Clinical trial NCT01078389: Effect of Febuxostat on Joint Damage in Hyperuricemic Subjects With Early Gout
Official title: A Multicenter, Randomized, Double-Blind, Phase 2 Study to Evaluate the Effect of Febuxostat Versus Placebo in Joint Damage in Hyperuricemic Subjects With Early Gout
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Joint Damage
Keywords: Gout
Hyperuricemia
Uric Acid
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2010-03-02
Enrollment: 314
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This purpose of this study is to assess the effect of febuxostat, once daily (QD), on joint damage in patients with elevated serum urate levels and gout.

Detailed description: Gout is caused by high levels of uric acid in the body, and is associated with a broad range of comorbidities including heart disease, chronic kidney disease and additional risk factors like obesity and high blood pressure. Hyperuricemia, which is defined as an elevation in serum urate levels, develops into gout when urate crystals form from supersaturated body fluids and settle in joints and other organs. Urate-lowering therapy is used to treat hyperuricemia in patients with gout.

Current treatments focus on initiating urate-lowering therapy in hyperuricemic gout patients who have experienced multiple acute gout flares within the past year. However, joint damage caused by crystal deposition may occur much earlier than previously considered. Monosodium urate crystals have been found present in the joints of people with hyperuricemia who do not have any symptoms. The presence of monosodium urate crystals would indicate that after the crystals form, they stay within the joint if serum urate levels are not reduced. Lowering uric acid levels and maintaining them may reduce acute gout flare episodes and possibly halt or reduce joint damage in patients with gout.

This study will evaluate the effect of febuxostat on joint damage in hyperuricemic patients with early gout. All patients will receive gout flare prophylaxis for the first 6 months of the study. Gout flares may also be treated throughout the study.

A variety of imaging techniques are in use to evaluate gout. Plain radiographs (x-rays), Magnetic Resonance Imaging (MRI) and Dual Energy Computed Tomography (DECT) will be utilized in this study. The modified Sharp/Van Der Heijde scoring method (named after Drs. Sharp and Van Der Heijde) for assessment of x-rays has been validated in patients with chronic gout and will be used in this study for evaluating erosion and joint space narrowing. Participants are expected to have 15 visits which will include plain radiographic examinations at 5 visits, 3 Magnetic Resonance Imaging (MRI) examinations and 3 DECT procedures at selected sites.

Eligibility criteria: Inclusion Criteria:

* The participant, or the participant's legally acceptable representative, signs a written informed consent form/Health Insurance Portability \& Accountability Act (HIPAA) Authorization prior to the initiation of any study procedures.
* Must have a history or presence of gout defined as having one or more of the following conditions of the American Rheumatism Association (ARA) preliminary criteria for the diagnosis of gout

  * A tophus proven to contain urate crystals by chemical or polarized light microscopic means and/or
  * Characteristic urate crystals in the joint fluid and/or
  * History of at least 6 of the following clinical, laboratory and x-ray phenomena\*: \*More than one flare criteria will be excluded for the purpose of this study if the participant has a history of only a single acute gout flare.

    * More than one attack of acute arthritis\*
    * maximum inflammation developed within 1 day
    * monoarticular arthritis
    * redness observed over joints
    * first metatarsophalangeal joint painful or swollen
    * unilateral first metatarsophalangeal joint attack
    * unilateral tarsal joint attack
    * tophus (proven or suspected)
    * hyperuricemia
    * asymmetric swelling within a joint on x-ray
    * sub-cortical cysts without erosions on x-ray
    * joint fluid culture negative for organisms during attacks
  * \*More than one flare criteria will be excluded for the purpose of this study if the participant has a history of only a single acute gout flare.
* Is male and at least 18 years of age OR;

  * Female ≥45 years of age and at least 2 years post-menopausal AND has a Follicle Stimulating Hormone (FSH) level ≥40 IU/L OR
  * Female receiving hormone replacement therapy (HRT) must be ≥55 years of age (FSH level not required).
* Has hyperuricemia defined as serum Uric Acid (sUA) level ≥7.0 mg/dL at Screening.
* Has a history of ≤2 (1 or 2) flares. In participants with a history of 2 flares, must have had only one flare in any 12 month period. The primary affected joint will be based on the location of the first gout flare which must be located within right or left metatarsophalangeal (MTP), interphalangeal (IP), ankle, metacarpophalangeal (MCP), Proximal Inter-Phalangeal (PIP), or distal inter-phalangeal (DIP) joints prior to Screening.
* Is capable of understanding and complying with protocol requirements, including scheduled clinic procedures.

Exclusion Criteria:

* Previously on urate-lowering therapy (allopurinol, febuxostat or probenecid).
* Has secondary hyperuricemia (eg due to myeloproliferative disorder or organ transplant).
* Has a history of xanthinuria.
* Has a known hypersensitivity to any component of the febuxostat formulation.
* Has rheumatoid arthritis.
* Has active peptic ulcer disease.
* Has a history of cancer, except basal cell carcinoma of the skin, which has not been in remission for at least 5 years prior to the first dose of study medication.
* Has experienced either a myocardial infarction (MI) or stroke within 90 days prior to the Screening visit.
* Has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values greater than 2.0 the upper limit of normal during the Screening period.
* Has a significant medical condition and/or conditions that would interfere with the treatment, safety or compliance with the protocol at the discretion of the Investigator.
* Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse with 5 years prior to the Screening visit. Participant consumes \>14 alcoholic beverages/week.
* Has received any investigational medicinal product within 30 days prior to the Screening visit. In addition, the participant has been previously randomized into this study and received at least one dose of double blind study drug treatment.
* Has an estimated Glomerular filtration rate (eGFR) \<60 mL/min calculated using the Modification of Diet in Renal Disease (MDRD) formula by the Central Laboratory.
* Has a serum creatinine at Screening greater than 2.0 mg/dL.
* Has a known history of infection with hepatitis B, hepatitis C or human immunodeficiency virus.
* Is a study site employee, or is an immediate family member (ie, spouse, parent, child, and sibling) of a study site employee involved in conduct of this study.
* Is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent form is available.
* Is required to take excluded medications.
* Magnetic Resolution Imaging:

  * Has a known hypersensitivity to gadolinium
  * Has history of severe asthma
  * Has an electronically, magnetically or mechanically activated implanted device
  * Has any object that could present a potential hazard or interfere with MRI interpretation secondary to the artifact (i.e. metallic foreign bodies)
  * Has a significant medical condition considered by the Investigator (or radiologist) to interfere with the participant's ability to receive gadolinium (eg Sickle cell anemia).

Primary outcomes:
measure: Mean Change From Baseline to Month 24 in the Modified Sharp/Van Der Heijde Erosion Score of the Single Affected Joint
timeFrame: Baseline and Month 24
Secondary outcomes:
measure: Mean Change From Baseline to Month 24 in the Modified Sharp/Van Der Heijde Total Scores From Full Hands and Feet Radiographs
timeFrame: Baseline and Month 24
measure: Mean Change From Baseline to Month 24 in the Modified Sharp/Van Der Heijde Erosion Scores From Full Hands and Feet Radiographs
timeFrame: Baseline and Month 24
measure: Mean Change From Baseline to Month 24 in the Rheumatoid Arthritis MRI Scoring System (RAMRIS) Score of the Single Affected Joint
timeFrame: Baseline and Month 24
measure: Mean Change From Baseline to Month 24 in the Modified Sharp/Van Der Heijde Total Score of the Single Affected Joint
timeFrame: Baseline and Month 24
Other outcomes:
Locations:
city: Mesa
country: United States
state: Arizona
city: Tucson
country: United States
state: Arizona
city: Burbank
country: United States
state: California
city: Carmichael
country: United States
state: California
city: Costa Mesa
country: United States
state: California
city: Irvine
country: United States
state: California
city: Orange
country: United States
state: California
city: Rancho Cucamonga
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Luis Obispo
country: United States
state: California
city: Trumbull
country: United States
state: Connecticut
city: Boynton Beach
country: United States
state: Florida
city: Daytona Beach
country: United States
state: Florida
city: Fort Lauderdale
country: United States
state: Florida
city: Hialeah
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Sanford
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Winter Park
country: United States
state: Florida
city: Honolulu
country: United States
state: Hawaii
city: Arlington Heights
country: United States
state: Illinois
city: Avon
country: United States
state: Indiana
city: Greenfield
country: United States
state: Indiana
city: Wichita
country: United States
state: Kansas
city: Rockport
country: United States
state: Maine
city: Chaska
country: United States
state: Minnesota
city: Belzoni
country: United States
state: Mississippi
city: Olive Branch
country: United States
state: Mississippi
city: Billings
country: United States
state: Montana
city: Missoula
country: United States
state: Montana
city: Bellevue
country: United States
state: Nebraska
city: Henderson
country: United States
state: Nevada
city: Las Vegas
country: United States
state: Nevada
city: Albuquerque
country: United States
state: New Mexico
city: Charlotte
country: United States
state: North Carolina
city: Lenoir
country: United States
state: North Carolina
city: Shelby
country: United States
state: North Carolina
city: Dayton
country: United States
state: Ohio
city: Franklin
country: United States
state: Ohio
city: Willoughby Hills
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Eugene
country: United States
state: Oregon
city: Duncansville
country: United States
state: Pennsylvania
city: East Providence
country: United States
state: Rhode Island
city: Columbia
country: United States
state: South Carolina
city: Rapid City
country: United States
state: South Dakota
city: Kingsport
country: United States
state: Tennessee
city: Austin
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Southlake
country: United States
state: Texas
city: Sugar Land
country: United States
state: Texas
city: Arlington
country: United States
state: Virginia
city: Burke
country: United States
state: Virginia
city: Manassas
country: United States
state: Virginia
city: Kenosha
country: United States
state: Wisconsin
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Dalbeth N, Saag KG, Palmer WE, Choi HK, Hunt B, MacDonald PA, Thienel U, Gunawardhana L. Effects of Febuxostat in Early Gout: A Randomized, Double-Blind, Placebo-Controlled Study. Arthritis Rheumatol. 2017 Dec;69(12):2386-2395. doi: 10.1002/art.40233.