Clinical trial NCT03316131: A Study to Assess the Effect of Intensive Uric Acid (UA) Lowering Therapy With RDEA3170, Febuxostat, Dapagliflozin on Urinary Excretion of UA
Official title: Quantifying Uric Acid Excretion With RDEA3170, Febuxostat and Dapagliflozin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asymptomatic Hyperuricemia
Keywords: Gout
Uric acid
Hyperuricemia
Asymptomatic gout
Febuxostat
Dapagliflozin
Uric acid transporter 1 (URAT1) Inhibitor
Xanthine Oxidase Inhibitor
Sodium-glucose cotransporter 2 (SGLT2) Inhibitor
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Contract Research Organization: USA
name: PAREXEL Early Phase Clinical Unit Baltimore
name: PAREXEL Early Phase Clinical Unit-Los Angeles
name: Clinical Laboratory: USA
name: Harbor Hospital Laboratory
name: GenX Laboratories Inc.
name: Analytical Laboratory (Pharmacokinetic Sample Analysis): USA
name: Covance Bioanalytical Services, LLC
First posted: 2017-10-20
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This is a randomized, placebo controlled, double-blind, 2-way crossover study conducted on asymptomatic hyperuricemic patients. The core study consists of screening period, 2 treatment periods (verinurad + febuxostat + dapagliflozin/placebo) and follow-up visit

Detailed description: This is a randomized, placebo controlled, double-blind, 2-way crossover study to assess the effect of intensive UA lowering therapy with verinurad (RDEA3170), febuxostat, and dapagliflozin on urinary excretion of UA, in asymptomatic hyperuricemic patients. Thirty-six asymptomatic hyperuricemic patients aged 18 to 65 years (inclusive) will be enrolled into this study at 2 study centers. Twenty-four patients have been enrolled and completed the study to date. Due to inadequate urine sampling, 12 additional patients were included to ensure an adequate sample size (at least 20 evaluable patients) to evaluate the effects of intensive UA lowering with verinurad, febuxostat and dapagliflozin on urinary excretion of UA. With 24 completers available during the interim analysis, this will provide for a total sample size of 36 evaluable patients.

Before any study specific assessments are performed, potential patients must provide informed consent. Each patient will undergo the below mentioned visits:

* A Screening period of maximum 28 days;
* Two treatment periods during which patients will be resident in the Clinical Unit from Day -2 to Day 1 and from Day 6 to Day 8; and
* A Follow-up Visit within 14 to 28 days after the first administration of Investigational Medicinal Product (IMP) in Treatment Period 2.

On Day -2 of Treatment period 1, patient will be randomized (1:1) to 1 of 2 treatment sequences (AB or BA). Each randomized patient will receive orally once daily fixed dose of the below mentioned 2 treatments for 7 consecutive days (1 treatment per treatment period).

* Treatment A: Verinurad + febuxostat + dapagliflozin
* Treatment B: Verinurad + febuxostat + placebo For each treatment period, baseline measurements will be performed. On Day 1, after all dosing and all assessments have been performed, patients will receive instruction to administer the IMP at home once daily in the morning from Day 2 to Day 6 and the IMP will be dispensed for home dosing. Patients will return to the Clinical Unit on Day 6 and will be residential in the Clinical Unit from Day 6 to Day 8.

Treatment Period 1 and Treatment Period 2 will be separated by a washout period of 7 to 21 days.

Patients will return to the Clinical Unit for a Follow-up Visit, 14 to 28 days after Day 1 of Treatment Period 2.

Eligibility criteria: Inclusion Criteria:

1. 18 to 65 years old
2. Asymptomatic hyperuricemia (sUA \> 6.0 mg/dL)
3. Body mass index between 18 and 35 kg/m2 inclusive and weight at least 50 kg and no more than 150 kg
4. Females must be non-pregnant, as well as post-menopausal or willing to use an acceptable method of contraception during the study.

Exclusion Criteria:

1. History of any clinically significant disease or disorder putting the patient at risk during the study, or influencing study results or ability to participate in the study
2. eGFR\* \< 45 mL/minute/1.73 m2 at Screening.
3. Type 2 diabetes mellitus with HbA1c \>8%.
4. History of diabetic ketoacidosis, hyperosmolar non-ketotic coma, gout, or alcohol or drug abuse.
5. Ongoing treatment with an SGLT2-inhibitor, a URAT1-inhibitor, and/or a xanthine oxidase inhibitor.
6. Positive test for hepatitis B, hepatitis C or HIV.
7. Use of any medications in the 2 weeks preceding first administration of study drug.

Primary outcomes:
measure: Change From Baseline in Peak Urinary Excretion of Uric Acid (UA) on Day 7
timeFrame: On Day -1 and Day 7 of each treatment period
measure: Change From Baseline in Plasma Concentration (Cmax) on Day 7
timeFrame: On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)
measure: Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7
timeFrame: On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)
measure: Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7
timeFrame: On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)
Secondary outcomes:
measure: Change From Baseline in Urinary Excretion of Serum UA (sUA) on Day 7
timeFrame: At Day -1 and Day 7
measure: Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7
timeFrame: On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)
measure: Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7
timeFrame: On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Research Site
state: California
city: Baltimore
country: United States
facility: Research Site
state: Maryland
Study officials:
References:
citation: Stack AG, Han D, Goldwater R, Johansson S, Dronamraju N, Oscarsson J, Johnsson E, Parkinson J, Erlandsson F. Dapagliflozin Added to Verinurad Plus Febuxostat Further Reduces Serum Uric Acid in Hyperuricemia: The QUARTZ Study. J Clin Endocrinol Metab. 2021 Apr 23;106(5):e2347-e2356. doi: 10.1210/clinem/dgaa748.