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

NCT02500641 | Completed Phase 4 Results

• 2 other identifiers: MEIN/14/FEB-PWV/0012014-005567-33
• Study Type: interventional
• Target: 196
• Locations: 6 countries
• Sites: 26

Brief Summary

There is a mounting and clear association between hyperuricaemia, gout and the presence of traditional cardiovascular (CV) risk factors and CV event-equivalent conditions such as chronic kidney disease, metabolic syndrome, and diabetes. Gout is associated with increased risk of CV events such as myocardial infarction and CV death. Furthermore hyperuricaemia is clearly associated with an increased arterial stiffness, a marker of pre-clinical atherosclerosis. Carotid-femoral pulse wave velocity (PWV) is the "gold standard" measurement of arterial stiffness and it is considered, in this trial, as a valid surrogate endpoint with clearly established relevance to predict cardiovascular disease (CVD) clinical outcome In this randomised trial conducted on adult subjects with a history of gout, we use surrogate endpoints to investigate the efficacy of febuxostat compared with allopurinol to predict (CVD) clinical outcome. Eligible subjects were randomised in a 1:1 ratio to the following treatment groups:

• Test product: febuxostat 80 mg or 120 mg once daily (120 mg daily, if serum urate was \>6 mg/dL after 2 weeks of treatment at 80 mg daily).
• Active comparator: allopurinol 100 mg once daily (up to a maximum dose of 600 mg daily escalated in 100 mg increments every 2 weeks, if serum urate acid (sUA) was \>6 mg/dL after 2 weeks of treatment at the previous dose). The study duration was 39 weeks, which included the:
• Run-in/screening period: 1 week (extendable up to a maximum of 30 days according to variability of sUA levels);
• Treatment period: 36 weeks;
• Safety follow-up period: 2 weeks.

Conditions

Gout

Keywords

Biological Markers; Cardiovascular disease; Humans; Pulse Wave Velocity; Cardiovascular risk factors; Allopurinol; Pulse Wave Analysis; Thiazoles; Inflammation; Uric acid; Febuxostat; Oxidative stress; Tumor Necrosis Factor; Arthritis; Hyperuricemia

Outcome Measures

Primary Outcomes (1)

• Pulse Wave Velocity

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

  36 weeks of treatment

Study Arms (2)

Febuxostat 80/120 mg/day

EXPERIMENTAL

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; Drug: Colchicine; Drug: Naproxen; Drug: Omeprazole

Allopurinol 100 up to 600 mg/day

ACTIVE COMPARATOR

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; Drug: Colchicine; Drug: Naproxen; Drug: Omeprazole

Interventions

Febuxostat 80/120mg/day DRUG

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.

Also known as: Adenuric

Febuxostat 80/120 mg/day

Allopurinol 100 up to 600mg/day DRUG

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.

Also known as: Allopurinol

Allopurinol 100 up to 600 mg/day

Colchicine DRUG

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

Allopurinol 100 up to 600 mg/day; Febuxostat 80/120 mg/day

Naproxen DRUG

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.

Also known as: Synflex

Allopurinol 100 up to 600 mg/day; Febuxostat 80/120 mg/day

Omeprazole DRUG

Omeprazole 20 mg capsules, co-administered to patients for gastric protection.

Also known as: Omeprazen

Allopurinol 100 up to 600 mg/day; Febuxostat 80/120 mg/day

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients 18 years and older;
• History of gout, flare free in the 4 weeks prior to study entry
• History of crystal (joint liquid) proven diagnosis or anamnestic diagnosis of gout according to Wallace at el. To be eligible, a subject had to present at least 6 of the following 12 clinical, laboratory, and x-ray phenomena:
• \. Maximum inflammation developed within 1 day, 2. More than one attack of acute arthritis, 3. Monoarticular arthritis attack, 4. Redness observed over joints, 5. First metatarsophalangeal (MTP) pain or swelling, 6. Unilateral first MTP joint attack, 7. Unilateral tarsal joint attack, 8. Suspected or proven tophus, 9. Hyperuricemia, 10. Asymmetric swelling within a joint on a X ray, 11. Subcortical cysts without erosions on X ray, 12. Negative organisms on culture of joint fluid; 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.
• \. Patients at study entry have elevated serum urate level \>8 mg/dl. 6. Overall Cardiovascular (CV) risk 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

You may not qualify if:

• Severe chronic renal failure (creatinine clearance \< 30 ml/min)
• Hepatic failure
• Active liver disease or hepatic dysfunction, defined as both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \>2 times the upper limit of normal.
• Diabetes mellitus type1
• 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
• Diagnosis of, or receiving treatment for malignancy (excluding basalioma skin cancer) in the previous 5 years
• Patients who have experienced either myocardial infarction or stroke
• Patients with inflammatory based arthritis (e.g.: rheumatoid arthritis, etc.)
• Patients with congestive heart failure, New York Heart Association (NYHA) Class III or IV
• Patients with untreated/uncontrolled thyroid function
• Patients with clinically severe peripheral arterial disease
• 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.
• Hypersensitivity to any one of the active substances or to any of the excipients
• Any contraindication to febuxostat or allopurinol (with reference to the summary of product characteristics).
• 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

Sponsors & Collaborators

• Menarini International Operations Luxembourg SA: lead

Study Sites (26)

Medizinische Klinik und Poliklinik III/Rheumatologie Universitätsklinikum "Carl Gustav Carus" Der Technischen Universität

Dresden, 01307, Germany

Location

Presidio Ospedaliero San Filippo e Nicola Università degli Studi dell'Aquila U.O.C Geriatria e Lungodegenza Geriatrica

Avezzano, L'Aquila, 67051, Italy

Location

Ospedale San Salvatore U.O.C. Medicina Interna e Nefrologia Dipartimento MeSVA Università degli Studi dell'Aquila

Coppito, L'Aquila, 67100, Italy

Location

Azienda Ospedaliero-Universitaria Policlinico Sant'Orsola-Malpighi

Bologna, 40138, Italy

Location

Ospedale Policlinico SS. Annunziata Università degli Studi "G. d'Annunzio". Dipartimento di Medicina e Scienze dell'Invecchiamento.

Chieti, 66100, Italy

Location

Reade Clinic

Amsterdam, 1056, Netherlands

Location

Gdańskie Centrum Zdrowia Sp.z o.o.

Gdansk, Poland

Location

Specjalistyczna Praktyka Lekarska Piotr Kubalski

Grudziądz, Poland

Location

Centrum Medyczne Pratia Katowice

Katowice, Poland

Location

Centrum Medyczne Plejady

Krakow, Poland

Location

Krakowski Szpital Specjalistyczny im. Jana Pawła II w Krakowie

Krakow, Poland

Location

Specjalistyczny Gabinet Dermatologiczno-Kosmetyczny

Krakow, Poland

Location

Oddział Kardiologiczny, WSS im. W. Biegańskiego w Łodzi

Lodz, Poland

Location

Polimedica

Lodz, Poland

Location

Pratia S,A

Warsaw, Poland

Location

Reumatika- Centrum Reumatologii

Warsaw, Poland

Location

Clinica Medicală Data Plus SRL

Bucharest, Sector 1, Romania

Location

Institutul Clinic Fundeni

Bucharest, Sector 2, Romania

Location

S.C. Centrul Medical Sana S.R.L.

Bucharest, Romania

Location

S.C. Cardiomed S.R.L.

Craiova, Romania

Location

Cabinet Medical Medicina Interna

Timișoara, Romania

Location

Institutul de Boli Cardiovasculare Clinica de Cardiologie si Recuperare Cardiovasculara

Timișoara, Romania

Location

Institut za kardiovaskularne bolesti Dedinje

Belgrade, Serbia

Location

Institut za reumatologiju

Belgrade, Serbia

Location

Kliničko-bolnički centar "Bežanijska kosa" Klinika za imunologiju i alergologiju

Belgrade, Serbia

Location

Vojnomedicinska akademija Klinika za reumatologiju

Belgrade, Serbia

Location

MeSH Terms

Conditions

Gout; Cardiovascular Diseases; Inflammation; Arthritis; Hyperuricemia

Interventions

Febuxostat; Allopurinol; Colchicine; Naproxen; Omeprazole

Condition Hierarchy (Ancestors)

Joint Diseases; Musculoskeletal Diseases; Crystal Arthropathies; Rheumatic Diseases; Purine-Pyrimidine Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Naphthaleneacetic Acids; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Pyridines; Benzimidazoles

Limitations and Caveats

No limitations or caveats are applicable to this summary

Results Point of Contact

• Title: Post-Registration Clinical Trial Responsible
• Organization: A. Menarini Industrie Farmaceutiche Riunite SrL

pfabrizzi@menarini.it

+39 055 5680459

Study Officials

• Claudio Borghi, Prof

  Policlinico S.Orsola - Malpighi Medicina Interna Borghi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The study physician, responsible for randomization and drug supply handling, was unblinded to study medications and therefore not 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) was blinded to study treatments.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 7, 2015
• First Posted: July 16, 2015
• Study Start: August 17, 2015
• Primary Completion: May 10, 2017
• Study Completion: May 10, 2017
• Last Updated: June 21, 2019
• Results First Posted: June 21, 2019

Record last verified: 2019-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (4); RO (6); SE (4); NL (1); DE (1); PL (10)