Allopurinol Combination Study (RDEA594-203)

Randomized, Double-Blind, Multicenter, Placebo-Controlled, Combination Study to Evaluate the Safety, Efficacy and Potential Pharmacokinetic Interaction of RDEA594 and Allopurinol in Gout Patients With an Inadequate Hypouricemic Response With Standard Doses of Allopurinol

To compare the proportion of subjects whose serum urate (sUA) levels are < 6.0 mg/dL following 4 weeks of continuous treatment of RDEA594 in combination with allopurinol to allopurinol alone in subjects with documented inadequate hypouricemic response with standard doses of allopurinol.

Study Overview

• Status: Completed
• Conditions: Gout
• Intervention / Treatment: Drug: Placebo; Drug: Allopurinol; Drug: RDEA594

• Study Type: Interventional
• Enrollment (Actual): 227
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Coquitlam, British Columbia, Canada, V3K 3P4
    • Kelowna, British Columbia, Canada, V1Y8E7
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, A1A 3R5
  • Ontario
    • Thornhill, Ontario, Canada, L4J 6W6
    • Toronto, Ontario, Canada, M9W 4L6
  • Quebec
    • Mirabel, Quebec, Canada, J7J 2K8
• Poland
  • Bydgoszcz, Poland, 85-168
  • Elblag, Poland, 82-300
  • Lublin, Poland, 20-607
  • Poznan, Poland, 60-773
  • Radom, Poland, 26-610
  • Torun, Poland, 87-100
• Spain
  • Bilbao, Spain, 48903
• Ukraine
  • Donetsk, Ukraine, 83045
  • Kharkiv, Ukraine, 61176
  • Kyiv, Ukraine, 01610
  • Kyiv, Ukraine, 02125
  • Vinnytsya, Ukraine, 21081
• United Kingdom
  • Lancashire
    • Blackpool, Lancashire, United Kingdom, FY4 3AD
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85050
  • California
    • La Jolla, California, United States, 92037
    • Los Angeles, California, United States, 90017
    • Stanford, California, United States, 94305
  • Florida
    • Boca Raton, Florida, United States, 33432
    • DeLand, Florida, United States, 32720
    • Fort Lauderdale, Florida, United States, 33334
    • Jupiter, Florida, United States, 33458
  • Idaho
    • Meridan, Idaho, United States, 83642
  • Kentucky
    • Lexington, Kentucky, United States, 40504
  • Maryland
    • Wheaton, Maryland, United States, 20902
  • Nevada
    • Las Vegas, Nevada, United States, 89183
    • Reno, Nevada, United States, 89502
  • North Carolina
    • Harrisburg, North Carolina, United States, 28075
  • Ohio
    • Cincinnati, Ohio, United States, 45242
    • Cleveland, Ohio, United States, 44122
    • Mayfield Village, Ohio, United States, 44143
  • South Carolina
    • Durham, South Carolina, United States, 27710
    • Rock Hill, South Carolina, United States, 29732
  • Tennessee
    • Germantown, Tennessee, United States, 38138
    • Jackson, Tennessee, United States, 38305
  • Texas
    • Dallas, Texas, United States, 75231
    • San Antonio, Texas, United States, 78221
  • Utah
    • West Jordan, Utah, United States, 84088
  • Virginia
    • Chesapeake, Virginia, United States, 23320

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or a post-menopausal or surgically sterile female.
2. 18 - 80 years of age.
3. Has been taking allopurinol as the sole urate lowering therapy for hyperuricemia for at least 6 weeks at a dose between 200 mg and 600 mg per day without an adequate response.
4. Has a sUA level ≥ 6 mg/dL at screening.
5. Meets criteria for the diagnosis of gout as per the American Rheumatism Association (ARA) Criteria for the Classification of Acute Arthritis of Primary Gout.
6. Willing and able to give informed consent and adhere to visit/protocol schedules (informed consent must be given before the first study procedure is performed).
7. Subjects entering the optional Extension Period must have completed 28 days of dosing in the Double-Blind Treatment Period and the Day 42 Visit in the Follow-up Period within 4 months and must not have experienced any serious adverse events considered possibly related to study drug.
8. Subjects entering the optional Open-Label Extension Period must continue to be compliant with the protocol through Week 44 of the Double-Blind Extension Period and must not have experienced any serious adverse events considered possibly related to study drug.

Exclusion Criteria:

1. Consumes more than 14 drinks of alcohol per week (e.g., 1 drink = 5 oz [150 ml] of wine, 12 oz [360 ml] of beer, or 1.5 oz [45 ml] of hard liquor).
2. History or suspicion of drug abuse.
3. History of documented or suspected kidney stones.
4. Has rheumatoid arthritis or other autoimmune disease requiring treatment.
5. Documented or suspicion of HIV infection.
6. Positive serology to HCV antibodies (Abs), and/or hepatitis B surface antigen (HBsAg).
7. History of malignancy within 5 years prior to the first dose of study medication, other than non-melanomatous skin cancer or cervical dysplasia.
8. History of cardiac abnormalities, including abnormal and clinically relevant ECG changes
9. Any condition predisposing to QT prolongation including pathological Q-wave (defined as Q-wave >40 msec or depth > 0.4-0.5 mV).
10. Any use of concomitant medications that prolong the QT/QTc interval within the 14 days prior to Baseline (Day 1).
11. QT interval corrected for heart rate according to Fridericia (QTcF) > 450 msec at Screening or pre-dose at Baseline (Day 1).
12. Uncontrolled hypertension (above 150/95).
13. Inadequate renal function [serum creatinine >1.5 mg/dL or creatinine clearance < 60 mL/min (by Cockroft-Gault formula)].
14. Hemoglobin < 10 g/dL (males) or < 9 g/dL (females).
15. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x upper limit of normal (ULN).
16. Gamma glutamyl transferase (GGT) > 3 x ULN.
17. Active peptic ulcer disease requiring treatment.
18. History of xanthinuria, active liver disease, or hepatic dysfunction.
19. Requires therapy with any other urate-lowering medication, other than the study medications.
20. Requires long-term use of salicylates; diuretics; losartan; azathioprine; mercaptopurine; theophylline; intravenous colchicine; cyclosporine; cyclophosphamide; pyrazinamide; sulfamethoxazole; or trimethoprim.
21. Taking medications known as enzyme inducers (see section 3.7 for listing).
22. Reports receiving a strong or moderate inhibitor of CYP3A4 or a P-gp inhibitor within 1 month prior to study drug dosing, due to potential interactions with colchicine.
23. Acute gout flare (exclusive of chronic synovitis/ arthritis) during the Screening-Period that has not resolved one week prior to the Baseline Visit (Day 0).
24. Pregnant or breast feeding.
25. Has received an investigational medication within 4 weeks prior to the screening visit for this study.
26. Previously participated in a clinical study involving RDEA806 or RDEA594.
27. Known hypersensitivity or allergy to RDEA594, allopurinol or colchicine or any components in their formulations.
28. Body mass index (BMI) >48 kg/m2.
29. Taking greater than 1000 mg/day of Vitamin C.
30. Any other medical or psychological condition, which in the opinion of the Investigator and/or Medical Monitor, might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements, or to complete the study.
31. Inadequate renal function after completing the Double-Blind Treatment period prior to entering Double-Blind Extension Period.
32. Requiring treatment with prohibited medications noted in exclusion criteria numbers 20-23 after completing the Double-Blind Treatment Period prior to entering the Extension Period.
33. Clinically relevant medical event as determined by the investigator in consultation with medical monitor prior to entering the Extension Period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RDEA594 200 mg qd; RDEA594 200 mg qd plus allopurinol qd	Drug: Allopurinol; Allopurinol; Drug: RDEA594; Uricosuric agent for the treatment of gout.
Experimental: RDEA594 200 mg, 400 mg qd; RDEA594 200 mg then 400 mg qd plus allopurinol qd. Patients on lesinurad 400 mg had their dose changed to lesinurad 200 mg after protocol amendment 16 dated 07 October 2015.	Drug: Allopurinol; Allopurinol; Drug: RDEA594; Uricosuric agent for the treatment of gout.
Placebo Comparator: Matching Placebo; RDEA594 matching placebo qd plus allopurinol qd, then allopurinol qd alone in open label period. Patients on allopurinol qd alone were discontinued after protocol amendment 16 dated 07 October 2015.	Drug: Placebo; Matching Placebo; Drug: Allopurinol; Allopurinol
Experimental: RDEA594 600 mg qd; RDEA594 200 mg then 400 mg then 600 mg plus allopurinol qd Patients on lesinurad 600 mg had their dose changed to lesinurad 200 mg after protocol amendment 16 dated 07 October 2015.	Drug: Allopurinol; Allopurinol; Drug: RDEA594; Uricosuric agent for the treatment of gout.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To compare the percent reduction from baseline in serum urate levels following 4 wks of continuous treatment of RDEA594 in combination with allopurinol to allopurinol alone in subjects with documented inadequate hypouricemic response.	28 days

Secondary Outcome Measures

Outcome Measure	Time Frame
To evaluate the proportion of subjects whose sUA levels are < 6.0 mg/dL, < 5.0 mg/dL and < 4.0 mg/dL at each study visit by treatment group in all subjects and in subjects who have an sUA ≥6 mg/dL at the baseline visit.	28 days and through extension
To evaluate the absolute and percent reduction from baseline in sUA levels at each visit.	28 days and through extension
To evaluate the percentage change in 24-hour urine urate level (excretion) from baseline to Day 28.	28 days and through extension
To evaluate the incidence of gout flares.	28 days and through extension
To evaluate the safety and tolerability of RDEA594 in combination with allopurinol in subjects with gout.	28 days and through extension
To compare the multiple-dose pharmacokinetics (PK) of allopurinol and oxypurinol in the absence versus presence of RDEA594 co-administration.	28 days
To evaluate the proportion of subjects whose sUA level decreases to or is maintained at <6.0 mg/dL and <5.0 mg/dL in the Double-Blind and Open-Label Extension Period.	3 years

Collaborators and Investigators

• Sponsor: Ardea Biosciences, Inc.

Publications and helpful links

General Publications

• Perez-Ruiz F, Sundy JS, Miner JN, Cravets M, Storgard C; RDEA594-203 Study Group. Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol. Ann Rheum Dis. 2016 Jun;75(6):1074-80. doi: 10.1136/annrheumdis-2015-207919. Epub 2016 Jan 7.

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: October 22, 2009
• First Submitted That Met QC Criteria: October 23, 2009
• First Posted (Estimate): October 26, 2009

Study Record Updates

• Last Update Posted (Estimate): January 24, 2017
• Last Update Submitted That Met QC Criteria: January 23, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Metabolism, Inborn Errors; Crystal Arthropathies; Purine-Pyrimidine Metabolism, Inborn Errors; Gout; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Renal Agents; Uricosuric Agents; Allopurinol; Lesinurad
• Other Study ID Numbers: RDEA594-203