Clinical Trial Results:
High Or Low Dose Syntocinon® (Oxytocin) for delay in labour. HOLDS: a pilot study.
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Summary
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EudraCT number |
2009-012752-24 |
Trial protocol |
GB |
Global end of trial date |
30 Sep 2011
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Jul 2019
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First version publication date |
19 Jul 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 |
RG_09-016
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Additional study identifiers
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ISRCTN number |
ISRCTN23847193 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
MREC number : 10/H0406/30, Funder I.D. : PB-PG- 0407-13193, CTA number: 21761/0249/001-0001 | ||
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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 |
Dr Birgit Whitman, University of Birmingham, +44 0121 4158011, B.Whitman@bham.ac.uk
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Scientific contact |
Dr Birgit Whitman, University of Birmingham, +44 0121 4158011, B.Whitman@bham.ac.uk
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Sponsor organisation name |
Birmingham Women's and Children's NHS Foundation Trust
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Sponsor organisation address |
Mindelsohn Way, Birmingham, United Kingdom, B15 2TG
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Public contact |
Elizabeth Adey, Birmingham Women's and Children's NHS Foundation Trust, +44 01213338749, e.adey@nhs.net
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Scientific contact |
Elizabeth Adey, Birmingham Women's and Children's NHS Foundation Trust, +44 01213338749, e.adey@nhs.net
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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 |
31 Aug 2011
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
05 Mar 2011
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Sep 2011
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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 |
This pilot study based in three maternity units will recruit approximately 100 women. It is the pilot for a proposed multicentre trial which would compare standard and high dose oxytocin in approximately 4300 women from 24 centres. The main hypothesis of the trial is that the use of high dose oxytocin will achieve more effective uterine contractions resulting not only in shorter labours but in a higher chance of vaginal birth in women who are diagnosed as having delay in the first stage of labour. The regimen we will evaluate has a higher starting dose, earlier attainment of conventional maximum doses (at 2 hours rather than over 4 hours) and the use of higher maximum doses of oxytocin compared to the standard regimen used at present.
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Protection of trial subjects |
The study was discussed with women and written information presented detailing no less than: the exact nature of the study; the implications of the protocol for both her and her baby. It was clearly stated that the woman was free to withdraw from the study at any time and for any reason without prejudice to future care, and with no obligation to give the reason for withdrawal. Women received information about the study in advance during the antenatal period with the process for providing information being individulised for each hospital. The administration of oxytocin does carry known side effects, which particiapnts were made aware of. In these cases the opinion of an obstetrician was sought. The side effects of oxytocin are that the uterus contracts too much (hyperstimulates ) which can cause the baby to become distressed. For this reason women on oxytocin were more intensively monitored. Participating in the study did not alter the care the woman or baby received in the instance of any anticipated or unanticipated problem and standard procedures, as defined within the local Maternity Unit protocols, were then followed. An Independent Oversight Committee reviewed Serious Adverse Events and information was fed back to the Project Management Group and Sponsor as appropriate. Participant's could be unblinded to treatment allocation if necessary.
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Background therapy |
Oxytocin is routinely given to nulliparous women who become delayed in labour and it is given via an intravenous cannula, which is attached to intravenous fluid to which oxytocin is added. This is usual practice for these women and their participation in the study will not alter the route of oxytocin administration. The dose of oxytocin will usually be administered using an infusion pump and will be routinely increased every half hour until contractions are occurring 4-5 every 10 minutes. The dose increments are "titrated" against uterine activity. If there is evidence of excess uterine activity the dosage increase is stopped or reversed (the half life of oxytocin is 5 minutes) and once effective contractions are achieved it is not increased further. Delay in labour is an everyday occurrence on UK Labour Wards and the titration of oxytocin to re-establish effective uterine contractions is a situation clinicians are used to managing effectively. Women receiving oxytocin for delay in labour are routinely monitored more intensively by the midwife caring for the woman and this would normally include monitoring of the strength and frequency of contractions, the woman's observations and fluid balance. She will also be offered support and effective pain relief. Electronic Fetal heart Monitoring (EFM) would routinely be offered to detect signs of fetal hypoxia should they occur. Care of women having continuous EFM in the presence of oxytocin will follow that advocated by the NICE Intrapartum Care Guideline. Should uterine tachysytole occur (defined as more than 5 contractions in 10 minutes for 20 minutes) this will be documented and obstetric opinion sought, as is usual practice. Should uterine hyperstimulation occur (defined as tachysystole with suspicious or pathological fetal heart rate) this will be documented and obstetric opinion sought, as is usual practice. | ||
Evidence for comparator |
A major cause of failure to achieve spontaneous vaginal birth (SVB) is delay in labour caused by presumed inefficient uterine action. This is relatively common as it occurs in over a third of women in their first labours. Current practice is to augment uterine activity with an intravenous infusion of oxytocin in the belief that this will maximise the number giving birth spontaneously. However, this has been challenged by a systematic review undertaken for the National institute of Clinical Excellence (NICE) Intrapartum Guideline which found that the use of standard escalating low dose oxytocin regimens was associated with a shorter labour without change in mode of birth. It is plausible that the lack of effect of oxytocin is due to either an inadequate dose or delay in achieving effective doses and there is some evidence to suggest that high starting doses of oxytocin and more rapid escalation may increase the numbers of women having a SVB. The published trials are too small to reliably detect a meaningful difference. Furthermore they do not have enough information on neonatal outcomes or the impact on women's experience of childbirth or the relationship with her baby. Maximising the number of women who have a SVB is an objective that clinicians strive to achieve. Women who experience delay in labour pose particular challenges as they often give birth either by caesarean section (CS) or by assisted vaginal birth. Information from University Hospitals Leicester (UHL) over 2005 and 2006, showed that of nulliparous women who become delayed in labour and are given oxytocin, 40% will have a SVB, 40% an instrumental birth and 20% CS. The latter two are associated with higher maternal and neonatal mortality and morbidity and associated health service costs. Many women who have a CS will go on to have another CS in subsequent pregnancies and this group of women are currently the single largest group of elective CSs. | ||
Actual start date of recruitment |
01 Nov 2010
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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: 94
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Worldwide total number of subjects |
94
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EEA total number of subjects |
94
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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) |
3
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Adults (18-64 years) |
91
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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 |
A total of 94 consenting nulliparous women at term with confirmed delay in labour were recruited from 3 UK teaching hospitals between November 2010 and May 2011. | |||||||||||||||
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Pre-assignment
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Screening details |
Women were eligible for inclusion if they were consenting nulliparous women with a singleton pregnancy at term (37-42 weeks) gestation and had confirmed delay in labour as defined by NICE Intrapartum Care Guideline and with ruptured membranes. | |||||||||||||||
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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 |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||
Blinding implementation details |
The study drug will be blinded, randomised and packaged by a Bilcare pharma, which is a Clinical Trial Supplier and holds an MHRA IMP Manufacturers Licence (May 2004), together with an Manufacture and Assembly Licence Specials. Should unblinding be required, unblinding codes will be held in the Pharmacy Departments of each Maternity Unit, as well as by the Trial Statistician. Reasons for unblinding will be documented.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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High dose Oxytocin | |||||||||||||||
Arm description |
The high dose oxytocin regimen started at 4 mU/min and increased to a maximum dose of 64 mU/min. The high dose solution contained 2 x 10iu in 50 mls. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Syntocinon injection ampoules 10 IU/ml
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Investigational medicinal product code |
N/A
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Other name |
High dose Oxytocin
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
The high dose regimen starts at 4 mU/min and increases to a maximum dose of 64 mU/min.
Oxytocin is routinely given to nulliparous women who become delayed in labour and it is given via an intravenous cannula, which is attached to intravenous fluid to which oxytocin is added. This is usual practice for these women and their participation in the study will not alter the route of oxytocin administration.
The dose of oxytocin will usually be administered using an infusion pump and will be routinely increased every half hour until contractions are occurring 4-5 every 10 minutes. The dose increments are "titrated" against uterine activity. If there is evidence of excess uterine activity the dosage increase is stopped or reversed (the half life of oxytocin is 5 minutes) and once effective contractions are achieved it is not increased further.
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Arm title
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Standard Dose Oxytocin | |||||||||||||||
Arm description |
The standard dose is recommended by NICE in their Induction of Labour Guideline and has been widely adopted in the United Kingdom (UK). This regimen has never been evaluated in a clinical trial and fulfils the requirements of the "low dose" defined in the systematic review. It starts at 2 mU/min and increases to a maximum dose of 32 mU/min (as advocated by NICE). | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Syntocinon injection ampoules 5 IU/ml
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Investigational medicinal product code |
N/A
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Other name |
Standard Dose Oxytocin
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Oxytocin is routinely given to nulliparous women who become delayed in labour and it is given via an intravenous cannula, which is attached to intravenous fluid to which oxytocin is added. This is usual practice for these women and their participation in the study will not alter the route of oxytocin administration.
The dose of oxytocin will usually be administered using an infusion pump and will be routinely increased every half hour until contractions are occurring 4-5 every 10 minutes. The dose increments are "titrated" against uterine activity. If there is evidence of excess uterine activity the dosage increase is stopped or reversed (the half life of oxytocin is 5 minutes) and once effective contractions are achieved it is not increased further. The dose starts at 2 mU/min and increases to a maximum dose of 32 mU/min.
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Baseline characteristics reporting groups
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Reporting group title |
High dose Oxytocin
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Reporting group description |
The high dose oxytocin regimen started at 4 mU/min and increased to a maximum dose of 64 mU/min. The high dose solution contained 2 x 10iu in 50 mls. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard Dose Oxytocin
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Reporting group description |
The standard dose is recommended by NICE in their Induction of Labour Guideline and has been widely adopted in the United Kingdom (UK). This regimen has never been evaluated in a clinical trial and fulfils the requirements of the "low dose" defined in the systematic review. It starts at 2 mU/min and increases to a maximum dose of 32 mU/min (as advocated by NICE). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
High dose Oxytocin
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Reporting group description |
The high dose oxytocin regimen started at 4 mU/min and increased to a maximum dose of 64 mU/min. The high dose solution contained 2 x 10iu in 50 mls. | ||
Reporting group title |
Standard Dose Oxytocin
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Reporting group description |
The standard dose is recommended by NICE in their Induction of Labour Guideline and has been widely adopted in the United Kingdom (UK). This regimen has never been evaluated in a clinical trial and fulfils the requirements of the "low dose" defined in the systematic review. It starts at 2 mU/min and increases to a maximum dose of 32 mU/min (as advocated by NICE). | ||
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End point title |
Rate of Spontaneous Vaginal Birth | ||||||||||||||||||||||||
End point description |
Mode of birth
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End point type |
Primary
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End point timeframe |
At birth
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| Notes [1] - Includes 1 woman that withdrew [2] - Includes 1 woman that withdrew |
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Statistical analysis title |
Primary analysis | ||||||||||||||||||||||||
Statistical analysis description |
The primary clinical endpoint for the HOLDS pilot study is the rate of Spontaneous Vaginal Birth (SVB). SVB rates for each arm will be calculated, and an odds ratio (OR) together with a 95% confidence interval (CI) will be calculated.
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Comparison groups |
High dose Oxytocin v Standard Dose Oxytocin
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Number of subjects included in analysis |
94
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | ||||||||||||||||||||||||
Method |
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Parameter type |
Risk ratio (RR) | ||||||||||||||||||||||||
Point estimate |
1.2
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Confidence interval |
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95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.6 | ||||||||||||||||||||||||
upper limit |
2.5 | ||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
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| Notes [3] - No hypothesis testing proposed as this was a pilot study. |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events were reported from randomisation until discharge from hospital.
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Adverse event reporting additional description |
All expected SAEs will be reported on the data collection forms and will be reviewed by the Project Management Group (PMG) at the end of the pilot study. If any of the serious adverse events occur they will be reported to the Oversight Group (OG) and will also be reviewed by the PMG at the end of the pilot study.
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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 |
14
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Reporting groups
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Reporting group title |
High Dose Oxytocin
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Reporting group description |
2 women did not receive the intervention due to giving birth before the intervention could be given | |||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard Dose Oxytocin
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Reporting group description |
1 woman did not receive the intervention due to giving birth before the intervention could be given | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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20 Sep 2010 |
Changes to the protocol (updated to v3.0 20/09/2010):
• An addition to the Expected Serious Adverse Events of maternal admission to HDU/ITU (page 20 and 29)
• Removed reference to collecting a copy of the consent form for the Study Office (page 17)
We have also added a sentence to the consent form regarding the participant giving consent for contact details to be collected and for data to be transferred to the Study Office. This is clearly explained in the Participant information leaflet. Questionnaires 1 and 2 also have minor changes to the wording for clarity.
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20 Jan 2011 |
Changes to the protocol (updated to v4.0 20/01/2011):
• To increase the numbers of women we are hoping to recruit as recruitment is going well and we have enough treatment packs to continue.
• We are also having a disappointing response to the postal questionnaire after birth and would like the local midwife to ask the women they make contact with (as part of our agreed processes) who have not returned a questionnaire or agreed to be interviewed a few questions about their experiences.
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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. | |||
| The pilot study was not powered to detect differences in clinical outcomes. Only explored women’s experiences following a diagnosis of delay in labour, when the majority of women had an epidural in situ. Lack of non-European participants | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/23786339 |
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