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Clinical Trial Results:
A randomised, multi-centre, open-label, active-comparator, pragmatic clinical trial of low-dose colchicine versus naproxen in patients with acute gout.

Summary
EudraCT number	2013-001354-95
Trial protocol	GB
Global end of trial date	31 Mar 2016

Results information
Results version number	v3(current)
This version publication date	27 Oct 2021
First version publication date	28 Apr 2017
Other versions	v1 , v2
Version creation reason	Changes to summary attachments Correction of data in line with published analysis amended following journal peer review. No change to overall conclusion. Longitudinal mixed model evaluation remodelled & results updated (primary endpoint mean difference -0.18, p=0.32; previously -0.19, p=0.28) . Endpoints section expanded to include descriptive summaries & statistical analyses for secondary outcomes.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

149/11

ISRCTN number

ISRCTN69836939

US NCT number

NCT01994226

WHO universal trial number (UTN)

Sponsor organisation name

Keele University

Sponsor organisation address

Keele University , Staffordshire, United Kingdom, ST5 5BG

Public contact

Dr Clark Crawford , Keele University, 01782 734714, research.governance@keele.ac.uk

Scientific contact

Dr Clark Crawford , Keele University, 01782 734714, research.governance@keele.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Mar 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Mar 2016

Global end of trial reached?

Yes

Global end of trial date

31 Mar 2016

Was the trial ended prematurely?

Main objective of the trial

The principal research objective is to compare the effectiveness of two licensed drugs, which are frequently prescribed within primary care, to reduce pain from acute gout; namely low-dose Colchicine and Naproxen.

Protection of trial subjects

The trial was performed in accordance with the recommendations guiding physicians in biomedical research involving human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964, amended at the 52nd World Medical Association General Assembly, Edinburgh, Scotland. Informed written consent was obtained from the participants prior to randomisation into the trial. The right of a participant to refuse participation without giving reasons was respected. The trial was submitted to and approved by a main Research Ethics Committee (main REC) and the appropriate Site Specific Assessor for each participating centre prior to entering participants into the trial. All information collected during the course of the trial is kept strictly confidential. Keele CTU comply with all aspects of the 1998 Data Protection Act.

Background therapy

None.

Evidence for comparator

The numerous previous trials of NSAIDs for acute gout have either compared NSAID to placebo or, more commonly, involved head-to-head comparisons of one NSAID against corticosteroids, or another NSAID or a COX-2 selective inhibitor . To date, oral NSAIDs have not been directly compared to low-dose colchicine. This randomised trial will be the first direct head-to-head comparison of the effectiveness of naproxen, a commonly used NSAID, with low-dose colchicine for the management of acute gout. It will also directly compare the side-effect profiles of these two treatments, which has important implications for patient safety in view of the increasing prevalence of gout with age, considerable associated comorbidity, and the frequent need to provide repeat prescriptions for recurrent attacks of acute gout. Both naproxen and colchicine have a licence to treat acute gout. Evidence-based guidelines for the management of acute gout state that there is no evidence of superiority of any one NSAID over another and, where use of a NSAID is considered appropriate, recommend the use of any fast-acting NSAID. We have chosen to use naproxen in this trial because it is of comparable effectiveness to oral prednisolone for the treatment of acute gout, is thought to be safer from a cardiovascular perspective than other commonly used NSAIDs such as diclofenac and indomethacin, and is inexpensive. Cardiovascular risk is an important consideration as gout has been shown to be an independent risk factor for coronary heart disease. This trial is needed to establish the effectiveness, safety and cost-effectiveness of low-dose colchicine as a viable alternative to NSAIDs for the first-line treatment of acute gout in primary care.

Actual start date of recruitment

29 Jan 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 399

Worldwide total number of subjects

399

EEA total number of subjects

399

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

240

From 65 to 84 years

154

85 years and over

Subject disposition

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Recruitment details

Participants with acute gout were recruited at a consultation with their general practitioner

Screening details

Prior to randomisation the following was completed: - Eligibility assessment - Informed Consent form - Baseline Questionnaire

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

The statistician was blind to participant's treatment allocation during the trial.

Are arms mutually exclusive

Yes

Naproxen

Arm description

750 mg immediately followed by 250 mg every eight hours for up to 7 days

Arm type

Active comparator

Investigational medicinal product name

Naproxen

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Naproxen (oral use): Single initial dose of 750mg (three tablets) followed by 250mg (one tablet) every eight hours up to seven days.

Low dose Colchicine

Arm description

500 mcg every eight hours for four days

Arm type

Active comparator

Investigational medicinal product name

Colchicine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Low-dose colchicine (oral use): 500mcg (one tablet) every eight hours for four days.

Number of subjects in period 1	Naproxen	Low dose Colchicine
Started	200	199
Completed	179	180
Not completed	21	19
Early Cessation of treatment	7	3
Protocol deviation	14	16

Baseline characteristics

Top of page

Reporting group title

Naproxen

Reporting group description

750 mg immediately followed by 250 mg every eight hours for up to 7 days

Reporting group title

Low dose Colchicine

Reporting group description

500 mcg every eight hours for four days

Reporting group values	Naproxen	Low dose Colchicine	Total
Number of subjects	200	199	399
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	58.7 ± 14.4	60 ± 13.4	-
Gender categorical
Units: Subjects
Female	27	25	52
Male	173	174	347
Site of Recruitment
Baseline characteristics are summarized for the two treatment groups using appropriate descriptive statistics: mean (SD) for normally distributed numerical variables; median (inter-quartile range) for skewed numerical variables; frequency counts for categorical variables.
Units: Subjects
Keele	55	52	107
Southampton	88	101	189
Nottingham	16	15	31
Oxford	41	31	72
Preferred mode of contact
Units: Subjects
Electronic	59	63	122
Postal	141	136	277
First instance of Gout
Units: Subjects
Yes	35	51	86
No	161	144	305
Missing Data	4	4	8
Number of body parts affecred
Units: Subjects
One	139	145	284
Two	34	27	61
Three	13	9	22
Four	6	13	19
more than or equal to 5	4	1	5
Missing data	4	4	8
Body Part affected - Shoulder
Units: Subjects
Shoulder Yes	2	1	3
Shoulder No	194	194	388
Shoulder missing	4	4	8
Body Part affected - Elbow
Units: Subjects
Elbow Yes	4	11	15
Elbow No	192	184	376
Elbow missing	4	4	8
Body Part affected - Wrist
Units: Subjects
Wrist Yes	8	7	15
Wrist No	188	188	376
Wrist missing	4	4	8
Body part affected - Thumb Base
Units: Subjects
Thumb base - Yes	5	9	14
Thumb Base - No	191	186	377
Thumb base - missing data	4	4	8
Body Part affected - Small finger joints
Units: Subjects
Small finger joints yes	11	8	19
Small finger joints no	185	187	372
small finger joints - missing data	4	4	8
Body Part affected - Hip
Units: Subjects
Hip - Yes	2	1	3
Hip - No	194	194	388
hip - missing data	4	4	8
Body part affected - Knee
Units: Subjects
Knee - Yes	17	19	36
Knee - No	179	176	355
Knee - missing data	4	4	8
Body part affected - Ankle
Units: Subjects
Ankle- Yes	31	33	64
Ankle - No	165	162	327
Ankle - missing data	4	4	8
Body part affected - Mid-foot
Units: Subjects
Mid Foot- Yes	41	32	73
Mid Foot - No	155	163	318
mid foot - missing data	4	4	8
Body part affected - Big Toe Bunion Joint
Units: Subjects
Big Toe Bunion Joint - Yes	142	135	277
Big Toe Bunion Joint - No	54	60	114
Big toe bunion joint - missing data	4	4	8
Body Part affected - other toes
Units: Subjects
Other Toes - Yes	28	28	56
Other Toes - No	168	167	335
other toes missing data	4	4	8
Body Part affected - missing data
Units: Subjects
Missing data - Yes	4	4	8
Missing data - No	196	195	391
Pain NRS
Units: 0-10
arithmetic mean (standard deviation)	7.1 ± 2.1	6.9 ± 2.2	-
EQ5D-5L
Units: EQ5D units
arithmetic mean (standard deviation)	0.665 ± 0.21	0.666 ± 0.225	-
Age when diagnosed
Units: Age
arithmetic mean (standard deviation)	52.1 ± 15.2	53.4 ± 14.6	-

Subject analysis set title

Main Analysis

Subject analysis set type

Full analysis

Subject analysis set description

Main analysis was by ITT with evaluation of randomized participants as per allocation assignment. 399 participants were randomised between 02/2014-12/2015; follow up of the primary pain outcome was 84% in the naproxen group and 86% in the colchicine arm at day 7, and 85% and 87% respectively at 4 weeks.

Subject analysis sets values	Main Analysis
Number of subjects	399
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	59.4 ± 13.9
Gender categorical
Units: Subjects
Female	52
Male	347
Site of Recruitment
Baseline characteristics are summarized for the two treatment groups using appropriate descriptive statistics: mean (SD) for normally distributed numerical variables; median (inter-quartile range) for skewed numerical variables; frequency counts for categorical variables.
Units: Subjects
Keele	107
Southampton	189
Nottingham	31
Oxford	72
Preferred mode of contact
Units: Subjects
Electronic	122
Postal	277
First instance of Gout
Units: Subjects
Yes	86
No	305
Missing Data	8
Number of body parts affecred
Units: Subjects
One	284
Two	61
Three	22
Four	19
more than or equal to 5	5
Missing data	8
Body Part affected - Shoulder
Units: Subjects
Shoulder Yes	3
Shoulder No	388
Shoulder missing	8
Body Part affected - Elbow
Units: Subjects
Elbow Yes	15
Elbow No	376
Elbow missing	8
Body Part affected - Wrist
Units: Subjects
Wrist Yes	15
Wrist No	376
Wrist missing	8
Body part affected - Thumb Base
Units: Subjects
Thumb base - Yes	14
Thumb Base - No	377
Thumb base - missing data	8
Body Part affected - Small finger joints
Units: Subjects
Small finger joints yes	19
Small finger joints no	372
small finger joints - missing data	8
Body Part affected - Hip
Units: Subjects
Hip - Yes	3
Hip - No	388
hip - missing data	8
Body part affected - Knee
Units: Subjects
Knee - Yes	36
Knee - No	355
Knee - missing data	8
Body part affected - Ankle
Units: Subjects
Ankle- Yes	64
Ankle - No	327
Ankle - missing data	8
Body part affected - Mid-foot
Units: Subjects
Mid Foot- Yes	73
Mid Foot - No	318
mid foot - missing data	8
Body part affected - Big Toe Bunion Joint
Units: Subjects
Big Toe Bunion Joint - Yes	277
Big Toe Bunion Joint - No	114
Big toe bunion joint - missing data	8
Body Part affected - other toes
Units: Subjects
Other Toes - Yes	56
Other Toes - No	335
other toes missing data	8
Body Part affected - missing data
Units: Subjects
Missing data - Yes	8
Missing data - No	391
Pain NRS
Units: 0-10
arithmetic mean (standard deviation)	7 ± 2.1
EQ5D-5L
Units: EQ5D units
arithmetic mean (standard deviation)	0.666 ± 0.217
Age when diagnosed
Units: Age
arithmetic mean (standard deviation)	52.8 ± 14.9

End points

Top of page

Reporting group title

Naproxen

Reporting group description

750 mg immediately followed by 250 mg every eight hours for up to 7 days

Reporting group title

Low dose Colchicine

Reporting group description

500 mcg every eight hours for four days

Subject analysis set title

Main Analysis

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Pain scores 1-7 days (primary outcome measure)

Top of page

End point title

Pain scores 1-7 days (primary outcome measure)

End point description

As above

End point type

Primary

End point timeframe

The main outcome measure is pain measured on a 0-10 pain intensity numeric rating scale measured over days 0-7. The primary outcome is change in pain from baseline measured across days 1-7.

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	170 ^[1]	174 ^[2]
Units: 0-10
arithmetic mean (standard deviation)
Day 1	0.6 ± 2.0	0.5 ± 2.1
Day 2	2.3 ± 2.7	1.8 ± 2.5
Day 3	3.3 ± 2.9	3.1 ± 2.7
Day 4	4.4 ± 2.9	4.1 ± 2.8
Day 5	4.9 ± 2.8	4.6 ± 2.9
Day 6	5.3 ± 2.7	5.0 ± 2.8
Day 7	5.7 ± 2.6	5.4 ± 2.7

Attachments

Graphs of Absolute and Change in Pain scores

Notes
[1] - 170 participants had >=1 follow up data on 1-7 days pain change in the naproxen group
[2] - 174 participants had >=1 follow-up data on 1-7 days pain change in the colchicine group

Primary endpoint - Overall 1-7 day pain change

Statistical analysis description

By intention to treat (ITT): mean difference (colchicine - naproxen) adjusted for age, sex, baseline pain.

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.32

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

0.17

Variability estimate

Standard error of the mean

Notes
[3] - For the primary/main endpoint analysis of between-group difference in average pain-change scores over 7 days through linear mixed model analysis adjusted for baseline pain score, age and gender: the mean difference was -0.18 (95% CI: -0.53, 0.17; p=0.32). This equated to a ‘small’ effect size (0.09) in favour of naproxen. Sensitivity analyses between-group mean differences were: (i) Unadjusted -0.24 (95% CI: -0.70, 0.23; p=0.31); (ii) Multiple imputation -0.22 (95% CI: -0.57, 0.13; p=0.22).

Analysis of pain change day 1

Statistical analysis description

By intention to treat (ITT): mean difference (colchicine - naproxen) adjusted for age, sex, baseline pain.

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.79

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

0.39

Variability estimate

Standard error of the mean

Analysis of pain change day 2

Statistical analysis description

By intention to treat (ITT): mean difference (colchicine - naproxen) adjusted for age, sex, baseline pain.

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.047

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.45

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

-0.01

Variability estimate

Standard error of the mean

Analysis of pain change day 3

Statistical analysis description

By intention to treat (ITT): mean difference (colchicine - naproxen) adjusted for age, sex, baseline pain.

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.48

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.61

upper limit

0.28

Variability estimate

Standard error of the mean

Analysis of pain change day 4

Statistical analysis description

By intention to treat (ITT): mean difference (colchicine - naproxen) adjusted for age, sex, baseline pain.

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.61

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.56

upper limit

0.33

Variability estimate

Standard error of the mean

Analysis of pain change day 5

Statistical analysis description

By intention to treat (ITT): mean difference (colchicine - naproxen) adjusted for age, sex, baseline pain.

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.58

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.57

upper limit

0.32

Variability estimate

Standard error of the mean

Analysis of pain change day 6

Statistical analysis description

By intention to treat (ITT): mean difference (colchicine - naproxen) adjusted for age, sex, baseline pain.

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.57

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.57

upper limit

0.31

Variability estimate

Standard error of the mean

Analysis of pain change day 7

Statistical analysis description

By intention to treat (ITT): mean difference (colchicine - naproxen) adjusted for age, sex, baseline pain.

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.34

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.65

upper limit

0.22

Variability estimate

Standard error of the mean

Overall 1-7 day pain change - Per protocol [1]

Statistical analysis description

Per protocol analysis [1] excluding participants with treatment violation by medical record note reporting (i.e. excluding treatment crossover and early cessation of treatment). Subset number analysed: 184 naproxen group; 182 colchicine group. Adjusted mean difference (colchicine group minus naproxen group).

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.32

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.54

upper limit

0.17

Variability estimate

Standard error of the mean

Overall 1-7 day pain change - Per protocol [2]

Statistical analysis description

Per protocol analysis [2] excluding participants with treatment violation by medical record note reporting plus at least 1-day use of randomised treatment by self-report. Subset number analysed: 149 naproxen group; 155 colchicine group. Adjusted mean difference (colchicine group minus naproxen group).

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.14

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.62

upper limit

0.09

Variability estimate

Standard error of the mean

Overall 1-7 day pain change - Per protocol [3]

Statistical analysis description

Per protocol analysis [3] excluding participants with treatment violation by medical record note reporting plus 7 days (4-7 days) use of randomised treatment naproxen (colchicine) by self-report. Subset number analysed: 118 naproxen group; 134 colchicine group. Adjusted mean difference (colchicine group minus naproxen group).

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.18

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.67

upper limit

0.13

Variability estimate

Standard error of the mean

Secondary: Daily Medication use within the first week of follow up

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End point title

Daily Medication use within the first week of follow up

End point description

Logistic regression models were used to model estimates for between-group comparisons of secondary outcomes (except pain change at 4 weeks): global assessment of response to treatment, another attack of gout, contact with health professionals (GP in the GP Practice, Practice nurse, emergency GP, Accident & emergency), use of other medications for pain relief, and side effects. Outcomes are shown as odds ratios (ORs) with 95% confidence intervals. Statistical analysis was performed only when all participants had completed 4 week follow-up. The main (ITT) primary outcome evaluation as well as secondary outcomes (except per protocol evaluation and HE evaluation) were carried out blind to treatment. All statistical estimates include 95% confidence intervals; p-values <0.05 (two-sided) denote statistical significance.

End point type

Secondary

End point timeframe

Days 1-7

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	175 ^[4]	180 ^[5]
Units: Number
Naproxen Day 1	155	0
Naproxen Day 2	157	0
Naproxen Day 3	157	0
Naproxen Day 4	147	1
Naproxen Day 5	145	3
Naproxen Day 6	137	7
Naproxen Day 7	136	7
Colchicine Day 1	0	159
Colchicine Day 2	1	160
Colchicine Day 3	2	157
Colchicine Day 4	4	143
Colchicine Day 5	4	67
Colchicine Day 6	3	47
Colchicine Day 7	4	44
Paracetamol Day 1	15	25
Paracetamol Day 2	13	19
Paracetamol Day 3	10	16
Paracetamol Day 4	10	13
Paracetamol Day 5	10	18
Paracetamol Day 6	10	11
Paracetamol Day 7	8	14
Tramadol Day 1	1	1
Tramadol Day 2	1	1
Tramadol Day 3	1	1
Tramadol Day 4	1	1
Tramadol Day 5	1	1
Tramadol Day 6	1	0
Tramadol day 7	1	0
Codeine Day 1	4	19
Codeine Day 2	3	16
Codeine Day 3	5	12
Codeine Day 4	3	8
Codeine Day 5	5	8
Codeine Day 6	4	7
Codeine Day 7	2	10
Ibuprofen Day 1	9	15
Ibuprofen Day 2	5	11
Ibuprofen Day 3	5	10
Ibuprofen Day 4	4	9
Ibuprofen Day 5	5	10
Ibuprofen Day 6	5	9
Ibuprofen Day 7	6	10
Diclofenac Day 1	1	1
Diclofenac Day 2	0	2
Diclofenac Day 3	0	3
Diclofenac Day 4	0	3
Diclofenac Day 5	0	4
Diclofenac Day 6	0	3
Diclofenac Day 7	1	3
Indomethacin Day 1	1	0
Indomethacin Day 2	0	0
Indomethacin Day 3	0	0
Indomethacin Day 4	0	0
Indomethacin Day 5	0	0
Indomethacin Day 6	0	0
Indomethacin Day 7	0	0
Prednisolone Day 1	0	0
Prednisolone Day 2	0	0
Prednisolone Day 3	1	1
Prednisolone Day 4	1	1
Prednisolone Day 5	1	1
Prednisolone Day 6	2	1
Prednisolone Day 7	2	3
Any 'other' analgesia Day 1	20	42
Any 'other' analgesia Day 2	17	32
Any 'other' analgesia Day 3	16	26
Any 'other' analgesia Day 4	14	20
Any 'other' analgesia Day 5	16	25
Any 'other' analgesia Day 6	15	17
Any 'other' analgesia Day 7	11	20
Any 'other' NSAIDS Day 1	10	16
Any 'other' NSAIDS Day 2	5	13
Any 'other' NSAIDS Day 3	5	13
Any 'other' NSAIDS Day 4	4	11
Any 'other' NSAIDS Day 5	5	14
Any 'other' NSAIDS Day 6	5	12
Any 'other' NSAIDS Day 7	6	13
Any 'other' medication Day 1	28	52
Any 'other' medication Day 2	21	40
Any 'other' medication Day 3	20	35
Any 'other' medication Day 4	18	30
Any 'other' medication Day 5	20	37
Any 'other' medication Day 6	20	28
Any 'other' medication Day 7	16	29

Notes
[4] - 175 is the number of participants who responded to at least one of the diary follow ups
[5] - 180 is the number of participants who responded to at least one of the diary follow ups

No statistical analyses for this end point

Secondary: Medication use over the first week and between weeks 2-4

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End point title

Medication use over the first week and between weeks 2-4

End point description

End point type

Secondary

End point timeframe

Medication use over the first week (1-7 days) and between weeks 2-4

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	164 ^[6]	170 ^[7]
Units: Number
Naproxen Days 1 -7	148	6
Naproxen Weeks 2-4	69	26
Colchicine Days 1-7	6	142
Colchicine Weeks 2-4	7	52
Paracetamol Days 1-7	20	34
Paracetamol Weeks 2-4	10	11
Ibruprofen Days 1-7	16	20
Ibruprofen Weeks 2-4	12	27
Diclofenac Days 1-7	2	4
Diclofenac Weeks 2-4	4	6
Indomethacin Days 1-7	1	0
Indomethacin Weeks 2-4	2	5
Tramadol Days 1-7	1	0
Tramadol Week 2-4	1	2
Codeine Days 1-7	7	21
Codeine Weeks 2 -4	12	8
Prednisolone Days 1-7	3	2
Prednisolone Weeks 2-4	2	1
'other' analgesia days 1-7	26	49
'other' analgesia week 2-4	22	19
'other' NSAIDS days 1-7	17	23
'other' NSAIDS week 2-4	18	37
'other' medication days 1-7	37	61
'other' medication weeks 2-4	37	52

Notes
[6] - 164 participants completed all diary or week 4 items (n=149 for 1-7 days; n=134 for 2-4 weeks)
[7] - 170 participants completed all diary or week 4 items (n=144 for 1-7 days; n=154 for 2-4 weeks)

Paracetamol 1-7 days

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.022

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.09

Confidence interval

level

95%

sides

2-sided

lower limit

1.11

upper limit

3.93

Variability estimate

Standard error of the mean

Paracetamol 2-4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.81

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.45

upper limit

2.82

Variability estimate

Standard error of the mean

Ibuprofen 1-7 days

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.27

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

3.29

Variability estimate

Standard error of the mean

Ibuprofen 2-4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.026

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.34

Confidence interval

level

95%

sides

2-sided

lower limit

1.11

upper limit

4.94

Variability estimate

Standard error of the mean

Codeine 1-7 days

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

3.62

Confidence interval

level

95%

sides

2-sided

lower limit

1.47

upper limit

8.93

Variability estimate

Standard error of the mean

Codeine 2-4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.32

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

1.65

Variability estimate

Standard error of the mean

Any analgesic or non-naproxen NSAID 1-7 days

Statistical analysis description

Odds ratio (colchicine relative to naproxen) where 'Any analgesic or non-naproxen NSAID' refers to paracetamol or codeine or tramadol or ibuprofen or diclofenac or inomethacin.

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.23

Confidence interval

level

95%

sides

2-sided

lower limit

1.35

upper limit

3.66

Variability estimate

Standard error of the mean

Any analgesic or non-naproxen NSAID 2-4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) where 'Any analgesic or non-naproxen NSAID' refers to paracetamol or codeine or tramadol or ibuprofen or diclofenac or inomethacin.

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.26

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

2.21

Variability estimate

Standard error of the mean

Secondary: Daily side effects within the first week of follow up

Top of page

End point title

Daily side effects within the first week of follow up

End point description

End point type

Secondary

End point timeframe

Days 1-7

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	175 ^[8]	180 ^[9]
Units: Number
Feeling Sick Day 1	17	15
Feeling Sick Day 2	11	16
Feeling Sick Day 3	7	17
Feeling Sick Day 4	6	11
Feeling Sick Day 5	6	6
Feeling Sick Day 6	2	6
Feeling Sick Day 7	3	5
Being Sick Day 1	3	1
Being Sick Day 2	2	1
Being Sick Day 3	1	1
Being Sick Day 4	0	0
Being Sick Day 5	0	0
Being Sick Day 6	0	1
Being Sick Day 7	0	0
Feeling/being Sick Day 1	19	16
Feeling/being Sick Day 2	12	17
Feeling/being Sick Day 3	7	18
Feeling/being Sick Day 4	6	11
Feeling/being Sick Day 5	6	6
Feeling/being Sick Day 6	2	7
Feeling/being Sick Day 7	3	5
Indigestion Day 1	10	13
Indigestion Day 2	11	11
Indigestion Day 3	11	14
Indigestion Day 4	9	11
Indigestion Day 5	5	7
Indigestion Day 6	6	6
Indigestion Day 7	4	6
Stomach Pain Day 1	5	7
Stomach Pain Day 2	6	8
Stomach Pain Day 3	7	8
Stomach Pain Day 4	7	8
Stomach Pain Day 5	3	9
Stomach Pain Day 6	2	6
Stomach Pain Day 7	4	6
Headache Day 1	9	16
Headache Day 2	10	12
Headache Day 3	3	13
Headache Day 4	3	13
Headache Day 5	5	10
Headache Day 6	4	5
Headache Day 7	3	4
Constipation Day 1	8	1
Constipation Day 2	15	2
Constipation Day 3	16	5
Constipation Day 4	8	4
Constipation Day 5	6	3
Constipation Day 6	6	2
Constipation Day 7	5	3
Diarrhoea Day 1	7	20
Diarrhoea Day 2	7	28
Diarrhoea Day 3	12	40
Diarrhoea Day 4	10	52
Diarrhoea Day 5	3	34
Diarrhoea Day 6	7	18
Diarrhoea Day 7	5	13
Skin Day 1	2	3
Skin Day 2	2	2
Skin Day 3	0	1
Skin Day 4	0	1
Skin Day 5	1	1
Skin Day 6	0	1
Skin Day 7	0	2
Any side effects Day 1	54	54
Any side effects Day 2	50	64
Any side effects Day 3	52	76
Any side effects Day 4	45	78
Any side effects Day 5	38	52
Any side effects Day 6	35	36
Any side effects Day 7	26	32

Notes
[8] - 175 is the number of participants who responded to at least one of the diary follow ups
[9] - 180 is the number of participants who responded to at least one of the diary follow ups

No statistical analyses for this end point

Secondary: Side effects over the first week and between weeks 2-4

Top of page

End point title

Side effects over the first week and between weeks 2-4

End point description

End point type

Secondary

End point timeframe

7 days and 4 week follow up

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	164 ^[10]	171 ^[11]
Units: Number
Nausea Days 1-7	21	30
Nausea Week 2-4	7	5
Indigestion Days 1-7	20	20
Indigestion Week 2-4	13	8
Stomach Pain Days 1-7	16	16
Stomach Pain Weeks 2-4	4	8
Headache Days 1-7	16	30
Headache Week 2-4	4	4
Constipation Days 1-7	29	7
Constipation Week 2-4	9	6
Diarrhoea Day 1-7	30	67
Diarrhoea Week 2-4	5	10
Skin Problems Day 1-7	3	3
Skin Problems Week 2-4	3	3
Any side effects days 1-7	91	101
Any side effects week 2-4	37	28

Notes
[10] - 164 participants completed all diary or week 4 items (n=150 for 1-7 days; n=134 for 2-4 weeks)
[11] - 171 participants completed all diary or week 4 items (n=146 for 1-7 days; n=154 for 2-4 weeks)

Nausea and/or vomiting 1-7 days

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.066

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.82

Confidence interval

level

95%

sides

2-sided

lower limit

0.96

upper limit

3.46

Variability estimate

Standard error of the mean

Nausea and/or vomiting 2-4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.51

Confidence interval

level

95%

sides

2-sided

lower limit

0.14

upper limit

1.83

Variability estimate

Standard error of the mean

Dyspepsia 1-7 days

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.95

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.48

upper limit

1.9

Variability estimate

Standard error of the mean

Dyspepsia 2-4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.094

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.44

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

1.15

Variability estimate

Standard error of the mean

Abdominal pain 1-7 days

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.86

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

2.25

Variability estimate

Standard error of the mean

Abdominal pain 2-4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.49

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.57

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

5.53

Variability estimate

Standard error of the mean

Headache 1-7 days

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.012

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.38

Confidence interval

level

95%

sides

2-sided

lower limit

1.21

upper limit

4.68

Variability estimate

Standard error of the mean

Headache 2-4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.91

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

3.86

Variability estimate

Standard error of the mean

Constipation 1-7 days

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.08

upper limit

0.48

Variability estimate

Standard error of the mean

Constipation 2-4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.22

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.16

upper limit

1.54

Variability estimate

Standard error of the mean

Diarrhoea 1-7 days

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

3.54

Confidence interval

level

95%

sides

2-sided

lower limit

2.1

upper limit

5.99

Variability estimate

Standard error of the mean

Diarrhoea 2-4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.32

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.75

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

5.26

Variability estimate

Standard error of the mean

Skin rash 1-7 days

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.88

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

5.83

Variability estimate

Standard error of the mean

Skin rash 2-4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.98

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.19

upper limit

5.09

Variability estimate

Standard error of the mean

Any side effect(s) 1-7 days

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.11

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

2.43

Variability estimate

Standard error of the mean

Any side effect(s) 2-4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Low dose Colchicine v Naproxen

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.064

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.58

Confidence interval

level

95%

sides

2-sided

lower limit

0.33

upper limit

1.03

Variability estimate

Standard error of the mean

Secondary: Global Change 7 days

Top of page

End point title

Global Change 7 days

End point description

End point type

Secondary

End point timeframe

After 7 days

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	160	152
Units: Number
Completely better now	52	43
Much better now	62	67
Somewhat better now	35	27
About the same	9	13
Somewhat worse now	2	0
Much worse now	0	2

No statistical analyses for this end point

Secondary: Global change 4 weeks

Top of page

End point title

Global change 4 weeks

End point description

End point type

Secondary

End point timeframe

4 weeks follow up

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	173	177
Units: Number
Completely better now	70	81
Much better now	70	62
Somewhat better now	19	20
About the same	11	12
Somewhat worse now	2	2
Much worse now	1	0

No statistical analyses for this end point

Secondary: Global Change Dichotomised 7 days

Top of page

End point title

Global Change Dichotomised 7 days

End point description

Categories were dichotomised as completely better/ much better and somewhat better/ about the same/ somewhat worse/ much worse

End point type

Secondary

End point timeframe

7 days

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	160	152
Units: Number
Completely/much better now	114	110
Not completely/much better	46	42

Global change day 7 analysis

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline pain score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.69

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.67

upper limit

1.84

Variability estimate

Standard error of the mean

Secondary: Global Change Dichotomised 4 weeks

Top of page

End point title

Global Change Dichotomised 4 weeks

End point description

End point type

Secondary

End point timeframe

4 weeks

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	173	177
Units: Number
Completely/much better now	140	143
not completely/much better	33	34

Global change week 4 analysis

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

350

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.64

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

1.52

Variability estimate

Standard error of the mean

Secondary: Resource use, costs and outcomes per participant over 4 weeks follow up

Top of page

End point title

Resource use, costs and outcomes per participant over 4 weeks follow up

End point description

End point type

Secondary

End point timeframe

4 weeks

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	200	199
Units: Mean (SD)
arithmetic mean (standard deviation)
GP visits	0.19 ± 0.34	0.27 ± 0.4
Nurse Visits	0.05 ± 0.19	0.07 ± 0.22
Emergency GP visits	0.05 ± 0.17	0.04 ± 0.18
A&E visits	0.006 ± 0.07	0.007 ± 0.07
Drug Costs	0.83 ± 2	1.2 ± 2.22
GP costs	6.44 ± 11.16	8.8 ± 13.16
Nurse Costs	0.66 ± 2.26	0.86 ± 2.71
Emergency GP costs	2.45 ± 8.54	2.14 ± 8.68
A&E costs	0.41 ± 5.1	0.48 ± 5.15
Intervention costs	6.77 ± 4.56	9.83 ± 6.32
Total Costs	17.57 ± 20.38	23.31 ± 23.46
Baseline EQ-5D	0.665 ± 0.21	0.663 ± 0.22
Day 7 EQ-5D	0.882 ± 0.13	0.873 ± 0.14
Week 4 EQ-5D	0.9 ± 0.11	0.894 ± 0.15
QALYS	0.0663 ± 0.008	0.0657 ± 0.01
Adjusted QALYS*	0.0662 ± 0	0.0658 ± 0
Time off work (days)	0.4 ± 2.47	0.35 ± 2.51
Productivity costs (£)	32.16 ± 190.4	28.44 ± 207.42

Attachments

Cost-effectiveness plane Naproxen v Colchicine
Cost-effectiveness acceptability curve

GP visits

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.15

upper limit

0.0002

Variability estimate

Standard error of the mean

Nurse visits

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.03

Variability estimate

Standard error of the mean

Emergency GP visits

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

0.04

Variability estimate

Standard error of the mean

A & E visits

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

-0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.01

Variability estimate

Standard error of the mean

Drug costs

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.78

upper limit

0.02

Variability estimate

Standard error of the mean

GP costs

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

-2.36

Confidence interval

level

95%

sides

2-sided

lower limit

-4.74

upper limit

0.12

Variability estimate

Standard error of the mean

Nurse costs

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

0.31

Variability estimate

Standard error of the mean

Emergency GP costs

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-1.28

upper limit

2.04

Variability estimate

Standard error of the mean

A & E costs

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-1.21

upper limit

0.95

Variability estimate

Standard error of the mean

Intervention cost

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

-3.06

Confidence interval

level

95%

sides

2-sided

lower limit

-4.17

upper limit

-2.08

Variability estimate

Standard error of the mean

Total cost

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

-5.74

Confidence interval

level

95%

sides

2-sided

lower limit

-10.03

upper limit

-1.64

Variability estimate

Standard error of the mean

EQ5D day 7

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

0.009

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.03

Variability estimate

Standard error of the mean

EQ5D week 4

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

0.006

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.03

Variability estimate

Standard error of the mean

QALYs

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

0.0006

Confidence interval

level

95%

sides

2-sided

lower limit

-0.001

upper limit

0.002

Variability estimate

Standard error of the mean

Time off work (days)

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

0.53

Variability estimate

Standard error of the mean

Productivity cost (£)

Statistical analysis description

Mean difference (naproxen - colchicine)

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

Method

Multiple Imputation regression

Parameter type

Mean difference (final values)

Point estimate

3.72

Confidence interval

level

95%

sides

2-sided

lower limit

-34.27

upper limit

40.73

Variability estimate

Standard error of the mean

Secondary: Recurrence of gout flare during 4-week follow up

Top of page

End point title

Recurrence of gout flare during 4-week follow up

End point description

End point type

Secondary

End point timeframe

4 weeks

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	133	154
Units: count
No	93	100
Yes	40	54

Recurrence of gout

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

287

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.33

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.28

Confidence interval

level

95%

sides

2-sided

lower limit

0.78

upper limit

2.13

Variability estimate

Standard error of the mean

Secondary: Pain change 4 weeks

Top of page

End point title

Pain change 4 weeks

End point description

End point type

Secondary

End point timeframe

4 weeks

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	170	174
Units: 0-10 numerical rating scale
arithmetic mean (standard deviation)	5.9 ± 2.9	5.7 ± 2.8

Pain change 4 weeks

Statistical analysis description

Analysed through linear mixed model. Mean difference (colchicine - naproxen) adjusted for age, sex, baseline score.

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.68

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

0.35

Variability estimate

Standard error of the mean

Pain change 4 weeks - Per protocol analysis [1]

Statistical analysis description

Analysed through linear mixed model. Mean difference (colchicine - naproxen) adjusted for age, sex, baseline score. Per protocol subset [1]: Excludes participants with treatment violation by medical record note reporting (i.e. treatment crossovers and eraly cessation of treatment). Subset number analysed: 184 naproxen group and 182 colchicine group.

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.29

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

0.2

Variability estimate

Standard error of the mean

Pain change 4 weeks - Per protocol analysis [2]

Statistical analysis description

Analysed through linear mixed model. Mean difference (colchicine - naproxen) adjusted for age, sex, baseline score. Per protocol subset [2]: No treatment violation by medical record note reporting plus at least 1-day use of randomised treatment by self-report. Subset number analysed: 149 naproxen group and 155 colchicine group.

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.038

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.48

Confidence interval

level

95%

sides

2-sided

lower limit

-0.94

upper limit

-0.03

Variability estimate

Standard error of the mean

Pain change 4 weeks - Per protocol analysis [3]

Statistical analysis description

Analysed through linear mixed model. Mean difference (colchicine - naproxen) adjusted for age, sex, baseline score. Per protocol subset [3]: No treatment violation by medical record note reporting plus 7 days (4-7 days) use of randomised treatment naproxen (colchicine) by self-report. Subset number analysed: 118 naproxen group and 134 colchicine group.

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.57

Confidence interval

level

95%

sides

2-sided

lower limit

-1.07

upper limit

-0.07

Variability estimate

Standard error of the mean

Secondary: Pain resolution 7 days

Top of page

End point title

Pain resolution 7 days

End point description

Classified as resolution = 0-1 score; no resolution = 2-10 score

End point type

Secondary

End point timeframe

7 days

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	171	173
Units: count
No	56	57
Yes	115	116

Pain resolution 7 days

Statistical analysis description

Mean difference (colchicine - naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

344

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.87

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

1.54

Variability estimate

Standard error of the mean

Secondary: Pain resolution 4 weeks

Top of page

End point title

Pain resolution 4 weeks

End point description

Classified as: resolution 0-1 score; no resolution 2-10 score

End point type

Secondary

End point timeframe

4 weeks

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	173	177
Units: count
No	43	47
Yes	130	130

Pain resolution 4 weeks

Statistical analysis description

Mean difference (colchicine - naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

350

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.46

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

1.36

Variability estimate

Standard error of the mean

Secondary: Re-consultation with health professional within 4 weeks

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End point title

Re-consultation with health professional within 4 weeks

End point description

End point type

Secondary

End point timeframe

4 weeks

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	133	154
Units: count
No	103	113
Yes	30	41

Re-consultation with health professional 4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

287

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.21

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.43

Confidence interval

level

95%

sides

2-sided

lower limit

0.82

upper limit

2.51

Variability estimate

Standard error of the mean

Secondary: Re-consultation with GP within 4 weeks

Top of page

End point title

Re-consultation with GP within 4 weeks

End point description

End point type

Secondary

End point timeframe

4 weeks

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	134	154
Units: count
No	108	115
Yes	26	39

Re-consultation with GP 4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

288

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.083

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

3.05

Variability estimate

Standard error of the mean

Secondary: Re-consultation with Practice nurse within 4 weeks

Top of page

End point title

Re-consultation with Practice nurse within 4 weeks

End point description

End point type

Secondary

End point timeframe

4 weeks

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	132	152
Units: count
No	125	142
Yes	7	10

Re-consultation with Practice nurse 4 weeks

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

284

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.61

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.31

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

3.64

Variability estimate

Standard error of the mean

Secondary: Re-consultation with emergency GP within 4 weeks

Top of page

End point title

Re-consultation with emergency GP within 4 weeks

End point description

End point type

Secondary

End point timeframe

4 weeks

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	134	152
Units: count
No	128	146
Yes	6	6

Re-consultation with emergency GP 4 weeks

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

286

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.77

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.26

upper limit

2.68

Variability estimate

Standard error of the mean

Secondary: Re-consultation with emergency department within 4 weeks

Top of page

End point title

Re-consultation with emergency department within 4 weeks

End point description

End point type

Secondary

End point timeframe

4 weeks

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	133	152
Units: count
No	132	151
Yes	1	1

No statistical analyses for this end point

Secondary: Time off work by 4 weeks

Top of page

End point title

Time off work by 4 weeks

End point description

End point type

Secondary

End point timeframe

4 weeks

End point values	Naproxen	Low dose Colchicine
Number of subjects analysed	128	151
Units: count
No	117	143
Yes	11	8

Time off work

Statistical analysis description

Odds ratio (colchicine relative to naproxen) adjusted for age, sex, baseline score

Comparison groups

Naproxen v Low dose Colchicine

Number of subjects included in analysis

279

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.33

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.61

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

1.64

Variability estimate

Standard error of the mean

Adverse events

Top of page

Timeframe for reporting adverse events

4 weeks

Assessment type

Systematic

Dictionary name

CTCAE

Dictionary version

4.0

Reporting group title

Naproxen

Reporting group description

Reporting group title

Colchicine

Reporting group description

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: Adverse events were a specified secondary endpoint are therefore reported under end-points.

Serious adverse events	Naproxen	Colchicine
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 200 (1.00%)	1 / 199 (0.50%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
General disorders and administration site conditions
None cardiac chest pain
Additional description: Non cardiac chest pain
subjects affected / exposed	1 / 200 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Osteomyelitis
Additional description: Osteomyelitis
subjects affected / exposed	0 / 200 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Complication of transcatheter aortic valve implantation procedure
Additional description: Complication of transcatheter aortic valve implantation procedure, patient re-admitted with Hospital acquired Pneumonia.
subjects affected / exposed	1 / 200 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Naproxen	Colchicine
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 200 (0.00%)	0 / 199 (0.00%)

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

12 Sep 2013

The trial data will be held on a database hosted on a secure server by the Primary Care Clinical Research and Trials Unit (PC-CRTU) at University of Birmingham. Previously this data was to be held on a secure server at Keele University. Provision of appropriate client server links/permissions will be given to authorised members of the trial team at Keele Clinical Trials Unit (CTU).

14 Nov 2013

Addition of sites

20 Dec 2013

Addition of sites

27 Feb 2014

Addition of sites

28 Mar 2014

Addition of sites

22 May 2014

Addition of sites

21 Jul 2014

Substantial - Change of protocol from Version 3.0 to Version 4.0 and change of 7 day pain diary to add an extra question at Day 1 of the 7 day pain diary. Also Letter of invitation and reminder letter of invitation updated from version 2.0 to version 3.0. Addition of 5 new sites . On advice of the TSC, an additional question to day 1 of the 7 day pain diary was added. It is often stated that Colchicine is less effective if first taken greater than 24 hours after symptom onset, although there is little research evidence to support this. The additional question asked about the time that had elapsed between the onset of symptoms and taking the trial medication. By comparing this between the two treatment groups, we were able to explore whether the elapsed time has an influence on the effectiveness of treatment. We also received phone calls from participants who has received a letter of invitation but were not clear on what they needed to do to enter the trial and whether any immediate action was needed. The letters of invitation were amended to provide clearer instructions about what action was required. This change was submitted to REC on 21/07/2014, however it was not submitted to the MHRA. On Inspection, the MHRA subsequently classified this as a substantial amendment which should have been notified to the MHRA. As the trial had ended recruitment, we could not submit a retrospective substantial amendment to the MHRA. Instead, the sponsor was advised to include this information as part of the update to this database at the end of the study.

16 Sep 2014

Addition of sites

19 Nov 2014

Addition of sites

26 Nov 2014

Addition of sites

04 Dec 2014

Addition of sites

15 Jan 2015

Addition of sites

05 Feb 2015

Addition of sites

27 Feb 2015

Change of protocol from Version 4.0_27_06_14 to Version 5.0_13_02_15 to remove 'expressed at study entry' for decision on self report data collection (either electronic or postal)

27 Feb 2015

Addition of sites

09 Mar 2015

Addition of sites

18 Mar 2015

Addition of sites

15 May 2015

Addition of sites

22 May 2015

Addition of sites

16 Jun 2015

Removal of 2 existing sites

16 Oct 2015

Closure of some sites

10 Dec 2015

Closure of some sites

24 Mar 2016

Update to protocol from version 5.0_13_02_2015 to version 6.0_24_Mar_2016 and Generation of participant letter to inform participants of the move of the CONTACT database from the University of Birmingham to Keele University

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A randomised, multi-centre, open-label, active-comparator, pragmatic clinical trial of low-dose colchicine versus naproxen in patients with acute gout.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Pain scores 1-7 days (primary outcome measure)

Primary: Pain scores 1-7 days (primary outcome measure)

Secondary: Daily Medication use within the first week of follow up

Secondary: Daily Medication use within the first week of follow up

Secondary: Medication use over the first week and between weeks 2-4

Secondary: Medication use over the first week and between weeks 2-4

Secondary: Daily side effects within the first week of follow up

Secondary: Daily side effects within the first week of follow up

Secondary: Side effects over the first week and between weeks 2-4

Secondary: Side effects over the first week and between weeks 2-4

Secondary: Global Change 7 days

Secondary: Global Change 7 days

Secondary: Global change 4 weeks

Secondary: Global change 4 weeks

Secondary: Global Change Dichotomised 7 days

Secondary: Global Change Dichotomised 7 days

Secondary: Global Change Dichotomised 4 weeks

Secondary: Global Change Dichotomised 4 weeks

Secondary: Resource use, costs and outcomes per participant over 4 weeks follow up

Secondary: Resource use, costs and outcomes per participant over 4 weeks follow up

Secondary: Recurrence of gout flare during 4-week follow up

Secondary: Recurrence of gout flare during 4-week follow up

Secondary: Pain change 4 weeks

Secondary: Pain change 4 weeks

Secondary: Pain resolution 7 days

Secondary: Pain resolution 7 days

Secondary: Pain resolution 4 weeks

Secondary: Pain resolution 4 weeks

Secondary: Re-consultation with health professional within 4 weeks

Secondary: Re-consultation with health professional within 4 weeks

Secondary: Re-consultation with GP within 4 weeks

Secondary: Re-consultation with GP within 4 weeks

Secondary: Re-consultation with Practice nurse within 4 weeks

Secondary: Re-consultation with Practice nurse within 4 weeks

Secondary: Re-consultation with emergency GP within 4 weeks

Secondary: Re-consultation with emergency GP within 4 weeks

Secondary: Re-consultation with emergency department within 4 weeks

Secondary: Re-consultation with emergency department within 4 weeks

Secondary: Time off work by 4 weeks

Secondary: Time off work by 4 weeks

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A randomised, multi-centre, open-label, active-comparator, pragmatic clinical trial of low-dose colchicine versus naproxen in patients with acute gout.