Heart Failure With Preserved Ejection Fraction
Conditions
Keywords
Heart failure, Heart failure with preserved ejection fraction, HFpEF
Brief summary
This is a randomised, double-blind, placebo-controlled, multi-center sequential phase 2b and Phase 3 study to evaluate the efficacy and safety of AZD4831 administered for up to 48 Weeks in participants with heart failure with left ventricular ejection fraction \> 40%. The study will consist of 2 separate parts, Part A and Part B, approximately 660 participants will be randomised in Part A, 820 in Part B.
Interventions
DRUGAZD4831
AZD4831
OTHERPlacebo
Placebo
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Part A 1. ≥ 40 to ≤ 85 years of age, at the time of signing the informed consent. 2. Documented stable symptomatic HF (New York Heart Association Class II-IV) for at least 1 month at Screening (Visit 1) (transient HF in the setting of an MI does not qualify), with a medical history of typical symptoms of HF and receiving optimal therapy for HF as determined by the health-care physician. 3. LVEF \> 40% at Screening (Visit 1). All participants will undergo a local echocardiogram at the Screening (Visit 1) with central reading to confirm the LVEF \> 40% eligibility criteria before randomisation. 4. 6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 3). Difference in 6MWD between Screening and Randomisation must be \< 50 meters. 5. KCCQ-TSS ≤ 90 points at Screening (Visit 1) and Randomisation (Visit 3) 6. NT-proBNP ≥ 250 pg/mL (sinus rhythm) or ≥ 500 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI ≤30 kg/m2. NT-proBNP ≥ 200 pg/mL (sinus rhythm) or ≥ 400 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI \> 30 kg/m2. The ECG performed at Screening should be used for heart rhythm evaluation. 7.At least one of the following: 1. Structural heart disease, ie, LA enlargement and/or left ventricular hypertrophy at the echocardiogram performed at Screening (Visit 1). Left atrial enlargement is defined by at least 1 of the following: LA width (diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI \> 34 mL/m2. Left ventricular hypertrophy is defined by septal thickness or posterior wall thickness ≥ 1.1 cm or LVMI \> 95 g/m2 in women and \> 115 g/m2 in men. 2. Spectral tissue Doppler echocardiography - E/e' ratio (average of septal and lateral) ≥ 13 at rest at the echocardiogram performed at Screening (Visit 1). 3. Indirectly estimated elevation of PASP by TRmax velocity \> 2.8 m/s (280 cm/s) (PASP \> 35 mmHg) at the echocardiogram performed at Screening (Visit 1) OR directly measured pulmonary capillary wedge pressure \> 15 mmHg at rest within the past 12 months or \> 25 mmHg at exercise documented by right heart catheterisation within 12 months prior to Screening (Visit 1). 4. HF decompensation within 6 months before Randomisation (Visit 3), defined as hospitalisation for HF or IV diuretic treatment for HF during an urgent, unscheduled visit without hospitalisation. 8.Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2 9.Male or female of non-childbearing potential. Part B 1. Participant must be ≥ 40 to ≤ 85 years of age, at the time of signing the informed consent. 2. Documented diagnosis of symptomatic HF (NYHA class II-IV) at Screening (Visit 1), and a medical history of typical symptoms/signs of heart failure ≥ 6 weeks before Screening (Visit 1), and receiving optimal therapy for HF as determined by the health-care physician, with at least intermittent need for diuretic treatment. 3. LVEF \>40% and evidence of structural heart disease (ie, left ventricular hypertrophy or left atrial enlargement \[defined by at least one of the following:LA enlargement and/or left ventricular hypertrophy at the echocardiogram performed at Screening (Visit 1). Left atrial enlargement is defined by at least 1 of the following: LA width (diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI \> 34 mL/m2. Left ventricular hypertrophy is defined by septal thickness or posterior wall thickness ≥ 1.1 cm or LVMI \> 95 g/m2 in women and \> 115 g/m2 in men.\]) documented by the most recent echocardiogram, or cardiac magnetic resonance imaging within the last 12 months prior to Screening (Visit 1). If no echocardiogram is available, it can be performed at Screening (Visit 1). 4. 6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 2). Difference in 6MWD between Screening and Randomisation must be \< 50 meters 5. KCCQ-TSS ≤ 90 points at Screening (Visit 1) and Randomisation (Visit 2). 6. NT-proBNP ≥ 250 pg/mL (sinus rhythm) or ≥ 500 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI ≤ 30 kg/m2. NT-proBNP ≥ 200 pg/mL (sinus rhythm) or ≥ 400 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with BMI \> 30 kg/m2. The ECG performed at Screening should be used for heart rhythm evaluation 7. Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2 8. Male or female of non-childbearing potential.
Exclusion criteria
Part A 1 eGFR \< 30 mL/min/1.73m2 (Chronic Kidney Disease-Epidemiology Collaboration formula) at Screening (Visit 1). 2\. Systolic blood pressure \< 90 mmHg or ≥ 160 mmHg if not on treatment with ≥ 3 blood pressure lowering medications or ≥ 180 mmHg irrespective of treatments at Randomisation 3\. Heart rate \> 110 bpm or \< 50 bpm at Randomisation 4\. Life expectancy \< 3 years due to other reasons than cardiovascular disease. 5\. History or ongoing allergy/hypersensitivity reactions to drugs (including but not limited to rash, angioedema, acute urticaria). 6\. Presence of any disease or condition rather than HF constituting the main reason for limiting the ability to exercise/reduced exercise capacity. 7\. Current decompensated HF and/or NT-proBNP \> 5000 pg/mL at Screening (Visit 1) 8\. Documented history of ejection fraction ≤ 40%.i.e. HF with recovered ejection fraction. Transient ejection fraction decrease e.g. in the setting of an MI does not apply 9\. Any planned cardiovascular procedure (eg, coronary revascularisation, ablation of atrial fibrillation/flutter, valve repair/replacement, aortic aneurysm surgery, etc). 10\. Any cardiac event (eg, myocardial infarction, unstable angina), coronary revascularisation (percutaneous coronary intervention or coronary artery bypass grafting), ablation of atrial fibrillation/flutter, valve repair/replacement, implantation of a cardiac resynchronisation therapy device within 12 weeks prior to Screening (Visit 1) or between Screening and Randomisation. Patients who underwent a successful atrial fibrillation/flutter cardioversion, can be enrolled in the study after 4 weeks. 14\. Hb \< 110 g/L (male) and \< 100 g/L (female) or iron-deficiency with/without anaemia requiring ongoing or planned IV iron treatment. 15\. Participants with hyperthyroidism, uncontrolled hypothyroidism (including but not limited to TSH ≥10 mIU/mL), or any clinically significant thyroid disease as judged by the investigator. 18\. ALT or AST ≥ 2 × ULN at Screening (Visit 1). 19\. Pulmonary arterial hypertension, chronic pulmonary embolism, severe pulmonary disease including COPD (ie, requiring home oxygen, chronic nebulizer therapy or chronic oral steroid therapy, or hospitalization for exacerbation of COPD requiring ventilatory support within 12 months prior to Screening (Visit 1). 20\. Any active infection requiring oral, intravenous or intramuscular treatment at Screening (Visit 1) and/or at Randomisation. 23 Any signs or confirmation of COVID-19 infection: * Suspected (as judged by PI) or confirmed COVID-19 within the last 2 weeks prior to Screening (Visit 1) or at Randomisation. * Hospitalisation for COVID-19 within the last 12 weeks prior to Screening (Visit 1). 24\. Any concomitant medications known to be a potent CYP3A4 inducers or inhibitors, eg, itraconazole, rifampicin, clarithromycin, or propylthiouracil 29\. Previous enrolment and randomisation in the present study. (Participants who where screened and screen failed and not randomised in Part A can be screened for possible entry to Part B). All
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Kansas City Cardiomyopathy Questionnaire -Total Symptom Score | Baseline - 16 weeks | Kansas City Cardiomyopathy Questionnaire -Total Symptom Score change from baseline at 16 weeks compared with placebo Part A. The score ranges from 0 to 100, where a higher score represents a better patient outcome |
| Six Minute Walk Distance | Baseline - 16 weeks | Six Minute Walk Distance change from baseline at 16 weeks compared with placebo Part A |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Left Ventricular Global Longitudinal Strain (LV-GLS) | Baseline - 16 and 24 weeks | LV-GLS change from baseline at 16 and 24 weeks compared with placebo Part A. Left ventricular global longitudinal strain (LV-GLS) is an echocardiographic measure expressing longitudinal shortening as a percentage. A negative change from baseline indicates a better outcome. |
| Left Atrial Volume Index (LAVI) | Baseline - 16 and 24 weeks | LAVI change from baseline at 16 and 24 weeks compared with placebo Part A. Left atrial volume index (LAVI) is an echocardiographic measure calculated by dividing LA volume by body surface area. A negative change from baseline indicates a better outcome. |
| Left Ventricular Mass Index (LVMI) | Baseline - 16 and 24 weeks | LVMI change from baseline at 16 and 24 weeks compared with placebo Part A. Left ventricular mass index (LVMI) is an echocardiographic measure calculated by dividing LVM by body surface area. A negative change from baseline indicates a better outcome. |
| Pharmacokinetics (AZD4831 Plasma Exposure) | Baseline, 4 weeks, 12 weeks, 16 weeks, 24 weeks, 48 weeks, 52 weeks | Plasma concentrations of AZD4831 summarised by timepoint and dose level Part A |
| High Sensitivity CRP (hsCRP) | Baseline - 16, 24 and 48 weeks | hsCRP change from baseline at 16, 24, and 48 weeks compared with placebo Part A |
| Interleukin 6 (IL-6) | Baseline - 16, 24 and 48 weeks | IL-6 change from baseline at 16, 24, and 48 weeks compared with placebo Part A |
| Kansas City Cardiomyopathy Questionnaire-Total Symptom Score | Baseline - 24 and 48 weeks | Kansas City Cardiomyopathy Questionnaire -Total Symptom Score change from baseline at 24 and 48 weeks compared with placebo Part A. The score ranges from 0 to 100, where a higher score represents a better patient outcome. |
| Six Minute Walk Distance | Baseline - 24 and 48 weeks | Six Minute Walk Distance change from baseline at 24 and 48 weeks compared with placebo Part A |
| N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | Baseline - 16, 24 and 48 weeks | NT-proBNP change from baseline at 16, 24, and 48 weeks compared with placebo Part A |
Other
| Measure | Time frame | Description |
|---|---|---|
| Clinical Laboratory (Chemistry) | Baseline - 52 weeks | Number of participants with outliers for clinical laboratory (chemistry) measurements Part A |
| Electrocardiogram (ECG) | Baseline - 52 weeks | Number of Participants With Abnormal ECG Last On-Study Value Part A |
| Adverse Events | Baseline - 52 weeks | Number of participants with Adverse Events Part A |
| Vital Signs | Baseline - 52 weeks | Number of participants with treatment emergent vital sign abnormalities Part A |
| Clinical Laboratory (Haematology) | Baseline - 52 weeks | Number of participants with outliers for clinical laboratory (chemistry) measurements Part A |
Countries
Australia, Belgium, Brazil, Bulgaria, Canada, Czechia, Denmark, France, Hungary, Japan, Netherlands, Poland, Russia, Slovakia, Sweden, Taiwan, Turkey (Türkiye), United States
Participant flow
Recruitment details
A total of 142 study centres in 18 countries randomised participants.
Pre-assignment details
Part B of the study was never started, results are only presented for Part A of the study. The discrepancy between the number of randomised participants and the number of participants in the full analysis set and the safety analysis set is because only randomized participants who have taken at least one dose of the investigational product (IP) were included in the analysis sets.
Participants by arm
| Arm | Count |
|---|---|
| AZD4831 2.5 mg Once-daily oral dosing of AZD4831 2.5 mg | 234 |
| AZD4831 5 mg Once-daily oral dosing of AZD4831 5 mg | 240 |
| Placebo Once-daily oral dosing of placebo | 235 |
| Total | 709 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 10 | 3 | 10 |
| Overall Study | Physician Decision | 3 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 2 | 4 |
Baseline characteristics
| Characteristic | AZD4831 2.5 mg | Total | Placebo | AZD4831 5 mg |
|---|---|---|---|---|
| Age, Continuous | 72.5 Years STANDARD_DEVIATION 7.3 | 72.4 Years STANDARD_DEVIATION 7.4 | 72.5 Years STANDARD_DEVIATION 7.8 | 72.1 Years STANDARD_DEVIATION 7.1 |
| Age, Customized 65 - 75 Years | 120 Participants | 343 Participants | 115 Participants | 108 Participants |
| Age, Customized < 65 Years | 34 Participants | 106 Participants | 30 Participants | 42 Participants |
| Age, Customized > 75 Years | 80 Participants | 260 Participants | 90 Participants | 90 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 35 Participants | 107 Participants | 36 Participants | 36 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 21 Participants | 6 Participants | 10 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 16 Participants | 51 Participants | 21 Participants | 14 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 218 Participants | 658 Participants | 214 Participants | 226 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 193 Participants | 579 Participants | 192 Participants | 194 Participants |
| Region of Enrollment Australia | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Belgium | 3 Participants | 9 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Brazil | 13 Participants | 42 Participants | 15 Participants | 14 Participants |
| Region of Enrollment Bulgaria | 33 Participants | 96 Participants | 31 Participants | 32 Participants |
| Region of Enrollment Canada | 8 Participants | 22 Participants | 6 Participants | 8 Participants |
| Region of Enrollment Czech Republic | 23 Participants | 67 Participants | 22 Participants | 22 Participants |
| Region of Enrollment Denmark | 8 Participants | 25 Participants | 8 Participants | 9 Participants |
| Region of Enrollment France | 6 Participants | 19 Participants | 6 Participants | 7 Participants |
| Region of Enrollment Hungary | 18 Participants | 56 Participants | 19 Participants | 19 Participants |
| Region of Enrollment Japan | 25 Participants | 75 Participants | 25 Participants | 25 Participants |
| Region of Enrollment Netherlands | 4 Participants | 14 Participants | 5 Participants | 5 Participants |
| Region of Enrollment Poland | 22 Participants | 69 Participants | 24 Participants | 23 Participants |
| Region of Enrollment Russian Federation | 5 Participants | 15 Participants | 5 Participants | 5 Participants |
| Region of Enrollment Slovakia | 25 Participants | 76 Participants | 25 Participants | 26 Participants |
| Region of Enrollment Sweden | 12 Participants | 37 Participants | 13 Participants | 12 Participants |
| Region of Enrollment Taiwan | 10 Participants | 30 Participants | 10 Participants | 10 Participants |
| Region of Enrollment Turkey | 1 Participants | 4 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States of America | 17 Participants | 50 Participants | 16 Participants | 17 Participants |
| Sex: Female, Male Female | 107 Participants | 322 Participants | 96 Participants | 119 Participants |
| Sex: Female, Male Male | 127 Participants | 387 Participants | 139 Participants | 121 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 234 | 3 / 240 | 10 / 235 |
| other Total, other adverse events | 49 / 234 | 44 / 240 | 45 / 235 |
| serious Total, serious adverse events | 60 / 234 | 57 / 240 | 56 / 235 |
Outcome results
Primary
Kansas City Cardiomyopathy Questionnaire -Total Symptom Score
Kansas City Cardiomyopathy Questionnaire -Total Symptom Score change from baseline at 16 weeks compared with placebo Part A. The score ranges from 0 to 100, where a higher score represents a better patient outcome
Time frame: Baseline - 16 weeks
Population: All participants who have been randomised to study treatment and who have received at least one dose of investigational product are included irrespective of their protocol adherence and continued participation in the study and with non-missing data at baseline and the analysis timepoint. Participants were analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD4831 2.5 mg | Kansas City Cardiomyopathy Questionnaire -Total Symptom Score | 10.70 Points |
| AZD4831 5 mg | Kansas City Cardiomyopathy Questionnaire -Total Symptom Score | 9.81 Points |
| Placebo | Kansas City Cardiomyopathy Questionnaire -Total Symptom Score | 11.62 Points |
p-value: 0.53795% CI: [-3.86, 2.02]ANCOVA
p-value: 0.22195% CI: [-4.71, 1.09]ANCOVA
Primary
Six Minute Walk Distance
Six Minute Walk Distance change from baseline at 16 weeks compared with placebo Part A
Time frame: Baseline - 16 weeks
Population: All participants who have been randomised to study treatment and who have received at least one dose of investigational product were included irrespective of their protocol adherence and continued participation in the study and with non-missing data at baseline and the analysis timepoint. Participants were analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AZD4831 2.5 mg | Six Minute Walk Distance | 15.3 Meters |
| AZD4831 5 mg | Six Minute Walk Distance | 18.2 Meters |
| Placebo | Six Minute Walk Distance | 12.9 Meters |
p-value: 0.55995% CI: [-5.7, 10.5]ANCOVA
p-value: 0.19595% CI: [-2.7, 13.3]ANCOVA
Secondary
High Sensitivity CRP (hsCRP)
hsCRP change from baseline at 16, 24, and 48 weeks compared with placebo Part A
Time frame: Baseline - 16, 24 and 48 weeks
Population: All participants who have been randomised to study treatment and who have received at least one dose of investigational product were included irrespective of their protocol adherence and continued participation in the study and with non-missing data at baseline and the analysis timepoint. Participants were analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AZD4831 2.5 mg | High Sensitivity CRP (hsCRP) | hsCRP change from baseline at 24 weeks | 1.029 mg/dL |
| AZD4831 2.5 mg | High Sensitivity CRP (hsCRP) | hsCRP change from baseline at 16 weeks | 0.940 mg/dL |
| AZD4831 2.5 mg | High Sensitivity CRP (hsCRP) | hsCRP change from baseline at 48 weeks | 1.120 mg/dL |
| AZD4831 5 mg | High Sensitivity CRP (hsCRP) | hsCRP change from baseline at 24 weeks | 1.101 mg/dL |
| AZD4831 5 mg | High Sensitivity CRP (hsCRP) | hsCRP change from baseline at 16 weeks | 1.105 mg/dL |
| AZD4831 5 mg | High Sensitivity CRP (hsCRP) | hsCRP change from baseline at 48 weeks | 1.127 mg/dL |
| Placebo | High Sensitivity CRP (hsCRP) | hsCRP change from baseline at 16 weeks | 0.914 mg/dL |
| Placebo | High Sensitivity CRP (hsCRP) | hsCRP change from baseline at 48 weeks | 0.972 mg/dL |
| Placebo | High Sensitivity CRP (hsCRP) | hsCRP change from baseline at 24 weeks | 0.926 mg/dL |
Comparison: Change from baseline at 16 weeksp-value: 0.7695% CI: [0.857, 1.236]ANCOVA
Comparison: Change from baseline at 16 weeksp-value: 0.03995% CI: [1.01, 1.448]ANCOVA
Comparison: Change from baseline at 24 weeksp-value: 0.24195% CI: [0.931, 1.326]ANCOVA
Comparison: Change from baseline at 24 weeksp-value: 0.04995% CI: [1.001, 1.414]ANCOVA
Comparison: Change from baseline at 48 weeksp-value: 0.15895% CI: [0.946, 1.401]ANCOVA
Comparison: Change from baseline at 48 weeksp-value: 0.13195% CI: [0.957, 1.404]ANCOVA
Secondary
Interleukin 6 (IL-6)
IL-6 change from baseline at 16, 24, and 48 weeks compared with placebo Part A
Time frame: Baseline - 16, 24 and 48 weeks
Population: All participants who have been randomised to study treatment and who have received at least one dose of investigational product were included irrespective of their protocol adherence and continued participation in the study and with non-missing data at baseline and the analysis timepoint. Participants were analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AZD4831 2.5 mg | Interleukin 6 (IL-6) | IL-6 change from baseline at 24 weeks | 1.0918 ng/L |
| AZD4831 2.5 mg | Interleukin 6 (IL-6) | IL-6 change from baseline at 16 weeks | 1.1326 ng/L |
| AZD4831 2.5 mg | Interleukin 6 (IL-6) | IL-6 change from baseline at 48 weeks | 1.3328 ng/L |
| AZD4831 5 mg | Interleukin 6 (IL-6) | IL-6 change from baseline at 24 weeks | 1.0700 ng/L |
| AZD4831 5 mg | Interleukin 6 (IL-6) | IL-6 change from baseline at 16 weeks | 1.0258 ng/L |
| AZD4831 5 mg | Interleukin 6 (IL-6) | IL-6 change from baseline at 48 weeks | 1.3094 ng/L |
| Placebo | Interleukin 6 (IL-6) | IL-6 change from baseline at 16 weeks | 1.1202 ng/L |
| Placebo | Interleukin 6 (IL-6) | IL-6 change from baseline at 48 weeks | 1.2698 ng/L |
| Placebo | Interleukin 6 (IL-6) | IL-6 change from baseline at 24 weeks | 0.9869 ng/L |
Comparison: Change from baseline at 16 weeksp-value: 0.87495% CI: [0.8819, 1.1592]ANCOVA
Comparison: Change from baseline at 16 weeksp-value: 0.295% CI: [0.8002, 1.0479]ANCOVA
Comparison: Change from baseline at 24 weeksp-value: 0.13595% CI: [0.969, 1.2631]ANCOVA
Comparison: Change from baseline at 24 weeksp-value: 0.2295% CI: [0.9527, 1.2339]ANCOVA
Comparison: Change from baseline at 48 weeksp-value: 0.46795% CI: [0.9211, 1.196]ANCOVA
Comparison: Change from baseline at 48 weeksp-value: 0.63695% CI: [0.908, 1.1711]ANCOVA
Secondary
Kansas City Cardiomyopathy Questionnaire-Total Symptom Score
Kansas City Cardiomyopathy Questionnaire -Total Symptom Score change from baseline at 24 and 48 weeks compared with placebo Part A. The score ranges from 0 to 100, where a higher score represents a better patient outcome.
Time frame: Baseline - 24 and 48 weeks
Population: All participants who have been randomised to study treatment and who have received at least one dose of investigational product were included irrespective of their protocol adherence and continued participation in the study and with non-missing data at baseline and the analysis timepoint. Participants were analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AZD4831 2.5 mg | Kansas City Cardiomyopathy Questionnaire-Total Symptom Score | Kansas City Cardiomyopathy Questionnaire -Total Symptom Score change from baseline at 24 weeks | 11.13 Points |
| AZD4831 2.5 mg | Kansas City Cardiomyopathy Questionnaire-Total Symptom Score | Kansas City Cardiomyopathy Questionnaire -Total Symptom Score change from baseline at 48 weeks | 12.78 Points |
| AZD4831 5 mg | Kansas City Cardiomyopathy Questionnaire-Total Symptom Score | Kansas City Cardiomyopathy Questionnaire -Total Symptom Score change from baseline at 24 weeks | 11.92 Points |
| AZD4831 5 mg | Kansas City Cardiomyopathy Questionnaire-Total Symptom Score | Kansas City Cardiomyopathy Questionnaire -Total Symptom Score change from baseline at 48 weeks | 11.98 Points |
| Placebo | Kansas City Cardiomyopathy Questionnaire-Total Symptom Score | Kansas City Cardiomyopathy Questionnaire -Total Symptom Score change from baseline at 24 weeks | 12.78 Points |
| Placebo | Kansas City Cardiomyopathy Questionnaire-Total Symptom Score | Kansas City Cardiomyopathy Questionnaire -Total Symptom Score change from baseline at 48 weeks | 13.03 Points |
Comparison: Change from baseline at 24 weeksp-value: 0.28995% CI: [-4.71, 1.41]ANCOVA
Comparison: Change from baseline at 24 weeksp-value: 0.57195% CI: [-3.86, 2.13]ANCOVA
Comparison: Change from baseline at 48 weeksp-value: 0.8995% CI: [-3.8, 3.3]ANCOVA
Comparison: Change from baseline at 48 weeksp-value: 0.55895% CI: [-4.55, 2.46]ANCOVA
Secondary
Left Atrial Volume Index (LAVI)
LAVI change from baseline at 16 and 24 weeks compared with placebo Part A. Left atrial volume index (LAVI) is an echocardiographic measure calculated by dividing LA volume by body surface area. A negative change from baseline indicates a better outcome.
Time frame: Baseline - 16 and 24 weeks
Population: All participants who have been randomised to study treatment and who have received at least one dose of investigational product were included irrespective of their protocol adherence and continued participation in the study and with non-missing data at baseline and the analysis timepoint. Participants were analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AZD4831 2.5 mg | Left Atrial Volume Index (LAVI) | LAVI change from baseline at 16 weeks | -0.940 mL/m2 |
| AZD4831 2.5 mg | Left Atrial Volume Index (LAVI) | LAVI change from baseline at 24 weeks | 1.096 mL/m2 |
| AZD4831 5 mg | Left Atrial Volume Index (LAVI) | LAVI change from baseline at 16 weeks | -1.894 mL/m2 |
| AZD4831 5 mg | Left Atrial Volume Index (LAVI) | LAVI change from baseline at 24 weeks | -0.376 mL/m2 |
| Placebo | Left Atrial Volume Index (LAVI) | LAVI change from baseline at 16 weeks | -1.300 mL/m2 |
| Placebo | Left Atrial Volume Index (LAVI) | LAVI change from baseline at 24 weeks | 0.439 mL/m2 |
Comparison: Change from baseline at 16 weeksp-value: 0.72595% CI: [-1.647, 2.366]ANCOVA
Comparison: Change from baseline at 16 weeksp-value: 0.55595% CI: [-2.571, 1.382]ANCOVA
Comparison: Change from baseline at 24 weeksp-value: 0.58695% CI: [-1.71, 3.025]ANCOVA
Comparison: Change from baseline at 24 weeksp-value: 0.48695% CI: [-3.108, 1.478]ANCOVA
Secondary
Left Ventricular Global Longitudinal Strain (LV-GLS)
LV-GLS change from baseline at 16 and 24 weeks compared with placebo Part A. Left ventricular global longitudinal strain (LV-GLS) is an echocardiographic measure expressing longitudinal shortening as a percentage. A negative change from baseline indicates a better outcome.
Time frame: Baseline - 16 and 24 weeks
Population: All participants who have been randomised to study treatment and who have received at least one dose of investigational product were included irrespective of their protocol adherence and continued participation in the study and with non-missing data at baseline and the analysis timepoint. Participants were analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AZD4831 2.5 mg | Left Ventricular Global Longitudinal Strain (LV-GLS) | LV-GLS change from baseline at 16 weeks | 0.1 Percentage (%) |
| AZD4831 2.5 mg | Left Ventricular Global Longitudinal Strain (LV-GLS) | LV-GLS change from baseline at 24 weeks | -0.6 Percentage (%) |
| AZD4831 5 mg | Left Ventricular Global Longitudinal Strain (LV-GLS) | LV-GLS change from baseline at 16 weeks | -0.5 Percentage (%) |
| AZD4831 5 mg | Left Ventricular Global Longitudinal Strain (LV-GLS) | LV-GLS change from baseline at 24 weeks | -0.9 Percentage (%) |
| Placebo | Left Ventricular Global Longitudinal Strain (LV-GLS) | LV-GLS change from baseline at 16 weeks | -0.4 Percentage (%) |
| Placebo | Left Ventricular Global Longitudinal Strain (LV-GLS) | LV-GLS change from baseline at 24 weeks | -1.0 Percentage (%) |
Comparison: Change from baseline at 16 weeksp-value: 0.89895% CI: [-0.8, 0.7]ANCOVA
Comparison: Change from baseline at 16 weeksp-value: 0.18395% CI: [-0.2, 1.2]ANCOVA
Comparison: Change from baseline at 24 weeksp-value: 0.31695% CI: [-0.4, 1.1]ANCOVA
Comparison: Change from baseline at 24 weeksp-value: 0.93495% CI: [-0.7, 0.8]ANCOVA
Secondary
Left Ventricular Mass Index (LVMI)
LVMI change from baseline at 16 and 24 weeks compared with placebo Part A. Left ventricular mass index (LVMI) is an echocardiographic measure calculated by dividing LVM by body surface area. A negative change from baseline indicates a better outcome.
Time frame: Baseline - 16 and 24 weeks
Population: All participants who have been randomised to study treatment and who have received at least one dose of investigational product were included irrespective of their protocol adherence and continued participation in the study and with non-missing data at baseline and the analysis timepoint. Participants were analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AZD4831 2.5 mg | Left Ventricular Mass Index (LVMI) | LVMI change from baseline at 16 weeks | 1.3 g/m2 |
| AZD4831 2.5 mg | Left Ventricular Mass Index (LVMI) | LVMI change from baseline at 24 weeks | 9.8 g/m2 |
| AZD4831 5 mg | Left Ventricular Mass Index (LVMI) | LVMI change from baseline at 16 weeks | -0.9 g/m2 |
| AZD4831 5 mg | Left Ventricular Mass Index (LVMI) | LVMI change from baseline at 24 weeks | 8.3 g/m2 |
| Placebo | Left Ventricular Mass Index (LVMI) | LVMI change from baseline at 16 weeks | 1.4 g/m2 |
| Placebo | Left Ventricular Mass Index (LVMI) | LVMI change from baseline at 24 weeks | 9.4 g/m2 |
Comparison: Change from baseline at 16 weeksp-value: 0.96895% CI: [-4.1, 3.9]ANCOVA
Comparison: Change from baseline at 16 weeksp-value: 0.25195% CI: [-6.3, 1.6]ANCOVA
Comparison: Change from baseline at 24 weeksp-value: 0.87295% CI: [-4.8, 5.7]ANCOVA
Comparison: Change from baseline at 24 weeksp-value: 0.68295% CI: [-6.2, 4.1]ANCOVA
Secondary
N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)
NT-proBNP change from baseline at 16, 24, and 48 weeks compared with placebo Part A
Time frame: Baseline - 16, 24 and 48 weeks
Population: All participants who have been randomised to study treatment and who have received at least one dose of investigational product were included irrespective of their protocol adherence and continued participation in the study and with non-missing data at baseline and the analysis timepoint. Participants were analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AZD4831 2.5 mg | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | NT-proBNP change from baseline at 24 weeks | 1.00 ng/L |
| AZD4831 2.5 mg | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | NT-proBNP change from baseline at 16 weeks | 1.00 ng/L |
| AZD4831 2.5 mg | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | NT-proBNP change from baseline at 48 weeks | 1.02 ng/L |
| AZD4831 5 mg | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | NT-proBNP change from baseline at 24 weeks | 1.00 ng/L |
| AZD4831 5 mg | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | NT-proBNP change from baseline at 16 weeks | 0.96 ng/L |
| AZD4831 5 mg | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | NT-proBNP change from baseline at 48 weeks | 1.00 ng/L |
| Placebo | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | NT-proBNP change from baseline at 16 weeks | 1.05 ng/L |
| Placebo | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | NT-proBNP change from baseline at 48 weeks | 1.08 ng/L |
| Placebo | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | NT-proBNP change from baseline at 24 weeks | 0.99 ng/L |
Comparison: NT-proBNP change from baseline at 16 weeksp-value: 0.31295% CI: [0.86, 1.05]ANCOVA
Comparison: NT-proBNP change from baseline at 16 weeksp-value: 0.0795% CI: [0.83, 1.01]ANCOVA
Comparison: NT-proBNP change from baseline at 24 weeksp-value: 0.91195% CI: [0.91, 1.12]ANCOVA
Comparison: NT-proBNP change from baseline at 24 weeksp-value: 0.83795% CI: [0.91, 1.12]ANCOVA
Comparison: NT-proBNP change from baseline at 48 weeksp-value: 0.3795% CI: [0.84, 1.07]ANCOVA
Comparison: NT-proBNP change from baseline at 48 weeksp-value: 0.20595% CI: [0.83, 1.04]ANCOVA
Secondary
Pharmacokinetics (AZD4831 Plasma Exposure)
Plasma concentrations of AZD4831 summarised by timepoint and dose level Part A
Time frame: Baseline, 4 weeks, 12 weeks, 16 weeks, 24 weeks, 48 weeks, 52 weeks
Population: All participants who have been randomised to study treatment and who have received at least one dose of investigational product were included irrespective of their protocol adherence and continued participation in the study and with non-missing data at baseline and the analysis timepoint. Participants were analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AZD4831 2.5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | 12 weeks (pre-dose) | 13.51 nmol/L | Geometric Coefficient of Variation 130.33 |
| AZD4831 2.5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | 24 weeks (pre-dose) | 12.87 nmol/L | Geometric Coefficient of Variation 146.45 |
| AZD4831 2.5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | 4 weeks (pre-dose) | 14.45 nmol/L | Geometric Coefficient of Variation 99.26 |
| AZD4831 2.5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | 48 weeks (pre-dose) | 10.36 nmol/L | Geometric Coefficient of Variation 188.55 |
| AZD4831 2.5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | 16 weeks (pre-dose) | 13.59 nmol/L | Geometric Coefficient of Variation 126.71 |
| AZD4831 2.5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | 52 weeks (pre-dose) | 1.14 nmol/L | Geometric Coefficient of Variation 49.22 |
| AZD4831 2.5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | Baseline (pre-dose) | 1.02 nmol/L | Geometric Coefficient of Variation 19.57 |
| AZD4831 5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | 52 weeks (pre-dose) | 1.27 nmol/L | Geometric Coefficient of Variation 74.56 |
| AZD4831 5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | Baseline (pre-dose) | 1.01 nmol/L | Geometric Coefficient of Variation 9.38 |
| AZD4831 5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | 4 weeks (pre-dose) | 26.44 nmol/L | Geometric Coefficient of Variation 141.88 |
| AZD4831 5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | 12 weeks (pre-dose) | 25.45 nmol/L | Geometric Coefficient of Variation 161.09 |
| AZD4831 5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | 16 weeks (pre-dose) | 25.31 nmol/L | Geometric Coefficient of Variation 159.79 |
| AZD4831 5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | 24 weeks (pre-dose) | 23.08 nmol/L | Geometric Coefficient of Variation 199.18 |
| AZD4831 5 mg | Pharmacokinetics (AZD4831 Plasma Exposure) | 48 weeks (pre-dose) | 21.18 nmol/L | Geometric Coefficient of Variation 229.28 |
Secondary
Six Minute Walk Distance
Six Minute Walk Distance change from baseline at 24 and 48 weeks compared with placebo Part A
Time frame: Baseline - 24 and 48 weeks
Population: All participants who have been randomised to study treatment and who have received at least one dose of investigational product were included irrespective of their protocol adherence and continued participation in the study and with non-missing data at baseline and the analysis timepoint. Participants were analysed according to their randomised study medication assignment, irrespective of the treatment actually received.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AZD4831 2.5 mg | Six Minute Walk Distance | Six Minute Walk Distance change from baseline at 24 weeks | 13.5 Meters |
| AZD4831 2.5 mg | Six Minute Walk Distance | Six Minute Walk Distance change from baseline at 48 weeks | 19.2 Meters |
| AZD4831 5 mg | Six Minute Walk Distance | Six Minute Walk Distance change from baseline at 24 weeks | 18.5 Meters |
| AZD4831 5 mg | Six Minute Walk Distance | Six Minute Walk Distance change from baseline at 48 weeks | 15.7 Meters |
| Placebo | Six Minute Walk Distance | Six Minute Walk Distance change from baseline at 24 weeks | 15.7 Meters |
| Placebo | Six Minute Walk Distance | Six Minute Walk Distance change from baseline at 48 weeks | 13.5 Meters |
Comparison: Change from baseline at 24 weeksp-value: 0.61995% CI: [-11.1, 6.6]ANCOVA
Comparison: Change from baseline at 24 weeksp-value: 0.52295% CI: [-5.8, 11.4]ANCOVA
Comparison: Change from baseline at 48 weeksp-value: 0.26795% CI: [-4.4, 15.8]ANCOVA
Comparison: Change from baseline at 48 weeksp-value: 0.65795% CI: [-7.6, 12.1]ANCOVA
Other Pre-specified
Adverse Events
Number of participants with Adverse Events Part A
Time frame: Baseline - 52 weeks
Population: All participants who received at least one dose of IP. Participants treated in error were accounted for in the treatment group of the treatment actually received. A participant who received any dose of the active IP was classified as in the active IP treatment group. A participant who received both doses of active IP was classified as in the highest dose treatment group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AZD4831 2.5 mg | Adverse Events | 173 Participants |
| AZD4831 5 mg | Adverse Events | 180 Participants |
| Placebo | Adverse Events | 173 Participants |
Other Pre-specified
Clinical Laboratory (Chemistry)
Number of participants with outliers for clinical laboratory (chemistry) measurements Part A
Time frame: Baseline - 52 weeks
Population: All participants who received at least one dose of IP. Participants treated in error were accounted for in the treatment group of the treatment actually received. A participant who received any dose of the active IP was classified as in the active IP treatment group. A participant who received both doses of active IP was classified as in the highest dose treatment group. Number analyzed is the number of participants per treatment group with a baseline value and at least one post-baseline value.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | AST > 5x ULN | 1 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | TSH >6 (mIU/L) | 19 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | ALP > 1.5x ULN | 9 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | AST or ALT > 3x ULN and TB > 2x ULN | 0 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | AST > 3x ULN | 3 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | ALP > 3x ULN | 0 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | Creatinine >= 1.5x baseline creatinine | 15 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | ALT > 10x ULN | 0 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | ALT > 3x ULN | 5 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | TSH > 6 and free T4 < LLN (mIU/L) | 2 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | ALT > 5x ULN | 2 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | AST or ALT > 3x ULN | 6 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | Creatinine >= 2x baseline creatinine | 3 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | TSH >=10 (mIU/L) | 12 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | TB > 2x ULN | 1 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | TSH >= 10 and free T4 < LLN (mIU/L) | 2 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | AST > 10x ULN | 0 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Chemistry) | TB > 1.5x ULN | 6 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | ALT > 10x ULN | 0 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | AST > 3x ULN | 3 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | AST > 5x ULN | 0 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | AST > 10x ULN | 0 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | Creatinine >= 1.5x baseline creatinine | 10 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | TB > 1.5x ULN | 1 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | TSH >= 10 and free T4 < LLN (mIU/L) | 0 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | TSH >6 (mIU/L) | 25 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | ALP > 1.5x ULN | 8 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | ALP > 3x ULN | 0 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | ALT > 3x ULN | 2 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | ALT > 5x ULN | 0 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | Creatinine >= 2x baseline creatinine | 0 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | TB > 2x ULN | 1 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | AST or ALT > 3x ULN | 3 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | AST or ALT > 3x ULN and TB > 2x ULN | 0 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | TSH >=10 (mIU/L) | 6 Participants |
| AZD4831 5 mg | Clinical Laboratory (Chemistry) | TSH > 6 and free T4 < LLN (mIU/L) | 1 Participants |
| Placebo | Clinical Laboratory (Chemistry) | Creatinine >= 2x baseline creatinine | 2 Participants |
| Placebo | Clinical Laboratory (Chemistry) | TSH >= 10 and free T4 < LLN (mIU/L) | 0 Participants |
| Placebo | Clinical Laboratory (Chemistry) | TB > 1.5x ULN | 12 Participants |
| Placebo | Clinical Laboratory (Chemistry) | TSH > 6 and free T4 < LLN (mIU/L) | 0 Participants |
| Placebo | Clinical Laboratory (Chemistry) | TB > 2x ULN | 2 Participants |
| Placebo | Clinical Laboratory (Chemistry) | Creatinine >= 1.5x baseline creatinine | 14 Participants |
| Placebo | Clinical Laboratory (Chemistry) | TSH >=10 (mIU/L) | 3 Participants |
| Placebo | Clinical Laboratory (Chemistry) | AST or ALT > 3x ULN | 4 Participants |
| Placebo | Clinical Laboratory (Chemistry) | AST > 10x ULN | 0 Participants |
| Placebo | Clinical Laboratory (Chemistry) | AST > 3x ULN | 4 Participants |
| Placebo | Clinical Laboratory (Chemistry) | AST or ALT > 3x ULN and TB > 2x ULN | 1 Participants |
| Placebo | Clinical Laboratory (Chemistry) | ALT > 3x ULN | 3 Participants |
| Placebo | Clinical Laboratory (Chemistry) | TSH >6 (mIU/L) | 18 Participants |
| Placebo | Clinical Laboratory (Chemistry) | ALT > 5x ULN | 1 Participants |
| Placebo | Clinical Laboratory (Chemistry) | ALP > 3x ULN | 1 Participants |
| Placebo | Clinical Laboratory (Chemistry) | AST > 5x ULN | 0 Participants |
| Placebo | Clinical Laboratory (Chemistry) | ALT > 10x ULN | 0 Participants |
| Placebo | Clinical Laboratory (Chemistry) | ALP > 1.5x ULN | 13 Participants |
Other Pre-specified
Clinical Laboratory (Haematology)
Number of participants with outliers for clinical laboratory (chemistry) measurements Part A
Time frame: Baseline - 52 weeks
Population: All participants who received at least one dose of IP. Participants treated in error were accounted for in the treatment group of the treatment actually received. A participant who received any dose of the active IP was classified as in the active IP treatment group. A participant who received both doses of active IP was classified as in the highest dose treatment group. Number analyzed is the number of participants per treatment group with a baseline value and at least one post-baseline value.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD4831 2.5 mg | Clinical Laboratory (Haematology) | Eosinophils >= 0.7 (10^9/L) | 4 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Haematology) | Eosinophils >= 1.5 (10^9/L) | 0 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Haematology) | Hemoglobin < 100 (g/L) | 9 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Haematology) | Hemoglobin < 80 (g/L) | 1 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Haematology) | Neutrophil count < 1.5 (10^9/L) | 2 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Haematology) | Neutrophil count < 1.0 (10^9/L) | 0 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Haematology) | Leukocytes < 3.0 (10^9/L) | 3 Participants |
| AZD4831 2.5 mg | Clinical Laboratory (Haematology) | Leukocytes < 2.0 (10^9/L) | 0 Participants |
| AZD4831 5 mg | Clinical Laboratory (Haematology) | Hemoglobin < 100 (g/L) | 11 Participants |
| AZD4831 5 mg | Clinical Laboratory (Haematology) | Leukocytes < 3.0 (10^9/L) | 5 Participants |
| AZD4831 5 mg | Clinical Laboratory (Haematology) | Hemoglobin < 80 (g/L) | 1 Participants |
| AZD4831 5 mg | Clinical Laboratory (Haematology) | Neutrophil count < 1.5 (10^9/L) | 7 Participants |
| AZD4831 5 mg | Clinical Laboratory (Haematology) | Neutrophil count < 1.0 (10^9/L) | 1 Participants |
| AZD4831 5 mg | Clinical Laboratory (Haematology) | Eosinophils >= 0.7 (10^9/L) | 4 Participants |
| AZD4831 5 mg | Clinical Laboratory (Haematology) | Eosinophils >= 1.5 (10^9/L) | 0 Participants |
| AZD4831 5 mg | Clinical Laboratory (Haematology) | Leukocytes < 2.0 (10^9/L) | 1 Participants |
| Placebo | Clinical Laboratory (Haematology) | Hemoglobin < 100 (g/L) | 6 Participants |
| Placebo | Clinical Laboratory (Haematology) | Eosinophils >= 1.5 (10^9/L) | 0 Participants |
| Placebo | Clinical Laboratory (Haematology) | Eosinophils >= 0.7 (10^9/L) | 8 Participants |
| Placebo | Clinical Laboratory (Haematology) | Hemoglobin < 80 (g/L) | 0 Participants |
| Placebo | Clinical Laboratory (Haematology) | Leukocytes < 3.0 (10^9/L) | 6 Participants |
| Placebo | Clinical Laboratory (Haematology) | Neutrophil count < 1.0 (10^9/L) | 0 Participants |
| Placebo | Clinical Laboratory (Haematology) | Neutrophil count < 1.5 (10^9/L) | 3 Participants |
| Placebo | Clinical Laboratory (Haematology) | Leukocytes < 2.0 (10^9/L) | 0 Participants |
Other Pre-specified
Electrocardiogram (ECG)
Number of Participants With Abnormal ECG Last On-Study Value Part A
Time frame: Baseline - 52 weeks
Population: All participants who received at least one dose of IP. Participants treated in error were accounted for in the treatment group of the treatment actually received. A participant who received any dose of the active IP was classified as in the active IP treatment group. A participant who received both doses of active IP was classified as in the highest dose treatment group. Number analyzed is the number of participants per treatment group with a baseline value and at least one post-baseline value.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD4831 2.5 mg | Electrocardiogram (ECG) | Normal with Abnormal, clinically significant at baseline | 0 Participants |
| AZD4831 2.5 mg | Electrocardiogram (ECG) | Normal with Abnormal, not clinically significant at baseline | 8 Participants |
| AZD4831 2.5 mg | Electrocardiogram (ECG) | Abnormal, not clinically significant with Normal at baseline | 17 Participants |
| AZD4831 2.5 mg | Electrocardiogram (ECG) | Abnormal, clinically significant with Abnormal, not clinically significant at baseline | 5 Participants |
| AZD4831 2.5 mg | Electrocardiogram (ECG) | Abnormal, not clinically significant with Abnormal, not clinically significant at baseline | 132 Participants |
| AZD4831 2.5 mg | Electrocardiogram (ECG) | Normal with Normal at baseline | 43 Participants |
| AZD4831 2.5 mg | Electrocardiogram (ECG) | Abnormal, not clinically significant with Abnormal, clinically significant at baseline | 6 Participants |
| AZD4831 2.5 mg | Electrocardiogram (ECG) | Abnormal, clinically significant last on-study value with Normal at baseline | 2 Participants |
| AZD4831 2.5 mg | Electrocardiogram (ECG) | Abnormal, clinically significant with Abnormal, clinically significant at baseline | 13 Participants |
| AZD4831 5 mg | Electrocardiogram (ECG) | Abnormal, not clinically significant with Abnormal, not clinically significant at baseline | 135 Participants |
| AZD4831 5 mg | Electrocardiogram (ECG) | Normal with Normal at baseline | 52 Participants |
| AZD4831 5 mg | Electrocardiogram (ECG) | Abnormal, not clinically significant with Normal at baseline | 19 Participants |
| AZD4831 5 mg | Electrocardiogram (ECG) | Abnormal, clinically significant last on-study value with Normal at baseline | 0 Participants |
| AZD4831 5 mg | Electrocardiogram (ECG) | Normal with Abnormal, not clinically significant at baseline | 14 Participants |
| AZD4831 5 mg | Electrocardiogram (ECG) | Abnormal, clinically significant with Abnormal, not clinically significant at baseline | 2 Participants |
| AZD4831 5 mg | Electrocardiogram (ECG) | Normal with Abnormal, clinically significant at baseline | 0 Participants |
| AZD4831 5 mg | Electrocardiogram (ECG) | Abnormal, not clinically significant with Abnormal, clinically significant at baseline | 7 Participants |
| AZD4831 5 mg | Electrocardiogram (ECG) | Abnormal, clinically significant with Abnormal, clinically significant at baseline | 10 Participants |
| Placebo | Electrocardiogram (ECG) | Abnormal, clinically significant last on-study value with Normal at baseline | 1 Participants |
| Placebo | Electrocardiogram (ECG) | Normal with Normal at baseline | 49 Participants |
| Placebo | Electrocardiogram (ECG) | Normal with Abnormal, clinically significant at baseline | 1 Participants |
| Placebo | Electrocardiogram (ECG) | Abnormal, not clinically significant with Normal at baseline | 14 Participants |
| Placebo | Electrocardiogram (ECG) | Abnormal, clinically significant with Abnormal, clinically significant at baseline | 7 Participants |
| Placebo | Electrocardiogram (ECG) | Abnormal, not clinically significant with Abnormal, not clinically significant at baseline | 137 Participants |
| Placebo | Electrocardiogram (ECG) | Normal with Abnormal, not clinically significant at baseline | 7 Participants |
| Placebo | Electrocardiogram (ECG) | Abnormal, not clinically significant with Abnormal, clinically significant at baseline | 12 Participants |
| Placebo | Electrocardiogram (ECG) | Abnormal, clinically significant with Abnormal, not clinically significant at baseline | 4 Participants |
Other Pre-specified
Vital Signs
Number of participants with treatment emergent vital sign abnormalities Part A
Time frame: Baseline - 52 weeks
Population: All participants who received at least one dose of IP. Participants treated in error were accounted for in the treatment group of the treatment actually received. A participant who received any dose of the active IP was classified as in the active IP treatment group. A participant who received both doses of active IP was classified as in the highest dose treatment group. Number analyzed is the number of participants per treatment group with a baseline value and at least one post-baseline value.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD4831 2.5 mg | Vital Signs | Diastolic blood pressure >= 90 and increase from baseline >= 10 (mmHg) | 62 Participants |
| AZD4831 2.5 mg | Vital Signs | Diastolic blood pressure < 60 and decrease from baseline >= 10 (mmHg) | 32 Participants |
| AZD4831 2.5 mg | Vital Signs | Pulse rate >= 100 and increase from baseline >= 20 (beats/min) | 15 Participants |
| AZD4831 2.5 mg | Vital Signs | Pulse rate < 50 and decrease from baseline >= 20 (beats/min) | 2 Participants |
| AZD4831 2.5 mg | Vital Signs | Systolic blood pressure >= 140 and increase from baseline >= 20 (mmHg) | 71 Participants |
| AZD4831 2.5 mg | Vital Signs | Systolic blood pressure < 90 and decrease from baseline >= 20 (mmHg) | 5 Participants |
| AZD4831 5 mg | Vital Signs | Systolic blood pressure < 90 and decrease from baseline >= 20 (mmHg) | 3 Participants |
| AZD4831 5 mg | Vital Signs | Diastolic blood pressure >= 90 and increase from baseline >= 10 (mmHg) | 60 Participants |
| AZD4831 5 mg | Vital Signs | Pulse rate < 50 and decrease from baseline >= 20 (beats/min) | 6 Participants |
| AZD4831 5 mg | Vital Signs | Systolic blood pressure >= 140 and increase from baseline >= 20 (mmHg) | 84 Participants |
| AZD4831 5 mg | Vital Signs | Diastolic blood pressure < 60 and decrease from baseline >= 10 (mmHg) | 42 Participants |
| AZD4831 5 mg | Vital Signs | Pulse rate >= 100 and increase from baseline >= 20 (beats/min) | 17 Participants |
| Placebo | Vital Signs | Diastolic blood pressure < 60 and decrease from baseline >= 10 (mmHg) | 33 Participants |
| Placebo | Vital Signs | Pulse rate >= 100 and increase from baseline >= 20 (beats/min) | 11 Participants |
| Placebo | Vital Signs | Systolic blood pressure < 90 and decrease from baseline >= 20 (mmHg) | 3 Participants |
| Placebo | Vital Signs | Pulse rate < 50 and decrease from baseline >= 20 (beats/min) | 8 Participants |
| Placebo | Vital Signs | Diastolic blood pressure >= 90 and increase from baseline >= 10 (mmHg) | 68 Participants |
| Placebo | Vital Signs | Systolic blood pressure >= 140 and increase from baseline >= 20 (mmHg) | 67 Participants |