Phase 2a RDEA3170 and Allopurinol Combination Study in Gout Subjects

• RDEA3170 2.5 mg (Drug): Cohort 1: RDEA3170 2.5 mg, 7.5 mg (2.5 mg × 3 tablets), and 15 mg (2.5 mg × 6 tablets). Cohort 2: RDEA3170 5 mg (2.5 mg × 2 tablets), 10 mg (2.5 mg × 4 tablets), and 20 mg (2.5 mg × 8 tablets).
• allopurinol 300 mg (Drug): allopurinol 300 mg, allopurinol 600 mg (300 mg x 2 tablets)

Primary outcomes

• Cohort 1 - Maximum Percentage (%) Change in Serum Urate of Multiple-dose RDEA3170 Administered in Combination With Allopurinol (Emax, CB (%)) [Screening, Days -1 , 1, 7, 14, 21, 28, and 35 (Pre-dose and Post-dose)]: Pharmacodynamics (PD) profile of multiple-dose RDEA3170 administered in combination with allopurinol (Cohort 1)
• Cohort 1 - Concentration of Serum Urate at 24hr of Multiple-dose RDEA3170 Administered in Combination With Allopurinol. [Screening, Days -1 , 1, 7, 14, 21, 28, and 35 (Pre-dose and Post-dose)]: Pharmacodynamics (PD) profile of multiple-dose RDEA3170 administered in combination with allopurinol (Cohort 1)
• Cohort 1 - Renal Xanthine Excretion at 0-24hr of Multiple-dose RDEA3170 Administered in Combination With Allopurinol (AeXO, CB (%)) [Screening, Days -1 , 1, 7, 14, 21, 28, and 35 (Pre-dose and Post-dose)]: Pharmacodynamics (PD) profile of multiple-dose RDEA3170 administered in combination with allopurinol (Cohort 1)
• Cohort 1 - Renal Hypoxanthine Excretion at 0-24hr of Multiple-dose RDEA3170 Administered in Combination With Allopurinol (AeHXO, CB (%)) [Screening, Days -1 , 1, 7, 14, 21, 28, and 35 (Pre-dose and Post-dose)]: Pharmacodynamics (PD) profile of multiple-dose RDEA3170 administered in combination with allopurinol (Cohort 1)
• Cohort 2 - Maximum Percentage (%) Change in Serum Urate of Multiple-dose RDEA3170 Administered in Combination With Allopurinol (Emax, CB (%)) [Screening, Days -1 , 1, 7, 14, 21, 28, and 35 (Pre-dose and Post-dose)]: Pharmacodynamics (PD) profile of multiple-dose RDEA3170 administered in combination with allopurinol (Cohort 2)
• Cohort 2 - Concentration of Serum Urate at 24hr of Multiple-dose RDEA3170 Administered in Combination With Allopurinol. [Screening, Days -1 , 1, 7, 14, 21, 28, and 35 (Pre-dose and Post-dose)]: Pharmacodynamics (PD) profile of multiple-dose RDEA3170 administered in combination with allopurinol (Cohort 2)
• Cohort 2 - Renal Xanthine Excretion at 0-24hr of Multiple-dose RDEA3170 Administered in Combination With Allopurinol (AeXO, CB (%)) [Screening, Days -1 , 1, 7, 14, 21, 28, and 35 (Pre-dose and Post-dose)]: Pharmacodynamics (PD) profile of multiple-dose RDEA3170 administered in combination with allopurinol (Cohort 2)
• Cohort 2 - Renal Hypoxanthine Excretion at 0-24hr of Multiple-dose RDEA3170 Administered in Combination With Allopurinol (AeHXO, CB (%)) [Screening, Days -1 , 1, 7, 14, 21, 28, and 35 (Pre-dose and Post-dose)]: Pharmacodynamics (PD) profile of multiple-dose RDEA3170 administered in combination with allopurinol (Cohort 2)

Secondary outcomes

• Maximum Observed Concentration (Cmax) [Day 7, 14, 21, 28 and 35 (predose through 24 hours postdose)]: Cmax of Allopurinol alone or in combination with RDEA3170
• Time of Occurrence of Maximum Observed Concentration (Tmax) [Day 7, 14, 21, 28 and 35 (predose through 24 hours postdose)]: Tmax of Allopurinol alone or in combination with RDEA3170
• Area Under the Concentration-time Curve From Time Zero up to 24 Hours Postdose (AUC 0-24) [Day 7, 14, 21, 28 and 35 (predose through 24 hours postdose)]: AUC 0-24 of Allopurinol alone or in combination with RDEA3170
• Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Sampling Timepoint (AUC Last) [Day 7, 14, 21, 28 and 35 (predose through 24 hours postdose)]: AUC last of Allopurinol alone or in combination with RDEA3170
• Apparent Terminal Half-life (t1/2) [Day 7, 14, 21, 28 and 35 (predose through 24 hours postdose)]: t1/2 of Allopurinol alone or in combination with RDEA3170
• Number of Participants With Treatment-Emergent Adverse Events [11 weeks]

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Subject is able to understand the study procedures and the risks involved and is willing to provide written informed consent before the first study-related activity.
* Subject meets one or more criteria for the diagnosis of gout as per the American Rheumatism Association Criteria for the Classification of Acute Arthritis of Primary Gout.
* Subject has a body weight ≥ 50 kg (110 lbs.) and a body mass index ≥ 18 and ≤ 45 kg/m2.
* Subject has a Screening serum urate level ≥ 8 mg/dL.
* Subject is free of any clinically significant disease or medical condition, per the Investigator's judgment.

Exclusion Criteria:

* Subject is unable to take colchicine for gout flare prophylaxis.
* Subject has a history or suspicion of kidney stones.
* Subject has any gastrointestinal disorder that affects motility and/or absorption.
* Subject had unstable angina, New York Heart Association class III or IV heart failure, ischemic heart disease, stroke, or deep venous thrombosis within 12 months prior to Day 1; or subject is currently receiving anticoagulants.
* Subject has Screening laboratory parameters that are outside the normal limits and are considered clinically significant by the Investigator.
* Subject has an estimated creatinine clearance < 60 mL/min calculated by the Cockcroft-Gault formula using ideal body weight during the Screening period.
* Subject is taking losartan, fenofibrate, guaifenesin, or sodium-glucose linked transporter-2 inhibitors; chronic and stable doses are permitted if doses are stable for at least 14 days prior to study medication dosing.
* Subject is unable or unwilling to comply with the study requirements or has a situation or condition that, in the opinion of the Investigator, may interfere with participation in the study.

Participant flow

Outcome results

• Cohort 1 - Maximum Percentage (%) Change in Serum Urate of Multiple-dose RDEA3170 Administered in Combination With Allopurinol (Emax, CB (%)) (Primary), Mean, Maximum Percentage (%) Change: Treatment A1 -40.2 +/- 3.29; Treatment A2q -55.0 +/- 4.96; Treatment A2b -56.8 +/- 4.52; Treatment R1 -48.1 +/- 2.91; Treatment R3 -61.0 +/- 2.59; Treatment R5 -69.5 +/- 2.09
• Cohort 1 - Concentration of Serum Urate at 24hr of Multiple-dose RDEA3170 Administered in Combination With Allopurinol. (Primary), Mean, mg/dL: Treatment A1 5.8 +/- 0.24; Treatment A2q 4.8 +/- 0.38; Treatment A2b 4.0 +/- 0.39; Treatment R1 5.5 +/- 0.24; Treatment R3 4.6 +/- 0.22; Treatment R5 3.8 +/- 0.18
• Cohort 1 - Renal Xanthine Excretion at 0-24hr of Multiple-dose RDEA3170 Administered in Combination With Allopurinol (AeXO, CB (%)) (Primary), Mean, Percentage (%) Change: Treatment A1 1065 +/- 138; Treatment A2q 1827 +/- 252; Treatment A2b 2633 +/- 255; Treatment R1 899 +/- 116; Treatment R3 958 +/- 128; Treatment R5 827 +/- 106
• Cohort 1 - Renal Hypoxanthine Excretion at 0-24hr of Multiple-dose RDEA3170 Administered in Combination With Allopurinol (AeHXO, CB (%)) (Primary), Mean, Percentage (%) Change: Treatment A1 400 +/- 74.6; Treatment A2q 517 +/- 106; Treatment A2b 827 +/- 136; Treatment R1 310 +/- 55.5; Treatment R3 311 +/- 51.8; Treatment R5 305 +/- 54.7
• Cohort 2 - Maximum Percentage (%) Change in Serum Urate of Multiple-dose RDEA3170 Administered in Combination With Allopurinol (Emax, CB (%)) (Primary), Mean, Maximum Percentage (%) Change: Treatment A1 -39.3 +/- 1.78; Treatment A2q -54.4 +/- 4.50; Treatment A2b -50.3 +/- 4.15; Treatment R2 -57.8 +/- 1.61; Treatment R4 -66.0 +/- 1.86; Treatment R6 -73.2 +/- 1.75
• Maximum Observed Concentration (Cmax) (Secondary), Geometric mean, µg/mL: Treatment A1 1.18 (1.03 to 1.36); Treatment A2q 2.43 (1.94 to 3.04); Treatment A2b 1.19 (0.997 to 1.42); Treatment R1 1.16 (0.911 to 1.47); Treatment R2 1.16 (0.937 to 1.43); Treatment R3 1.14 (0.905 to 1.44); Treatment R4 1.11 (0.928 to 1.33); Treatment R5 1.12 (0.877 to 1.44); Treatment R6 1.26 (1.02 to 1.56)
• Time of Occurrence of Maximum Observed Concentration (Tmax) (Secondary), Geometric mean, hr: Treatment A1 1.50 (0.500 to 6.02); Treatment A2q 2.98 (0.983 to 4.00); Treatment A2b 2.02 (0.500 to 8.00); Treatment R1 2.01 (0.967 to 6.00); Treatment R2 2.49 (0.500 to 3.97); Treatment R3 1.73 (0.500 to 6.00); Treatment R4 2.98 (0.500 to 6.02); Treatment R5 1.73 (0.500 to 6.00); Treatment R6 1.97 (0.500 to 4.03)
• Area Under the Concentration-time Curve From Time Zero up to 24 Hours Postdose (AUC 0-24) (Secondary), Geometric mean, µg·hr/mL: Treatment A1 3.94 (3.52 to 4.42); Treatment A2q 11.0 (8.87 to 13.7); Treatment A2b 8.64 (7.13 to 10.5); Treatment R1 4.06 (3.24 to 5.10); Treatment R2 4.10 (3.53 to 4.77); Treatment R3 3.81 (3.13 to 4.64); Treatment R4 3.83 (3.15 to 4.65); Treatment R5 3.88 (3.15 to 4.77); Treatment R6 3.82 (3.27 to 4.46)
• Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Sampling Timepoint (AUC Last) (Secondary), Geometric mean, µg·hr/mL: Treatment A1 3.70 (3.28 to 4.18); Treatment A2q 10.9 (8.74 to 13.5); Treatment A2b 4.25 (3.57 to 5.07); Treatment R1 3.59 (2.87 to 4.49); Treatment R2 3.76 (3.20 to 4.41); Treatment R3 3.71 (3.04 to 4.54); Treatment R4 3.53 (2.84 to 4.39); Treatment R5 3.74 (3.21 to 4.34); Treatment R6 3.74 (3.21 to 4.34)
• Apparent Terminal Half-life (t1/2) (Secondary), Geometric mean, hr: Treatment A1 1.21 (1.14 to 1.27); Treatment A2q 1.47 (1.33 to 1.62); Treatment A2b 1.25 (1.13 to 1.38); Treatment R1 1.20 (1.10 to 1.30); Treatment R2 1.14 (1.03 to 1.25); Treatment R3 1.17 (1.10 to 1.25); Treatment R4 1.16 (1.08 to 1.24); Treatment R5 1.13 (1.04 to 1.22); Treatment R6 1.13 (1.03 to 1.24)
• Number of Participants With Treatment-Emergent Adverse Events (Secondary), Number, Number of participants: Cohort 1 6; Cohort 2 6
• Cohort 2 - Concentration of Serum Urate at 24hr of Multiple-dose RDEA3170 Administered in Combination With Allopurinol. (Primary), Mean, mg/dL: Treatment A1 6.2 +/- 0.22; Treatment A2q 5.0 +/- 0.61; Treatment A2b 4.6 +/- 0.33; Treatment R2 4.8 +/- 0.22; Treatment R4 4.1 +/- 0.22; Treatment R6 3.5 +/- 0.20
• Cohort 2 - Renal Xanthine Excretion at 0-24hr of Multiple-dose RDEA3170 Administered in Combination With Allopurinol (AeXO, CB (%)) (Primary), Mean, Percentage (%) Change: Treatment A1 952 +/- 77.2; Treatment A2q 2027 +/- 203; Treatment A2b 2138 +/- 164; Treatment R2 812 +/- 76.3; Treatment R4 797 +/- 65.7; Treatment R6 816 +/- 71.1
• Cohort 2 - Renal Hypoxanthine Excretion at 0-24hr of Multiple-dose RDEA3170 Administered in Combination With Allopurinol (AeHXO, CB (%)) (Primary), Mean, Percentage (%) Change: Treatment A1 372 +/- 33.9; Treatment A2q 645 +/- 76.9; Treatment A2b 681 +/- 63.9; Treatment R2 268 +/- 24.1; Treatment R4 267 +/- 23.4; Treatment R6 286 +/- 25.6

Adverse events

Time frame: 11 Weeks.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Reliable urine uric acid values were not obtained due to sample processing errors, and this has resulted in the inability to assess the PD effects of RDEA3170 and/or allopurinol in urine.

• Results publication: Fleischmann R, Winkle P, Miner JN, Yan X, Hicks L, Valdez S, Hall J, Liu S, Shen Z, Gillen M, Hernandez-Illas M. Pharmacodynamic and pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with gout: a phase IIa, open-label study. RMD Open. 2018 Feb 8;4(1):e000584. doi: 10.1136/rmdopen-2017-000584. eCollection 2018. PMID 29531784

• Jesse Hall, MD, Study director, Ardea Biosciences, Inc.