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Intensive Urate Lowering Therapy of Febuxostat Compared to Allopurinol on Cardiovascular Risk in Patients With Gout (FORWARD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02500641
Recruitment Status : Completed
First Posted : July 16, 2015
Last Update Posted : September 5, 2017
Sponsor:
Information provided by (Responsible Party):
Menarini International Operations Luxembourg SA

Brief Summary:
Comparison of the effects of Febuxostat and Allopurinol on Pulse Wave Velocity (PWV) after 36 weeks of treatment.

Condition or disease Intervention/treatment Phase
Gout Drug: Febuxostat 80/120mg/day Drug: Allopurinol 100 up to 600mg/day Drug: Colchicine Drug: Naproxen Drug: Omeprazole Phase 4

Detailed Description:

The study physician responsible for randomization and drug supply handling is unblinded to study medications and therefore will not be involved in the main efficacy evaluations of each patient randomized in the study.

Conversely, the study physician/s responsible for the main efficacy evaluation (Pulse Wave Velocity) will be blind to study treatments.

Key efficacy variables will be performed by an independent centralized laboratory.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 197 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Effect of Intensive Urate Lowering Therapy (ULT) With Febuxostat in Comparison With Allopurinol on Cardiovascular Risk in Patients With Gout Using Surrogate Markers: a Randomized, Controlled Trial
Actual Study Start Date : August 17, 2015
Actual Primary Completion Date : May 10, 2017
Actual Study Completion Date : May 10, 2017

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Gout
MedlinePlus related topics: Gout

Arm Intervention/treatment
Experimental: Febuxostat 80/120 mg/day

Febuxostat 80/120 mg film coated tablets.The initial daily dose is 80 mg given orally. In case a patient has serum urate level 6 mg/dl after 2 weeks of treatment the dose will be escalated to 120 mg and if tolerated will be maintained during the study treatment period.

To prevent flares in the initial stages of treatment, patients will be treated for at least 6 months with colchicine 0.5 - 1 mg quaque die (QD ) or in case of colchicine intolerance, Naproxen 550 mg bis in die (BID) with Omeprazole (20-40 mg once daily), if indicated to be used.

Drug: Febuxostat 80/120mg/day
Starting dose and dose regimen of Febuxostat : the initial daily dose is 80 mg. In case the patient has the serum urate concentration > 6 mg/dl after 2 weeks of treatment the dose will be escalated to 120 mg and if tolerated will be maintained for the duration of the study.
Other Name: Adenuric

Drug: Colchicine
Colchicine 0.5 mg tablets.To prevent flares in the initial stages of treatment, patients will be treated for at least 6 months with colchicine 0.5 - 1 mg QD

Drug: Naproxen
Naproxen sodium 550 mg film coated tablets. In case of colchicine intolerance patients will be treated for at least 6 months with Naproxen 550 mg BID and Omeprazole (20-40 mg once daily), if indicated to be used.
Other Name: Synflex

Drug: Omeprazole
Omeprazole 20 mg capsules, co-administered to patients for gastric protection.
Other Name: Omeprazen

Active Comparator: Allopurinol 100 up to 600 mg/day

Allopurinol 100/300 mg tablets.The initial daily allopurinol dose is 100 mg given orally, to be escalated of 100 mg every 2 weeks in patients with serum urate concentration >6 mg/dl.

The maximum dose of allopurinol achievable in the study will depend on kidney function and tolerability, but will not exceed 600 mg daily.To prevent flares in the initial stages of treatment, patients will be treated for at least 6 months with colchicine 0.5 - 1 mg QD or in case of colchicine intolerance, Naproxen 550 mg BID with Omeprazole (20-40 mg once daily), if indicated to be used.

Drug: Allopurinol 100 up to 600mg/day
Starting dose and dose regimen of allopurinol : the initial daily allopurinol dose is 100 mg, to be increased by 100 mg every 2 weeks in patients with serum urate concentration >6 mg/dl. The maximum daily dose of allopurinol achievable in the study will depend on kidney function and tolerability, but will not exceed 600 mg.
Other Name: Allopurinol

Drug: Colchicine
Colchicine 0.5 mg tablets.To prevent flares in the initial stages of treatment, patients will be treated for at least 6 months with colchicine 0.5 - 1 mg QD

Drug: Naproxen
Naproxen sodium 550 mg film coated tablets. In case of colchicine intolerance patients will be treated for at least 6 months with Naproxen 550 mg BID and Omeprazole (20-40 mg once daily), if indicated to be used.
Other Name: Synflex

Drug: Omeprazole
Omeprazole 20 mg capsules, co-administered to patients for gastric protection.
Other Name: Omeprazen




Primary Outcome Measures :
  1. Pulse Wave Velocity [ Time Frame: 36 weeks of treatment ]
    Comparison of the effects of Febuxostat and Allopurinol on Pulse Wave Velocity (PWV) after 36 weeks of treatment.


Secondary Outcome Measures :
  1. Changes in Brain natriuretic peptide (BNP) and NTproBNP values [ Time Frame: 12, 24 and 36 weeks of treatment ]
  2. Changes in inflammation markers [ Time Frame: 12, 24 and 36 weeks of treatment ]
    Changes in hsCRP, TNF-alfa, plasma fibrinogen

  3. Changes in oxidative stress parameters [ Time Frame: 12,24 and 36 weeks of treatment ]
    Change in: MDA, MPO, Ox-LDL, PON1 and PON2

  4. Changes in lipid profile [ Time Frame: 12,24 and 36 weeks of treatment ]
    Changes in: Total Cholesterol, LDL, HDL, Triglycerides

  5. Percentage of gout patients with a serum Urate acid (sUA) concentration of less than 6 mg/dl [ Time Frame: 12,24 and 36 weeks of treatment ]
  6. Time to achieve sUA target levels [ Time Frame: 36 weeks ]
    Time calculated for patients stratified for sUA levels at baseline as follows: 8.1-8.8 mg/dl, 8.9-9.6 mg/dl, 9.7-10.3 mg/dl, 10.4-11.00 mg/dl, >11 mg/dl

  7. Changes in Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: 12,24 and 36 weeks of treatment ]
    Calculated with Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula

  8. Changes in urine albumin excretion [ Time Frame: 12,24 and 36 weeks of treatment ]
    Evaluated by first morning urine albumin/creatinine ratio (mg/g)

  9. Percentage of patients above the sUA target levels [ Time Frame: 12,24 and 36 weeks of treatment after having reached the sUA target levels at week 2 ]
  10. Tender and swollen joint count [ Time Frame: 12,24 and 36 weeks of treatment ]
  11. Pulse Wave Analysis [ Time Frame: 12,24 and 36 weeks of treatment ]
    Including modifications of PWV, arterial stiffness, central blood pressure and augmentation index

  12. Changes in endothelial activation/adhesion markers [ Time Frame: 12,24 and 36 weeks of treatment ]
    Changes in sVCAM, sICAM, vWF, e-selectine

  13. Number of participants with adverse events as a measure of Safety and Tolerability [ Time Frame: 36 weeks of treatment ]
    Safety and Tolerability assessed by following parameters: collection and assessment of AEs, Physical examination, Vital signs (blood pressure, pulse, body weight, axillary body temperature), Laboratory evaluation (Blood chemistry, haematology, urinalysis)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female patients 18 years and older;
  2. History of gout, flare free in the 4 weeks prior to study entry
  3. History of crystal (joint liquid) proven diagnosis or anamnestic diagnosis of gout according to Wallace at el. Preliminary criteria for the classification of the acute arthritis of primary gout; Arthritis Rheum, 1977
  4. Naive to ULT or previously treated with ULT, but with no ULT treatment in the last 1 month prior to study entry and only if reason for ULT interruption was not due to safety concerns.
  5. Patients at study entry have elevated serum urate level >8 mg/dl.
  6. Overall Cardiovascular (CV) risk factor based on the scoring proposed by the Joint Task Force of the European Society of Cardiology and other European Societies on cardiovascular disease prevention in clinical practice between 5 and 15-% (inclusive). Patients with diabetes mellitus type 2 could be included in the study if their CV risk score is calculated as ≤7%.

Allowed concomitant medications should be maintained stable during the last 2 weeks before randomisation

Exclusion Criteria:

  1. Severe chronic renal failure (creatinine clearance < 30 ml/min)
  2. Hepatic failure
  3. Active liver disease or hepatic dysfunction, defined as both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >2 times the upper limit of normal.
  4. Diabetes mellitus type1
  5. Life-threatening co-morbidity or with a significant medical condition and/or conditions that would interfere with the treatment, the safety or the compliance with the protocol
  6. Diagnosis of, or receiving treatment for malignancy (excluding basalioma skin cancer) in the previous 5 years
  7. Patients who have experienced either myocardial infarction or stroke
  8. Patients with inflammatory based arthritis (e.g.: rheumatoid arthritis, etc.)
  9. Patients with congestive heart failure, New York Heart Association (NYHA) Class III or IV
  10. Patients with untreated/uncontrolled thyroid function
  11. Patients with clinically severe peripheral arterial disease
  12. Concomitant administration of any of the following: azathioprine, mercaptopurine, theophylline, meclofenamate, sulfinpyrazone, trimethoprim-sulfamethoxazole, cyclophosphamide, benzbromarone, pyrazinamide, captopril and enalapril (for Allopurinol), tegafur, pegloticase and tacrolimus.
  13. Hypersensitivity to any one of the active substances or to any of the excipients
  14. Any contraindication to febuxostat or allopurinol (with reference to the summary of product characteristics).
  15. Subject is unable to take either of the protocol-required gout flare prophylactic medications (NSAID or colchicine) due to contraindications or intolerance, e.g. hypersensitivity, active gastric ulcer disease, renal impairment and/or changes in liver enzymes
  16. Participation in another trial of an investigational drug or device within 30 days prior to screening, or prior treatment with investigational product(s)
  17. Women of childbearing potential (WOCBP), including peri-menopausal women who have had a menstrual period within 1 year, not willing to use highly effective method of birth control throughout the study period and for 4 weeks after study completion defined as a method which results in a failure rate of less than 1% per year.
  18. Severe psychiatric disorders/neurological disorders
  19. Severe concurrent pathology, including terminal illness (cancer, AIDS, etc)
  20. Abuse of alcohol, analgesics, or psychotropic drugs
  21. Inability or unwillingness, in the investigator's opinion, to follow study procedures
  22. Inability or unwillingness to issue the informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02500641


Locations
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Germany
Dresden, Germany
Italy
Avezzano, Italy
Bologna, Italy
Brescia, Italy
Chieti, Italy
Coppito, Italy
Netherlands
Reade
Amsterdam, Netherlands
Poland
Gdansk, Poland
Grudziadz, Poland
Katowice, Poland
Krakow, Poland
Lodz, Poland
Warsaw, Poland
Zgierz, Poland
Romania
Bucharest, Romania
Craiova, Romania
Timisoara, Romania
Serbia
Belgrade, Serbia
Sponsors and Collaborators
Menarini International Operations Luxembourg SA
Investigators
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Study Director: Claudio Borghi, Prof Policlinico S.Orsola - Malpighi Medicina Interna Borghi

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Responsible Party: Menarini International Operations Luxembourg SA
ClinicalTrials.gov Identifier: NCT02500641     History of Changes
Other Study ID Numbers: MEIN/14/FEB-PWV/001
2014-005567-33 ( EudraCT Number )
First Posted: July 16, 2015    Key Record Dates
Last Update Posted: September 5, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Menarini International Operations Luxembourg SA:
Febuxostat
Biological Markers
Cardiovascular disease
Humans
Pulse Wave Velocity
Cardiovascular risk factors
Allopurinol
Pulse Wave Analysis
Thiazoles
Inflammation
Uric acid
Oxidative stress
Tumor Necrosis Factor
Arthritis
Hyperuricemia

Additional relevant MeSH terms:
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Febuxostat
Gout
Arthritis
Joint Diseases
Musculoskeletal Diseases
Crystal Arthropathies
Rheumatic Diseases
Purine-Pyrimidine Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Omeprazole
Naproxen
Allopurinol
Colchicine
Uric Acid
Anti-Ulcer Agents
Gastrointestinal Agents
Proton Pump Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Gout Suppressants