gout overview and review of the confirms trial

GOUT

Aneet Kaur MD

PGY-2

Internal Medicine

History

The word gout is believed to be derived from the Latin lsquoguttarsquo which means lsquodroprsquo-referring to the ldquonotion of the lsquodroppingrsquo of a morbid material from the blood in and around the jointsrdquo

Gout was commonly known as lsquothe disease of Kingsrsquo or lsquorich manrsquos diseasersquo as a result of the assumption that an affluent lifestyle was the cause of this painful inflammatory condition

Definition

Gout is an inflammatory arthritis associated

with hyperuricemia resulting from

deposition of monosodium urate crystals in

joint tendons and surrounding tissue

Risk factors for gout

Hyperuricemia is the most important risk factor for the

development of gout with the likelihood of developing

gout rising exponentially in line with serum urate levels

Despite this strong association the majority of patients

with hyperuricemia do not develop gout the annual

incidence of gout is estimated to be only 5 in patients

with levels of serum urate above 9 mgdl

Mechanisms of hyperuricemia and gout

Other risk factors

Hypertension hypertriglyceridemia

hypercholesterolemia diabetes and obesity are also

each associated with higher risk of incident gout andor

gout flare

Gout is extremely uncommon in premenopausal women

but postmenopausal women are at risk

Studies have indicated that menopause especially at an

earlier age increased the risk of gout in women

whereas post menopausal hormone therapy modestly

reduced risk of gout

Clinical gout is about five times more common in men

than in women

MANAGEMENT OF

GOUT

DRUGS USED IN GOUT AND THEIR MECHANISM OF ACTION

2012 ACR Management Guidelines

Lifestyle Modification for all patients with gout

Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering

pharmacologic therapy

Target sUA lt6 at minimum sUA lt5 better

Continue prophylaxis for 3 (no tophi) ndash 6 months (tophi)

after achieving target sUA


Consider HLA screening for HLA-B5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome

Koreans with stage 3 CKD or worse

Han Chinese

Thai descent

Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone

Pegloticase appropriate for severe refractory disease or intolerance of standard regimens (Pegloticase is a porcine uricase which was approved by the FDA in September 2010 for the treatment of gout in patients who had failed conventional therapy)

2012 ACR Management Guidelines for

Acute Gouty Arthritis

The choice of pharmacologic agent depends on severity of the attack

Monotherapy for mildmoderate attack

Combination therapy for severe attack or those refractory to monotherapy

Acceptable combination therapy approaches include

Colchicine and NSAIDS

Oral steroids and colchicine

Intra-articular steroids with all other modalities

Continue current therapy during flare

Patient education on signs of flare for self treatment

Indications for pharmacological

treatment of gout

Any patient with established diagnosis of gouty arthritis

Tophus or tophi by clinical exam or imaging study

Frequent attacks of gouty arthritis (gt= 2 attacksyr)

CKD stage 2 or worse

Past urolithiasis

23

Gout Management Approach

bullTreat acute flare rapidly with anti-

inflammatory agent

bullInitiate urate-lowering therapy to

achieve sUA lt6

bullUse concomitant anti-inflammatory

prophylaxis for up to 6 mo to prevent

mobilization flares

INITIATE(acute flare)

RESOLVE(urate-lowering therapy)

bullContinue urate lowering therapy

to control flares and avoid crystal

deposition

bullProphylaxis use for at least 3-6

months until sUA normalizes

MAINTAIN(treatment to control sUA)

24

Allopurinol vs Febuxostat

Allopurinol Febuxostat (Uloric)

FDA-approved 1966 FDA-approved 2009

Purine-selective XO Inhibitor Non-Purine Selective XO

Inhibitor

Prevents uric acid production Prevents uric acid production

Renal Metabolism Liver Metabolism

FEBUXOSTAT

For treatment of hyperuricemia in patients with gout

febuxostat is recommended at 40 mg or 80 mg once daily and

can be increased to 120 mg once daily if clinically indicated

The adverse effects associated with febuxostat therapy

include nausea diarrhea arthralgia headache increased

hepatic serum enzyme levels and rash

The manufacturer recommends liver function monitoring on

initiation of therapy at two and four months after initiation

and periodically thereafter

FEBUXOSTAT

Febuxostat is US Food and Drug Administration pregnancy

category C2

Febuxostat is contraindicated with concomitant use of

theophylline and chemotherapeutic agents namely

azathioprine and 6- mercaptopurine because it could

increase blood plasma concentrations of these drugs and

therefore their toxicity

Dosage adjustments are unnecessary for mild to moderate

renal or hepatic impairment

A one-month supply of 40 or 80-mg febuxostat costs

$28243 This price far exceeds the cost of allopurinol

which is $2424 for 100 100 mg tablets

CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg

Maintenance Doses of Allopurinol for

Adults based on CrCl

28

Hande KR et al Am J Med 1984

Stage 1 renal damage with

normal GFR

(GFR gt 90 mlmin)

Stage 2 Mild CKD (GFR = 60-

89 mlmin)

Stage 3 Moderate CKD (GFR

= 30-59 mlmin)

Stage 4 Severe CKD (GFR =

15-29 mlmin)

Stage 5 End Stage CKD (GFR

lt15 mlmin)

Allopurinol Hypersensitivity

Syndrome

2 of all allopurinol users develop cutaneous rash

Frequency of hypersensitivity 1 in 260

DRESS syndrome

Drug Reaction Eosinophilia Systemic Symptoms

20 mortality rate

Life threatening toxicity vasculitis rash eosinophilia hepatitis progressive renal failure

Treatment early recognition withdrawal of drug supportive care Steroids N-acetyl-cysteine dialysis prn

29

Markel A IMAJ 2005

Terkeltaub RA in Primer on the Rheumatic Disease 13th ed 2008

The urate lowering efficacy and safety

of febuxostat in the treatment of the

hyperuricemia of gout

The CONFIRMS trial

Becker MA Schumacher HR Espinoza LR et al The urate-lowering efficacy and safety of

febuxostat in the treatment of the hyperuricemia of gout the CONFIRMS trial Arthritis Res

Ther 201012(2)R63

Many long and short-term clinical trials have

proved the efficacy of Febuxostat in the treatment

of gout and lowering uric acid levels In these

studies Febuxostat was found to be superior to

allopurinol in reducing the serum uric acid levels

Some notable landmark clinical trials are FACT

APEX EXCEL FOCUS and CONFIRMS

Febuxostat versus Allopurinol Controlled Trial

(FACT) 2005

52 week randomized double-blind multicenter clinical trial that compared the safety and efficacy of febuxostat with allopurinol

760 patients with gout and a sUA gt80 mgdl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks

The primary endpoint was the proportion of patients to achieve a sUA concentration below 60 mgdl at the last three monthly measurements

The primary endpoint was achieved in 53 of patients receiving 80 mg febuxostat 62 of patients receiving 120mg and 21 of those receiving allopurinol (p lt0001 for each febuxostat group compared with allopurinol)

There was no statistical significance in the change in tophi size and number or the incidence of gout flare between the groups

Allopurinol Placebo controlled Efficacy study

of febuxostat (APEX) 2008

28 week randomized double-blind study of 1072 patients comparing the safety and efficacy of febuxostat allopurinol and placebo

Patients were randomized to a once daily fixed dose of placebo febuxostat 80mg120mg or 240 mg or allopurinol 300mg or 100mg depending on their baseline serum creatinine (le15 mgdl or ge16 to lt20 mgdl respectively)

After 1 year of treatment 82 of the patients in all febuxostat groups achieved sUA levels below 60 mgdl compared with 39 of the patients in both allopurinol groups In groups with moderate renal impairment the primary endpoint was achieved by 44 receiving febuxostat 80mg 45 receiving 120mg and 60 receiving 240mg compared with 0 in the allopurinol and placebo groups

However clinical endpoints were not statistically significant

The number of patients with moderate renal impairment was small

Febuxostat Comparative Extension Long-Term

study (EXCEL) 2009

160 week extension study for patients completing FACT and APEX

The studyrsquos aim was to determine long-term efficacy in sUA

lowering clinical benefits and safety of febuxostat or allopurinol

1086 patients were enrolled to receive fixed daily doses of

febuxostat 80mg or 120 mg or allopurinol 300 mg

After the first month of treatment nearly 80 of patients receiving

either febuxostat dose achieved sUA less than 6 mgdl compared

with only 46 of subjects on allopurinol There was no difference in

gout flare incidence and tophi reduction between the groups

Overall adverse events did not show significant differences among

groups

Febuxostat Open Label of Urate-Lowering

Efficacy and Safety (FOCUS) 2009

The FOCUS trial was a 5-year extension study that

assessed reduction and maintenance of sUA levels below

60 mgdl as the primary efficacy endpoint A total of

116 patients were initially enrolled to receive a dose of

80mg febuxostat with dose adjustment to either 40 or

120mg between weeks 4 and 24 93 maintained a sUA

level below 60 mgdl at 5 years

Objectives of CONFIRMS trial

The three-fold objectives of this Phase 3 double-blind RCT study were

1) To compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice

2) To evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment

3) To gain prospective uniformly reviewed information regarding the safety of these agents particularly their comparative CV safety

Materials and methods

Subjects aged 18 to 85 years with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria and sUA ge 80 mgdL were eligible for enrollment

Subjects were enrolled at 324 sites in the United States

IRB approval was obtained and all the subjects provided written informed consent

At least 35 of subjects enrolled were to have mild or moderate renal impairment defined as baseline estimated creatinine clearance (eCLcr) of 60 to 89 mlminutes or 30 to 59 mlminutes

Subjects successfully completing either of the previously

reported long-term open-label febuxostat or

febuxostatallopurinol extension studies were also eligible for

enrollment

Exclusion criteria secondary hyperuricemia (for example

due to myeloproliferative disorder) xanthinuria severe renal

impairment (eCLcr lt30 mlminutes) alanine

aminotransferase and aspartate aminotransferase values gt15

times the upper limit of normal consumption of more than 14

alcoholic drinks per week or a history of alcoholism or drug

abuse within five years or a medical condition that in the

investigators opinion would interfere with treatment safety

or adherence to the protocol

Baseline characteristics of randomized subjects

Baseline characteristics of randomized subjects (cont)


2269 Subjects were randomized 111 on Day 1 to

receive daily febuxostat 40 mg febuxostat 80 mg or

allopurinol Among subjects randomized to allopurinol

those with normal renal function or mild renal

impairment received 300 mg daily and those with

moderate renal impairment received 200 mg

Throughout the subsequent six-month treatment period for all subjects prophylaxis for gout flares was given either as colchicine 06 mg daily or naproxen 250 mg twice daily All subjects receiving naproxen prophylaxis also received lansoprazole 15 mg daily

Choice of prophylaxis regimen was made by the investigator and subject taking into account prior drug tolerance and prophylaxis experience

In addition subjects with eCLcr lt50 mlminute were not to receive naproxen

Gout flares were regarded as expected gout manifestations rather than as AEs

The primary efficacy endpoint was the proportion of

subjects in each treatment group with sUA lt60 mgdL

at the final visit

Secondary efficacy variables included

1) The proportion of subjects with mild or moderate

renal impairment and final sUA lt60 mgdL

2) The proportion of subjects with sUA lt60 mgdL lt50

mgdL and lt40 mgdL at each visit

Efficacy analysisResults

Primary efficacy endpoint

1) The proportions of subjects achieving a final visit sUA lt60

mgdL were 452 671 and 421 in the febuxostat 40 mg

febuxostat 80 mg and allopurinol groups respectively

2) UL by febuxostat 40 mg was non-inferior to that by

allopurinol but the difference in the response rates between

the two groups (31 95 CI -19 to 81) was not significant

3) However the greater UL response rate with febuxostat 80 mg

compared with either febuxostat 40 mg (219) or allopurinol

(249) was significant (P lt 0001)

Secondary efficacy endpoints

Among subjects with any (mild or moderate) renal

impairment the UL response rate in the febuxostat 80

mg group (716 360503) significantly exceeded those

observed in the febuxostat 40 mg (497 238479) and

allopurinol (423 212501) groups (P le 0001 for each

comparison)

In addition among the total group of subjects with

renal impairment the UL response rate in the

febuxostat 40 mg group was significantly higher than

that in the allopurinol 300200 mg group (P = 0021)

At any sUA endpoint (lt60 mgdL lt50 mgdL or lt40 mgdL) and at any scheduled visit a significantly higher proportion of subjects receiving febuxostat 80 mg achieved the target endpoint than subjects receiving febuxostat 40 mg or allopurinol (P lt 0001)

Greater proportion of subjects in the febuxostat 40 mg group than the allopurinol group achieved sUAlt60 mgdL (at Month 2 visit P = 0031) and lt50 mgdL (at two- and six month visits P le 005) but significant differences were not seen at other visits including the final visit

Effect of baseline characteristic on treatment response

Adverse events

Adverse events

CONCLUSIONS

Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300200 mg daily

At all levels of renal function studied UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300200 mg and was comparably safe

In subjects with mildly or moderately impaired renal function however febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol

At the doses studied safety of febuxostat and allopurinol including CV safety was comparable

Febuxostat at 40 mg or 80 mg daily offers a well-tolerated UL alternative to allopurinol particularly for patients with mild or moderate renal impairment

Study limitations

The study does not address the efficacy of febuxostat compared with allopurinol in reducing clinically meaningful acute flares of gout

No mention is made of long-term cost-effectiveness of therapy

Additionally this study does not address the efficacy of febuxostat compared with allopurinol dosing that is more aggressive (ie gt 300 mg daily)

Allopurinol dosing was not titrated

The study population was not similar to the general population (majority of patients were white males)

Possible funding bias

Uloric Related Current Clinical

Trials

References

Dalbeth N Gracey E Pool B et al Identification of dairy fractions with anti-inflammatory properties in models of acute gout Ann

Rheum Dis 2010 69766ndash769

Choi HK Willett W Curhan G Coffee consumption and risk of incident gout in men a prospective study Arthritis Rheum 2007 562049ndash

2055

Hak AE Curhan GC Grodstein F Choi HK Menopause postmenopausal hormone use and risk of incident gout Ann Rheum Dis 2010

691305ndash1309

Becker MA Schumacher HR Wortmann RL et al (December 2005) Febuxostat compared with allopurinol in patients with hyperuricemia

and gout N Engl J Med 353 (23) 2450ndash61

Sarawate CA Patel PA Schumacher HR Yang W Brewer KK Bakst AW Serum urate levels and gout flares analysis from managed care

data J Clin Rheumatol 2006 1261-65

Schumacher HR Jr Becker MA Lloyd E MacDonald PA Lademacher C Febuxostat in the treatment of gout 5-yr findings of the FOCUS

efficacy and safety study Rheumatology (Oxford) 2009 48188-194

14 Becker MA Schumacher HR MacDonald PA Lloyd E Lademacher C Clinical efficacy and safety of successful long-term urate

lowering with febuxostat or allopurinol in subjects with gout J Rheumatol 2009 361273-1278

2012 ACR guidelines for management of gout

Uptodate

Medcape

Statistical Power

Power

The probability that the study will support the research hypothesis if it is true

1 Sample size (n)

2 Effect Size (d)

3 Significance Level (α)

4 Power (β)

As effect size increases power increases

As sample size increases power increases

As significance level increases power increases

Resources

httpwwwncbinlmnihgovpmcarticlesPMC3409926

httpswwwsealedenvelopecompowerbinary-superiority

SUBGROUP ANALYSES OF PRIMARY ENDPOINT IN SUBGROUP ANALYSES THE PRIMARY ENDPOINT WAS STRATIFIED BY BASELINE SUA RENAL FUNCTIONAL STATUS PRESENCE OF TOPHI AT BASELINE AND PRIOR PARTICIPATION IN A ULT TRIAL A SEPARATE LOGISTIC REGRESSION MODEL WAS FIT FOR EACH SUBGROUP FACTOR TO ASSESS THE ASSOCIATION BETWEEN EACH SUBGROUP AND ACHIEVEMENT OF THE SUA ENDPOINT EACH MODEL INCLUDED TREATMENT SUBGROUP AND THE INTERACTION BETWEEN TREATMENT AND SUBGROUP AS EXPLANATORY VARIABLES

The urate-lowering efficacy and safety of

febuxostat in the treatment of the hyperuricemiaof gout the CONFIRMS trial

Statistical QuestionHow do the values of certain subgroup characteristics (renal function baseline serum urate baseline tophi presence or prior febuxostat study participation) affect probability of each binary outcome achieving or not achieving sUA lt 60 mgdL

Regression statistical tool describing and assessing the relationship between two or more variables

Description based upon an assumed model of the relationship

Assessment indicates how well the model fits the data

ŷ = value of y predicted by the regression line formula y = a + bx

Goodness of Fit a good-fitting regression line will have regression components large in absolute value relative to the residual components whereas theopposite is true for poor-fitting regression lines

The equation used to fit the data can be of nearly any form not just a straight line

LimitationThe independent variable (x axis)

and the dependent variable (y axis) must both be continuous variables

Not able to analyze dichotomous or binary outcomes

Our situation several categorical variables for each of 3 treatment groupsExample subject with mild renal impairment baseline sUA lt 90 no tophi participated in prior febuxostat trial randomized to allopurinal treatment group (categorical)

Outcome achieving or not achieving treatment goal (binary)

General CaseHow to analyze the effect of multiple independent variables ndash including continuous categorical and binary variables ndash on a binary outcome

Answer Logistic Regression

We can make the binary dependent variable into a continuous variable by considering the probability of a positive outcome or ldquosuccessrdquo (achieving low serum urate)

p = probability of positive outcome1 - p = probability of negative outcome

Linear Regression vs Logistic Regression

P = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk

whereα = constantẞ1 = coefficient (derived from data)X1 = subgroup characteristic (eg tophi status yes tophi = 1

no tophi = 0)

If 67100 subjects with no tophi mild renal impairment baseline sUA gt 10 and no previous study participation reach the treatment goal then

P = 067 = α + ẞ1x0 + ẞ2x2 + hellip

Repeat for every subgroup combination to solve for α and ẞs

Problem

For our probability equationP = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk

we have no way to ensure P is between 0 and 1 so convert to log formhellip

ln(P(1-P) = α + ẞ1X1 + ẞ2X2 + hellip ẞkXk

- infin lt ln(P(1-P) lt + infin)

P = exp(α + ẞ1X1 + ẞ2X2 + hellip)___1 + exp(α + ẞ1X1 + ẞ2X2 + hellip)

By comparing the probabilities of outcomes based upon this equation (H1) with one where all the ẞs are replaced with zero (H0) we have pairs of outcomes which can be compared using a Chi-square type test Hence we can calculate p values

Now we can repeat for every subgroup combination to solve for α and ẞs

Thus the value of each ẞ tells us how much each subgroup affects the

outcome ndash eg in all treatment groups having mild renal impairment

significantly ( p lt 0001) increases the likelihood of achieving the desired

serum uric acid level

History

The word gout is believed to be derived from the Latin lsquoguttarsquo which means lsquodroprsquo-referring to the ldquonotion of the lsquodroppingrsquo of a morbid material from the blood in and around the jointsrdquo

Gout was commonly known as lsquothe disease of Kingsrsquo or lsquorich manrsquos diseasersquo as a result of the assumption that an affluent lifestyle was the cause of this painful inflammatory condition

Definition














Other risk factors




gout flare








than in women

MANAGEMENT OF

GOUT












Han Chinese

Thai descent















treatment of gout





Past urolithiasis

23



inflammatory agent


achieve sUA lt6



mobilization flares





deposition




24





Inhibitor



FEBUXOSTAT










FEBUXOSTAT


category C2











CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg



28



normal GFR

(GFR gt 90 mlmin)


89 mlmin)


= 30-59 mlmin)


15-29 mlmin)


lt15 mlmin)


Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












Definition














Other risk factors




gout flare








than in women

MANAGEMENT OF

GOUT












Han Chinese

Thai descent















treatment of gout





Past urolithiasis

23



inflammatory agent


achieve sUA lt6



mobilization flares





deposition




24





Inhibitor



FEBUXOSTAT










FEBUXOSTAT


category C2











CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg



28



normal GFR

(GFR gt 90 mlmin)


89 mlmin)


= 30-59 mlmin)


15-29 mlmin)


lt15 mlmin)


Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem





















Other risk factors




gout flare








than in women

MANAGEMENT OF

GOUT












Han Chinese

Thai descent















treatment of gout





Past urolithiasis

23



inflammatory agent


achieve sUA lt6



mobilization flares





deposition




24





Inhibitor



FEBUXOSTAT










FEBUXOSTAT


category C2











CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg



28



normal GFR

(GFR gt 90 mlmin)


89 mlmin)


= 30-59 mlmin)


15-29 mlmin)


lt15 mlmin)


Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem



















than in women

MANAGEMENT OF

GOUT












Han Chinese

Thai descent















treatment of gout





Past urolithiasis

23



inflammatory agent


achieve sUA lt6



mobilization flares





deposition




24





Inhibitor



FEBUXOSTAT










FEBUXOSTAT


category C2











CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg



28



normal GFR

(GFR gt 90 mlmin)


89 mlmin)


= 30-59 mlmin)


15-29 mlmin)


lt15 mlmin)


Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












MANAGEMENT OF

GOUT












Han Chinese

Thai descent















treatment of gout





Past urolithiasis

23



inflammatory agent


achieve sUA lt6



mobilization flares





deposition




24





Inhibitor



FEBUXOSTAT










FEBUXOSTAT


category C2











CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg



28



normal GFR

(GFR gt 90 mlmin)


89 mlmin)


= 30-59 mlmin)


15-29 mlmin)


lt15 mlmin)


Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem























Han Chinese

Thai descent















treatment of gout





Past urolithiasis

23



inflammatory agent


achieve sUA lt6



mobilization flares





deposition




24





Inhibitor



FEBUXOSTAT










FEBUXOSTAT


category C2











CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg



28



normal GFR

(GFR gt 90 mlmin)


89 mlmin)


= 30-59 mlmin)


15-29 mlmin)


lt15 mlmin)


Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem
























treatment of gout





Past urolithiasis

23



inflammatory agent


achieve sUA lt6



mobilization flares





deposition




24





Inhibitor



FEBUXOSTAT










FEBUXOSTAT


category C2











CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg



28



normal GFR

(GFR gt 90 mlmin)


89 mlmin)


= 30-59 mlmin)


15-29 mlmin)


lt15 mlmin)


Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












23



inflammatory agent


achieve sUA lt6



mobilization flares





deposition




24





Inhibitor



FEBUXOSTAT










FEBUXOSTAT


category C2











CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg



28



normal GFR

(GFR gt 90 mlmin)


89 mlmin)


= 30-59 mlmin)


15-29 mlmin)


lt15 mlmin)


Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












24





Inhibitor



FEBUXOSTAT










FEBUXOSTAT


category C2











CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg



28



normal GFR

(GFR gt 90 mlmin)


89 mlmin)


= 30-59 mlmin)


15-29 mlmin)


lt15 mlmin)


Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












FEBUXOSTAT










FEBUXOSTAT


category C2











CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg



28



normal GFR

(GFR gt 90 mlmin)


89 mlmin)


= 30-59 mlmin)


15-29 mlmin)


lt15 mlmin)


Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












FEBUXOSTAT


category C2











CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg



28



normal GFR

(GFR gt 90 mlmin)


89 mlmin)


= 30-59 mlmin)


15-29 mlmin)


lt15 mlmin)


Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem















CrCl (mLmin)

Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg



28



normal GFR

(GFR gt 90 mlmin)


89 mlmin)


= 30-59 mlmin)


15-29 mlmin)


lt15 mlmin)


Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem













Syndrome



DRESS syndrome


20 mortality rate



29

Markel A IMAJ 2005





The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem















The CONFIRMS trial



Ther 201012(2)R63









(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem




















(FACT) 2005














study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem




















study (EXCEL) 2009











groups























enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem


































enrollment

























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem



























at the final visit























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem





























comparison)








Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem















Adverse events

Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












Adverse events

CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












CONCLUSIONS






Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












Study limitations








Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem













Trials

References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












References




2055


691305ndash1309










Uptodate

Medcape

Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












Statistical Power

Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












Power


1 Sample size (n)

2 Effect Size (d)


4 Power (β)




Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












Resources

























no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem


































no tophi = 0)


P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem













P = 067 = α + ẞ1x0 + ẞ2x2 + hellip


Problem












Problem












gout overview and review of the confirms trial

Health & Medicine