Clinical trial NCT04492722: A Study to Evaluate the Safety and Efficacy of AZD5718 in Participants With Proteinuric Chronic Kidney Disease
Official title: A Phase 2b Randomised, Double-Blind, Placebo-Controlled, Multi-Centre, Dose-Ranging Study of AZD5718 in Participants With Proteinuric Chronic Kidney Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Kidney Disease
Keywords: Nephrology
Chronic kidney disease
Proteinuria
Diabetic kidney disease
Diabetes mellitus
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
name: George Clinical Pty Ltd
First posted: 2020-07-30
Enrollment: 613
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change From Baseline in Reduction of Urine Albumin to Creatinine Ratio (ACR) to Week 20
timeFrame: Week 1 (Baseline) to Week 20
Secondary outcomes:
measure: Change From Baseline in Reduction of Urine ACR to Week 12
timeFrame: Week 1 (Baseline) to Week 12
measure: Number of Participants With Adverse Events and Serious Adverse Events
timeFrame: From Screening (Week -4 to 0) to Week 24
measure: Change From Baseline in 24-hours Mean Systolic Blood Pressure to Week 12
timeFrame: Week 1 (Baseline) to Week 12
measure: Plasma Concentrations of AZD5718
timeFrame: From Week 2 to Week 20
measure: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) to Week 12
timeFrame: Week 1 (Baseline), Week 2, Week 4, Week 8, and Week 12
Other outcomes:
Locations:
city: Canoga Park
country: United States
facility: Research Site
state: California
city: La Mesa
country: United States
facility: Research Site
state: California
city: San Carlos
country: United States
facility: Research Site
state: California
city: San Francisco
country: United States
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state: California
city: Victorville
country: United States
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state: California
city: Denver
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state: Colorado
city: Jacksonville
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state: Florida
city: Winter Haven
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state: Florida
city: Columbus
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state: Georgia
city: Roseville
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state: Michigan
city: Hazelwood
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state: Missouri
city: Fresh Meadows
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state: New York
city: Great Neck
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city: Jamaica
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state: New York
city: Blue Ash
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state: Ohio
city: East Providence
country: United States
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state: Rhode Island
city: Memphis
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state: Tennessee
city: Austin
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state: Texas
city: Houston
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city: Pearland
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city: Schertz
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city: Bahia Blanca
country: Argentina
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city: Buenos Aires
country: Argentina
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city: Cordoba
country: Argentina
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city: Cordoba
country: Argentina
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city: Cordoba
country: Argentina
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city: Junín
country: Argentina
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city: Mar del Plata
country: Argentina
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city: Belem
country: Brazil
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city: Brasilia
country: Brazil
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city: Curitiba
country: Brazil
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city: Fortaleza
country: Brazil
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city: Meireles
country: Brazil
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city: Porto Alegre
country: Brazil
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city: Porto Alegre
country: Brazil
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city: Santo Andre
country: Brazil
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city: Sao Paulo
country: Brazil
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city: São Paulo
country: Brazil
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city: São Paulo
country: Brazil
facility: Research Site
city: Aschaffenburg
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Essen
country: Germany
facility: Research Site
city: Trier
country: Germany
facility: Research Site
city: Balatonfüred
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
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city: Budapest
country: Hungary
facility: Research Site
city: Debrecen
country: Hungary
facility: Research Site
city: Szentes
country: Hungary
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city: Szigetvár
country: Hungary
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city: Afula
country: Israel
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city: Ashdod
country: Israel
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city: Ashkelon
country: Israel
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city: Haifa
country: Israel
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city: Jerusalem
country: Israel
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city: Ageo
country: Japan
facility: Research Site
city: Asahikawa-shi
country: Japan
facility: Research Site
city: Chiba-shi
country: Japan
facility: Research Site
city: Hiroshima
country: Japan
facility: Research Site
city: Kasugai-shi
country: Japan
facility: Research Site
city: Kitakyushu
country: Japan
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city: Koga-shi
country: Japan
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city: Kyoto-shi
country: Japan
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city: Mito-shi
country: Japan
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city: Morioka-shi
country: Japan
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city: Osaka-shi
country: Japan
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city: Osaka-shi
country: Japan
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city: Osaka
country: Japan
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city: Sashima-gun
country: Japan
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city: Shizuoka-shi
country: Japan
facility: Research Site
city: Toride-shi
country: Japan
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city: Yokohama-shi
country: Japan
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city: Yokohama-shi
country: Japan
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city: Yokohama-shi
country: Japan
facility: Research Site
city: Kota Kinabalu
country: Malaysia
facility: Research Site
city: Kuala Lumpur
country: Malaysia
facility: Research Site
city: Kuala Lumpur
country: Malaysia
facility: Research Site
city: Kuala Lumpur
country: Malaysia
facility: Research Site
city: Malacca
country: Malaysia
facility: Research Site
city: Seremban
country: Malaysia
facility: Research Site
city: Seri Manjung
country: Malaysia
facility: Research Site
city: Sibu
country: Malaysia
facility: Research Site
city: Bialystok
country: Poland
facility: Research Site
city: Białystok
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Oswiecim
country: Poland
facility: Research Site
city: Rzeszow
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Kaohsiung City
country: Taiwan
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: Keelung
country: Taiwan
facility: Research Site
city: New Taipei City
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taipei 112
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Dnipro
country: Ukraine
facility: Research Site
city: Dnipro
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Lviv
country: Ukraine
facility: Research Site
city: Uzhhorod
country: Ukraine
facility: Research Site
city: Vinnytsia
country: Ukraine
facility: Research Site
city: Vinnytsia
country: Ukraine
facility: Research Site
city: Zaporizhzhia
country: Ukraine
facility: Research Site
city: Zhytomyr
country: Ukraine
facility: Research Site
Study officials:
affiliation: Department of Clinical Pharmacy and Pharmacology University Medical Centre Groningen
name: Hiddo J. L. Heerspink
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.