high versus low dosing of oral colchicine

High Versus Low Dosing of Oral Colchicine forEarly Acute Gout Flare

Twenty-Four–Hour Outcome of the First Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Comparison Colchicine St

udy

Arthritis Rheum 2010 62 4. Apr; ( )

-10608:

Piti Niyomsirivanich, MD.

• Colchicine is mainly used in the treatment and prophylaxis of gout flare, – although the evidence for its use in treating ac

ute gout flare remains limited.

Traditional treatment

Only 1 randomized, placebo-controlled trial

• N = 43

• The regimen in that study was two

• 0.5-mg tablets q 2 hours until relief or marked toxicity (such as diarrhea, nausea, or vomiting) occurred

Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med 1987;17:301–4.

Does colchicine work? The results of the first controlled study in acute gout.

Aust N Z J Med 1987;17:301–4.

However Lower-dose regimens of colchicine have been suggested.

• But there is no Clinical Trial.

• In acute gout, lower doses of colchicine are effective yet less toxic than traditional regimens We suggest that in acute gouty arthritis colchicine should be used at a dose of 500 µg three times a day or less frequently.

• Morris I, Varughese G, Mattingly P. Colchicine in acute gout. BMJ 2003;327:1275–6.

• Today many clinicians recommend that doses be taken every 2 to 6 hours to reduce side effects

• Firestein: Kelley's Textbook of Rheumatology, 8th ed.

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• Rheumatology for the Non-rheumatologist สมาคมรู�มาติสซั่� มแห่�งปรูะเทศไทย พ.ศ. 2551

AGREE

• Acute Gout Flare Receiving Colchicine Evaluation

• study compared low- and high-dose.

• A randomized, placebo-controlled trial.

Participants

• Colchicine, United States Pharmacopeia (USP) 0.6-mg tablets (Colcrys), was provided by URL Pharma (Philadelphia, PA).

PATIENTS AND METHODSpharmacokinetics.

• Healthy volunteer• LOW DOSE (n=15)

• 1.2 mg then 0.6 mg in 1 hr [1.8 mg total]

• HIGH DOSE (n=13)• 1.2 mg followed by 0.6 mg q 6 hrs [4.8 mg total]

• Single-dose (n=25)• 0.6 mg once

Pharmacokinetic in healthy normal volunteers

PATIENTS AND METHODSInclusion criteria

• Male and postmenopausal female patients

• >18 years of age

• a confirmed past diagnosis of gout (according to the American College of Rheumatology [ACR] classification criteria [9])

• 2 gout flares within the prior 12 months

• urate-lowering therapy

575 patients 2007Apr - 2008Oct .

“low-dose” colchicine

1.2 mg 0.6 mg in 1 hour placebo q 1 hour

“high-dose” colchicine

1.2 mg 0.6 mg q 6 hours

placebo

placebo q 6 hr

575 patients 2007 - 2008 .

“low-dose” colchicine

1.2 mg 0.6 mg in 1 hour placebo q 1 hour

“high-dose” colchicine

1.2 mg 0.6 mg q 6 hours

placebo

placebo q 6 hr

PATIENTS AND METHODSstudy design

• a multicenter, randomized,double-blind, placebo-controlled, parallel-group, dose comparison study

• conducted between April 2007 and October 2008.

• A total of 54 centers in the US

• patients were enrolled and were dispensed a double-blinded blister card of study medication,

• at screening, prior to the onset of a gout flare.– Gout Flare Call Center before taking study

medication.

– Pt. were instructed to take all of the study medication, regardless of pain status.

A standard script was used

• confirm that flare onset was within the prior 12 hours

• 4 cardinal signs of inflammation were present, that joint pain was assessed at 4 on a 0–10 numeric rating scale.

• no use of prohibited medication or change in medical history since randomization.

Adverse effect assessment

• The patient was specifically asked about the presence of – nausea, vomiting, diarrhea, and abdominal pain

• along with an open-ended question about other adverse events (AEs).

• Patients were permitted to stop study medication due to AEs.

Pain assessment

• Patients rated intensity of joint pain on an 11-point Likert scale that ranged from 0 (no pain) to 10 (worst possible pain).

• Ratings were to be made at baseline hourly X 8 hrs every 8 hoursuntil 72 hrs

following the initial dose or symptom resolution.

• NSAIDs was permitted if intolerable pain continued after taking at least 1 dose of study drug.

Follow Up

• Patients were to return to the study clinic as soon as possible following the onset of the flare– first post flare visit being within 48 hours.

– there were up to 3 more planned visits, the last being 7 days after flare onset.

• The intensity of AEs was graded as mild, moderate, or severe – based on US Food and Drug Administration (FDA)

criteria were used to define serious AEs (10).

Ethics.

• informed consent

• The study was reviewed, and approval was provided by the central ethics review board (Sterling Institutional Review Board).

Statistical analysis and end points.

• Responders were defined as – having a pretreatment pain score within 12

hours of flare onset

– a 50% reduction in pain within 24 hours of the first dose of study

• medication without the use of NSAIDs during that time frame.

The Primary Endpoints

– treatment response based on the target joint pain score 24 hours after the first dose.

The Secondary Endpoints

–treatment response based on the target joint pain score 32 hours after the first dose.

–treatment response based on at least a 2-unit reduction in the target joint pain score 24 hours after the first dose

–treatment response based on at least a 2-unit reduction in the target joint pain score 32 hours after the first dose

Statistics

• unstratified chi-square test by generating the 95% confidence interval

• All analyses were performed using SAS software, version 9.1 (SAS Institute, Cary, NC).

Baseline Characteristics

Efficacy Analysis

The overall AE rates

Critical Appraisal

Are the results of this study valid ?

• Was the assignment of patients to treatment randomized? – Yes, the assignment of patients was

randomized.

– Randomized before gout flare ??


• Was the randomization concealed ?– dispensed a double-blinded blister card of

study medication, at screening, – prior to the onset of a gout flare. ??

• Were the groups similar at the start of the trial?– There were some differences between to groups

within baseline characteristics• There were differences use of allopurinol in “low dose

group” VS “high dose group” VS “placebo group”– 10(19.2) VS 29(39.2) VS 15(25.4)


• Was the followup complete?Yes, due to natural history of the disease and it was

a positive trial.

• Were patients analyzed in the groups to which they were randomized? – Yes, the patients was analyzed in the groups

to which they were randomized. (intension to treat analysis)


• Were patients, their clinicians, and study personnel "blind" to treatment?– Yes, a multicenter, randomized,double-blind, placebo-

controlled trial

• Overencapsulated

• Aside from the experimental intervention, were the groups treated equally?

• Besides the intervention the groups were treated equally

What were the results?

• How large was the treatment effect? • Low dose VS placebo

– Risk without therapy (Baseline risk): 9 (15.5)%– Risk with therapy: 28 (37.8)%– Risk Difference: 22.3 %– Odds ratio: 3.31– NNT = 4.48

• High dose VS placebo– Risk without therapy (Baseline risk): 9 (15.5)%– Risk with therapy: 17 (32.7)%– Risk Difference: 17.2 %– Odds ratio: 2.64– NNT = 5.81


• How precise was the estimate of treatment effect?– High-dose colchicine vs. placebo– 95% Confidence Interval 2.64 (1.06–6.62)

0.034

– Low-dose colchicine vs. placebo– 95% Confidence Interval 3.31 (1.41–7.77)

0.005


• Were all clinically important outcomes considered? – Yes , the adverse effects of treatment were

considered.– AE has occurred in high dose >> low dose

esp. diarrhea

– Number need to harm (high dose VS low dose) = 2.47

Can the results be applied to our patient care?

• Is our patient so different from those in the study?– Not so difference, the pathophysiology of the

diseases are same.

• Is the treatment feasible in our setting?– Yes, colchicine is an old drug,of which has been

use for decades.

high versus low dosing of oral colchicine

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