Evaluate the PK, PD, and Safety of Arhalofenate in Combination With Febuxostat for Hyperuricemia in Patients With Gout
Primary Purpose
Gout, Hyperuricemia
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Arhalofenate
Febuxostat
Arhalofenate
Febuxostat
Colchicine
Sponsored by
About this trial
This is an interventional treatment trial for Gout
Eligibility Criteria
Inclusion Criteria:
- Male or female patient, 18 to 75 years of age, inclusive
- Known gout diagnosis (per criteria of the American Rheumatism Association)
- Has an sUA ≥ 7.5 mg/dL
- A female patient must be surgically sterile or post-menopausal (at least 45 years of age with no history of menses for at least two years), or must agree to use two medically accepted methods of contraception including a barrier method for the entire duration of study participation unless she reports compete sexual abstinence. A female patient must also not be pregnant or lactating
- Estimated creatinine clearance (eCrCl) ≥ 60 ml/min, as calculated by Cockcroft-Gault method
- ALT or AST ≤ 3 times upper limit of normal (ULN) or total bilirubin ≤ 2 times ULN (Gilbert's syndrome is permitted)
- All other clinical laboratory parameters must be within normal limits or considered not clinically significant
- ECG must be normal, or if abnormal, considered not clinically significant
- A patient who is taking a medication or agent (other than a ULT) known to influence sUA levels must be on a stable dose and regimen of the medication for at least two weeks prior to screening and must be willing to continue the same dose and regimen during study participation
- Expected to be able to tolerate a short course of oral NSAIDs and/or oral steroids as may be needed to treat a gout flare
- Must be able to swallow tablets
Exclusion Criteria:
- Treatment with any ULT (e.g., allopurinol, febuxostat, probenecid, or benzbromarone) within two weeks, or pegloticase within six months, prior to the sUA assessment at Day 1
- Occurrence of a gout flare that has not resolved within one week prior to Day 1
- Known or suspected secondary hyperuricemia (e.g., due to myeloproliferative disorder or organ transplant)
- Diagnosis of xanthinuria
- Fractional excretion of urate > 10%
- History of documented or suspected kidney stones within five years prior to screening
- Known infection with the human immunodeficiency virus (HIV) or history of hepatitis B or C
- Recent use/abuse of an illicit drug as determined by a positive urine drug screen
- Uncontrolled hypertension that, in the opinion of the Investigator, would preclude participation in the study
- History of stroke, transient ischemic attack, acute myocardial infarction, congestive heart failure (NYHA class II - IV), angina pectoris, coronary intervention procedure, lower extremity bypass procedure, systemic or intracoronary fibrinolytic therapy within 5 years of screening
- History of cancer within five years of screening, with the following exceptions: adequately treated non-melanoma skin cancer, non-metastatic prostate cancer, or in situ cervical cancer
- Body mass index (BMI) > 42 kg/m2
- Current or expected requirement for anticoagulant therapy, except for low dose (≤ 81 mg/day) aspirin, clopidogrel (Plavix) ≤ 75 mg/day, or prasugrel (Effient) ≤ 10 mg/day
- Use of any of the following within eight weeks prior to screening: potent CYP3A4 inhibitors, cytotoxic agents (including azathioprine, mercaptopurine, cyclosporine, cyclophosphamide, etc.), ranolazine, digoxin, theophylline, sulphonylureas, thiazolidinediones (e.g., rosiglitazone or pioglitazone), desipramine, atypical antipsychotic agents, loop diuretics, warfarin, or phenytoin
- Chronic treatment with NSAIDs that cannot be safely discontinued-term use of NSAIDs is permitted, e.g., when used to treat gout flares
- Known hypersensitivity or intolerance to febuxostat or colchicine
- Treatment with any other investigational therapy within 30 days or within five half-lives, whichever is longer prior to Day 1
- Any other condition that would compromise the safety of the patient, prevent compliance with the study protocol, or compromise the quality of the clinical study, as judged by the Investigator and/or Medical Monitor
Sites / Locations
- Vince & Associates Clinical Research
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Arhalofenate with febuxostat (PK cohort)
Arhalofenate with febuxostat (non-PK cohort)
Arm Description
Outcomes
Primary Outcome Measures
Proportion of patients achieving a target sUA < 6.0, < 5.0, < 4.0, and < 3.0 mg/dL on Day 29 after treatment with arhalofenate 800 mg and febuxostat 80 mg
Proportion of patients achieving an sUA reduction of ≥ 2.0, ≥ 3.0, and ≥ 4.0 mg/dL from baseline on Day 29 after treatment with arhalofenate 800 mg and febuxostat 80 mg
Absolute and percent reduction in sUA from baseline on Day 29 after treatment with arhalofenate 800 mg and febuxostat 80 mg
AUC(0-t) of arhalofenate 800 mg and febuxostat 80 mg when administered separately and in combination
AUC(0-tau) of arhalofenate 800 mg and febuxostat 80 mg when administered separately and in combination
Tmax of arhalofenate 800 mg and febuxostat 80 mg when administered separately and in combination
Cmax of arhalofenate 800 mg and febuxostat 80 mg when administered separately and in combination
Secondary Outcome Measures
Proportion of patients achieving a target sUA < 6.0, < 5.0, < 4.0, and < 3.0 mg/dL on Day 29 after treatment with arhalofenate 600 mg and febuxostat 40 mg
Proportion of patients achieving an sUA reduction of ≥ 2.0, ≥ 3.0, and ≥ 4.0 mg/dL from baseline on Day 29 after treatment with arhalofenate 600 mg and febuxostat 40 mg
Absolute and percent reduction in sUA from baseline on Day 29 after treatment with arhalofenate 600 mg and febuxostat 40 mg
Proportion of patients achieving a target sUA < 6.0, < 5.0, < 4.0, and < 3.0 mg/dL on Day 22 after treatment with arhalofenate 800 mg and febuxostat 40 mg, and with arhalofenate 600 mg and febuxostat 80 mg
Proportion of patients achieving an sUA reduction of ≥ 2.0, ≥ 3.0, and ≥ 4.0 mg/dL from baseline on Day 22 after treatment with arhalofenate 800 mg and febuxostat 40 mg, and with arhalofenate 600 mg and febuxostat 80 mg
Absolute and percent reduction in sUA from baseline on Day 22 after treatment with arhalofenate 800 mg and febuxostat 40 mg, and with arhalofenate 600 mg and febuxostat 80 mg
Proportion of patients achieving a target sUA < 6.0, < 5.0, < 4.0, and < 3.0 mg/dL after monotherapy treatment with arhalofenate 600 or 800 mg, or febuxostat 40 or 80 mg
Proportion of patients achieving an sUA reduction of ≥ 2.0, ≥ 3.0, and ≥ 4.0 mg/dL from baseline after monotherapy treatment with arhalofenate 600 or 800 mg, or febuxostat 40 or 80 mg
Absolute and percent reduction in sUA from baseline on Day 15 after monotherapy treatment with arhalofenate 600 or 800 mg
Absolute and percent reduction in sUA from baseline on Day 43 after monotherapy treatment with febuxostat 40 or 80 mg
Kel and T1/2 of arhalofenate 800 mg and febuxostat 80 mg, if possible, when administered separately and in combination
Full Information
NCT ID
NCT02252835
First Posted
September 20, 2014
Last Updated
March 30, 2015
Sponsor
CymaBay Therapeutics, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT02252835
Brief Title
Evaluate the PK, PD, and Safety of Arhalofenate in Combination With Febuxostat for Hyperuricemia in Patients With Gout
Official Title
A Phase 2, Open-label, Drug-Drug Interaction Study to Evaluate the Pharmacodynamics, Pharmacokinetics, and Safety of Arhalofenate in Combination With Febuxostat for the Treatment of Hyperuricemia in Patients With Gout
Study Type
Interventional
2. Study Status
Record Verification Date
March 2015
Overall Recruitment Status
Completed
Study Start Date
August 2014 (undefined)
Primary Completion Date
December 2014 (Actual)
Study Completion Date
December 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
CymaBay Therapeutics, Inc.
4. Oversight
5. Study Description
Brief Summary
The purpose of this study is to evaluate pharmacokinetics, pharmacodynamics, safety and potential for drug-drug interaction of arhalofenate when combined with febuxostat in adult population with gout.
Detailed Description
Patients entering the six-week Treatment Period will receive once daily oral dosing of arhalofenate during Weeks 1 and 2 (Days 1 through 14), combined once daily oral dosing of arhalofenate and febuxostat during Weeks 3 and 4 (Days 15 through 28), and once daily oral dosing of febuxostat during Weeks 5 and 6 (Days 29 through 42). In addition, all patients will receive once daily oral dosing of colchicine throughout the Treatment Period.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gout, Hyperuricemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
32 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arhalofenate with febuxostat (PK cohort)
Arm Type
Experimental
Arm Title
Arhalofenate with febuxostat (non-PK cohort)
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Arhalofenate
Intervention Description
800 mg once daily orally for four weeks
Intervention Type
Drug
Intervention Name(s)
Febuxostat
Intervention Description
40 mg once daily orally for 1 week then up-titrated to 80 mg once daily orally for another three weeks
Intervention Type
Drug
Intervention Name(s)
Arhalofenate
Intervention Description
600 mg once daily orally for four weeks
Intervention Type
Drug
Intervention Name(s)
Febuxostat
Intervention Description
80 mg once daily orally for 1 week then down-titrated to 40 mg once daily orally for another three weeks
Intervention Type
Drug
Intervention Name(s)
Colchicine
Intervention Description
0.6 mg daily
Primary Outcome Measure Information:
Title
Proportion of patients achieving a target sUA < 6.0, < 5.0, < 4.0, and < 3.0 mg/dL on Day 29 after treatment with arhalofenate 800 mg and febuxostat 80 mg
Time Frame
Day 29
Title
Proportion of patients achieving an sUA reduction of ≥ 2.0, ≥ 3.0, and ≥ 4.0 mg/dL from baseline on Day 29 after treatment with arhalofenate 800 mg and febuxostat 80 mg
Time Frame
Day 29
Title
Absolute and percent reduction in sUA from baseline on Day 29 after treatment with arhalofenate 800 mg and febuxostat 80 mg
Time Frame
Day 29
Title
AUC(0-t) of arhalofenate 800 mg and febuxostat 80 mg when administered separately and in combination
Time Frame
Days 14, 28, and 42
Title
AUC(0-tau) of arhalofenate 800 mg and febuxostat 80 mg when administered separately and in combination
Time Frame
Days 14, 28, and 42
Title
Tmax of arhalofenate 800 mg and febuxostat 80 mg when administered separately and in combination
Time Frame
Days 14, 28, and 42
Title
Cmax of arhalofenate 800 mg and febuxostat 80 mg when administered separately and in combination
Time Frame
Days 14, 28, and 42
Secondary Outcome Measure Information:
Title
Proportion of patients achieving a target sUA < 6.0, < 5.0, < 4.0, and < 3.0 mg/dL on Day 29 after treatment with arhalofenate 600 mg and febuxostat 40 mg
Time Frame
Day 29
Title
Proportion of patients achieving an sUA reduction of ≥ 2.0, ≥ 3.0, and ≥ 4.0 mg/dL from baseline on Day 29 after treatment with arhalofenate 600 mg and febuxostat 40 mg
Time Frame
Day 29
Title
Absolute and percent reduction in sUA from baseline on Day 29 after treatment with arhalofenate 600 mg and febuxostat 40 mg
Time Frame
Day 29
Title
Proportion of patients achieving a target sUA < 6.0, < 5.0, < 4.0, and < 3.0 mg/dL on Day 22 after treatment with arhalofenate 800 mg and febuxostat 40 mg, and with arhalofenate 600 mg and febuxostat 80 mg
Time Frame
Day 22
Title
Proportion of patients achieving an sUA reduction of ≥ 2.0, ≥ 3.0, and ≥ 4.0 mg/dL from baseline on Day 22 after treatment with arhalofenate 800 mg and febuxostat 40 mg, and with arhalofenate 600 mg and febuxostat 80 mg
Time Frame
Day 22
Title
Absolute and percent reduction in sUA from baseline on Day 22 after treatment with arhalofenate 800 mg and febuxostat 40 mg, and with arhalofenate 600 mg and febuxostat 80 mg
Time Frame
Day 22
Title
Proportion of patients achieving a target sUA < 6.0, < 5.0, < 4.0, and < 3.0 mg/dL after monotherapy treatment with arhalofenate 600 or 800 mg, or febuxostat 40 or 80 mg
Time Frame
Day 15 or Day 43
Title
Proportion of patients achieving an sUA reduction of ≥ 2.0, ≥ 3.0, and ≥ 4.0 mg/dL from baseline after monotherapy treatment with arhalofenate 600 or 800 mg, or febuxostat 40 or 80 mg
Time Frame
Day 15 or Day 43
Title
Absolute and percent reduction in sUA from baseline on Day 15 after monotherapy treatment with arhalofenate 600 or 800 mg
Time Frame
Day 15
Title
Absolute and percent reduction in sUA from baseline on Day 43 after monotherapy treatment with febuxostat 40 or 80 mg
Time Frame
Day 43
Title
Kel and T1/2 of arhalofenate 800 mg and febuxostat 80 mg, if possible, when administered separately and in combination
Time Frame
Days 14, 28, and 42
Other Pre-specified Outcome Measures:
Title
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
Time Frame
Days 1 through 43
Title
Change in physical examination findings
Time Frame
Days 1 through 43
Title
Change in vital signs and safety laboratory tests
Time Frame
Days 1 through 43
Title
Safety-related study drug discontinuations
Time Frame
Days 1 through 43
Title
Deaths
Time Frame
Days 1 through 43
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female patient, 18 to 75 years of age, inclusive
Known gout diagnosis (per criteria of the American Rheumatism Association)
Has an sUA ≥ 7.5 mg/dL
A female patient must be surgically sterile or post-menopausal (at least 45 years of age with no history of menses for at least two years), or must agree to use two medically accepted methods of contraception including a barrier method for the entire duration of study participation unless she reports compete sexual abstinence. A female patient must also not be pregnant or lactating
Estimated creatinine clearance (eCrCl) ≥ 60 ml/min, as calculated by Cockcroft-Gault method
ALT or AST ≤ 3 times upper limit of normal (ULN) or total bilirubin ≤ 2 times ULN (Gilbert's syndrome is permitted)
All other clinical laboratory parameters must be within normal limits or considered not clinically significant
ECG must be normal, or if abnormal, considered not clinically significant
A patient who is taking a medication or agent (other than a ULT) known to influence sUA levels must be on a stable dose and regimen of the medication for at least two weeks prior to screening and must be willing to continue the same dose and regimen during study participation
Expected to be able to tolerate a short course of oral NSAIDs and/or oral steroids as may be needed to treat a gout flare
Must be able to swallow tablets
Exclusion Criteria:
Treatment with any ULT (e.g., allopurinol, febuxostat, probenecid, or benzbromarone) within two weeks, or pegloticase within six months, prior to the sUA assessment at Day 1
Occurrence of a gout flare that has not resolved within one week prior to Day 1
Known or suspected secondary hyperuricemia (e.g., due to myeloproliferative disorder or organ transplant)
Diagnosis of xanthinuria
Fractional excretion of urate > 10%
History of documented or suspected kidney stones within five years prior to screening
Known infection with the human immunodeficiency virus (HIV) or history of hepatitis B or C
Recent use/abuse of an illicit drug as determined by a positive urine drug screen
Uncontrolled hypertension that, in the opinion of the Investigator, would preclude participation in the study
History of stroke, transient ischemic attack, acute myocardial infarction, congestive heart failure (NYHA class II - IV), angina pectoris, coronary intervention procedure, lower extremity bypass procedure, systemic or intracoronary fibrinolytic therapy within 5 years of screening
History of cancer within five years of screening, with the following exceptions: adequately treated non-melanoma skin cancer, non-metastatic prostate cancer, or in situ cervical cancer
Body mass index (BMI) > 42 kg/m2
Current or expected requirement for anticoagulant therapy, except for low dose (≤ 81 mg/day) aspirin, clopidogrel (Plavix) ≤ 75 mg/day, or prasugrel (Effient) ≤ 10 mg/day
Use of any of the following within eight weeks prior to screening: potent CYP3A4 inhibitors, cytotoxic agents (including azathioprine, mercaptopurine, cyclosporine, cyclophosphamide, etc.), ranolazine, digoxin, theophylline, sulphonylureas, thiazolidinediones (e.g., rosiglitazone or pioglitazone), desipramine, atypical antipsychotic agents, loop diuretics, warfarin, or phenytoin
Chronic treatment with NSAIDs that cannot be safely discontinued-term use of NSAIDs is permitted, e.g., when used to treat gout flares
Known hypersensitivity or intolerance to febuxostat or colchicine
Treatment with any other investigational therapy within 30 days or within five half-lives, whichever is longer prior to Day 1
Any other condition that would compromise the safety of the patient, prevent compliance with the study protocol, or compromise the quality of the clinical study, as judged by the Investigator and/or Medical Monitor
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alexandra Steinberg, MD, PhD
Organizational Affiliation
CymaBay Therapeutics, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Vince & Associates Clinical Research
City
Overland Park
State/Province
Kansas
ZIP/Postal Code
66212
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
27980008
Citation
Steinberg AS, Vince BD, Choi YJ, Martin RL, McWherter CA, Boudes PF. The Pharmacodynamics, Pharmacokinetics, and Safety of Arhalofenate in Combination with Febuxostat When Treating Hyperuricemia Associated with Gout. J Rheumatol. 2017 Mar;44(3):374-379. doi: 10.3899/jrheum.161062. Epub 2016 Dec 15.
Results Reference
derived
Learn more about this trial
Evaluate the PK, PD, and Safety of Arhalofenate in Combination With Febuxostat for Hyperuricemia in Patients With Gout
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