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

Sponsor

AstraZeneca (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04492722

Collaborator

Parexel (Industry), George Clinical Pty Ltd (Industry)

613

Enrollment

111

Locations

Arms

Anticipated Duration (Months)

5.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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. 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

613 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 :

Oct 1, 2020

Anticipated Primary Completion Date :

Aug 31, 2022

Anticipated Study Completion Date :

Aug 31, 2022

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

Change from baseline in urine ACR to Week 20 [Week 1 to Week 20]
To evaluate the dose response effect of AZD5718 on urine ACR at 20 weeks

Secondary Outcome Measures

Change from baseline in urine ACR to Week 12 [Week 1 to Week 12]
To evaluate the dose response effect of AZD5718 on urine ACR at 12 weeks
Number of participants with adverse events and serious adverse events [Screening to Week 24]
To assess the safety and tolerability profile of AZD5718 treatment
Change from baseline in 24-hours mean systolic blood pressure to Week 12 [Week 1 to Week 12]
To evaluate the effect of AZD5718 on ambulatory blood pressure
Plasma concentrations of AZD5718 [Week 2 to Week 20]
To assess the PK of AZD5718 after repeated oral dosing for 20 weeks
Change from baseline in estimated glomerular filtration rate (eGFR) to Week 12 [Week 1 to Week 12]
To assess the effect of AZD5718 on renal function

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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;

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:

History of QT prolongation associated with other medications that required discontinuation of that medication, and 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.
Stroke within 3 months, heart failure, and anticipated dialysis or renal transplantation within 1 year.
Any other condition or clinically relevant abnormal findings in physical examination, laboratory results or ECG during screening period.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Canoga Park	California	United States	91303
2	Research Site	La Mesa	California	United States	91942
3	Research Site	San Carlos	California	United States	94070
4	Research Site	San Francisco	California	United States	94110
5	Research Site	Victorville	California	United States	92392
6	Research Site	Denver	Colorado	United States	80045
7	Research Site	Jacksonville	Florida	United States	32216
8	Research Site	Winter Haven	Florida	United States	33880
9	Research Site	Columbus	Georgia	United States	31904
10	Research Site	Roseville	Michigan	United States	48066
11	Research Site	Hazelwood	Missouri	United States	63042
12	Research Site	Fresh Meadows	New York	United States	11365
13	Research Site	Great Neck	New York	United States	11021
14	Research Site	Jamaica	New York	United States	11432
15	Research Site	Blue Ash	Ohio	United States	45242
16	Research Site	East Providence	Rhode Island	United States	02914
17	Research Site	Memphis	Tennessee	United States	38104-2127
18	Research Site	Austin	Texas	United States	78738
19	Research Site	Houston	Texas	United States	77099
20	Research Site	Pearland	Texas	United States	77584
21	Research Site	San Antonio	Texas	United States	78215
22	Research Site	Schertz	Texas	United States	78154
23	Research Site	Bahia Blanca		Argentina	B8109
24	Research Site	Buenos Aires		Argentina	1280
25	Research Site	Buenos Aires		Argentina	B7600FYW
26	Research Site	Cordoba		Argentina	5000
27	Research Site	Cordoba		Argentina	X5016KEH
28	Research Site	Cordoba		Argentina	X5016KET
29	Research Site	Junín		Argentina	6000
30	Research Site	Belem		Brazil	66073-005
31	Research Site	Brasilia		Brazil	71625-175
32	Research Site	Curitiba		Brazil	80215-901
33	Research Site	Fortaleza		Brazil	60430-375
34	Research Site	Meireles		Brazil	60160-230
35	Research Site	Porto Alegre		Brazil	90035-074
36	Research Site	Porto Alegre		Brazil	90430-001
37	Research Site	Santo Andre		Brazil	09090-790
38	Research Site	Sao Paulo		Brazil	05403-9000
39	Research Site	São Paulo		Brazil	01323-020
40	Research Site	São Paulo		Brazil	05016-090
41	Research Site	Aschaffenburg		Germany	63739
42	Research Site	Berlin		Germany	13509
43	Research Site	Essen		Germany	45136
44	Research Site	Trier		Germany	54292
45	Research Site	Balatonfüred		Hungary	8230
46	Research Site	Budapest		Hungary	1083
47	Research Site	Budapest		Hungary	1115
48	Research Site	Debrecen		Hungary	4032
49	Research Site	Szentes		Hungary	6600
50	Research Site	Szigetvár		Hungary	7900
51	Research Site	Afula		Israel	1834111
52	Research Site	Ashdod		Israel	7747629
53	Research Site	Ashkelon		Israel	78306
54	Research Site	Haifa		Israel	34362
55	Research Site	Jerusalem		Israel	91031
56	Research Site	Ageo		Japan	362-8588
57	Research Site	Asahikawa-shi		Japan	070-8530
58	Research Site	Chiba-shi		Japan	261-0004
59	Research Site	Hiroshima		Japan	732-0057
60	Research Site	Kasugai-shi		Japan	486-8510
61	Research Site	Kitakyushu		Japan	805-8508
62	Research Site	Koga-shi		Japan	306-0041
63	Research Site	Kyoto-shi		Japan	604-8845
64	Research Site	Mito-shi		Japan	311-4198
65	Research Site	Morioka-shi		Japan	020-0066
66	Research Site	Osaka-shi		Japan	530-0005
67	Research Site	Osaka-shi		Japan	558-8558
68	Research Site	Osaka		Japan	553-0003
69	Research Site	Sashima-gun		Japan	306-0433
70	Research Site	Shizuoka-shi		Japan	420-8630
71	Research Site	Toride-shi		Japan	302-0022
72	Research Site	Yokohama-shi		Japan	234-0054
73	Research Site	Yokohama-shi		Japan	236-0004
74	Research Site	Yokohama-shi		Japan	247-8581
75	Research Site	Kota Kinabalu		Malaysia	88586
76	Research Site	Kuala Lumpur		Malaysia	50586
77	Research Site	Kuala Lumpur		Malaysia	56000
78	Research Site	Kuala Lumpur		Malaysia	59100
79	Research Site	Malacca		Malaysia	78300
80	Research Site	Seremban		Malaysia	70300
81	Research Site	Seri Manjung		Malaysia	32040
82	Research Site	Sibu		Malaysia	96000
83	Research Site	Bialystok		Poland	15-375
84	Research Site	Białystok		Poland	15-435
85	Research Site	Kraków		Poland	31-559
86	Research Site	Oswiecim		Poland	32-600
87	Research Site	Rzeszow		Poland	35-055
88	Research Site	Łódź		Poland	92-213
89	Research Site	Kaohsiung City		Taiwan	82445
90	Research Site	Kaohsiung		Taiwan	833
91	Research Site	Keelung		Taiwan	20448
92	Research Site	New Taipei City		Taiwan	23148
93	Research Site	Taichung		Taiwan	40443
94	Research Site	Taichung		Taiwan	40705
95	Research Site	Taichung		Taiwan	433
96	Research Site	Taipei 112		Taiwan
97	Research Site	Taipei		Taiwan	100
98	Research Site	Taipei		Taiwan	116
99	Research Site	Dnipro		Ukraine	49005
100	Research Site	Dnipro		Ukraine	49038
101	Research Site	Ivano-Frankivsk		Ukraine	76000
102	Research Site	Ivano-Frankivsk		Ukraine	76014
103	Research Site	Kyiv		Ukraine	02125
104	Research Site	Kyiv		Ukraine	03049
105	Research Site	Kyiv		Ukraine	1004
106	Research Site	Lviv		Ukraine	79010
107	Research Site	Uzhhorod		Ukraine	88018
108	Research Site	Vinnytsia		Ukraine	21001
109	Research Site	Vinnytsia		Ukraine	21010
110	Research Site	Zaporizhzhia		Ukraine	69600
111	Research Site	Zhytomyr		Ukraine	10002