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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04492722
Recruitment Status : Recruiting
First Posted : July 30, 2020
Last Update Posted : October 28, 2020
Sponsor:
Collaborators:
Parexel
George Clinical Pty Ltd
Information provided by (Responsible Party):
AstraZeneca

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.

Condition or disease Intervention/treatment Phase
Chronic Kidney Disease Drug: AZD5718 Drug: Dapagliflozin 10 mg Drug: Placebo Phase 2

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. The eligibility check to enter treatment period 2 will be done at Visit 7 (Week 12) using the last available urine albumin to creatinine ratio (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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 632 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: No member of the study team at AstraZeneca, or representative, personnel at study centres, or any CRO handling data will have access to the randomization scheme prior to unblinding for the primary analysis.
Primary Purpose: Treatment
Official Title: A Phase 2b Randomised, Double-Blind, Placebo-Controlled, Multi-Centre, Dose-Ranging Study of AZD5718 in Participants With Proteinuric Chronic Kidney Disease
Actual Study Start Date : October 1, 2020
Estimated Primary Completion Date : October 27, 2022
Estimated Study Completion Date : October 27, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

Arm Intervention/treatment
Experimental: 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.
Drug: AZD5718
Participants will receive once daily oral dose of AZD5718 as per the arms they are randomised, and will continue until Week 20.

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

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

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

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

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

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

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




Primary Outcome Measures :
  1. Change from baseline in urine ACR to Week 20 [ Time Frame: Week 1 to Week 20 ]
    To evaluate the dose response effect of AZD5718 on urine ACR at 20 weeks


Secondary Outcome Measures :
  1. Change from baseline in urine ACR to Week 12 [ Time Frame: Week 1 to Week 12 ]
    To evaluate the dose response effect of AZD5718 on urine ACR at 12 weeks

  2. Number of participants with adverse events and serious adverse events [ Time Frame: Screening to Week 24 ]
    To assess the safety and tolerability profile of AZD5718 treatment

  3. Change from baseline in 24-hours mean systolic blood pressure to Week 12 [ Time Frame: Week 1 to Week 12 ]
    To evaluate the effect of AZD5718 on ambulatory blood pressure

  4. Plasma concentrations of AZD5718 [ Time Frame: Week 2 to Week 20 ]
    To assess the PK of AZD5718 after repeated oral dosing for 20 weeks

  5. Change from baseline in estimated glomerular filtration rate (eGFR) to Week 12 [ Time Frame: Week 1 to Week 12 ]
    To assess the effect of AZD5718 on renal function



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Capable of giving signed informed consent.
  • Male or female adults, >= 18 years of age at study entry.
  • Participants to be enrolled in Japan, aged 18 to < 20 years, 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 (CKD-EPI) equation at 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.
  • 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 (ACEi) or angiotensin II receptor blockers (ARB) for at least 4 weeks prior to 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 NSAIDs); 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.
  • Any concomitant medications known to be associated with Torsades de Pointes or potent inducers/inhibitors of cytochrome P450 3A4.
  • Treatment with zileuton, cilastatin (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.
  • 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 CRO, or the study site, regardless of the employee's role.
  • Participants who are legally institutionalized.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04492722


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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United States, Alabama
Research Site Not yet recruiting
Birmingham, Alabama, United States, 35294
United States, California
Research Site Not yet recruiting
Canoga Park, California, United States, 91303
Research Site Not yet recruiting
La Mesa, California, United States, 91942
Research Site Not yet recruiting
San Carlos, California, United States, 94070
Research Site Not yet recruiting
San Francisco, California, United States, 94110
Research Site Recruiting
Victorville, California, United States, 92392
United States, Michigan
Research Site Not yet recruiting
Roseville, Michigan, United States, 48066
United States, Missouri
Research Site Not yet recruiting
Hazelwood, Missouri, United States, 63042
United States, New York
Research Site Not yet recruiting
Great Neck, New York, United States, 11021
Research Site Not yet recruiting
Jamaica, New York, United States, 11432
United States, Ohio
Research Site Not yet recruiting
Cincinnati, Ohio, United States, 45242
Research Site Not yet recruiting
Cleveland, Ohio, United States, 44106
Research Site Not yet recruiting
Toledo, Ohio, United States, 43614
United States, Rhode Island
Research Site Not yet recruiting
East Providence, Rhode Island, United States, 02914
United States, Texas
Research Site Not yet recruiting
Austin, Texas, United States, 78738
Research Site Not yet recruiting
San Antonio, Texas, United States, 78215
Research Site Not yet recruiting
Tomball, Texas, United States, 77375
Argentina
Research Site Not yet recruiting
Buenos Aires, Argentina, C1425BGN
Research Site Not yet recruiting
Cordoba, Argentina, 5000
Research Site Not yet recruiting
Cordoba, Argentina, X5000AVE
Research Site Not yet recruiting
Cordoba, Argentina, X5016KET
Japan
Research Site Not yet recruiting
Iwate, Japan, 020-0066
Research Site Not yet recruiting
Toride-shi, Japan, 302-0022
Research Site Not yet recruiting
Yokohama-shi, Japan, 236-0004
Research Site Not yet recruiting
Yokohama-shi, Japan, 247-8581
Poland
Research Site Not yet recruiting
Rzeszow, Poland, 35-055
Sponsors and Collaborators
AstraZeneca
Parexel
George Clinical Pty Ltd
Investigators
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Principal Investigator: Hiddo J. L. Heerspink Department of Clinical Pharmacy and Pharmacology University Medical Centre Groningen
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04492722    
Other Study ID Numbers: D7551C00001
2020-002263-54 ( EudraCT Number )
First Posted: July 30, 2020    Key Record Dates
Last Update Posted: October 28, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Nephrology
Chronic kidney disease
Proteinuria
Diabetic kidney disease
Diabetes mellitus
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Urologic Diseases
Renal Insufficiency
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs