Clinical Trial Results:
Remifentanil intravenous patient controlled analgesia (PCA) versus intramuscular pethidine for pain relief in labour: a randomised controlled trial
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Summary
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EudraCT number |
2012-005257-22 |
Trial protocol |
GB |
Global end of trial date |
03 Sep 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Nov 2017
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First version publication date |
03 Nov 2017
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Other versions |
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Summary report(s) |
RESPITE Clinical Trial summary report |
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 |
RG_12-151
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Additional study identifiers
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ISRCTN number |
ISRCTN29654603 | ||
US NCT number |
NCT02179294 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
IRAS number: 116638 | ||
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Sponsors
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Sponsor organisation name |
University of Birmingham
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Sponsor organisation address |
Edgbaston, Birmingham, United Kingdom, B152TT
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Public contact |
Sean Jennings, University of Birmingham, Research Support Group, +44 01214143794, researchgovernance@contacts.bham.ac.uk
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Scientific contact |
Sean Jennings, University of Birmingham, Research Support Group, +44 01214143794, researchgovernance@contacts.bham.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 Nov 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 Sep 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Sep 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 |
To conduct a RCT to determine if remifentanil PCA administered for pain relief in labour, reduces the proportion of women who subsequently require an epidural for pain relief in comparison to intermittent intramuscular pethidine (current practice).
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Protection of trial subjects |
The trial protocol dictated that all women randomised were to receive one-to-one midwifery care. Observations including excessive sedation score, oxygen saturation and respiratory depression were recorded every 30mins until delivery or transfer to theatre. Women who were randomised to receive remifentanil PCA, in the event of excess sedation being recorded by regular observation of respiratory function, the regimen was altered by reduction of the remifentanil bolus dose to 30µg with a lock-out interval of 2 minutes.
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Background therapy |
After the administration of analgesia, all women received one-to-one midwifery care and had observations recorded including: o Respiratory rate and continuous oxygen saturation monitoring by pulse oximetry o Sedation score every 30 minutes o Visual analogue pain score every 30 minutes | ||
Evidence for comparator |
Remifentanil is a novel synthetic opioid with a very rapid onset (blood-brain equilibration 1.2-1.4 minutes) and short duration of action (context specific half-life 2-3 minutes), giving it an analgesic profile which potentially makes it ideal for providing pain relief over 1-2 uterine contractions after a single intravenous dose. It is subject to rapid redistribution and metabolism by non-specific blood and tissue esterases, negating the potential for accumulation in mother or foetus. Administration of remifentanil by PCA has been investigated in several small studies in comparison to pethidine and shown to provide useful, although not complete, pain relief in labour. Thus far, there is no evidence of detrimental neonatal effects in comparison to other opioids. Some units are starting to offer this form of pain relief in cases where pain relief is requested, but an epidural is contraindicated, for example in the case of maternal clotting abnormality or platelet dysfunction. However the use of remifentanil PCA is not currently widespread or routine. Crucially, there is some evidence from the studies performed thus far that the proportion of women who require rescue pain relief with an epidural after remifentanil PCA is reduced in comparison to pethidine, although no study has yet investigated this as a primary end-point. If such an effect were proven and remifentanil demonstrated to be at least as safe and effective as pethidine, the number of women requiring an epidural in labour could potentially be reduced with a concomitant beneficial reduction in instrumental vaginal delivery and associated morbidity including incontinence and sexual dysfunction, relative to spontaneous delivery. | ||
Actual start date of recruitment |
13 May 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: 401
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Worldwide total number of subjects |
401
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EEA total number of subjects |
401
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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) |
6
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Adults (18-64 years) |
395
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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 |
The first patient was recruited and randomised into the trial on 13/05/2014 and the last patient was randomised into the trial on 02/09/2016. The study was open in the UK only and was open in 16 centres in total. 2 centres closed prematurely after failing to recruit any women and 1 centre closed prematurely after only recruiting one woman. | |||||||||
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Pre-assignment
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Screening details |
A total of 2950 eligible women were screened for the trial. Of those 2549 women were not randomised and 401 women were randomised. Of the 2549 women not randomised, 1797 declined and 752 women were not recruited due to an 'other' reason e.g consented but did not proceed to randomisation. | |||||||||
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Period 1
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Period 1 title |
Baseline period (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 |
N/A
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Pethidine | |||||||||
Arm description |
100mg by intramuscular injection, up to 4 hourly in frequency (up to a maximum of 4 doses). The maximum dose being 400mg in 24 hours. | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Pethidine
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Investigational medicinal product code |
N/A
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Other name |
Pethidine hydrochloride
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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 |
100mg by intramuscular injection, up to 4 hourly in frequency (up to a maximum of 4 doses). The maximum dose being 400mg in 24 hours.
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Arm title
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Remifentanil PCA | |||||||||
Arm description |
• Dedicated intravenous cannula for remifentanil administration • PCA protocol o PCA bolus remifentanil 40 µg o Lockout interval 2 minutes | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Remifentanil PCA
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Investigational medicinal product code |
N/A
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Other name |
Remifentanil hydrochloride
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Pharmaceutical forms |
Powder for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
• Dedicated intravenous cannula for remifentanil administration
• PCA protocol
o PCA bolus remifentanil 40 µg
o Lockout interval 2 minutes
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 200 women were randomised to the Pethidine arm. 1 woman in the Pethidine arm withdrew her consent to use her data. I have attempted to document this as 200 'started' in the Pethidine arm and 199 'completed' in the Pethidine arm with 1 lady withdrawing consent therefore the total decreases from 200 to 199. This has not been accepted within the system and I have been advised by a member of the EudraCT team to enter the information as 199 'started' and 199 'completed'. |
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Baseline characteristics reporting groups
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Reporting group title |
Pethidine
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Reporting group description |
100mg by intramuscular injection, up to 4 hourly in frequency (up to a maximum of 4 doses). The maximum dose being 400mg in 24 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Remifentanil PCA
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Reporting group description |
• Dedicated intravenous cannula for remifentanil administration • PCA protocol o PCA bolus remifentanil 40 µg o Lockout interval 2 minutes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Pethidine
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Reporting group description |
100mg by intramuscular injection, up to 4 hourly in frequency (up to a maximum of 4 doses). The maximum dose being 400mg in 24 hours. | ||
Reporting group title |
Remifentanil PCA
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Reporting group description |
• Dedicated intravenous cannula for remifentanil administration • PCA protocol o PCA bolus remifentanil 40 µg o Lockout interval 2 minutes | ||
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End point title |
The proportion of women who have an epidural placed for pain relief in labour, in each group | |||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
During labour
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Statistical analysis title |
Primary analysis | |||||||||||||||
Statistical analysis description |
Primary ITT (Intention-to-Treat) Unadjusted Analysis. The primary analysis is a comparison of the rate of conversion to epidural between Remifentanil PCA and Pethidine (usual care) using a log-binomial model.
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Comparison groups |
Pethidine v Remifentanil PCA
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Number of subjects included in analysis |
400
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | |||||||||||||||
P-value |
= 0.05 [2] | |||||||||||||||
Method |
Chi-squared | |||||||||||||||
Parameter type |
Risk ratio (RR) | |||||||||||||||
Point estimate |
0.5
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Confidence interval |
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95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.3 | |||||||||||||||
upper limit |
0.7 | |||||||||||||||
Variability estimate |
Standard deviation
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| Notes [1] - Primary ITT (Intention-to-Treat) Unadjusted Analysis. The primary analysis is a comparison of the rate of conversion to epidural between Remifentanil PCA and Pethidine (usual care) using a log-binomial model. [2] - P value result for the primary analysis of the primary outcome was <0.0001. P-value stated above relates to the significance level in calculating the sample size |
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Adverse events information [1]
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Timeframe for reporting adverse events |
The time period for occurrence of SAEs relevant to reporting is from the participant’s entry to the study until hospital discharge. In the case of a neonatal SAE, the period is from birth to discharge.
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Adverse event reporting additional description |
*1 x neonatal SAE included diagnosis of sepsis and pyrexia (Remifentanil arm)
† 1 x neonatal SAE included diagnosis of hypertrophic cardiomyopathy, pneumonia and pulmonary hypertension (Pethidine arm)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
11
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Reporting groups
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Reporting group title |
Pethidine
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Reporting group description |
100mg by intramuscular injection, up to 4 hourly in frequency (up to a maximum of 4 doses). The maximum dose being 400mg in 24 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Remifentanil PCA
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Reporting group description |
• Dedicated intravenous cannula for remifentanil administration • PCA protocol o PCA bolus remifentanil 40 µg o Lockout interval 2 minutes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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: Low respiratory rate, high sedation score and low oxygen saturation were considered adverse reactions that would require attention from an anaesthetist. Observations were collected and recorded in the Pain Relief and Maternal Observations form but were not reported specifically using an Adverse Event form. Non-serious adverse events, not directly linked to trial interventions, were not collected. |
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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04 Dec 2013 |
Substantial amendment 2. Change in wording of eligibility criteria to make in line with the randomisation form. Section 5.1.2 of protocol ‘continuous’ added to oxygen saturation monitoring and removal of ‘30 mins’ from timing. Protocol updated to v1.2. |
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14 Oct 2014 |
Substantial amendment 5. Addition of TSC and DMC members, amended TMG members, updated BCTU address and addition of Clinicaltrials.gov NCT number. Section 3.3 wording amended so consent can be obtained once patient enters established labour up to and including the point that the patient requests opioid analgesia. Section 3.4 removed patient initials, parity and gestational age as these are not being collected on screening logs. Section 5.1.3 clarification that no additional temperature monitoring of trial drugs is required beyond established Trust protocols. Section 5.2 clarification that consenting investigator nor research midwife are party to the decision to progress to epidural. Section 6.1.3 list of anticipated SAEs added which are not considered to be related to Pethidine and/or Remifentanil. Protocol updated to v1.3 |
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15 Oct 2015 |
Substantial amendment 10. Various clarifications around eligibility assessment, delegated roles, SAE assessment, definition of established labour, scope for co-enrolment, data transferred to University of Aberdeen for randomisations performed via the 24/7 automated telephone system, drug storage and dispensing and the exclusion criteria regarding systemic opioids. Additional information has been added regarding breastfeeding with Pethidine and Remifentanil, incentives for sites in recognition of reaching recruitment targets and extending the recruitment end date. Addition of DMC member, addition of collaborator, change of details for Trial Coordinator. Protocol updated to v2.0 |
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25 Jul 2016 |
Substantial amendment 12. Change of BCTU logo, update to table 1 - list of previous studies of remifentanil for analgesia in labour, clarification of secondary outcomes and update to the reference list. Protocol updated to v3.0 |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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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 | |||||||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/27955688 |
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