SAPPHIRE: A Study of Verinurad and Allopurinol in Patients With Chronic Kidney Disease and Hyperuricaemia

Sponsor

AstraZeneca (Industry)

Overall Status

Completed

CT.gov ID

NCT03990363

Collaborator

(none)

861

Enrollment

166

Locations

Arms

Actual Duration (Months)

5.2

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this clinical research study is to establish the dose of verinurad combined with allopurinol 300 mg once daily that will elicit the desired response; ie, reduction in urinary albumin to creatinine ratio (UACR) at 6 months.

Condition or Disease	Intervention/Treatment	Phase
Chronic Kidney Disease	Drug: Verinurad Drug: Allopurinol Drug: Placebo for Verinurad Drug: Placebo for Allopurinol	Phase 2

Detailed Description

Evidence shows independent associations between hyperuricaemia and the risk of hypertension, myocardial infarction, chronic kidney disease (CKD), type 2 diabetes, heart failure, and metabolic syndrome, including obesity Furthermore, gout, an inflammatory arthritis caused by deposition of monosodium urate crystals in joints, is associated with an increased risk of all-cause death, as well as cardiovascular (CV) death.

Hyperuricaemia is a prerequisite for development of gout, thus linking high levels of sUA to gout and to poor outcomes. However, the causal relationship between hyperuricaemia / gout and the aforementioned diseases and outcomes remains to be proven.

Uric acid transporter 1 (URAT1) is responsible for reabsorption of uric acid (UA in the proximal tubule. Inhibition of URAT1 results in increased urinary excretion of UA.

Verinurad (RDEA3170) is a novel URAT1 inhibitor in Phase 2 development for chronic kidney disease and heart failure.

Verinurad combined with the xanthine oxidase (XO)inhibitor (XOI) febuxostat or allopurinol has been shown to lower sUA in patients with recurrent gout in Phase 2 studies by up to 80%..

The primary objective of this study is to assess the effects of treatment with verinurad and allopurinol, allopurinol alone, and placebo on UACR at 6 months.

In this study, change in UACR at 6 months of treatment is the primary endpoint for the efficacy evaluation of treatment with the combination of verinurad and allopurinol vs. placebo.

A key secondary objective is evaluation of verinurad plus allopurinol on the reduction in UACR at 12 months.

Further, standard safety parameters such as adverse event (AEs), serious adverse event (SAEs), and laboratory evaluations will be employed to assess the safety profile of the study drugs.

Verinurad, allopurinol and oxypurinol plasma concentrations over time will also be measured.

The study will recruit patients with Chronic Kidney Disease and Hyperuricaemia.

Study Design

Study Type:

Interventional

Actual Enrollment :

861 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

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

Primary Purpose:

Treatment

Official Title:

A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled Study of Verinurad and Allopurinol in Patients With Chronic KIdney Disease and Hyperuricaemia

Actual Study Start Date :

Jul 23, 2019

Actual Primary Completion Date :

Nov 22, 2021

Actual Study Completion Date :

Nov 22, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High Dose High Dose (mg) (verinurad/allopurinol) Step 1 - titration_ 3/100 Step 2 - titration_ 7.5/200 Step 3 - target dose_ 12/300	Drug: Verinurad Study treatments will be titrated in 3 steps for target low dose (3 mg), intermediate dose ( 7.5 mg) and High Dose (12 mg) Verinurad. As per Protocol Version 5.0, Patients from 3 mg dose will be switched to 24 mg at visit 9 Drug: Allopurinol Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol
Experimental: Intermediate Dose Intermediate Dose (mg) verinurad/allopurinol Step 1 - titration_ 3/100 Step 2 - titration_ 7.5/200 Step 3 - target dose_ 7.5/300	Drug: Verinurad Study treatments will be titrated in 3 steps for target low dose (3 mg), intermediate dose ( 7.5 mg) and High Dose (12 mg) Verinurad. As per Protocol Version 5.0, Patients from 3 mg dose will be switched to 24 mg at visit 9 Drug: Allopurinol Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol
Experimental: Low Dose Low Dose (mg) verinurad/allopurinol Step 1 - titration_3/100 Step 2 - titration_3/200 Step 3 - target dose_3/300. As per Protocol Version 5.0, Patients from 3 mg dose will be switched to 24 mg at Visit 9.	Drug: Verinurad Study treatments will be titrated in 3 steps for target low dose (3 mg), intermediate dose ( 7.5 mg) and High Dose (12 mg) Verinurad. As per Protocol Version 5.0, Patients from 3 mg dose will be switched to 24 mg at visit 9 Drug: Allopurinol Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol
Experimental: Allopurinol alone (0/300 mg) Step 1 - titration_0/100 Step 2 - titration_0/200 Step 3 - target dose_0/300	Drug: Allopurinol Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol
Placebo Comparator: Placebo (0/0 mg) Placebo (mg) in 3 steps_0/0	Drug: Placebo for Verinurad Matching Capsule Other Names: Placebo Drug: Placebo for Allopurinol Matching tablet Other Names: Placebo

Outcome Measures

Primary Outcome Measures

Ratio of urinary albumin to urinary creatinine [At 6 months]
Change from baseline in urinary albumin to creatinine ratio (UACR).

Secondary Outcome Measures

Estimated glomerular filtration rate (eGFR) [At 6 months, 12 months.]
Change from baseline in estimated glomerular filtration rate
Serum cystatin C [At 6 months, 12 months.]
Change from baseline in cystatin-C.
Serum creatinine [At 6 months, 12 months.]
Change from baseline in creatinine.
Ratio of urinary albumin to urinary creatinine [At 6 months, 12 months.]
Change from baseline in urinary albumin to urinary creatinine ratio (UACR).
Serum uric acid [At 6 months, 12 months.]
Change from baseline in Serum uric acid (sUA)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

The subject has given written informed consent prior to any mandatory study specific procedures, sampling, and analyses, and is able to understand and comply with all study procedures
Adult Patient ≥18 years of age with CKD for >3 months.
Patients with background standard of care treatment for albuminuria and/or T2DM and treated according to locally recognised guidelines. Therapy optimised and stable for ≥4 weeks before study entry and including an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, unless justified.
If treated with a sodium-glucose transport protein (SGLT2) inhibitor, stable dose for ≥4 weeks before randomisation.
Meeting screening criteria for sUA and eGFR (Visit 2): sUA ≥6.0 mg/dL. ∙ eGFR ≥25 mL/min/1.73 m2 Chronic Kidney Disease Epidemiology Collaboration
UACR between 30 mg/g and 5000 mg/g.
Female patients: Negative pregnancy test for childbearing potential. 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception during the study and 4 weeks after the last dose of study treatment.

Exclusion Criteria:

Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or anti-neutrophil cytoplasmic antibody associated vasculitis (granulomatosis with polyangiitis [Wegener's granulomatosis], microscopic polyangiitis, or eosinophilic granulomatosis with polyangiitis [Churg-Strauss syndrome]).
History of renal transplantation
Known carrier of the Human Leukocyte Antigen-B *58:01 allele.
Patients diagnosed with tumor lysis syndrome or Lesch-Nyhan syndrome
Patients who in the opinion of investigator are unable to perform the patients' tasks associated with the protocol or Presence of any condition which, places the patient at undue risk or potentially jeopardises the quality of the data to be generated
History of stroke, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft in the past 6 months
Uncontrolled hypertension presenting with systolic blood pressure >180 mm Hg and/or diastolic blood pressure >100 mm Hg
Diagnosed with heart failure and New York Heart Association Functional Classification Class IV at the time of randomisation
QT interval corrected by the Fridericia formula >470 msec; patients diagnosed with long QT syndrome; patients with a family history of long QT syndrome.
Subjects with severe hepatic impairment, as judged by the investigator, of Child-Pugh Class C (decompensated cirrhosis), or with major cirrhosis complications (eg, hepatorenal syndrome)
Receiving cytotoxic or immunosuppressive therapy or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment
Treated with any drug for hyperuricaemia in the 6 months preceding randomisation.
Dose of ACEi, ARBs, fenofibrate, guaifenesin, or SGLT2 inhibitors changed within 4 weeks of randomisation or further dose titration expected after randomization

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Huntsville	Alabama	United States	35805
2	Research Site	Bakersfield	California	United States	93309
3	Research Site	Canyon Country	California	United States	91351
4	Research Site	Laguna Hills	California	United States	92653
5	Research Site	Long Beach	California	United States	90807
6	Research Site	Northridge	California	United States	91324
7	Research Site	Orange	California	United States	92868
8	Research Site	Thousand Oaks	California	United States	91360
9	Research Site	Vacaville	California	United States	95687
10	Research Site	Victorville	California	United States	92395
11	Research Site	Denver	Colorado	United States	80230
12	Research Site	Bloomfield	Connecticut	United States	06002
13	Research Site	Washington	District of Columbia	United States	20037
14	Research Site	Altamonte Springs	Florida	United States	32701
15	Research Site	Hialeah	Florida	United States	33012
16	Research Site	Jacksonville	Florida	United States	32204
17	Research Site	Lauderdale Lakes	Florida	United States	33313
18	Research Site	Miami Lakes	Florida	United States	33014
19	Research Site	Miami	Florida	United States	33015
20	Research Site	Miami	Florida	United States	33126-2956
21	Research Site	Miami	Florida	United States	33165
22	Research Site	Ocala	Florida	United States	34471
23	Research Site	Ocoee	Florida	United States	34761
24	Research Site	Pembroke Pines	Florida	United States	33026
25	Research Site	Port Charlotte	Florida	United States	33952
26	Research Site	Lawrenceville	Georgia	United States	30046
27	Research Site	Wauconda	Illinois	United States	60084
28	Research Site	Paducah	Kentucky	United States	42003
29	Research Site	Takoma Park	Maryland	United States	20912
30	Research Site	Flint	Michigan	United States	48504
31	Research Site	Flint	Michigan	United States	48532
32	Research Site	Saint Clair Shores	Michigan	United States	48081
33	Research Site	Minneapolis	Minnesota	United States	55404
34	Research Site	Bronx	New York	United States	10461
35	Research Site	Jamaica	New York	United States	11432
36	Research Site	Asheville	North Carolina	United States	28801
37	Research Site	Asheville	North Carolina	United States	28803
38	Research Site	Rocky Mount	North Carolina	United States	27804
39	Research Site	Wilmington	North Carolina	United States	28401
40	Research Site	Winston-Salem	North Carolina	United States	27103
41	Research Site	Philadelphia	Pennsylvania	United States	19107
42	Research Site	Goose Creek	South Carolina	United States	29445
43	Research Site	Orangeburg	South Carolina	United States	29118
44	Research Site	Knoxville	Tennessee	United States	37923
45	Research Site	Arlington	Texas	United States	76015
46	Research Site	El Paso	Texas	United States	79935
47	Research Site	Houston	Texas	United States	77004
48	Research Site	Lampasas	Texas	United States	76550
49	Research Site	Lewisville	Texas	United States	75057
50	Research Site	Pearland	Texas	United States	77584
51	Research Site	San Antonio	Texas	United States	78212
52	Research Site	San Antonio	Texas	United States	78231
53	Research Site	San Antonio	Texas	United States	78258
54	Research Site	Alexandria	Virginia	United States	22304
55	Research Site	Milwaukee	Wisconsin	United States	53226
56	Research Site	Frydek		Czechia	738 01
57	Research Site	Praha 2		Czechia	128 08
58	Research Site	Praha 6		Czechia	160 00
59	Research Site	Slany		Czechia	274 01
60	Research Site	Třebíč		Czechia	674 01
61	Research Site	Annonay		France	07103
62	Research Site	Grenoble cedex 9		France	38043
63	Research Site	Marseille cedex 5		France	13385
64	Research Site	Paris		France	75018
65	Research Site	Paris		France	75970
66	Research Site	Rouen		France	76031
67	Research Site	Tours		France	37000
68	Research Site	Baja		Hungary	6500
69	Research Site	Balatonfured		Hungary	8230
70	Research Site	Budapest		Hungary	1033
71	Research Site	Budapest		Hungary	1036
72	Research Site	Debrecen		Hungary	4025
73	Research Site	Debrecen		Hungary	4032
74	Research Site	Hatvan		Hungary	3000
75	Research Site	Kaposvár		Hungary	7400
76	Research Site	Nyíregyháza		Hungary	4400
77	Research Site	Nyíregyháza		Hungary	4405
78	Research Site	Szeged		Hungary	6725
79	Research Site	Zalaegerszeg		Hungary	8900
80	Research Site	Afula		Israel	1834111
81	Research Site	Ashdod		Israel	77000
82	Research Site	Ashkelon		Israel	78278
83	Research Site	Beer Sheba		Israel	8410101
84	Research Site	Haifa		Israel	3109601
85	Research Site	Haifa		Israel	34362
86	Research Site	Haifa		Israel	35152
87	Research Site	Holon		Israel	58100
88	Research Site	Kfar Sava		Israel	44281
89	Research Site	Nahariya		Israel	22100
90	Research Site	Nazareth		Israel	16100
91	Research Site	Petach-Tikva		Israel	49100
92	Research Site	Ramat Gan		Israel	52621
93	Research Site	Rehovot		Israel	7642001
94	Research Site	Safed		Israel	13100
95	Research Site	Tel-Aviv		Israel	61480
96	Research Site	Tiberias		Israel	15208
97	Research Site	Genova		Italy	16132
98	Research Site	Milano		Italy	20132
99	Research Site	Parma		Italy	43126
100	Research Site	Pavia		Italy	27100
101	Research Site	Verona		Italy	37124
102	Research Site	Ciudad Madero		Mexico	89440
103	Research Site	Estado de Mexico		Mexico	54800
104	Research Site	Guadalajara		Mexico	44650
105	Research Site	Mexico		Mexico	03100
106	Research Site	Mexico		Mexico	06700
107	Research Site	Tijuana		Mexico	22500
108	Research Site	Veracruz		Mexico	91910
109	Research Site	Krakow		Poland	31-559
110	Research Site	Lodz		Poland	90-302
111	Research Site	Lublin		Poland	20-538
112	Research Site	Poznań		Poland	61-655
113	Research Site	Rzeszów		Poland	35-055
114	Research Site	Warszawa		Poland	00-465
115	Research Site	Wroclaw		Poland	50-127
116	Research Site	Bucuresti		Romania	010192
117	Research Site	Bucuresti		Romania	010825
118	Research Site	Bucuresti		Romania	050538
119	Research Site	Bucuresti		Romania	40172
120	Research Site	Deva		Romania	330084
121	Research Site	Ploiesti		Romania	100342
122	Research Site	Satu Mare		Romania	440055
123	Research Site	Timișoara		Romania	300456
124	Research Site	Bardejov		Slovakia	085 01
125	Research Site	Bratislava		Slovakia	85101
126	Research Site	Hlohovec		Slovakia	920 01
127	Research Site	Kosice		Slovakia
128	Research Site	Kralovsky Chlmec		Slovakia	077 01
129	Research Site	Lucenec		Slovakia	984 01
130	Research Site	Puchov		Slovakia	2001
131	Research Site	Rimavska Sobota		Slovakia	979 01
132	Research Site	Svidnik		Slovakia	08901
133	Research Site	Benoni		South Africa	1501
134	Research Site	Cape Town		South Africa	1730
135	Research Site	Cape Town		South Africa	7505
136	Research Site	Cape Town		South Africa	7570
137	Research Site	Cape Town		South Africa	7925
138	Research Site	Durban		South Africa	4001
139	Research Site	Durban		South Africa	4092
140	Research Site	George		South Africa	6530
141	Research Site	Johannesburg		South Africa	2001
142	Research Site	Johannesburg		South Africa	2132
143	Research Site	Krugersdorp		South Africa	1739
144	Research Site	Lenasia		South Africa	1827
145	Research Site	Paarl		South Africa	7647
146	Research Site	Stanger		South Africa	4450
147	Research Site	Tshwane		South Africa	0084
148	Research Site	Worcester		South Africa	6850
149	Research Site	Alicante		Spain	03010
150	Research Site	Alicante		Spain	03550
151	Research Site	Barcelona		Spain	08003
152	Research Site	Barcelona		Spain	08023
153	Research Site	Barcelona		Spain	08035
154	Research Site	Barcelona		Spain	08036
155	Research Site	Ciudad Real		Spain	13005
156	Research Site	Cordoba		Spain	14004
157	Research Site	Girona		Spain	17007
158	Research Site	Granada		Spain	18012
159	Research Site	L'Hospitalet De Llobregat		Spain	08907
160	Research Site	Málaga		Spain	29011
161	Research Site	Palma de Mallorca		Spain	7120
162	Research Site	Puerto De Sagunto		Spain	46520
163	Research Site	Santander		Spain	39010
164	Research Site	Sevilla		Spain	41071
165	Research Site	Valencia		Spain	46014
166	Research Site	Valencia		Spain	46017