A Study to Evaluate the Safety and Efficacy of AZD5718 in Participants With Proteinuric Chronic Kidney Disease

Chronic Kidney Disease Clinical Trial

Official title:

A Phase 2b Randomised, Double-Blind, Placebo-Controlled, Multi-Centre, Dose-Ranging Study of AZD5718 in Participants With Proteinuric Chronic Kidney Disease

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04492722
• Other study ID #: D7551C00001
• Secondary ID: 2020-002263-54
• Status: Terminated
• Phase: Phase 2
• Start date: October 1, 2020
• Est. completion date: September 6, 2022

Study information

• Verified date: December 2023
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to evaluate the dose-response efficacy, safety, and pharmacokinetics (PK) of AZD5718 in participants with proteinuric chronic kidney disease.

Description:

The study will be conducted in approximately 118 study centers across 12 countries. The overall study period will be around 28 weeks. Approximately 632 participants comprising of 67% diabetic kidney disease (DKD) and 33% non-DKD participants will be enrolled. After a screening period of up to 4 weeks, the participants will be randomised in a 1:1:1:1 ratio to receive one of the doses of AZD5718 and/or placebo for the first 12 weeks (Day 85 [treatment period 1]), with an add-on therapy of 8 weeks of dapagliflozin for all participants from Week 12 to 20 (Day 85 to 141 [treatment period 2]). Only participants still taking their assigned treatment from treatment period 1 will progress to treatment period 2. Any participant with urine albumin to creatinine ratio (ACR) < 30 mg/g at Week 12 will be excluded from treatment period 2. The eligibility check to enter treatment period 2 will be done at Visit 7 (Week 12) using the last available urine ACR result. The final analysis will be done after all participants have completed follow-up period of up to 4 weeks. The expected total study duration, including the Screening Period, for each participant will be at least 28 weeks.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 613
• Est. completion date: September 6, 2022
• Est. primary completion date: September 6, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

Inclusion Criteria:

• Capable of giving signed informed consent form.

• Male or female adults, >= 18 years of age at study entry.

• For participants who haven't reached the age of maturity according to local regulations in their country, a written informed consent should be obtained from the participant and participants legally acceptable representative.

• Body weight within 50-150 kg and body mass index within the range 18 to 45 kg/m^2.

• Participants with proteinuric CKD defined as:

• eGFR 20 - 75 mL/min/1.73m^2 based on Chronic Kidney Disease Epidemiology Collaboration equation at Screening Visit 1.

• Albuminuria defined as 200 -5000 mg albumin/g creatinine based on the geometric mean of the replicated measurements using 3 sequential first morning void urine at Visit 2.

• Participants with diagnosis of Type 2 Diabetes Mellitus (DM) [for DKD sub-group only].

• Females of non-childbearing potential must have been surgically sterilized or be postmenopausal, and all female participants must have a negative pregnancy test at screening and prior to study drug administration.

• Male participants must be surgically sterile or agree to use highly effective contraceptives. Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a male condom with spermicide from Day 1 to 3 months after the last dose of the study drug. Approved/Certified measurements in Japan are as Vasectomy, tubal occlusion, intrauterine device (provided coils are copper banded), levonorgestrel intrauterine system (eg, Mirena®). These measurements are acceptable forms of highly effective birth control in Japan. Not Approved/Certified measurements in Japan are as: Cerazette® (desogestrel) pills, medroxyprogesterone injections (eg, Depo-Provera®), etonogestrel implants (eg, Implanon®, Norplan®), normal and low dose combined oral pills, norelgestromin/ethinylestradiol transdermal system (eg, Evra® Patch), intravaginal device (eg, NuvaRing®).

• Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional exploratory genetic research.

• Participants should have: a) stable blood pressure (BP [BP <= 150/100 mmHg at Visit 1, and 3]); b)stable dose of angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARB) for at least 4 weeks prior to Screening Visit 1; c) participants who have been unable to tolerate ACEi or ARB therapy may be enrolled.

• Participants must have been on a stable dose for at least 4 weeks prior to Screening Visit 1, who have been on additional antihypertensives (including diuretics); on treatment with drugs with potential to influence albuminuria eg., non-steroidal anti-inflammatory drug; on renin inhibitor or an aldosterone antagonist in combination with an ACEi or an ARB.

• Participants on Sodium-glucose co-transporter-2 inhibitors (SGLT2i) or Glucagon-like peptide-1 receptor agonist (GLP1-RA) treatment, the participants must have been on a stable dose for at least 4 weeks prior to randomization visit.

Exclusion Criteria:

• Participants with recent positive hepatitis B or hepatitis C.

• Diagnosis of polycystic kidney disease or anatomical causes of CKD.

• Diagnosis of Type 1 DM.

• Participants with severe hepatic impairment (Child-Pugh class C).

• Abnormal laboratory findings at Screening Visit 1.

• Any of the following concomitant conditions or diseases at Screening Visit 1:

1. History of QT prolongation associated with other medications that required discontinuation of that medication, and congenital long QT syndrome.

2. Acute coronary syndrome, percutaneous coronary intervention, coronary artery bypass grafting within 6 months.

3. High degree atrioventricular block II-III, sinus node dysfunction.

4. Stroke within 3 months, heart failure, and anticipated dialysis or renal transplantation within 1 year.

5. Any other condition or clinically relevant abnormal findings in physical examination, laboratory results or ECG during screening period.

6. History of substance dependence or a positive screen for drugs or alcohol abuse. Alcohol and drug screening to be completed for all participants locally with laboratory kits provided by the central laboratory.

• 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.

• Ongoing use of any biologic drug and/or small molecule targeting the immune system.

• Any serum creatinine-altering drugs within 1 month prior to Screening Visit 1.

• Treatment with any concomitant medications known to be associated with Torsades de Pointes or potent inducers/inhibitors of cytochrome P450 3A4 within 4 weeks of Visit 3 (Randomization).

• Treatment with zileuton, cilastatin (dipeptidase-1 [DPEP1] inhibitor), or leukotriene receptor antagonists (eg, montelukast) within 4 weeks of Screening Visit 1.

• Treatment with simvastatin, lovastatin, and atorvastatin at doses > 40 mg per day within 1 month prior to Screening Visit 1.

• Concurrent enrollment in another clinical study involving an investigational treatment or drug or participation in a device study within 3 months prior to Screening Visit 1.

• Participants with a known hypersensitivity to AZD5718 or any of the excipients of the product. Participants with a known hypersensitivity to dapagliflozin or any of the excipients of the product.

• 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).

• Plasma donation within 60 days prior to Day 1.

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study center).

• 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.

• For women only - currently pregnant (a negative serum pregnancy test is required at Screening Visit 1 and urine pregnancy test at Day 1 [Visit 3]) or breast-feeding.

• An employee, or close relative of an employee, of AstraZeneca, the Contract Research Organisation, or the study site, regardless of the employee's role.

• Participants who are legally institutionalized.

• Participants working night shifts, and who cannot avoid strenuous manual labour during the study.

Related Conditions & MeSH terms

• Chronic Kidney Disease
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• AZD5718
Participants will receive once daily oral dose of AZD5718 as per the arms they are randomised, and will continue until Week 20.
• Dapagliflozin 10 mg
Participants will receive once daily oral dose of 10 mg dapagliflozin for 8 weeks as an add-on therapy.
• Placebo
Participants will receive once daily oral dose of placebo matched to AZD5718, and will continue until Week 20.

Locations

Country	Name	City	State
Argentina	Research Site	Bahia Blanca
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Cordoba
Argentina	Research Site	Cordoba
Argentina	Research Site	Cordoba
Argentina	Research Site	Junín
Argentina	Research Site	Mar del Plata
Brazil	Research Site	Belem
Brazil	Research Site	Brasilia
Brazil	Research Site	Curitiba
Brazil	Research Site	Fortaleza
Brazil	Research Site	Meireles
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Santo Andre
Brazil	Research Site	Sao Paulo
Brazil	Research Site	São Paulo
Brazil	Research Site	São Paulo
Germany	Research Site	Aschaffenburg
Germany	Research Site	Berlin
Germany	Research Site	Essen
Germany	Research Site	Trier
Hungary	Research Site	Balatonfüred
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Szentes
Hungary	Research Site	Szigetvár
Israel	Research Site	Afula
Israel	Research Site	Ashdod
Israel	Research Site	Ashkelon
Israel	Research Site	Haifa
Israel	Research Site	Jerusalem
Japan	Research Site	Ageo
Japan	Research Site	Asahikawa-shi
Japan	Research Site	Chiba-shi
Japan	Research Site	Hiroshima
Japan	Research Site	Kasugai-shi
Japan	Research Site	Kitakyushu
Japan	Research Site	Koga-shi
Japan	Research Site	Kyoto-shi
Japan	Research Site	Mito-shi
Japan	Research Site	Morioka-shi
Japan	Research Site	Osaka
Japan	Research Site	Osaka-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Sashima-gun
Japan	Research Site	Shizuoka-shi
Japan	Research Site	Toride-shi
Japan	Research Site	Yokohama-shi
Japan	Research Site	Yokohama-shi
Japan	Research Site	Yokohama-shi
Malaysia	Research Site	Kota Kinabalu
Malaysia	Research Site	Kuala Lumpur
Malaysia	Research Site	Kuala Lumpur
Malaysia	Research Site	Kuala Lumpur
Malaysia	Research Site	Malacca
Malaysia	Research Site	Seremban
Malaysia	Research Site	Seri Manjung
Malaysia	Research Site	Sibu
Poland	Research Site	Bialystok
Poland	Research Site	Bialystok
Poland	Research Site	Kraków
Poland	Research Site	Lódz
Poland	Research Site	Oswiecim
Poland	Research Site	Rzeszow
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Kaohsiung City
Taiwan	Research Site	Keelung
Taiwan	Research Site	New Taipei City
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei 112
Ukraine	Research Site	Dnipro
Ukraine	Research Site	Dnipro
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Lviv
Ukraine	Research Site	Uzhhorod
Ukraine	Research Site	Vinnytsia
Ukraine	Research Site	Vinnytsia
Ukraine	Research Site	Zaporizhzhia
Ukraine	Research Site	Zhytomyr
United States	Research Site	Austin	Texas
United States	Research Site	Blue Ash	Ohio
United States	Research Site	Canoga Park	California
United States	Research Site	Columbus	Georgia
United States	Research Site	Denver	Colorado
United States	Research Site	East Providence	Rhode Island
United States	Research Site	Fresh Meadows	New York
United States	Research Site	Great Neck	New York
United States	Research Site	Hazelwood	Missouri
United States	Research Site	Houston	Texas
United States	Research Site	Jacksonville	Florida
United States	Research Site	Jamaica	New York
United States	Research Site	La Mesa	California
United States	Research Site	Memphis	Tennessee
United States	Research Site	Pearland	Texas
United States	Research Site	Roseville	Michigan
United States	Research Site	San Antonio	Texas
United States	Research Site	San Carlos	California
United States	Research Site	San Francisco	California
United States	Research Site	Schertz	Texas
United States	Research Site	Victorville	California
United States	Research Site	Winter Haven	Florida

Sponsors (3)

Lead Sponsor	Collaborator
AstraZeneca	George Clinical Pty Ltd, Parexel

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Germany,  Hungary,  Israel,  Japan,  Malaysia,  Poland,  Taiwan,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Reduction of Urine Albumin to Creatinine Ratio (ACR) to Week 20	The dose response effect of AZD5718 on urine ACR at 20 weeks was evaluated. Values less than 1 indicate improvement from baseline.	Week 1 (Baseline) to Week 20
Secondary	Change From Baseline in Reduction of Urine ACR to Week 12	The dose response effect of AZD5718 on urine ACR at 12 weeks was evaluated. Values less than 1 indicate improvement from baseline.	Week 1 (Baseline) to Week 12
Secondary	Number of Participants With Adverse Events and Serious Adverse Events	The safety and tolerability profile of AZD5718 treatment was assessed	From Screening (Week -4 to 0) to Week 24
Secondary	Change From Baseline in 24-hours Mean Systolic Blood Pressure to Week 12	The effect of AZD5718 on ambulatory blood pressure was assessed	Week 1 (Baseline) to Week 12
Secondary	Plasma Concentrations of AZD5718	The PK of AZD5718 after repeated oral dosing for 20 weeks was evaluated	From Week 2 to Week 20
Secondary	Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12	The effect of AZD5718 on renal function was evaluated	Week 1 (Baseline), Week 2, Week 4, Week 8, and Week 12

External Links

•   Clinical Study Protocol
•   Clinical Study Results Synopsis
•   Statistical Analysis Plan