| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Proteinuric Chronic Kidney Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| A gradual loss of kidney function over time accompanied by the presence of excess proteins in the urine |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
| MedDRA Classification |
| 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 dose-response effect of AZD5718 on urine albumin creatinine ratio (UACR) at 20 weeks in participants with proteinuric CKD (on treatment with dapagliflozin from Weeks 12 to 20) |
|
| E.2.2 | Secondary objectives of the trial |
1) To evaluate the dose-response effect of AZD5718 on urine albumin:creatinine ratio (UACR) at 12 weeks (on current standard of care)
2) To evaluate the safety and tolerability of AZD5718 in participants with proteinuric CKD
3) To evaluate the effect of AZD5718 on ambulatory blood pressure in participants with proteinuric CKD
4) To assess the PK of AZD5718 after repeated oral dosing for 20 weeks in participants with proteinuric CKD
5) To assess the effect of AZD5718 on renal function in participants with proteinuric CKD with and without the addition of dapagliflozin |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Diabetic retinopathy study |
|
| E.3 | Principal inclusion criteria |
1. Male or female, aged at least 18 years.
2. Participants with proteinuric CKD defined as:
- eGFR 20 – 75 mL/min/1.73m2
- albuminuria defined as 200 -5000 mg albumin/g creatinine
- diagnosis of T2DM (for DKD sub-group only)
3. Body weight within 50-150 kg and BMI within the range 18 to 45 kg/m2 (inclusive).
4. Female participants must be of non-childbearing potential and must have been be surgically sterilized or be postmenopausal. All female participants must have a negative serum pregnancy test.
5. Male participants must be surgically sterile or agree to use highly effective contraceptives. Non sterilised male participants who are sexually active with a female partner of childbearing potential must use a male condom with spermicide.
6. Blood Pressure ≤ 150/100 mmHg and a stable dose of ACEi or ARB and other antihypertensive therapy including diuretic for at least 4 weeks prior to Screening Visit 1.
7. For participants on any additional antihypertensive medication (including diuretic therapy), the doses must be stable for at least 4 weeks prior to Screening Visit 1.
8. The participants must have been on a stable dose for at least 4 weeks prior to randomisation visit:
- if on SGLT2i or GLP1-RA treatment; no new additional SGLT2i or GLP1-RA therapy is permitted until the 8-week extension period.
- if on treatment with other drugs with potential to influence albuminuria, eg NSAIDs
- the renin inhibitor or an aldosterone antagonist in combination with an ACEi or an ARB (dual renin angiotensin aldosterone system inhibitor therapy) is permitted
9. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional exploratory genetic research that supports Genomic Initiative |
|
| E.4 | Principal exclusion criteria |
1. Recent hepatitis, or positive screening test for hepatitis B (hepatitis B virus surface antigen) or hepatitis C (hepatitis C antibody).
2. Diagnosis of:
- polycystic kidney disease or anatomical causes of CKD
- T1DM
3. Participants with severe hepatic impairment (Child-Pugh class C).
4. Abnormal laboratory findings at Screening Visit 1:
- Alanine aminotransferase or AST > 2 × ULN or total bilirubin > 2 × ULN (unless due to Gilbert’s disease) or evidence of chronic liver disease.
- Serum potassium > 5.5 mmol/L that cannot be adjusted to values ≤ 5.5 mmol/L by appropriate management.
- HbA1c level > 12.0%.
5. Corrected QT interval by Fridericia (QTcF) values > 470 ms (an average of the 12-lead triplicate ECGs) at Screening Visit 1.
6. Any of the following concomitant conditions or diseases at Screening Visit 1:
- History of QT prolongation associated with other medications that required discontinuation of that medication
- Congenital long QT syndrome
- Acute coronary syndrome, percutaneous coronary intervention, coronary artery bypass grafting within 6 months
- High degree atrioventricular block II-III, sinus node dysfunction with significant sinus pause, untreated with pacemaker
- Stroke within 3 months
- Heart failure New York Heart Association classification III-IV
- Anticipated dialysis or renal transplantation within 1 year
- History of substance dependence or a positive screen for drugs or alcohol abuse
- Prior malignancy other than non-melanoma skin cancer or cervical cancer in situ treated with apparent success with curative therapy (response duration of > 5 years).
- Any other condition or clinically relevant abnormal findings in physical examination, laboratory results or ECG during screening period
7. Participant with abnormal thyroid function tests (thyroid stimulating hormone [TSH], free thyroxine [fT4] and free triiodothyronine [fT3] values > 1.25 × ULN and/or < 0.75 × LLN), which are considered by the investigators as clinically relevant abnormal findings.
8. 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.
9. Ongoing use of any biologic drug and/or small molecule targeting the immune system
10. Any serum creatinine-altering drugs within 1 month prior to Screening Visit 1
11. Any concomitant medications known to be associated with Torsades de Pointes or potent inducers/inhibitors of cytochrome P450 3A4.
12. Treatment with:
- zileuton, cilastatin (DPEP1 inhibitor), or leukotriene receptor antagonists within 4 weeks of Screening Visit 1.
- simvastatin, lovastatin, and atorvastatin at doses > 40 mg per day within 1 month prior to Screening Visit 1.
13. 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).
14. Plasma donation within 60 days prior to Day 1.
15. Female currently pregnant or breast-feeding.
16. Participants who are legally institutionalized.
17. Participants with a known hypersensitivity to dapagliflozin or any of the excipients of the product. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in log-transformed urine albumin:creatinine ratio (UACR) from baseline to Week 20 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Change in log-transformed urine albumin to creatinine Ratio from baseline to Week 12
2) Number of participants with adverse events and serious adverse events
3) Change in 24-hour mean Systolic Blood Pressure (SBP)
4) Plasma concentrations of AZD5718
5) Change in estimated glomerular filtration rate (eGFR) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) From baseline to Week 12
2) From screening to Week 24
3) From baseline to Week 12
4) From Week 2 to Week 20
5) From baseline to Week 12 and from Week 12 to Week 20 |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
| Argentina |
| Brazil |
| Israel |
| Japan |
| Malaysia |
| Taiwan |
| United States |
| Poland |
| Germany |
| Hungary |
| 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 last visit of the last participant |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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