Clinical Trial Results:
The introduction and use of Entonox as an alternative method of pain relief for intrauterine contraception device insertions.
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Summary
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EudraCT number |
2015-003628-29 |
Trial protocol |
GB |
Global end of trial date |
04 Aug 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Oct 2019
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First version publication date |
12 Oct 2019
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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 |
REGC-15-035.R1
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
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Other trial identifiers |
EudraCT number: 2015-003628-29 | ||
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Sponsors
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Sponsor organisation name |
University of Brighton
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Sponsor organisation address |
Village Way, Brighton, United Kingdom, BN1 9PH
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Public contact |
Theofanis Fotis, University of Brighton, +44 (0)1273 644512, T.Fotis@brighton.ac.uk
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Scientific contact |
Theofanis Fotis, University of Brighton, +44 (0)1273 644512, T.Fotis@brighton.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 |
04 Aug 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
04 Aug 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 principal research objective is to see if Entonox® helps to reduce the level of pain experienced by women during intrauterine contraception device insertions in a community contraception and sexual health clinic compared to local anaesthetic intracervical injection.
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Protection of trial subjects |
Entonox has recognised benefits for its use as a method of pain relief for procedural pain, however there is no published data into its benefits for IUC insertion. There is the potential for it to be inadequate for this purpose and the client may experience a greater level of pain and or anxiety than if she were receiving a commonly used method. Some women may experience side effects to the Entonox that they find unacceptable, such as nausea. Participants will be informed that should they require additional or alternate analgesia during the procedure they can opt out of the study at that point and receive an alternative method of pain relief.
Women who are allocated to receive intracervical LA injection will be counselled pre procedure regarding the possibility of discomfort at the administration of the anaesthesia and can opt out of participation if they feel this is unacceptable to them or they require additional pain relief.
Intracervical injection has the minimal but serious risks of accidental intravenous administration and anaphylactic reaction. Practitioners undertaking this procedure are trained to recognise signs and symptoms of these, are trained in basic life support, anaphylaxis and the administration of emergency drugs. Emergency drugs of Adrenaline and Atropine are available in the clinical room during all procedures. All women choosing IUC as their preferred method of contraception are offered local anaesthetic intracervical injection as routine for IUCD insertion currently and women will only be eligible for the study if they are requesting analgesia for this procedure.
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Background therapy |
As per standard care, participants were asked to take oral over the counter pain relief prior to their appointment which was optional. | ||
Evidence for comparator |
Local anaesthetic intracervical and paracervical injections are widely used as pain relief for intrauterine device insertion although evidence supporting it's efficacy is conflicting (Lopez et al 2015, Pergialiotis et al 2014,). Lidocaine 1% solution for injection is a local aesthetic of the amide group which acts by suspending the sensation of pain without effecting consciousness (Braun 2005). Injection into mucosa provides an anaesthetising effect within one to five minutes, lasts for one to three hours and is confined area of application. Entonox (nitrous oxide 50/air 50%) is a low potency inhalation anaesthetic and high potency analgesic which acts on the pain centres of the brain and spinal cord, releasing endogenous neurotransmitters and activating opioid receptors (BOC 2014, Emmanouil and Quock 2007). It works within two to three minutes of inhalation with a rapid fall in arterial concentration within thirty seconds of discontinuation making it highly suitable for procedures where the pain is predictable (Pedani 2003). B.Braun. (2005). 1% w/v Lidocaine Injection:Summary of product characteristics. Germany. B.Braun Melsungen AG Emmanouil, D.E., and R.M. Quock. 2007. Advances in understanding the actions of nitrous oxide. Anesthesia Progress 54 (1): 9-18. Lopez, L.M., A. Bernholc, Y. Zeng, R.H. Allen, D. Bartz, P.A. O'Brien, and D. Hubacher. 2015. Interventions for pain with intrauterine device insertion. The Cochrane database of systematic reviews, 2015 (7). Pediani, R. 2003. Patient-administered inhalation of nitrous oxide and oxygen gas for procedural pain relief. World Wide Wounds. [Online]. Available from: www.worldwidewounds.com/2003/october/ Pediani/Entonox-Pain-Relief.html. [20/11/14] Pergialiotis, V., D.G. Vlachos, A. Protopappas, and G.D. Vlachos. 2014. Analgesic options for placement of an intrauterine contraceptive: A meta-analysis. The European Journal of Contrac | ||
Actual start date of recruitment |
01 Dec 2015
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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: 51
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Worldwide total number of subjects |
51
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EEA total number of subjects |
51
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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) |
51
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
All women over the age of 16 years attending the contraceptive service requesting and eligible for intrauterine contraception were advised of the trial from the period December 2015 to August 2016 from two sites within a community based sexual health service. | |||||||||
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Pre-assignment
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Screening details |
Participants were women between the ages of 18-54 years, requesting and eligible for intrauterine contraception with no contraindications to the use of Entonox inhalation analgesia or local anaesthetic injection and desiring of pain relief for this procedure. 103 participants were eligible for inclusion. | |||||||||
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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 |
Not blinded | |||||||||
Blinding implementation details |
no blinding occured
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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pain relief - Entonox | |||||||||
Arm description |
Entonox will be administered through a one way demand valve system mouthpiece. The participant will begin inhalation of the anaesthetic following speculum insertion until they begin to feel sedated and have adequate analgesic effect for the procedure. They will be informed to discontinue inhalation if minor side effects occur and that they will soon recover. Inhalation can be repeated through the procedure as required by the participant. The participant will be advised to discontinue Entonox if they experience ear ache and an alternative method of analgesia will be offered. Pain will be scored on a visual analogue scale at two points, following tenaculum placement and following IUC insertion. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Entonox
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Investigational medicinal product code |
0735/5017
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Other name |
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Pharmaceutical forms |
Medicinal gas, compressed
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Routes of administration |
Inhalation use
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Dosage and administration details |
self administered inhalation throughout procedure
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Arm title
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pain relief - LA injection | |||||||||
Arm description |
If recruited to receive intracervical LA injection, following speculum insertion, participants will be given 0.5ml lidocaine 1% placed superficially to the cervix at the 12 and/or 6 o’clock position using a 22mm gauge needle, tenaculum will be placed at the 12 and/or 6 O'clock position and 2ml lidocaine 1% will be administered intracervicaly at the 4 and 8 o’clock positions on the cervix. Participants will be asked to score their pain on a visual analogue scale following LA injection at two points, following tenaculum placement and following IUC insertion. | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Lidocaine 1%
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Investigational medicinal product code |
PRD568902
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intracervical use
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Dosage and administration details |
If recruited to receive intracervical LA injection participants will be given 0.5ml lidocaine 1% placed superficially to the cervix at the 12 and/or 6 o’clock position using a 22mm gauge needle, pre tenaculum placement and 2mls lidocaine 1% intracervicaly at both the 4 and 8 o’clock positions on the cervix following tenaculum placement. This will be given following speculum insertion.
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Investigational medicinal product name |
Entonox
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Investigational medicinal product code |
0735/5017
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Other name |
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Pharmaceutical forms |
Medicinal gas, compressed
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Routes of administration |
Inhalation use
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Dosage and administration details |
Participant directed self administered inhalation throughout procedure
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Baseline characteristics reporting groups
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Reporting group title |
pain relief - Entonox
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Reporting group description |
Entonox will be administered through a one way demand valve system mouthpiece. The participant will begin inhalation of the anaesthetic following speculum insertion until they begin to feel sedated and have adequate analgesic effect for the procedure. They will be informed to discontinue inhalation if minor side effects occur and that they will soon recover. Inhalation can be repeated through the procedure as required by the participant. The participant will be advised to discontinue Entonox if they experience ear ache and an alternative method of analgesia will be offered. Pain will be scored on a visual analogue scale at two points, following tenaculum placement and following IUC insertion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
pain relief - LA injection
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Reporting group description |
If recruited to receive intracervical LA injection, following speculum insertion, participants will be given 0.5ml lidocaine 1% placed superficially to the cervix at the 12 and/or 6 o’clock position using a 22mm gauge needle, tenaculum will be placed at the 12 and/or 6 O'clock position and 2ml lidocaine 1% will be administered intracervicaly at the 4 and 8 o’clock positions on the cervix. Participants will be asked to score their pain on a visual analogue scale following LA injection at two points, following tenaculum placement and following IUC insertion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
pain relief - Entonox
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Reporting group description |
Entonox will be administered through a one way demand valve system mouthpiece. The participant will begin inhalation of the anaesthetic following speculum insertion until they begin to feel sedated and have adequate analgesic effect for the procedure. They will be informed to discontinue inhalation if minor side effects occur and that they will soon recover. Inhalation can be repeated through the procedure as required by the participant. The participant will be advised to discontinue Entonox if they experience ear ache and an alternative method of analgesia will be offered. Pain will be scored on a visual analogue scale at two points, following tenaculum placement and following IUC insertion. | ||
Reporting group title |
pain relief - LA injection
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Reporting group description |
If recruited to receive intracervical LA injection, following speculum insertion, participants will be given 0.5ml lidocaine 1% placed superficially to the cervix at the 12 and/or 6 o’clock position using a 22mm gauge needle, tenaculum will be placed at the 12 and/or 6 O'clock position and 2ml lidocaine 1% will be administered intracervicaly at the 4 and 8 o’clock positions on the cervix. Participants will be asked to score their pain on a visual analogue scale following LA injection at two points, following tenaculum placement and following IUC insertion. | ||
Subject analysis set title |
overall satisfaction with pain relief received
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Participants were asked two questions- how satisfied were you with the method of pain relief you received and would you recommend this method to a friend or family member.
Results were compared from descriptive data as percentages.
82.6% of participants found Entonox helpful or very helpful.
92.9% of participants found LA injection helpful or very helpful.
72.6% of participants would recommend or highly recommend Entonox to a friend or family member
82.2% of participants would recommend or highly recommend LA injection to a friend or family member.
7.1% of participants would not recommend LA injection.
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Subject analysis set title |
Age of participants
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Age range is described as percentages from descriptive data.
The mean age of participants was 31 years.
The highest percentage of participants was in the age range 26-35 years.
The lowest percentage of participants was in the age range 46-55 years.
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End point title |
Pain as scored on a visual analogue scale following intrauterine insertion | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Participants were asked to score the level of pain experienced following Intrauterine insertion on a 0-100 visual analogue scale
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Statistical analysis title |
Post IUC insertion | ||||||||||||
Statistical analysis description |
Participants were asked to rate the level of pain experienced following IUC insertion on a 0-100 VAS. Data was normally distributed and parametric testing was applied. An independant samples T-test was performed to compare VAS pain scores between the two groups, Entonox and LA injection.
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Comparison groups |
pain relief - Entonox v pain relief - LA injection
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Number of subjects included in analysis |
51
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
P-value |
> 0.05 [2] | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-11
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-27.7 | ||||||||||||
upper limit |
5.2 | ||||||||||||
Variability estimate |
Standard deviation
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Dispersion value |
47.5
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| Notes [1] - Analysis was performed using IBM SPSS , Armonk, NY, USA. [2] - Entonox, M= 53.7 SD 30.5 N23 LA Injection M=42.46 SD 27.8 N28 T= (49) -1.378 p=.175 r=0.059 |
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End point title |
Pain as scored on a visual analogue scale following tenaculum placement . | ||||||||||||
End point description |
Participants were asked to assess the level of pain experienced following tenaculum placement on a 0-100 mm visual analogue scale (VAS). Data was of non normal distribution and non parametric testing was applied. A Mann_Whitney U test was performed to compare VAS pain scores in two groups, LA injection and Entonox
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End point type |
Primary
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End point timeframe |
Participants were asked to assess the level of pain following tenaculum placement.
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Statistical analysis title |
Post tenaculum placement | ||||||||||||
Statistical analysis description |
Participants were asked to rate the level of pain experienced following tenaculum placement on a 0-100 mm visual analogue scale (VAS). Data was non normally distributed and parametric testing was applied. A Mann-Whitney U test was performed to compare pain scores from two groups, Entonox and LA injection.
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Comparison groups |
pain relief - Entonox v pain relief - LA injection
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Number of subjects included in analysis |
51
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [3] | ||||||||||||
P-value |
> 0.05 [4] | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||
Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0 | ||||||||||||
upper limit |
75 | ||||||||||||
Variability estimate |
Standard deviation
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Dispersion value |
21.7
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| Notes [3] - Data was analysed using IBM SPSS version 25 [4] - comparison of two groups; Both methods combined Md=20 M=25 SD21.7 N=51 LA injection Md=15.5 M=24.8 SD 24.4 N=23 Entonox MD=24 M=25.3 sd18.2 n=28 u=299 z=.436 R=0.017 |
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Adverse events information [1]
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Timeframe for reporting adverse events |
within 3 days of event.
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Adverse event reporting additional description |
Any serious adverse event will be documented and reported as per Part 5, medicines for Human Use (Clinical trials) Regulations 2004.
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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 |
2004
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| Frequency threshold for reporting non-serious adverse events: 0% | |||
| 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: This was a student lead research project comparing a method of pain relief offered and commonly accepted for the procedure of IUC insertion within the research setting with an inhalation anaesthetic know to have limited side effects and/or complications when used within the research parameters. |
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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 | |||
