Overview
International, Multicenter, Double-Blind, Placebo-Controlled and Event-driven study to assess efficacy, safety and Tolerability of Baxdrostat in combination with Dapagliflozin on renal outcomes and cardiovascular mortality in participants with chronic kidney disease and high blood pressure
Description
The purpose of this study is to investigate the efficacy, safety, and tolerability of baxdrostat in combination with dapagliflozin, compared with placebo and dapagliflozin, in reducing the risk of the composite of >= 50% sustained decline in eGFR, kidney failure, or CV death, in individuals with CKD and HTN.
This study consists of a 4-week dapagliflozin Run-in Period for participants untreated with SGLT2i at screening, and a double-blinded period where participants will receive either baxdrostat/dapagliflozin or placebo/dapagliflozin.
Site visits will take place at 2-, 4-, 8-, 16-, 34, and 52-weeks following randomisation. Thereafter visits will occur approximately every 4 months.
The study closure procedures will be initiated when the predetermined number of primary endpoint events is predicted to have occurred ie, the PACD. All randomised participants including any participants who have prematurely discontinued study intervention will be scheduled for a SCV within a few weeks of the PACD. This period can be extended by the Sponsor.
In case of premature discontinuation of blinded study intervention, participants will continue in the study and receive dapagliflozin, unless the participant meets dapagliflozin specific discontinuation criteria. If study intervention is temporarily or permanently discontinued, the participant should remain in the study, and it is important that the scheduled study visits (including the PTDV for participants with permanent discontinuation of study intervention) and data collection continue according to the study protocol until the SCV.
Eligibility
Inclusion Criteria:
- Participants of any sex and gender must be ≥ 18 years of age at the time of signing the informed consent.
- Participants with (a) or (b):
- eGFR 30-59 mL/min/1.73 m² (local or central laboratory value) AND:
- UACR ≥ 30 mg/g (3.39 mg/mmol) and < 500 mg/g (56.5 mg/mmol) (central laboratory value only), or
- UACR ≥ 500 mg/g (56.5 mg/mmol) and ≤ 5000 mg/g (565 mg/mmol) (local or central laboratory value), or
- UPCR ≥ 700 mg/g (79 mg/mmol) and ≤ 7000 mg/g (790 mg/mmol) (local
laboratory value only).
(b) eGFR 60-75 mL/min/1.73 m² (local or central laboratory value) AND:
- UACR ≥ 500 mg/g (56.5 mg/mmol) ) and ≤ 5000 mg/g (565 mg/mmol) (local or central laboratory value), or
- UPCR ≥ 700 mg/g (79 mg/mmol) and ≤ 7000 mg/g (790 mg/mmol) (local laboratory value only)
- eGFR 30-59 mL/min/1.73 m² (local or central laboratory value) AND:
- [obsolete]
- Participants with history of HTN and a SBP ≥ 130 mmHg (the most recent value within 4 weeks prior to screening or at the Screening Visit) and ≥ 120 mmHg at the Randomisation Visit.
- Stable and maximum tolerated dose of an ACEi or an ARB (not both) for at least 4 weeks prior to Screening Visit.
- Participants with:
- Serum or plasma potassium ≥ 3.0 and ≤ 4.8 mmol/L if eGFR ≥ 45 mL/min/1.73 m2
(local or central
Exclusion Criteria:
- Systolic blood pressure > 180 mmHg, or diastolic BP > 110 mmHg at screening.
- Known hyperkalaemia, defined as potassium of ≥ 5.5 mmol/L within 3 months at screening.
- Serum sodium < 135 mmol/L (central or local laboratory values obtained within 4 weeks prior to screening or at the Screening Visit).
- Participants with T1DM will be excluded, except:
- Serum or plasma potassium ≥ 3.0 and ≤ 4.8 mmol/L if eGFR ≥ 45 mL/min/1.73 m2
(local or central
- For US only: patients with T1DM treated with SGLT2i for at least 4 months, without
DKA during that period, and who have experience with ketone monitoring are eligible for inclusion.
- For Japan only: patients with T1DM treated with dapagliflozin 10 mg for at least 4
months, without DKA during the period of dapagliflozin treatment are eligible for
inclusion.
5 Uncontrolled T2DM with HbA1c > 10.5% (> 91 mmol/mol) (central or local laboratory values obtained within 3 months prior to screening or at the Screening Visit).
6 New York Heart Association functional HF class IV at screening.
7 Stroke, transient ischaemic cerebral attack, valve implantation or valve replacement, carotid surgery, or carotid angioplasty, acute coronary syndrome, or hospitalisation for worsening heart failure within previous 3 months prior to randomisation.
8 Documented history of adrenal insufficiency.
9 Any dialysis (including for acute kidney injury) within 3 months prior to Screening Visit.
10 Any acute kidney injury within 3 months prior to the Screening Visit.
11 History of organ transplant or bone marrow transplant, or planned organ transplant within 6 months following randomisation (including kidney transplant).
12 Any clinical condition requiring systemic immunosuppression therapy other than maintenance therapy (stable for at least 3 months prior to Visit 1).