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

NCT ID: NCT04492722

Last Updated: 2024-12-20

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 613 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-01
• Study Completion Date: 2022-09-06

Brief 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.

Detailed 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.

Conditions

Chronic Kidney Disease

Keywords

Nephrology; Chronic kidney disease; Proteinuria; Diabetic kidney disease; Diabetes mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

AZD5718 Dose 1 + Dapagliflozin 10 mg

Participants will receive once daily oral dose 1 of AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.

Group Type: EXPERIMENTAL

AZD5718

Intervention Type: DRUG

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

Intervention Type: DRUG

Participants will receive once daily oral dose of 10 mg dapagliflozin for 8 weeks as an add-on therapy.

AZD5718 Dose 2 + Dapagliflozin 10 mg

Participants will receive once daily oral dose 2 of AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.

Group Type: EXPERIMENTAL

AZD5718

Intervention Type: DRUG

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

Intervention Type: DRUG

Participants will receive once daily oral dose of 10 mg dapagliflozin for 8 weeks as an add-on therapy.

AZD5718 Dose 3 + Dapagliflozin 10 mg

Participants will receive once daily oral dose 3 of AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.

Group Type: EXPERIMENTAL

AZD5718

Intervention Type: DRUG

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

Intervention Type: DRUG

Participants will receive once daily oral dose of 10 mg dapagliflozin for 8 weeks as an add-on therapy.

Placebo + Dapagliflozin 10 mg

Participants will receive once daily oral dose of placebo matched to AZD5718 for 12 weeks, thereafter add-on therapy of 10 mg dapagliflozin for 8 weeks.

Group Type: PLACEBO_COMPARATOR

Dapagliflozin 10 mg

Intervention Type: DRUG

Participants will receive once daily oral dose of 10 mg dapagliflozin for 8 weeks as an add-on therapy.

Placebo

Intervention Type: DRUG

Participants will receive once daily oral dose of placebo matched to AZD5718, and will continue until Week 20.

Interventions

AZD5718

Participants will receive once daily oral dose of AZD5718 as per the arms they are randomised, and will continue until Week 20.

Intervention Type: DRUG

Dapagliflozin 10 mg

Participants will receive once daily oral dose of 10 mg dapagliflozin for 8 weeks as an add-on therapy.

Intervention Type: DRUG

Placebo

Participants will receive once daily oral dose of placebo matched to AZD5718, and will continue until Week 20.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 130 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Parexel

INDUSTRY

Sponsor Role: collaborator

Emerald Clinical Inc.

INDUSTRY

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hiddo J. L. Heerspink

Role: PRINCIPAL_INVESTIGATOR

Department of Clinical Pharmacy and Pharmacology University Medical Centre Groningen

Locations

Research Site

Canoga Park, California, United States

Research Site

La Mesa, California, United States

Research Site

San Carlos, California, United States

Research Site

San Francisco, California, United States

Research Site

Victorville, California, United States

Research Site

Denver, Colorado, United States

Research Site

Jacksonville, Florida, United States

Research Site

Winter Haven, Florida, United States

Research Site

Columbus, Georgia, United States

Research Site

Roseville, Michigan, United States

Research Site

Hazelwood, Missouri, United States

Research Site

Fresh Meadows, New York, United States

Research Site

Great Neck, New York, United States

Research Site

Jamaica, New York, United States

Research Site

Blue Ash, Ohio, United States

Research Site

East Providence, Rhode Island, United States

Research Site

Memphis, Tennessee, United States

Research Site

Austin, Texas, United States

Research Site

Houston, Texas, United States

Research Site

Pearland, Texas, United States

Research Site

San Antonio, Texas, United States

Research Site

Schertz, Texas, United States

Research Site

Bahía Blanca, , Argentina

Research Site

Buenos Aires, , Argentina

Research Site

Córdoba, , Argentina

Research Site

Córdoba, , Argentina

Research Site

Córdoba, , Argentina

Research Site

Junín, , Argentina

Research Site

Mar del Plata, , Argentina

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Belém, , Brazil

Research Site

Brasília, , 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 André, , Brazil

Research Site

São Paulo, , Brazil

Research Site

São Paulo, , Brazil

Research Site

São Paulo, , Brazil

Research Site

Aschaffenburg, , Germany

Research Site

Berlin, , Germany

Research Site

Essen, , Germany

Research Site

Trier, , Germany

Research Site

Balatonfüred, , Hungary

Research Site

Budapest, , Hungary

Research Site

Budapest, , Hungary

Research Site

Debrecen, , Hungary

Research Site

Szentes, , Hungary

Research Site

Szigetvár, , Hungary

Research Site

Afula, , Israel

Research Site

Ashdod, , Israel

Research Site

Ashkelon, , Israel

Research Site

Haifa, , Israel

Research Site

Jerusalem, , Israel

Research Site

Ageo, , Japan

Research Site

Asahikawa-shi, , Japan

Research Site

Chiba, , Japan

Research Site

Hiroshima, , Japan

Research Site

Kasugai-shi, , Japan

Research Site

Kitakyushu, , Japan

Research Site

Koga-shi, , Japan

Research Site

Kyoto, , Japan

Research Site

Mito, , Japan

Research Site

Morioka, , Japan

Research Site

Osaka, , Japan

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Osaka, , Japan

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Osaka, , Japan

Research Site

Sashima-gun, , Japan

Research Site

Shizuoka, , Japan

Research Site

Toride-shi, , Japan

Research Site

Yokohama, , Japan

Research Site

Yokohama, , Japan

Research Site

Yokohama, , Japan

Research Site

Kota Kinabalu, , Malaysia

Research Site

Kuala Lumpur, , Malaysia

Research Site

Kuala Lumpur, , Malaysia

Research Site

Kuala Lumpur, , Malaysia

Research Site

Malacca, , Malaysia

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Seremban, , Malaysia

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Seri Manjung, , Malaysia

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Sibu, , Malaysia

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Bialystok, , Poland

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Bialystok, , Poland

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Krakow, , Poland

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Lodz, , Poland

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Oświęcim, , Poland

Research Site

Rzeszów, , Poland

Research Site

Kaohsiung City, , 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, , Taiwan

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, , Ukraine

Countries

South Korea; United States; Argentina; Brazil; Germany; Hungary; Israel; Japan; Malaysia; Poland; Taiwan; Ukraine

References

Heerspink HJL, Law G, Psachoulia K, Connolly K, Whatling C, Ericsson H, Knochel J, Lindstedt EL, MacPhee I. Design of FLAIR: a Phase 2b Study of the 5-Lipoxygenase Activating Protein Inhibitor AZD5718 in Patients With Proteinuric CKD. Kidney Int Rep. 2021 Aug 27;6(11):2803-2810. doi: 10.1016/j.ekir.2021.08.018. eCollection 2021 Nov.

Reference Type: DERIVED

PMID: 34805632 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&amp;parentIdentifier=D7551C00001&amp;attachmentIdentifier=d8fc6532-dec8-43e7-937b-828cf4d0d085&amp;fileName=CSP.pdf&amp;versionIdentifier=

Clinical Study Protocol

https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&amp;parentIdentifier=D7551C00001&amp;attachmentIdentifier=18780c46-89ba-4175-b893-33b0b39ce0bf&amp;fileName=SAP.pdf&amp;versionIdentifier=

Statistical Analysis Plan

https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&amp;parentIdentifier=D7551C00001&amp;attachmentIdentifier=817aeaff-7ef5-4bdc-8cd2-858d351426a0&amp;fileName=CSR_Synopsis.pdf&amp;versionIdentifier=

Clinical Study Results Synopsis

Other Identifiers

2020-002263-54

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

D7551C00001

Identifier Type: -

Identifier Source: org_study_id