protocol analysis set consisted of all participants who received the additional treatment with dapagliflozin post-Week 12 and who did not violate the terms of the protocol in a way that could affect the primary efficacy endpoint significantly.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Change From Baseline in Reduction of Urine Albumin to Creatinine Ratio (ACR) to Week 20 | 0.79 milligram/gram (mg/g) |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Change From Baseline in Reduction of Urine Albumin to Creatinine Ratio (ACR) to Week 20 | 0.81 milligram/gram (mg/g) |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Change From Baseline in Reduction of Urine Albumin to Creatinine Ratio (ACR) to Week 20 | 0.77 milligram/gram (mg/g) |
| Placebo + Dapagliflozin 10 mg | Change From Baseline in Reduction of Urine Albumin to Creatinine Ratio (ACR) to Week 20 | 0.84 milligram/gram (mg/g) |
Secondary
Change From Baseline in 24-hours Mean Systolic Blood Pressure to Week 12
The effect of AZD5718 on ambulatory blood pressure was assessed
Time frame: Week 1 (Baseline) to Week 12
Population: All participants in the Full Analysis Population who had valid Ambulatory Blood Pressure data for change from baseline analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Change From Baseline in 24-hours Mean Systolic Blood Pressure to Week 12 | -2.06 millimeter mercury (mm Hg) | Standard Deviation 10.782 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Change From Baseline in 24-hours Mean Systolic Blood Pressure to Week 12 | 1.56 millimeter mercury (mm Hg) | Standard Deviation 11.407 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Change From Baseline in 24-hours Mean Systolic Blood Pressure to Week 12 | -1.83 millimeter mercury (mm Hg) | Standard Deviation 9.986 |
| Placebo + Dapagliflozin 10 mg | Change From Baseline in 24-hours Mean Systolic Blood Pressure to Week 12 | 3.76 millimeter mercury (mm Hg) | Standard Deviation 11.779 |
Secondary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12
The effect of AZD5718 on renal function was evaluated
Time frame: Week 1 (Baseline), Week 2, Week 4, Week 8, and Week 12
Population: Per-protocol analysis set consisted of all participants who received the additional treatment with dapagliflozin post-Week 12.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 12 | -0.612 milliliter/minute/1.73m^2 | Standard Deviation 6.2138 |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 8 | -0.760 milliliter/minute/1.73m^2 | Standard Deviation 6.0304 |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 2 | -0.470 milliliter/minute/1.73m^2 | Standard Deviation 6.3936 |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 4 | -0.735 milliliter/minute/1.73m^2 | Standard Deviation 6.5764 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 4 | 0.140 milliliter/minute/1.73m^2 | Standard Deviation 5.2628 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 2 | -0.140 milliliter/minute/1.73m^2 | Standard Deviation 5.2801 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 8 | -0.535 milliliter/minute/1.73m^2 | Standard Deviation 5.8865 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 12 | -1.149 milliliter/minute/1.73m^2 | Standard Deviation 6.1783 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 8 | -1.144 milliliter/minute/1.73m^2 | Standard Deviation 6.5142 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 12 | -0.394 milliliter/minute/1.73m^2 | Standard Deviation 6.4678 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 4 | -0.817 milliliter/minute/1.73m^2 | Standard Deviation 6.1986 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 2 | -0.429 milliliter/minute/1.73m^2 | Standard Deviation 5.7175 |
| Placebo + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 12 | -0.257 milliliter/minute/1.73m^2 | Standard Deviation 6.4508 |
| Placebo + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 2 | 0.547 milliliter/minute/1.73m^2 | Standard Deviation 5.7124 |
| Placebo + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 4 | 0.058 milliliter/minute/1.73m^2 | Standard Deviation 6.3583 |
| Placebo + Dapagliflozin 10 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12 | Week 8 | -0.068 milliliter/minute/1.73m^2 | Standard Deviation 5.3729 |
Secondary
Change From Baseline in Reduction of Urine ACR to Week 12
The dose response effect of AZD5718 on urine ACR at 12 weeks was evaluated. Values less than 1 indicate improvement from baseline.
Time frame: Week 1 (Baseline) to Week 12
Population: Per-protocol analysis set consisted of all participants who received the additional treatment with dapagliflozin post-Week 12 and who did not violate the terms of the protocol in a way that could affect the primary efficacy endpoint significantly.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Change From Baseline in Reduction of Urine ACR to Week 12 | 0.94 mg/g |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Change From Baseline in Reduction of Urine ACR to Week 12 | 1.03 mg/g |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Change From Baseline in Reduction of Urine ACR to Week 12 | 0.96 mg/g |
| Placebo + Dapagliflozin 10 mg | Change From Baseline in Reduction of Urine ACR to Week 12 | 1.10 mg/g |
Secondary
Number of Participants With Adverse Events and Serious Adverse Events
The safety and tolerability profile of AZD5718 treatment was assessed
Time frame: From Screening (Week -4 to 0) to Week 24
Population: All participants who were randomised and received any study treatment. Participants were evaluated according to the actual treatment they received. If a participant had received a different treatment dose than randomised throughout the study, they would have been analysed according to the treated dose, not the randomisation dose.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE | 82 Participants |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE leading to withdrawal from study | 7 Participants |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE leading to dose interruption | 7 Participants |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE with outcome = death | 0 Participants |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE possibly related to study treatment as assessed by investigator | 14 Participants |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any SAE (including events with outcome = death) | 12 Participants |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE leading to discontinuation of study treatment | 12 Participants |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE leading to withdrawal from study | 0 Participants |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE leading to discontinuation of study treatment | 2 Participants |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any SAE (including events with outcome = death) | 8 Participants |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE leading to dose interruption | 6 Participants |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE possibly related to study treatment as assessed by investigator | 12 Participants |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE with outcome = death | 0 Participants |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE | 81 Participants |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE leading to discontinuation of study treatment | 3 Participants |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE | 104 Participants |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE with outcome = death | 0 Participants |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any SAE (including events with outcome = death) | 11 Participants |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE leading to dose interruption | 5 Participants |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE leading to withdrawal from study | 1 Participants |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE possibly related to study treatment as assessed by investigator | 8 Participants |
| Placebo + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any SAE (including events with outcome = death) | 6 Participants |
| Placebo + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE possibly related to study treatment as assessed by investigator | 14 Participants |
| Placebo + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE leading to withdrawal from study | 1 Participants |
| Placebo + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE with outcome = death | 1 Participants |
| Placebo + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE | 80 Participants |
| Placebo + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE leading to dose interruption | 10 Participants |
| Placebo + Dapagliflozin 10 mg | Number of Participants With Adverse Events and Serious Adverse Events | Any AE leading to discontinuation of study treatment | 6 Participants |
Secondary
Plasma Concentrations of AZD5718
The PK of AZD5718 after repeated oral dosing for 20 weeks was evaluated
Time frame: From Week 2 to Week 20
Population: All participants in the Full Analysis Population who have at least one detectable AZD5718 plasma concentration measurement post-treatment. The Pharmacokinetic Population was used for all PK analyses. Here n is the number of participants included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 2 (pre-dose) | 4.771 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 113.047 |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (pre-dose) | 3.975 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 85.449 |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 8 (pre-dose) | 3.947 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 77.097 |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 12 (pre-dose) | 4.107 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 79.068 |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 16 (pre-dose) | 4.115 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 76.378 |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 20 (pre-dose) | 3.813 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 65.605 |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (post-dose, 1-2 hours) | 16.321 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 115.673 |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (post-dose, 2-5 hours) | 18.376 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 77.409 |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (post-dose, 5-8 hours) | 16.713 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 65.648 |
| AZD5718 Dose 1 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (post dose, 8-12 hours) | 14.434 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 52.414 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (post-dose, 5-8 hours) | 76.834 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 59.503 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 2 (pre-dose) | 12.181 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 116.038 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 20 (pre-dose) | 10.200 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 122.277 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 16 (pre-dose) | 10.006 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 97.216 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (pre-dose) | 11.207 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 111.951 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (post dose, 8-12 hours) | 53.706 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 68.16 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (post-dose, 2-5 hours) | 86.464 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 103.733 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 8 (pre-dose) | 11.579 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 113.404 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (post-dose, 1-2 hours) | 71.279 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 128.551 |
| AZD5718 Dose 2 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 12 (pre-dose) | 11.041 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 81.967 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (post-dose, 2-5 hours) | 464.721 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 79.567 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 12 (pre-dose) | 33.568 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 127.405 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 16 (pre-dose) | 35.662 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 130.148 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 20 (pre-dose) | 33.063 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 100.32 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (post-dose, 5-8 hours) | 343.531 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 90.628 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (post-dose, 1-2 hours) | 340.794 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 147.394 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 2 (pre-dose) | 37.346 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 138.565 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (post dose, 8-12 hours) | 234.913 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 97.174 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 4 (pre-dose) | 37.525 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 127.66 |
| AZD5718 Dose 3 + Dapagliflozin 10 mg | Plasma Concentrations of AZD5718 | Week 8 (pre-dose) | 35.903 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 116.207 |