E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart Failure with Left Ventricular Ejection Fraction (LVEF) Below 55% and Chronic Kidney Disease |
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E.1.1.1 | Medical condition in easily understood language |
Heart Failure and Chronic Kidney Disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019279 |
E.1.2 | Term | Heart failure |
E.1.2 | System Organ Class | 100000004849 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of AZD9977 and dapagliflozin in combination and alone compared with placebo on UACR |
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E.2.2 | Secondary objectives of the trial |
To assess the dose-response relationship of placebo, AZD9977 (150 mg) alone, dapagliflozin (10 mg) alone and 3 doses of AZD9977 (15, 50, or 150 mg) combined with dapagliflozin (10 mg) on UACR |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1 Participant must be 21 years of age or older, at the time of signing the informed consent. 2 Documented diagnosis of stable symptomatic HF (NYHA class II-III) at screening (Visit 1), and a medical history of typical symptoms and signs of HF who are currently receiving loop diuretic treatment. 3 Left ventricular ejection fraction <55% documented by the most recent echocardiogram 2D or 3D or cardiac magnetic resonance imaging within the last 12 months prior to screening (Visit 1). 4 Stable background treatment for heart failure, hypertension, diabetes mellitus or renal disease for at least 3 weeks prior to randomisation (Visit 3)/within the 3 weeks run-in period. 5 NT-proBNP ≥600 pg/mL for patients with sinus rhythm or ≥900 pg/mL for patients with atrial fibrillation at screening. 6 eGFR ≥30 and ≤60 mL/min (by CKD-EPI formula) and UACR >30 mg/g (3 mg/mmol) and <3000 mg/g (300 mg/mmol). 7 Serum K+ level ≥3.5 and <5.0 mmol/L within 5 days prior to randomisation (Visit 3) from local laboratory. 8 Serum Na+ level within normal reference values within 5 days prior to randomisation (Visit 3) from local laboratory. 9 Systolic BP ≥100 and <150 mmHg at randomisation (Visit 3), with no change to antihypertensive treatments in previous 3 weeks. 10 Diastolic BP ≥60 and <90 mmHg at randomisation (Visit 3), with no change to antihypertensive treatments in previous 3 weeks. 11 No prior medical treatment with an MRA or SGLT2i taken for 3 months or longer during the 12 months prior to screening (Visit 1). 12 No current or prior (within the 3 weeks run-in period prior to randomisation [Visit 3]) treatment with MRA or SGLT2i and other prohibited concomitant medications. 13 No current or prior treatment within 6 months prior to screening (Visit 1) with cytotoxic therapy, immunosuppressive therapy or other immunotherapy. 14 Body mass index less than 40 kg/m2 . 15 Male or female of non-childbearing potential. 16 Female patients must have a negative pregnancy test at screening, must not be lactating and must be of nonchild-bearing potential, confirmed at screening by fulfilling one of the following criteria: (a) Postmenopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and LH and FSH levels in the postmenopausal range. (b) Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. 17 Male patients must be surgically sterile or using, in conjunction with their female partner, a highly effective method of contraception for the duration of the study (from the time they sign consent) and for 3 months after the last dose of study drug to prevent pregnancy in a partner. Male study participants must not donate or bank sperm during this same time period. 8 Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol. 19 Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses. 20 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative. |
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E.4 | Principal exclusion criteria |
1 Primary glomerulopathy, vasculitic renal disease, prior dialysis or unstable rapidly progressing renal disease, Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or ANCA-associated vasculitis. 2 Patients with unstable HF requiring hospitalisation for optimisation of HF treatment and are not on stable HF therapy at the time of enrolment. 3 HF due to cardiomyopathies that would primarily require specific other treatment such as cardiomyopathy due to amyloidosis or infiltrative diseases, primary hypertrophic cardiomyopathy, cardiomyopathy related to current toxic or infective conditions. 4 High output HF. 5 HF due to pericardial disease, congenital heart disease or clinically significant uncorrected primary cardiac valvular disease, or planned cardiac valve repair/replacement. 6 Patients with uncontrolled diabetes mellitus (HbA1c >12%). 7 Patients with T1DM. 8 Intermittent or persistent 2nd or 3rd degree atrioventricular block, sinus node dysfunction with clinically significant bradycardia or sinus pauses, not treated with a pacemaker. 9 Prolonged QT interval (QTcF >470ms) on ECG at screening (Visit 1), known congenital long QT syndrome or history of QT prolongation associated with other medications. 10 History of any life-threatening cardiac dysrhythmia or uncontrolled ventricular rate in patients with atrial fibrillation or atrial flutter. 11 Acute coronary syndrome and/or elective/non-elective percutaneous cardiac interventions (within 3 months) or open chest cardiovascular surgery (within 12 months) prior to screening is planned to undergo any of these procedures during the study. 12 Heart transplantation or left ventricular assist device at any time or if these are planned. 13 Kidney or any organ transplantation or if these are planned. 14 Addison’s disease. 15 History or ongoing allergy/hypersensitivity, as judged by the investigator, to SGLT2i (eg, dapagliflozin, empagliflozin). 16 Any clinically significant disease or disorder which, as judged by the investigator, might put the patient at risk because of participation in the study, or probable alternative primary reason for patient’s symptoms in judgement of investigator, including but not limited to: (a) Isolated pulmonary arterial hypertension (PAP≥25 mmHg at rest) or right ventricular failure; in the absence of left-sided HF. (b) Anaemia defined as haemoglobin level <100g/l or 10g/dl within 5 days prior to randomisation. (c) Severe chronic obstructive pulmonary disease or other lung disease including but not limited to pulmonary fibrosis requiring chronic O2therapy, regular nebuliser use or oral steroid therapy. 17 Stroke, transient ischaemic attack, carotid surgery or carotid angioplasty within previous 3 months prior to screening. 18 Active malignancy requiring treatment (except for basal cell or squamous cell carcinomas of the skin). 19 Hepatic disease, including hepatitis and/or hepatic impairment (Child-Pugh class A-C), AST or ALT >2×ULN; or TBL >2×ULN at time of screening (Visit 1) and/or within 5 days prior to randomisation (Visit 3). An isolated increase in bilirubin in patients with known Gilbert’s syndrome is not a reason for exclusion. 20 Prior or ongoing drug or alcohol abuse. 21 Patients treated with strong or moderate CYP3A4 inhibitor or inducer. 22 Patients with newly detected pathological laboratory values or an ongoing disease condition requiring investigation and/or initiation or adjustment of current treatment. 23 Any condition outside the renal and cardiovascular disease area, such as but not limited to malignancy, with a life expectancy of less than 2 years based on investigator´s clinical judgement. 24 Any of the following signs or confirmation of COVID-19 infection: (a) Optional in case RT-PCR is available at the site with an appropriate turnaround time: Patient has a positive test result for SARS-CoV-2 before randomisation. (b) Clinical signs and symptoms consistent with COVID-19 or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or at randomisation. (c) Patient has been previously hospitalised with COVID-19 infection. 25 Participation in another clinical study with an investigational product administered in the last 3 months prior to randomisation. 26 Involvement in the planning and/or conduct of the study. 27 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. 28 Previous randomisation in the present study. 29 Plasma donation within 1 month of the visit at the clinic or any blood donation/blood loss >500 mL during the 3 months prior to any visit at the clinic. 30 Previous allogeneic bone marrow transplant. 31 Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint for this study is the percent change from baseline in UACR at 12 weeks. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline at 12 weeks. Baseline for UACR will be defined as the value obtained at Visit 3 before the first dose of study treatment. |
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E.5.2 | Secondary end point(s) |
The dose-response relationship of percent change from baseline in UACR at 12 weeks will be assessed using data from placebo, AZD9977 (150 mg) alone, dapagliflozin (10 mg) alone and 3 doses of AZD9977 (15, 50, or 150 mg) combined with dapagliflozin (10 mg). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline at 12 weeks. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 6 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 95 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Bulgaria |
Canada |
Czechia |
Denmark |
Germany |
Hungary |
Italy |
Japan |
Korea, Republic of |
Lithuania |
Poland |
Russian Federation |
Slovakia |
Spain |
Sweden |
Taiwan |
Thailand |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the date of the last visit of the last participant in the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |