Clinical Trial Results:
A double blind randomised control trial to measure the effect of the addition of clindamycin to flucloxacillin for the treatment of limb cellulitis
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Summary
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EudraCT number |
2013-001218-14 |
Trial protocol |
GB |
Global end of trial date |
04 Jan 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Jul 2018
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First version publication date |
12 Jul 2018
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ME/2012/4078
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01876628 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University Hospitals Bristol NHS Foundation Trust
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Sponsor organisation address |
Trust Headquarters, Marlborough Street, Bristol, United Kingdom, BS1 3NW
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Public contact |
Jessica Bisset, University Hospitals Bristol NHS Foundation Trust, 44 117 342 0233, research@UHBristol.nhs.uk
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Scientific contact |
Jessica Bisset, University Hospitals Bristol NHS Foundation Trust, 44 117 342 0233, research@UHBristol.nhs.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
04 Jan 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
04 Jan 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
04 Jan 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The aim of this study is to see whether the addition of Clindamycin, a protein inhibiting antibiotic, to the standard antibiotic treatment of limb cellulitis, with Flucloxacillin, results in less tissue damage and a more rapid resolution of both systemic and local features, in a cost-effective manner.
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Protection of trial subjects |
It is very unusual for people to have any side-effects from the low dose of active capsules which were given to patients, as long as they are careful to follow the instructions about how to take them. Very occasionally however, some people may get slight digestive discomfort or some looseness of stools. Patients were provided with a telephone contact number to ring if they had any worries.
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Background therapy |
All patients will be on flucloxacillin. Patients must be in the trial within 48 hours of first dose of flucloxacillin. The flucloxacillin can be either oral (500mg every 6 hours) or intravenous (IV) (1g every 6 hours) but an IV to PO switch should occur as soon as clinically stable. | ||
Evidence for comparator |
The comparator in the trial is a placebo. A comparator was used in order to be able to determine whether the addition of Clindamycin, a protein inhibiting antibiotic, to the standard antibiotic treatment of limb cellulitis, with Flucloxacillin, results in less tissue damage and a more rapid resolution of both systemic and local features, in a cost-effective manner. | ||
Actual start date of recruitment |
02 Sep 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 410
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Worldwide total number of subjects |
410
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EEA total number of subjects |
410
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
332
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From 65 to 84 years |
64
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85 years and over |
14
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Recruitment
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Recruitment details |
Potential participants were screened from emergency departments, hospital inpatients and referrals to hospital from general practice (family physicians) across 20 hospitals in England. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
All adult patients with unilateral limb cellulitis were eligible; the key exclusion criteria were antibiotic treatment for longer than 48 hours, previous Clostridium difficile infection, past MRSA carriage, allergy to either penicillin or clindamycin (self-reported or from their medical records), pre-existing diarrhoea and obvious abscess. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Clindamycin Arm | |||||||||||||||||||||
Arm description |
Flucloxacillin, at a minimum of 500mg four times per day for five days, with clindamycin 300mg four times per day for two days given orally | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Clindamycin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
300 mg, four times per day, two days (2.4 g)
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
Flucloxacillin, at a minimum of 500mg four times per day for five days, with placebo | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
300 mg four times per day for two days given orally
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Baseline characteristics reporting groups
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Reporting group title |
Clindamycin Arm
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Reporting group description |
Flucloxacillin, at a minimum of 500mg four times per day for five days, with clindamycin 300mg four times per day for two days given orally | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Flucloxacillin, at a minimum of 500mg four times per day for five days, with placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Clindamycin Arm
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Reporting group description |
Flucloxacillin, at a minimum of 500mg four times per day for five days, with clindamycin 300mg four times per day for two days given orally | ||
Reporting group title |
Placebo
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Reporting group description |
Flucloxacillin, at a minimum of 500mg four times per day for five days, with placebo | ||
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End point title |
Improvement at Day 5 Visit | |||||||||||||||
End point description |
The primary outcome was improvement at the Day 5 follow-up visit. This was defined in the protocol, as being afebrile (<37.5°C) and either having a reduction in limb swelling (measured by limb circumference) or a reduction in erythema (measured by skin-surface temperature) of 0.2 standard deviations or more for both local measurements. The reduction in limb swelling and limb temperature was determined using the difference between affected and unaffected limbs to reduce confounding by ambient temperature, clothing and posture.
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End point type |
Primary
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End point timeframe |
Primary Outcome is measured at Day 5.
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Statistical analysis title |
Primary Outcome Analysis | |||||||||||||||
Comparison groups |
Clindamycin Arm v Placebo
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Number of subjects included in analysis |
328
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.174 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||
Point estimate |
1.55
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.81 | |||||||||||||||
upper limit |
3.01 | |||||||||||||||
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End point title |
Pain Score at Day 10 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
10 days
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Statistical analysis title |
Comparison of Day 10 Pain Scores between groups | ||||||||||||
Comparison groups |
Placebo v Clindamycin Arm
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Number of subjects included in analysis |
286
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.61 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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End point title |
Return to normal activities at Day 30 | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 30
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Statistical analysis title |
Return to normal activities at day 30 by group | |||||||||
Comparison groups |
Clindamycin Arm v Placebo
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Number of subjects included in analysis |
250
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | |||||||||
P-value |
= 0.774 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
0.9
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.44 | |||||||||
upper limit |
1.84 | |||||||||
| Notes [1] - This analysis adjusts for the following baseline characteristics due to some observed baseline imbalances between the arms; total affected area, difference between affected and unaffected limb circumferences, difference between affected and unaffected limb temperature and neutrophil count (logged). |
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End point title |
C-Reactive Protein at Day 10 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 10.
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Statistical analysis title |
C-Reactive Protein at Day 10 between groups | ||||||||||||
Comparison groups |
Clindamycin Arm v Placebo
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Number of subjects included in analysis |
274
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | ||||||||||||
P-value |
= 0.199 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||
Point estimate |
1.22
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.9 | ||||||||||||
upper limit |
1.66 | ||||||||||||
| Notes [2] - As C-Reactive Protein follows a log normal distribution the analysis uses the logged value. This means the parameter estimates are ratios of geometric means. The analysis adjusts for the following baseline characteristics as imbalances between the arms at baseline were observed; total affected area, difference between affected and unaffected limb circumference, difference between affected and unaffected limb temperature, neutrophil count (logged) and the baseline C-Reactive Protein (logged). |
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End point title |
Urea at Day 5 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 5
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Statistical analysis title |
Comparison of Urea at Day 5 between groups | ||||||||||||
Comparison groups |
Clindamycin Arm v Placebo
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Number of subjects included in analysis |
324
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
= 0.085 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||
Point estimate |
0.95
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.9 | ||||||||||||
upper limit |
1.01 | ||||||||||||
| Notes [3] - As urea follows a log normal distribution, the logarithm has been used in the analysis. This means the parameter estimates are in terms of the geometric means. The analysis adjusts for the following baseline characteristics as imbalances were observed between the groups; total affected area, difference between the affected and unaffected limb circumference, difference between the affected and unaffected limb temperature, neutrophil (logged) and urea (logged). |
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End point title |
Neutrophil at Day 5 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 5
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Statistical analysis title |
Neutrophil at Day 5 between groups | ||||||||||||
Comparison groups |
Clindamycin Arm v Placebo
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Number of subjects included in analysis |
324
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | ||||||||||||
P-value |
= 0.947 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Ratio of geometric means | ||||||||||||
Point estimate |
1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.92 | ||||||||||||
upper limit |
1.09 | ||||||||||||
| Notes [4] - As the neutrophil count follows a log normal distribution, the logarithm was used in the analysis, so the parameter estimates are in terms of ratios of geometric means. The analysis adjusts for some baseline characteristics as imbalances were observed between arms; total affected area, difference between unaffected and affected limb circumference, difference between unaffected and affected limb temperature and neutrophil count (logged). |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events were collected at day 5 and day 10. However the total number of serious adverse events reported between day 0 and day 10 have not been broken down by time period.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
10
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Reporting groups
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Reporting group title |
Clindamycin Arm
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Reporting group description |
Flucloxacillin, at a minimum of 500mg four times per day for five days, with clindamycin 300mg four times per day for two days given orally | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Placebo given with Flucloxacillin, at a minimum of 500mg four times per day for five days given alone | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Notes [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The number of subject exposed to this adverse event is less because fewer patients completed days 0 – 5 and days 5 – 10 days follow up – see section Subject Disposition, table titled ‘Number of subjects in period 1’ [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The number of subject exposed to this adverse event is less because fewer patients completed days 0 – 5 and days 5 – 10 days follow up – see section Subject Disposition, table titled ‘Number of subjects in period 1’ [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The number of subject exposed to this adverse event is less because fewer patients completed days 0 – 5 and days 5 – 10 days follow up – see section Subject Disposition, table titled ‘Number of subjects in period 1’ [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The number of subject exposed to this adverse event is less because fewer patients completed days 0 – 5 and days 5 – 10 days follow up – see section Subject Disposition, table titled ‘Number of subjects in period 1’ [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The number of subject exposed to this adverse event is less because fewer patients completed days 0 – 5 and days 5 – 10 days follow up – see section Subject Disposition, table titled ‘Number of subjects in period 1’ [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The number of subject exposed to this adverse event is less because fewer patients completed days 0 – 5 and days 5 – 10 days follow up – see section Subject Disposition, table titled ‘Number of subjects in period 1’ [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: The number of subject exposed to this adverse event is less because fewer patients completed days 0 – 5 and days 5 – 10 days follow up – see section Subject Disposition, table titled ‘Number of subjects in period 1’ |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
