The study compared the efficacy and safety of low-dose and high-dose oral colchicine regimens for treating acute gout flares in 575 patients. It found that both low-dose (1.2mg then 0.6mg in 1hr) and high-dose (1.2mg then 0.6mg every 6hrs) regimens were more effective than placebo in reducing pain within 24 hours. However, high-dose treatment caused more diarrhea and other adverse effects. The results provide evidence that lower doses of colchicine can effectively treat acute gout flares while causing fewer side effects.

1. High Versus Low Dosing of Oral Colchicine for
Early Acute Gout Flare
Twenty-Four–Hour Outcome of the First Multicenter, Randomized, Double-
Blind, Placebo-Controlled, Parallel-Group, Dose-Comparison Colchicine
Study
Arthritis Rheum. Apr; -
Piti Niyomsirivanich, MD.

2. • Colchicine is mainly used in the treatment
and prophylaxis of gout flare,
– although the evidence for its use in treating
acute gout flare remains limited.

3. Traditional treatment

4. Only 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 ; : –

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

6. 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
•
0.5-0.6
3
• Rheumatology for the Non-rheumatologist
. . 2551

7. AGREE
• Acute Gout Flare Receiving Colchicine
Evaluation
• study compared low- and high-dose.
• A randomized, placebo-controlled trial

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

9. PATIENTS AND METHODS
pharmacokinetics
• 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

10. Pharmacokinetic in healthy normal volunteers

11. PATIENTS AND METHODS
Inclusion criteria
• Male and postmenopausal female patients
• > years of age
• a confirmed past diagnosis of gout
(according to the American College of
Rheumatology [ACR] classification criteria
• gout flares within the prior months
• urate-lowering therapy

12. 575 patients
Apr - Oct
“low-dose” colchicine “high-dose” colchicine placebo
1.2 mg 1.2 mg placebo q 6 hr
 0.6 mg in hour  0.6 mg q 6 hours
 placebo q 1 hour

13. 575 patients
Apr - Oct
“low-dose” colchicine “high-dose” colchicine placebo
1.2 mg 1.2 mg placebo q 6 hr
 0.6 mg in hour  0.6 mg q 6 hours
 placebo q 1 hour

14. 575 patients
Apr - Oct
“low-dose” colchicine “high-dose” colchicine placebo
1.2 mg 1.2 mg placebo q 6 hr
 0.6 mg in hour  0.6 mg q 6 hours
 placebo q 1 hour

15. 575 patients
Apr - Oct .
“low-dose” colchicine “high-dose” colchicine placebo
1.2 mg 1.2 mg placebo q 6 hr
 0.6 mg in hour  0.6 mg q 6 hours
 placebo q 1 hour

16. PATIENTS AND METHODS
study design
• a multicenter, randomized,double-blind,
placebo-controlled, parallel-group, dose
comparison study
• conducted between April and
October
• A total of centers in the US

17. • 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.

18. A standard script was used
• confirm that flare onset was within the
prior hours
• 4 cardinal signs of inflammation were
present, that joint pain was assessed at
on a – numeric rating scale.
• no use of prohibited medication or change
in medical history since randomization.

19. 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.

20. 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 hoursuntil 72 hrs
following the initial dose or symptom resolution.
• NSAIDs was permitted if intolerable pain continued after
taking at least dose of study drug.

21. 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 hours.
– there were up to 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 (

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

24. Statistical analysis and end points.
• Responders were defined as
– having a pretreatment pain score within
hours of flare onset
– a % reduction in pain within hours of the
first dose of study
• medication without the use of NSAIDs
during that time frame.

25. 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

26. Statistics
• unstratified chi-square test by generating
the % confidence interval
• All analyses were performed using SAS
software, version . (SAS
Institute, Cary, NC).

27. Baseline Characteristics

28. Efficacy Analysis

29. The overall AE rates

30. Critical Appraisal

31. 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 ??

32. Are the results of this study valid ?
• 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)

33. Are the results of this study valid ?
• 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)

34. Are the results of this study valid ?
• 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

35. 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

36. What were the results?
• How precise was the estimate of treatment
effect?
– High-dose colchicine vs. placebo
– % Confidence Interval . ( . –
– Low-dose colchicine vs. placebo
– % Confidence Interval . ( . –

37. What were the results?
• 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

38. 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.