Clinical trial NCT01001338: Allopurinol Combination Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Gout
Lead sponsor: Ardea Biosciences, Inc.
Sponsor class: INDUSTRY
First posted: 2009-10-26
Enrollment: 227
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: 28 days
Secondary outcomes:
measure: 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.
timeFrame: 28 days and through extension
measure: To evaluate the absolute and percent reduction from baseline in sUA levels at each visit.
timeFrame: 28 days and through extension
measure: To evaluate the percentage change in 24-hour urine urate level (excretion) from baseline to Day 28.
timeFrame: 28 days and through extension
measure: To evaluate the incidence of gout flares.
timeFrame: 28 days and through extension
measure: To evaluate the safety and tolerability of RDEA594 in combination with allopurinol in subjects with gout.
timeFrame: 28 days and through extension
measure: To compare the multiple-dose pharmacokinetics (PK) of allopurinol and oxypurinol in the absence versus presence of RDEA594 co-administration.
timeFrame: 28 days
measure: 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.
timeFrame: 3 years
Other outcomes:
Locations:
city: Phoenix
country: United States
state: Arizona
city: La Jolla
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Stanford
country: United States
state: California
city: Boca Raton
country: United States
state: Florida
city: DeLand
country: United States
state: Florida
city: Fort Lauderdale
country: United States
state: Florida
city: Jupiter
country: United States
state: Florida
city: Meridan
country: United States
state: Idaho
city: Lexington
country: United States
state: Kentucky
city: Wheaton
country: United States
state: Maryland
city: Las Vegas
country: United States
state: Nevada
city: Reno
country: United States
state: Nevada
city: Harrisburg
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Cleveland
country: United States
state: Ohio
city: Mayfield Village
country: United States
state: Ohio
city: Durham
country: United States
state: South Carolina
city: Rock Hill
country: United States
state: South Carolina
city: Germantown
country: United States
state: Tennessee
city: Jackson
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: West Jordan
country: United States
state: Utah
city: Chesapeake
country: United States
state: Virginia
city: Coquitlam
country: Canada
state: British Columbia
city: Kelowna
country: Canada
state: British Columbia
city: St. John's
country: Canada
state: Newfoundland and Labrador
city: Thornhill
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Mirabel
country: Canada
state: Quebec
city: Bydgoszcz
country: Poland
city: Elblag
country: Poland
city: Lublin
country: Poland
city: Poznan
country: Poland
city: Radom
country: Poland
city: Torun
country: Poland
city: Bilbao
country: Spain
city: Donetsk
country: Ukraine
city: Kharkiv
country: Ukraine
city: Kyiv
country: Ukraine
city: Kyiv
country: Ukraine
city: Vinnytsya
country: Ukraine
city: Blackpool
country: United Kingdom
state: Lancashire
Study officials:
affiliation: Ardea Biosciences, Inc.
name: Nihar Bhakta, MD
role: STUDY_DIRECTOR
References:
citation: 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.