Efficacy and Safety of Extended Release and Immediate Release Febuxostat in Participants With Gout

• ClinicalTrials.gov Identifier: NCT02139046
• Recruitment Status: Completed
• First Posted: May 15, 2014
• Results First Posted: November 3, 2016
• Last Update Posted: November 3, 2016
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: May 13, 2014
• First Posted Date: May 15, 2014
• Results First Submitted Date: September 15, 2016
• Results First Posted Date: November 3, 2016
• Last Update Posted Date: November 3, 2016
• Study Start Date: April 2014
• Actual Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: May 13, 2014): Percentage of Participants With Serum Urate <5.0 mg/dL at Month 3 [ Time Frame: Month 3 ]
• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT02139046 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: September 15, 2016)

• Percentage of Participants With at Least One Gout Flare Requiring Treatment [ Time Frame: Baseline to Month 3 ]
  A participant was considered to have a gout flare if the following criteria were met: Participant-reported acute particular pain typical of a gout attack that was deemed by participant and/or investigator to require treatment and was treated with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids, Participant experienced at least 3 or more of: 1) Joint swelling, 2) Redness, 3) Tenderness, 4) Pain, Participant experienced at least one or more of: 1) Rapid onset of pain, 2) Decreased range of motion, 3) Joint warmth, 4) Other symptoms similar to a prior gout flare.
• Percentage of Participants With Serum Urate <6.0 mg/dL at Month 3 [ Time Frame: Month 3 ]

Original Secondary Outcome Measures (submitted: May 13, 2014)

• Percentage of Participants With at Least One Gout Flare Requiring Treatment [ Time Frame: Baseline to Month 3 ]
• Percentage of Participants With Serum Urate <6.0 mg/dL at Month 3 [ Time Frame: Month 3 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of Extended Release and Immediate Release Febuxostat in Participants With Gout
• Official Title: A Phase 3, Randomized, Double Blind, Multicenter, Placebo Controlled Study to Evaluate the Efficacy and Safety of Febuxostat 40 mg XR, 80 mg XR, 40 mg IR and 80 mg IR in Subjects With Gout
• Brief Summary: The purpose of this study is to evaluate the efficacy and safety of febuxostat 40 mg extended release (XR) and 80 mg XR in comparison with febuxostat 40 mg immediate release (IR) and 80 mg IR, respectively, in participants with gout.

Detailed Description

The drug being tested in this study is called febuxostat. Febuxostat is being tested to decrease and maintain serum urate in people who have gout. This study will look at serum urate levels in people who take febuxostat extended release (XR) capsules compared to febuxostat immediate release (IR) capsules and placebo.

The study will enroll approximately 1750 patients. Participants will be randomly assigned (by chance) to one of the five treatment groups—which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

• Febuxostat 40 mg XR
• Febuxostat 80 mg XR
• Febuxostat 40 mg IR
• Febuxostat 80 mg IR
• Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient.

All participants will be asked to take one capsule at the same time each day throughout the study, and will be asked to call an interactive voice response system any time they are having a gout flare up. In addition to study medication, participants will also take 0.6 mg of colchicine every day or every other day, or naproxen 250 mg twice a day and lansoprazole 15 mg once a day to prevent gout flare ups.

This multi-centre trial will be conducted in the United States. The overall time to participate in this study is up to approximately 4 months and participants will make up to 7 visits to the clinic.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Gout

Intervention

• Drug: Febuxostat IR
  Febuxostat IR over-encapsulated tablets
  Other Name: Uloric
• Drug: Febuxostat XR
  Febuxostat XR over-encapsulated capsules
  Other Name: Uloric
• Drug: Febuxostat placebo
  Febuxostat placebo-matching capsules
• Drug: Colchicine
  Colchicine tablets
• Drug: Naproxen
  Naproxen tablets
• Drug: Lansoprazole
  Lansoprazole capsules

Study Arms

• Active Comparator: Febuxostat IR 40 mg
  Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day (for participants with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min) or every other day (if eGFR ≥ 15 - ≤ 59 mL/min), or, alternatively, if colchicine is not tolerated and the subject's eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
  Interventions:

  • Drug: Febuxostat IR
  • Drug: Colchicine
  • Drug: Naproxen
  • Drug: Lansoprazole
• Active Comparator: Febuxostat IR 80 mg
  Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject's eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
  Interventions:

  • Drug: Febuxostat IR
  • Drug: Colchicine
  • Drug: Naproxen
  • Drug: Lansoprazole
• Experimental: Febuxostat XR 40 mg
  Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject's eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
  Interventions:

  • Drug: Febuxostat XR
  • Drug: Colchicine
  • Drug: Naproxen
  • Drug: Lansoprazole
• Experimental: Febuxostat XR 80 mg
  Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject's eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
  Interventions:

  • Drug: Febuxostat XR
  • Drug: Colchicine
  • Drug: Naproxen
  • Drug: Lansoprazole
• Placebo Comparator: Placebo
  Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject's eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
  Interventions:

  • Drug: Febuxostat placebo
  • Drug: Colchicine
  • Drug: Naproxen
  • Drug: Lansoprazole

• Publications *: Saag KG, Becker MA, Whelton A, Hunt B, Castillo M, Kisfalvi K, Gunawardhana L. Efficacy and Safety of Febuxostat Extended and Immediate Release in Patients With Gout and Renal Impairment: A Phase III Placebo-Controlled Study. Arthritis Rheumatol. 2019 Jan;71(1):143-153. doi: 10.1002/art.40685.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 15, 2016): 1790
• Original Estimated Enrollment (submitted: May 13, 2014): 1750
• Actual Study Completion Date: November 2015
• Actual Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedure.

3. Has a history or presence of gout defined as having one or more of the American Rheumatism Association (ARA) criteria for the diagnosis of gout:

   1. A tophus proven to contain urate crystals by chemical or polarized light microscopic means, AND/OR;
   2. Characteristic urate crystals in the joint fluid, AND/OR;
   3. History of at least 6 of the following clinical, laboratory, and x-ray phenomena:

   i. more than one attack of acute arthritis, ii. maximum inflammation developed within 1 day, iii. monoarticular arthritis, iv. redness observed over joints, v. first metatarsophalangeal joint painful or swollen, vi. unilateral first metatarsophalangeal joint attack, vii. unilateral tarsal joint attack, viii. tophus (proven or suspected), ix. Hyperuricemia, x. asymmetric swelling within a joint on x-ray, xi. subcortical cysts without erosions on x-ray; xii. joint fluid culture negative for organisms during attack.

4. Is male or female at least 18 years of age, inclusive.
5. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study.
6. Have a serum urate (sUA) level ≥8.0 mg/dL at the Day -4 Visit or at the retest visit.
7. Has an estimated Glomerular Filtration Rate (eGRF) ≥15 mL/min using the Modification of Diet in Renal Disease (MDRD) formula at the Screening visit (Day -21 for participants on urate lowering therapy (ULT) and Day -4 for participants not on ULT) or at the retest visit.
8. Has at least one gout flare within 12 months prior to Screening visit.

Exclusion Criteria:

1. Has received any investigational compound within 30 days prior to Screening.
2. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
3. Is breastfeeding or pregnant.
4. Has secondary hyperuricemia (eg, due to myeloproliferative disorder).
5. Has a history of xanthinuria.
6. Has received ULT (ie, allopurinol, probenecid, etc.) within 20 days prior to Day 1/Randomization Visit.
7. Has a known hypersensitivity to febuxostat or any components of their formulation; has a known hypersensitivity to naproxen, any other nonsteroidal anti-inflammatory drug (NSAID), aspirin, lansoprazole, colchicine or any components in their formulation.
8. Has active peptic ulcer disease.
9. Has a history of cancer (other than basal cell carcinoma of the skin) within 5 years prior to the Screening Visit.
10. Has alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values >2 x the upper limit of normal (ULN).
11. Has rheumatoid arthritis which requires treatment.
12. Has a significant medical condition and/or conditions that would interfere with the treatment, safety, or compliance with the protocol.
13. Has experienced a myocardial infarction (MI), stroke, hospitalized unstable angina, cardiac or cerebrovascular revascularization procedure or hospitalized transient ischemic attack (TIA) - except in participants who have severe renal impairment.
14. Participants with severe renal impairment had a MI or stroke within 90 days prior to initial screening visit or has a MI or stroke during the screening period prior to Day 1/Randomization Visit.
15. Participant consumes >14 alcoholic beverages/week. Has a history of alcoholism or illicit drug abuse within 5 years.
16. Has participated in another investigational study within the 30 days prior to the Screening Visit.
17. Has a known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus.
18. Is required to take excluded medications.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02139046
• Other Study ID Numbers: FEB-XR_301; U1111-1152-4040 ( Other Identifier: World Health Organization )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Takeda
• Study Sponsor: Takeda
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director Clinical Science; Takeda

• PRS Account: Takeda
• Verification Date: September 2016