MIRACLE: Efficacy, Safety and Tolerability of AZD9977 and Dapagliflozin in Participants With Heart Failure and Chronic Kidney Disease

Sponsor

AstraZeneca (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04595370

Collaborator

(none)

500

Enrollment

226

Locations

Arms

28.9

Anticipated Duration (Months)

2.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the efficacy and safety of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone and to assess the dose-response relationship, dapagliflozin alone and 3 doses of AZD9977 combined with dapagliflozin on urinary albumin to creatinine ratio (UACR). The study will be conducted in participants with heart failure (HF) with left ventricular ejection fraction (LVEF [below 60%]) and chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR [between ≥ 20 and ≤ 60 mL/min/1.73 m^{2, with at least 20% of participants with eGFR ≥ 20 to <30 mL/min/1.73}2 and a maximum of 35% of participants with eGFR ≥ 45 mL/min/1.73 m^2]).

Condition or Disease	Intervention/Treatment	Phase
Heart Failure Chronic Kidney Disease	Drug: AZD9977 Drug: Dapagliflozin	Phase 2

Detailed Description

After screening, eligible participants will undergo a run-in period where all participants receive dapagliflozin for up to 7 weeks depending on pre-study use of SGLT2i or not. At the end of the run-in period, eligible participants will be randomly assigned with a 1:1:1:1 ratio to receive once daily administration of one of the following 4 study treatments group for 12 weeks. To ensure blinding, the study treatment will be administered in the form of 3 oral capsules of AZD9977 or placebo and 1 oral tablet or dapagliflozin.

AZD9977 Dose A + dapagliflozin 10 mg
AZD9977 Dose B + dapagliflozin 10 mg
AZD9977 Dose C + dapagliflozin 10 mg
Dapagliflozin 10 mg

Participants will be randomized to one of the above treatment group, according to type 2 diabetes mellitus [T2DM (yes/no)] and eGFR (≥ 20 to <30 mL/min/1.73^{2; or ≥ 30 to < 45
mL/min/1.73}2; or ≥45 mL/min/1.73^2).

The total duration of participation will be approximately 22 to 24weeks.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

500 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Participants who meet the eligibility criteria will be randomized to one of the following treatment group: AZD9977 Dose A + dapagliflozin 10 mg AZD9977 Dose B + dapagliflozin 10 mg AZD9977 Dose C + dapagliflozin 10 mg Dapagliflozin 10 mgParticipants who meet the eligibility criteria will be randomized to one of the following treatment group:AZD9977 Dose A + dapagliflozin 10 mg AZD9977 Dose B + dapagliflozin 10 mg AZD9977 Dose C + dapagliflozin 10 mg Dapagliflozin 10 mg

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase 2b, Randomised, Double-Blind, Active Controlled, Multi Centre Study to Evaluate the Efficacy, Safety and Tolerability of Oral AZD9977 and Dapagliflozin Treatment in Patients With Heart Failure and Chronic Kidney Disease

Actual Study Start Date :

Jan 26, 2021

Anticipated Primary Completion Date :

Jun 26, 2023

Anticipated Study Completion Date :

Jun 26, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AZD9977 Dose A + dapagliflozin 10 mg Participants will receive once daily oral dose A of AZD9977 and 10 mg dapagliflozin for 12 weeks.	Drug: AZD9977 Participants will receive AZD9977 as per the arms they are randomized. Drug: Dapagliflozin Participants will receive dapagliflozin as per the arms they are randomized.
Experimental: AZD9977 Dose B + dapagliflozin 10 mg Participants will receive once daily oral dose B of AZD9977 and 10 mg dapagliflozin for 12 weeks.	Drug: AZD9977 Participants will receive AZD9977 as per the arms they are randomized. Drug: Dapagliflozin Participants will receive dapagliflozin as per the arms they are randomized.
Experimental: AZD9977 Dose C + dapagliflozin 10 mg Participants will receive once daily oral dose C of AZD9977 and 10 mg dapagliflozin for 12 weeks.	Drug: AZD9977 Participants will receive AZD9977 as per the arms they are randomized. Drug: Dapagliflozin Participants will receive dapagliflozin as per the arms they are randomized.
Experimental: Dapagliflozin 10 mg Participants will receive once daily oral dose of dapagliflozin 10 mg alone for 12 weeks.	Drug: Dapagliflozin Participants will receive dapagliflozin as per the arms they are randomized.

Outcome Measures

Primary Outcome Measures

Percent change from baseline in UACR at 12 weeks [Baseline (Day 1) until Week 12 (Day 85)]
Evaluating the effect of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone on UACR.

Secondary Outcome Measures

Percent change from baseline in UACR at 12 weeks to assess dose-response relationship [Baseline (Day 1) until Week 12 (Day 85)]
Assessment of the dose-response relationship of dapagliflozin (10 mg) alone and 3 doses of AZD9977 (A, B, or C) combined with dapagliflozin (10 mg) on UACR.

Other Outcome Measures

Number of participants with adverse events (AEs) and serious adverse events (SAEs) [From baseline (Day 1) until Day 113 (Safety Follow-up)]
Assessment of the general safety and tolerability of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone.
Absolute value of serum potassium over time [Days 1, and 3 until Day 85]
Assessment of the effect of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone on serum potassium.
Change from baseline in serum potassium over time [From baseline (Day 1), Day 3 until Day 85]
Assessment of the effect of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone on serum potassium.
Absolute value of eGFR over time [Days 1, and 3 until Day 85]
Assessment of the effect of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone on eGFR.
Change from baseline in eGFR over time [From baseline (Day 1), Day 3 until Day 85]
Assessment of the effect of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone on eGFR.

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participants are included in the study if any of the following criteria apply:

Documented diagnosis of stable symptomatic HF (New York Heart Association class II-III) at screening, and a medical history of typical symptoms and signs of HF in those who are currently receiving loop diuretic treatment
Left ventricular ejection fraction <60% documented by the most recent echocardiogram or cardiac magnetic resonance imaging within the last 12 months prior to screening
Stable background treatment for HF, hypertension, diabetes mellitus or renal disease according to guidelines
N-terminal-pro-brain natriuretic peptide (NT proBNP) ≥300 pg/mL for participants with sinus rhythm at screening; and NT proBNP ≥600 pg/mL for participants with atrial fibrillation/flutter at screening
The eGFR ≥30 and ≤60 mL/min/1.73^2 (by CKD- EPI formula) and UACR ≥30 mg/g (3 mg/mmol) and <3000 mg/g (300 mg/mmol)
Body mass index less than 40 kg/m^2
Serum/plasma K+ level ≥ 3.5 and < 5.0 mmol/L within 10 days prior to randomization
Serum/ plasma Na+ level within normal reference values within 10 days prior to randomization
Systolic blood pressure should be at protocol defined range at randomization (Visit 3), with no change to antihypertensive treatments in previous 3 weeks
Male or female of non-childbearing potential
All participants must follow protocol defined contraceptives procedures

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

Primary glomerulopathy, vasculitic renal disease, prior dialysis or unstable rapidly progressing renal disease, autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or anti-neutrophil cytoplasm antibody-associated vasculitis
Participants with currently decompensated HF requiring hospitalization for optimization of HF treatment and are not on stable HF therapy at the time of enrollment
HF due to cardiomyopathies
High output HF (e.g., due to hyperthyroidism or Paget's disease)
HF due to pericardial disease, congenital heart disease or clinically significant uncorrected primary cardiac valvular disease or planned cardiac valve repair/replacement
Participants with uncontrolled diabetes mellitus (Glycated hemoglobin >10%)
Participants with Type 1 diabetes mellitus
Intermittent or persistent 2nd or 3rd degree atrioventricular block, sinus node dysfunction with clinically significant bradycardia or sinus pauses, not treated with a pacemaker
History of any life-threatening cardiac dysrhythmia or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter
Acute coronary syndrome and/or elective/non-elective percutaneous cardiac interventions (within 3 months) prior to randomisation or is planned to undergo any of these procedures during the study
Any major cardiovascular (eg, open chest, coronary artery bypass grafting or valvular repair/replacement) or major non-cardiovascular surgery within 3 months prior to randomisation or is planned to undergo any cardiovascular surgery during the study
Heart transplantation or left ventricular assist device at any time or if these are planned
Kidney or any organ transplantation or if these are planned
Medical conditions associated with development of hyperkalaemia (Addison's disease )
History or ongoing allergy/hypersensitivity, to sodium-glucose co-transporter-2 inhibitor (SGLT2i e.g., dapagliflozin, empagliflozin)
Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within previous 3 months prior to randomisation
Hepatic disease, including hepatitis and/or hepatic impairment (Child-Pugh class A-C), and aspartate aminotransferase or alanine transaminase or total bilirubin should be in protocol defined range at time of screening and/ or within 7 days prior to randomization
Participants with newly detected pathological laboratory values or an ongoing disease condition
If the participants clinical signs and symptoms consistent with COVID-19, and has been previously hospitalized with COVID-19 infection and did not fully recover their previous health status
Previous randomization in the present study
Prior medical treatment with an mineralocorticoid receptor antagonist where the medication was taken within 90 days prior to screening
Current or prior treatment within 6 months prior to screening with cytotoxic therapy, immunosuppressive therapy, or other immunotherapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Hot Springs National Park	Arkansas	United States	71913
2	Research Site	Beverly Hills	California	United States	90211
3	Research Site	Fountain Valley	California	United States	92708
4	Research Site	Northridge	California	United States	91324
5	Research Site	S. Gate	California	United States	90280
6	Research Site	Danbury	Connecticut	United States	06810
7	Research Site	Newark	Delaware	United States	19718
8	Research Site	Jacksonville	Florida	United States	32216
9	Research Site	Miami	Florida	United States	33125
10	Research Site	Miami	Florida	United States	33155
11	Research Site	Miami	Florida	United States	33256
12	Research Site	Ocala	Florida	United States	34474
13	Research Site	Tampa	Florida	United States	33603
14	Research Site	Augusta	Georgia	United States	30904
15	Research Site	Columbus	Georgia	United States	31904
16	Research Site	Eatonton	Georgia	United States	31024
17	Research Site	Chicago	Illinois	United States	60611
18	Research Site	Baltimore	Maryland	United States	21287
19	Research Site	Baltimore	Maryland	United States	21287
20	Research Site	Methuen	Massachusetts	United States	01844
21	Research Site	Columbia	Missouri	United States	65212
22	Research Site	Saint Louis	Missouri	United States	63136
23	Research Site	Bronx	New York	United States	10455
24	Research Site	Charlotte	North Carolina	United States	28210
25	Research Site	Rapid City	South Dakota	United States	57701
26	Research Site	Memphis	Tennessee	United States	38119
27	Research Site	Houston	Texas	United States	77087
28	Research Site	Houston	Texas	United States	77099
29	Research Site	Kingwood	Texas	United States	77339
30	Research Site	McKinney	Texas	United States	75069
31	Research Site	San Antonio	Texas	United States	78207
32	Research Site	Sherman	Texas	United States	75092
33	Research Site	Sherman	Texas	United States	75092
34	Research Site	Webster	Texas	United States	77598
35	Research Site	Puyallup	Washington	United States	98372
36	Research Site	Aalst		Belgium	9300
37	Research Site	Brasschaat		Belgium	2930
38	Research Site	Bruxelles		Belgium	1200
39	Research Site	Edegem		Belgium	2650
40	Research Site	Gent		Belgium	9000
41	Research Site	Roeselare		Belgium	8800
42	Research Site	Montana		Bulgaria	3400
43	Research Site	Pleven		Bulgaria	5800
44	Research Site	Pleven		Bulgaria	5800
45	Research Site	Plovdiv		Bulgaria	1606
46	Research Site	Plovdiv		Bulgaria	4002
47	Research Site	Plovdiv		Bulgaria	4003
48	Research Site	Sofia		Bulgaria	1233
49	Research Site	Sofia		Bulgaria	1309
50	Research Site	Sofia		Bulgaria	1407
51	Research Site	Sofia		Bulgaria	1431
52	Research Site	Sofia		Bulgaria	1505
53	Research Site	Sofia		Bulgaria	1510
54	Research Site	Sofia		Bulgaria	1527
55	Research Site	Sofia		Bulgaria	1606
56	Research Site	Sofia		Bulgaria	1784
57	Research Site	Stara Zagora		Bulgaria	6000
58	Research Site	Veliko Turnovo		Bulgaria	5000
59	Research Site	Brampton	Ontario	Canada	L6V 1B4
60	Research Site	Cambridge	Ontario	Canada	N1R 6V6
61	Research Site	Oshawa	Ontario	Canada	L1H 1B9
62	Research Site	Peterborough	Ontario	Canada	K9J 0B2
63	Research Site	Stoney Creek	Ontario	Canada	L8J 3W2
64	Research Site	Toronto	Ontario	Canada	M4N 3M5
65	Research Site	Toronto	Ontario	Canada	M5B 1W8
66	Research Site	York	Ontario	Canada	M9N 1W4
67	Research Site	Montreal	Quebec	Canada	H2X 0A9
68	Research Site	Terrebonne	Quebec	Canada	J6V 2H2
69	Research Site	Quebec		Canada	G1R 2J6
70	Research Site	Brno		Czechia	625 00
71	Research Site	Brno		Czechia	656 91
72	Research Site	Pardubice		Czechia	532 03
73	Research Site	Praha 2		Czechia	120 00
74	Research Site	Praha 2		Czechia	128 08
75	Research Site	Praha 5		Czechia	158 00
76	Research Site	Aalborg		Denmark	9000
77	Research Site	Aarhus		Denmark	8200
78	Research Site	Aarhus		Denmark	8200
79	Research Site	Copenhagen O		Denmark	2100
80	Research Site	Herlev		Denmark	2730
81	Research Site	Herlev		Denmark	2730
82	Research Site	Hillerød		Denmark	3400
83	Research Site	Hvidovre		Denmark	2650
84	Research Site	Svendborg		Denmark	5700
85	Research Site	Bad Nauheim		Germany	61231
86	Research Site	Dortmund		Germany	44137
87	Research Site	Dresden		Germany	1307
88	Research Site	Frankfurt		Germany	60313
89	Research Site	Hagen		Germany	58135
90	Research Site	Hamburg		Germany	20099
91	Research Site	Hamburg		Germany	21075
92	Research Site	Homburg		Germany	66421
93	Research Site	Jena		Germany	07747
94	Research Site	Leipzig		Germany	04103
95	Research Site	München		Germany	80363
96	Research Site	Rostock		Germany	18057
97	Research Site	Warendorf		Germany	48231
98	Research Site	Balatonfüred		Hungary	8230
99	Research Site	Budapest		Hungary	1036
100	Research Site	Budapest		Hungary	1088
101	Research Site	Budapest		Hungary	1122
102	Research Site	Budapest		Hungary	1134
103	Research Site	Budapest		Hungary	1204
104	Research Site	Dombovar		Hungary	7200
105	Research Site	Nagykanizsa		Hungary	8800
106	Research Site	Nyíregyháza		Hungary	4400
107	Research Site	Oroshaza		Hungary	H-5900
108	Research Site	Zalaegerszeg		Hungary	H-8900
109	Research Site	Bergamo		Italy	24127
110	Research Site	Brescia		Italy	25100
111	Research Site	Brescia		Italy	25123
112	Research Site	Firenze		Italy	50134
113	Research Site	Foggia		Italy	70126
114	Research Site	Napoli		Italy	80131
115	Research Site	Pavia		Italy	27100
116	Research Site	Pavia		Italy	81100
117	Research Site	Piacenza		Italy	29121
118	Research Site	Roma		Italy	00100
119	Research Site	Roma		Italy	00168
120	Research Site	Roma		Italy	00168
121	Research Site	Rome		Italy	00161
122	Research Site	Siena		Italy	53100
123	Research Site	Azumino-shi		Japan	399-8292
124	Research Site	Chuo-ku		Japan	103-0027
125	Research Site	Hachioji-shi		Japan	192-0918
126	Research Site	Hamada-shi		Japan	697-8511
127	Research Site	Kasugai-shi		Japan	487-0016
128	Research Site	Kawaguchi		Japan	333-0842
129	Research Site	Kishiwada-shi		Japan	596-8522
130	Research Site	Kobe		Japan	654-0026
131	Research Site	Kobe		Japan	654-0155
132	Research Site	Matsudo-Shi		Japan	271-0077
133	Research Site	Matsumoto-shi		Japan	390-8621
134	Research Site	Nagano		Japan	399-8695
135	Research Site	Nakagami-gun		Japan	901-2393
136	Research Site	Oita-shi		Japan	870-0855
137	Research Site	Sayama		Japan	350-1305
138	Research Site	Takarazuka-shi		Japan	665-0873
139	Research Site	Takasaki-shi		Japan	370-0829
140	Research Site	Tsu-shi		Japan	514-1101
141	Research Site	Ueda-shi		Japan	386-8610
142	Research Site	Yokohama-shi		Japan	236-0004
143	Research Site	Gangwon-do		Korea, Republic of	26426
144	Research Site	Gwangju		Korea, Republic of	61469
145	Research Site	Seongnam-si		Korea, Republic of	463-707
146	Research Site	Seoul		Korea, Republic of	03080
147	Research Site	Seoul		Korea, Republic of	06351
148	Research Site	Seoul		Korea, Republic of	06591
149	Research Site	Seoul		Korea, Republic of	08308
150	Research Site	Kaunas		Lithuania	50177
151	Research Site	Klaipeda		Lithuania	LT-92288
152	Research Site	Siauliai		Lithuania	LT-76231
153	Research Site	Vilnius		Lithuania	08661
154	Research Site	Bydgoszcz		Poland	85-065
155	Research Site	Gdansk		Poland	80-952
156	Research Site	Katowice		Poland	40-040
157	Research Site	Kraków		Poland	30-688
158	Research Site	Ostrowiec Świętokrzyski		Poland	27-400
159	Research Site	Oława		Poland	55-200
160	Research Site	Oświęcim		Poland	32-600
161	Research Site	Pabianice		Poland	95-200
162	Research Site	Poznań		Poland	60-702
163	Research Site	Skorzewo		Poland	60-185
164	Research Site	Sopot		Poland	81-717
165	Research Site	Szczecin		Poland	71-434
166	Research Site	Toruń		Poland	87-100
167	Research Site	Warszawa		Poland	01-192
168	Research Site	Warszawa		Poland	02-097
169	Research Site	Łódź		Poland	90-127
170	Research Site	Łódź		Poland	92-213
171	Research Site	Łódź		Poland	95-513
172	Research Site	Kazan, Tatarstan		Russian Federation	420012
173	Research Site	Kazan		Russian Federation	420101
174	Research Site	Kemerovo		Russian Federation	650002
175	Research Site	Moscow		Russian Federation	111539
176	Research Site	Moscow		Russian Federation	121552
177	Research Site	Moscow		Russian Federation	125284
178	Research Site	Moscow		Russian Federation	129110
179	Research Site	Saint-Petersburg		Russian Federation	195257
180	Research Site	Saint-Petersburg		Russian Federation	197349
181	Research Site	St Petersburg		Russian Federation	195067
182	Research Site	St. Petersburg		Russian Federation	197022
183	Research Site	St. Petersburg		Russian Federation	197089
184	Research Site	Yaroslavl		Russian Federation	150023
185	Research Site	Banska Bystrica		Slovakia	974 01
186	Research Site	Brezno		Slovakia	977 01
187	Research Site	Lucenec		Slovakia	984 01
188	Research Site	Presov		Slovakia	080 01
189	Research Site	Svidnik		Slovakia	08901
190	Research Site	Trencin		Slovakia	911 01
191	Research Site	Trnava		Slovakia	91775
192	Research Site	Barcelona		Spain	08003
193	Research Site	Coruña		Spain	15006
194	Research Site	El Palmar		Spain	30120
195	Research Site	Madrid		Spain	28041
196	Research Site	Málaga		Spain	29010
197	Research Site	Málaga		Spain	29010
198	Research Site	Santiago(A Coruña)		Spain	15706
199	Research Site	Sevilla		Spain	41009
200	Research Site	Valencia		Spain	46010
201	Research Site	Valencia		Spain	46026
202	Research Site	Goeteborg		Sweden	413 46
203	Research Site	Stockholm		Sweden	14186
204	Research Site	Stockholm		Sweden	18288
205	Research Site	Kaohsiung		Taiwan	80756
206	Research Site	Taichung		Taiwan	40201
207	Research Site	Taipei		Taiwan	10449
208	Research Site	Taipei		Taiwan	11217
209	Research Site	Taoyuan		Taiwan	33305
210	Research Site	Bangkok		Thailand	10400
211	Research Site	Bangkok		Thailand	10700
212	Research Site	Chaingmai		Thailand	50200
213	Research Site	Khon Kaen		Thailand	40002
214	Research Site	Klong Luang		Thailand	12120
215	Research Site	Cherkasy		Ukraine	18009
216	Research Site	Ivano-Frankivsk		Ukraine	76018
217	Research Site	Kharkiv		Ukraine	61002
218	Research Site	Kharkiv		Ukraine	61039
219	Research Site	Kyiv		Ukraine	02002
220	Research Site	Kyiv		Ukraine	02091
221	Research Site	Kyiv		Ukraine	02660
222	Research Site	Kyiv		Ukraine	03037
223	Research Site	Kyiv		Ukraine	03680
224	Research Site	M. Lviv		Ukraine	79011
225	Research Site	M. Odesa		Ukraine	65006
226	Research Site	Zaporizhzhia		Ukraine	69005