Clinical Trial Results:
A randomised controlled trial to compare the clinical effectiveness and safety of gentamicin and ceftriaxone in the treatment of gonorrhoea.
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Summary
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EudraCT number |
2014-001823-56 |
Trial protocol |
GB |
Global end of trial date |
20 Jan 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Jan 2020
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First version publication date |
26 Jan 2020
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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 |
RRK5104
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Additional study identifiers
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ISRCTN number |
ISRCTN51783227 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University Hospitals Birmingham NHS Foundation Trust
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Sponsor organisation address |
Queen Elizabeth Hospital Birmingham, Middelsohn Way, Birmingham, United Kingdom, B15 2WB
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Public contact |
G-ToG Study manager, Nottingham Clinical Trials Unit, g-tog@nottingham.ac.uk
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Scientific contact |
G-ToG Study manager, Nottingham Clinical Trials Unit, g-tog@nottingham.ac.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 |
22 Jun 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
20 Jan 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
20 Jan 2017
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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 principle objective of the study is to determine whether gentamicin is an acceptable alternative to ceftriaxone, in the treatment of gonorrhoea. This will be done by determining whether the clearance rate of gonorrheoa in participants receiving gentamicin is no worse than the rate in participants receiving ceftriaxone. In parallel, the safety of both treatments will be assessed.
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Protection of trial subjects |
In previous trials a 240 mg dose of gentamicin was most commonly used and the use of different doses has not demonstrated a significant dose-response effect across studies. The dose of ceftriaxone was chosen to be consistent with current UK gonorrhoea treatment guidelines 29.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Sep 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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: 720
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Worldwide total number of subjects |
720
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EEA total number of subjects |
720
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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) |
13
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Adults (18-64 years) |
701
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From 65 to 84 years |
6
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment, across 14 sexual health clinics in England, commenced in October 2014 and continued until November 2016 when the recruitment target was met. | |||||||||
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Pre-assignment
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Screening details |
1762 participants who had a provisional or confirmed diagnosis of gonorrhoea were asked if they were interested in participating in the study. If they indicated interest, an appropriately qualified member of the research team provided them with a patient information leaflet, explained the study procedures. | |||||||||
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Period 1
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Period 1 title |
pre-assignment (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, Data analyst, Assessor | |||||||||
Blinding implementation details |
Only the nurse/doctor administering the treatment will know what treatment the participant has been randomised to. Members of the research team who are aware of the treatment allocation will not have any role in data collection. The participant and staff involved in the care and assessment of the participant will not know what treatment they have been randomised to. This should ensure the minimisation of any bias in assessment due to knowledge of the treatment administered.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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gentamicin | |||||||||
Arm description |
• Gentamicin (240mg) administered as a single intramuscular injection. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
gentamicin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
a single intramuscular injection (IM) of gentamicin (240mg)
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Arm title
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ceftriaxone | |||||||||
Arm description |
• Ceftriaxone (500mg) administered as a single intramuscular injection. | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
ceftriaxone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
a single dose (500mg) of intramuscular injection
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Baseline characteristics reporting groups
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Reporting group title |
gentamicin
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Reporting group description |
• Gentamicin (240mg) administered as a single intramuscular injection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ceftriaxone
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Reporting group description |
• Ceftriaxone (500mg) administered as a single intramuscular injection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
number of participants randomised, without imputation of missing data
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End points reporting groups
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Reporting group title |
gentamicin
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Reporting group description |
• Gentamicin (240mg) administered as a single intramuscular injection. | ||
Reporting group title |
ceftriaxone
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Reporting group description |
• Ceftriaxone (500mg) administered as a single intramuscular injection. | ||
Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
number of participants randomised, without imputation of missing data
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End point title |
Clearance of gonorrhoeae at 2 weeks | ||||||||||||
End point description |
The primary outcome measure is clearance of N. gonorrhoeae at all infected sites confirmed by a negative NAAT, two weeks post treatment (as recommended by the British Association for Sexual Health and HIV). The results from the AC NAAT will be considered primary.
Infection sites include genital, rectal and pharyngeal sites. Note that urine and urethra are interchangeable genital samples and as are vagina and cervix.
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End point type |
Primary
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End point timeframe |
gonorrhoeae clearance at 2 weeks post randomisation
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Statistical analysis title |
generalised estimating equations | ||||||||||||
Statistical analysis description |
The primary approach to between-group comparative analyses will be by intention-to-treat without imputation of missing outcome data for clearance of gonorrhoea at 2 weeks. The evaluation of the proportion of participants with clearance of gonorrhoea at 2 weeks will be performed using a generalised estimating equations (GEE) for binary outcomes adjusted by recruiting centre as a random effect.
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Comparison groups |
ceftriaxone v gentamicin
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Number of subjects included in analysis |
598
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
P-value |
= 0.002 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||
Point estimate |
-0.064
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.104 | ||||||||||||
upper limit |
-0.024 | ||||||||||||
Variability estimate |
Standard error of the mean
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| Notes [1] - Gentamicin will be regarded as non-inferior if the lower 95% confidence limit for the risk difference (Gentamicin group versus Ceftriaxone group) in confirmed clearance is -5 percentage points or greater. |
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End point title |
resolution of symptom (genital discharge) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
at 2 weeks post randomisation
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Statistical analysis title |
generalised estimating equations | |||||||||
Comparison groups |
gentamicin v ceftriaxone
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Number of subjects included in analysis |
276
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Mixed models analysis | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
-0.001
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-0.055 | |||||||||
upper limit |
0.052 | |||||||||
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End point title |
resolution of symptom (dysuria) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post randomisaiton
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Statistical analysis title |
generalised estimating equations | |||||||||
Comparison groups |
gentamicin v ceftriaxone
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Number of subjects included in analysis |
234
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Mixed models analysis | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
-0.077
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-0.136 | |||||||||
upper limit |
0.019 | |||||||||
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End point title |
resolution of symptom (anorectal pain) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post randomisation
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Statistical analysis title |
generalised estimating equations | |||||||||
Comparison groups |
gentamicin v ceftriaxone
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Number of subjects included in analysis |
20
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
Method |
Mixed models analysis | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
-0.244
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-0.625 | |||||||||
upper limit |
0.137 | |||||||||
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End point title |
resolution of symptom (sore thoat) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post randomisation
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Statistical analysis title |
generalised estimating equations | |||||||||
Comparison groups |
gentamicin v ceftriaxone
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Number of subjects included in analysis |
92
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Mixed models analysis | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
0.04
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-0.074 | |||||||||
upper limit |
0.154 | |||||||||
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End point title |
resolution of symptom (rectal bleeding) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post randomisation
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Statistical analysis title |
Fisher's exact test | |||||||||
Comparison groups |
gentamicin v ceftriaxone
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Number of subjects included in analysis |
15
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Fisher exact | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
0.125
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-0.104 | |||||||||
upper limit |
0.354 | |||||||||
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End point title |
resolution of symptom (rectal discharge) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post randomisation
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Statistical analysis title |
generalised estimating equations | |||||||||
Comparison groups |
gentamicin v ceftriaxone
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Number of subjects included in analysis |
20
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Mixed models analysis | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
-0.099
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-0.437 | |||||||||
upper limit |
0.239 | |||||||||
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End point title |
resolution of symptom (tenesmus) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post randomisation
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Statistical analysis title |
Fisher's exact test | |||||||||
Comparison groups |
gentamicin v ceftriaxone
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Number of subjects included in analysis |
10
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Fisher exact | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
0.125
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-0.104 | |||||||||
upper limit |
0.354 | |||||||||
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End point title |
resolution of symptom (intermentrual bleeding) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post randomisation
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Statistical analysis title |
Fisher's exact test | |||||||||
Comparison groups |
gentamicin v ceftriaxone
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Number of subjects included in analysis |
14
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Fisher exact | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
0.111
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-0.094 | |||||||||
upper limit |
0.316 | |||||||||
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End point title |
resolution of symptom (constipation) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post rando
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Statistical analysis title |
generalised estimating equations | |||||||||
Comparison groups |
ceftriaxone v gentamicin
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Number of subjects included in analysis |
15
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.05 | |||||||||
Method |
Mixed models analysis | |||||||||
Parameter type |
Risk difference (RD) | |||||||||
Point estimate |
-0.126
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-0.578 | |||||||||
upper limit |
0.326 | |||||||||
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End point title |
side effect (nausea) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post rando
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| No statistical analyses for this end point | ||||||||||
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End point title |
side effect (vomitting) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post rando
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| No statistical analyses for this end point | ||||||||||
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End point title |
side effect (reduction in hearing) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post rando
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| No statistical analyses for this end point | ||||||||||
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End point title |
side effect (dizziness and unsteadiness) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post rando
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| No statistical analyses for this end point | ||||||||||
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End point title |
side effect (skin rash) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post rando
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| No statistical analyses for this end point | ||||||||||
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End point title |
side effect (injection pain) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 weeks post rando
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
2 weeks post randomisation
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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 |
17.1
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Reporting groups
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Reporting group title |
gentamicin
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ceftriaxone
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0.05% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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: number exposed for reporting group is the total randomised however number exposed to adverse event is the total who received treatment as randomised and who provided adverse event information at 2 week follow up. |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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27 May 2014 |
Summary of changes:
• Inclusion/exclusion criteria amended to clarify meaning of untreated gonorrhoea, exclude patients with bacterial vaginosis and Trichomonas vaginalis and diagnosis of gonorrhoea must be within 4 weeks of trial entry
• Removal of the pharmacokinetic sub-study
• Clarification of Visit 2 timelines (as close as possible to 14 days, not before, but up to Day 60)
• SAE reporting required for events of dizziness and hearing loss of grade 3 or above,
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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 | |||
