| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Heart Failure and Chronic Kidney Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Heart Failure and Chronic Kidney Disease |
|
| 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 |
|
| 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 |
|
| 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 in combination with dapagliflozin compared with dapagliflozin alone on UACR
|
|
| E.2.2 | Secondary objectives of the trial |
To assess the dose-response relationship of dapagliflozin (10 mg) alone and 3 doses of AZD9977 (15, 50, or 150 mg) combined with dapagliflozin
(10 mg) on UACR
|
|
| 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 1a), and a medical history of typical symptoms and signs of HF in those who are currently receiving loop diuretic treatment.
3 Left ventricular ejection fraction <60% documented by the most recent echocardiogram 2D or 3D or cardiac magnetic resonance imaging within the last 12 months prior to screening.
4 Patients should be treated for HF, hypertension, T2DM, or renal disease according to guidelines.
5 NT-proBNP ≥300 pg/mL for patients with sinus rhythm at screening ; and NT-proBNP ≥600 pg/mL for patients with atrial fibrillation/flutter at screening or using local laboratory sample.
6 eGFR ≥30 and ≤60 mL/min/1.73m2 (by CKD-EPI formula) based on local laboratory sample.
7 UACR at screening: spot urine sample analysed at local laboratory ≥ 30 mg/g (3 mg/mmol) and < 3000 mg/g (300 mg/mmol) for participants
on SGLT2i; spot urine sample analysed at local laboratory ≥ 50 mg/g (5mg/mmol) and < 3000 mg/g (300 mg/mmol) for participants not on
SGLT2i.
8 Body mass index less than 40 kg/m2 .
9 Male or female of non-childbearing potential.
10 Female patients must be of non-childbearing potential.
Women of non-childbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomisation without an alternative medical cause. The following age-specific requirements apply:
(a) Women <50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and FSH levels in the postmenopausal range.
(b) Women ≥50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.
11 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.
12 Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
13 Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses. NOTE: For the optional pre-
screening visit there is a separate informed consent. Refer to Section 4.1.1
14 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.
Participants are eligible to be randomised in the study only if all of the
following criteria apply at randomisation (Visit 3):
15 eGFR ≥ 30 mL/min/1.73 m2 (by CKD-EPI formula at central
laboratory) based on results from pre-randomisation Visit 2.
16 UACR ≥ 30 mg/g (3 mg/mmol) and < 3000 mg/g (300 mg/mmol)
based on central laboratory samples collected at pre-randomisation Visit 2. Refer to
Section 8.1.1.
17 Serum/plasma K+ level ≥ 3.5 and < 5.0 mmol/L within 10 days prior
to randomisation (Visit 3) from local laboratory.
18 Serum/plasma sodium (Na+ ) level within normal reference values
within 10 days prior to randomisation (Visit 3) from local laboratory.
19 Systolic BP ≥ 90 and < 150 mmHg (or < 180mmHg if the patient is
already receiving 3 or more antihypertensive drugs) at randomisation (Visit 3), with no change
to antihypertensive treatments in previous 3 weeks. Antihypertensive
drugs include, but are not limited to, a diuretic, ACEI, ARB, beta-blocker and calcium channel blocker.
|
|
| 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 currently decompensated unstable HF requiring hospitalisation for optimisation of HF treatment and 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 >10%).
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 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) prior to randomisation or is planned to undergo any of these procedures during the study.
12 Any major cardiovascular or major non-cardiovascular surgery within 3 months prior to randomisation or is planned to undergo any of these procedures during the study.
13 Heart transplantation or left ventricular assist device at any time or if these are planned.
14 Kidney or any organ transplantation or if these are planned.
15Addison’s disease.
16 History or ongoing allergy/hypersensitivity to SGLT2i.
17 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 at time of screening (Visit 1a).
(c) Severe chronic obstructive pulmonary disease or other lung disease including but not limited to pulmonary fibrosis requiring chronic oxygen therapy, regular nebuliser use or oral steroid therapy.
18 Stroke, transient ischaemic attack, carotid surgery or carotid angioplasty within previous 3 months prior to randomisation.
19 Active malignancy requiring treatment (except for basal cell or squamous cell carcinomas of the skin).
20 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 1a) and/or within 7 days prior to randomisation (Visit 3). An isolated increase in bilirubin in patients with known Gilbert’s syndrome is not a reason for exclusion.
21 Prior or ongoing drug or alcohol abuse.
22 Patients treated with strong or moderate CYP3A4 inhibitor or inducer.
23 Patients with newly detected pathological laboratory values or an ongoing disease condition requiring investigation and/or initiation or adjustment of current treatment.
24 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.
25 Any of the following signs or confirmation of COVID-19 infection:
(a) Optional in case RT-PCR is available at site with appropriate turnaround time:
Patient has positive test result for SARS-CoV-2 at visit 2 before randomisation.
(b) Clinical signs and symptoms consistent with COVID-19 or confirmed infection by laboratory test within the last 4 weeks prior screening (Visit 1a) or at randomisation (Visit 3).
(c) Patient has been previously hospitalised with COVID-19 infection and did not fully recover health status
Please refer to the section 5.2 of the protocol for additional information |
|
| 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 the end of 12 weeks of study treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline at the end of 12 weeks of study treatment.
|
|
| E.5.2 | Secondary end point(s) |
Percent change from baseline in UACR at the end of 12 weeks of study treatment.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From baseline at the end of 12 weeks of study treatment |
|
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Dapagliflozin 10 mg as active comparator |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 128 |
| 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 |
| Canada |
| Japan |
| Korea, Republic of |
| Taiwan |
| Thailand |
| United States |
| Lithuania |
| Poland |
| Sweden |
| Bulgaria |
| Spain |
| Czechia |
| Germany |
| Belgium |
| Denmark |
| Hungary |
| Russian Federation |
| Slovakia |
| Ukraine |
|
| 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
|
| The end of the study is defined as the date of the last visit of the last participant in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 9 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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