Clinical trial NCT02085213: GOT-IT Trial: Glyceryl Trinitrate for Retained Placenta
Official title: GOT-IT Trial: A Pragmatic Group Sequential Placebo Controlled Randomised Trial to Determine the Effectiveness of Glyceryl Trinitrate for Retained Placenta.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Placenta, Retained
Keywords: Retained placenta
Manual Removal of Placenta
Glyceryl Trinitrate
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
Collaborators: name: University of Aberdeen
name: NHS Lothian
First posted: 2014-03-12
Enrollment: 1107
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A retained placenta (RP) is a complication after a normal birth, which affects nearly 11,000 women in the UK per year. This is where the placenta is not delivered spontaneously after giving birth. It is a major cause of postpartum haemorrhage (major loss of blood) which can lead to the death of the mother. The recommended treatment for RP is a surgical procedure - manual removal of placenta (MROP). This is a painful and unpleasant intervention for the women, involving additional hospital stay, and is an expensive outcome for the NHS. It is widely recognised that non-surgical management options for RP are limited and it has been recommended that research is needed into new medical treatments for RP. New effective treatments for RP would dramatically reduce the number of women requiring MROP with the operation being restricted to the small minority of women with particularly stuck placentae. The reduction in operative interventions would have cost benefits for the NHS and also for women in terms of increased satisfaction, less separation of mother and baby immediately after birth, and reduced morbidity.

This study will try to prove the clinical and cost effectiveness of a known treatment for angina, Glyceryl trinitrate (GTN) used to treat RP. The investigators will compare GTN against a placebo (dummy treatment) in a randomised controlled blinded trial (GOT-IT).

The GOT-IT Trial will be conducted in two phases. The first phase will involve an internal pilot study where the aim will be to test out and refine trial procedures in a small number of hospital sites. The second phase will be the main trial where recruitment will be extended to a larger number of hospitals in order to determine clinical and cost effectiveness.

Detailed description: Although a growing body of evidence supports a use for GTN for treatment of RP, much of this evidence is based on anecdotal case-reports or clinical "trials" which are non-randomised, do not include a placebo arm and are underpowered. Further, in the context of constrained maternity resources in a publicly funded health system, it is important to quantify the costs associated with the use of GTN (including any subsequent monitoring costs and costs associated with complications) in relation to its effectiveness and any subsequent cost savings it may deliver over standard practice. There is therefore an urgent need for a pragmatic clinical trial of GTN for RP to determine whether GTN is efficacious, safe, acceptable and cost-effective as a treatment for RP before a treatment which may (or may not) work is embedded within routine clinical practice. Our proposed randomised placebo controlled double blind pragmatic UK wide GOT-IT trial RCT (with internal pilot study) will definitively determine whether sublingual GTN is (or is not) clinically and cost effective for management of RP.

Eligibility criteria: Inclusion Criteria:

* Women with retained placenta.
* Women aged 16 or over.
* Women with vaginal delivery (including women with a previous caesarean section).
* Haemodynamically stable (systolic blood pressure more than 100mg Hg and pulse less than 110 beats per min).
* \> 14 weeks gestation.

Exclusion Criteria:

* Unable to give informed consent.
* Suspected placenta accreta/increta/percreta.
* Multiple pregnancy.
* Women having an instrumental vaginal delivery in theatre
* Allergy or hypersensitivity to nitrates or any other constituent of the formulation.
* Taken alcohol in the last 24 hours.
* Concomitant use with phosphodiesterase inhibitors (such as sildenafil, tadalafil, or vardenafil).
* Contra-indication due to one of the following: Severe anaemia, constrictive pericarditis, extreme bradycardia, incipient glaucoma, Glucose-6- phosphatedehydrogenase-deficiency, cerebral haemorrhage and brain trauma, aortic and / or mitral stenosis and angina caused by hypertrophic obstructive cardiomyopathy. Circulatory collapse, cardiogenic shock and toxic pulmonary oedema.
* Currently participating in another CTIMP.

Primary outcomes:
measure: Need for Manual Removal of Placenta
timeFrame: From time of randomisation up to 15-minutes post administration of study treatment
Secondary outcomes:
measure: Fall in haemoglobin
timeFrame: First postnatal day (approximately 24 hours since the birth).
measure: Time from randomisation to delivery of placenta.
timeFrame: From time of randomisation and administration of the study treatment to delivery of placenta (up to approximately 2 hours).
measure: Need for earlier than planned MROP on the basis of the clinical condition.
timeFrame: From time of randomisation and administration of the study treatment to delivery of placenta (up to approximately 2 hours).
measure: Systolic and diastolic blood pressure.
timeFrame: Study treatment to 15 minutes postadministration.
measure: Need for blood transfusion
timeFrame: From the time of delivery of the placenta to time of discharge from hospital (up to 7 days).
measure: Need for general anaesthesia
timeFrame: From time of randomisation and administration of the study treatment to delivery of placenta (up to approximately 2 hours).
measure: Maternal Pyrexia
timeFrame: Within 72 hours of delivery or discharge from hospital if discharge occurs sooner
measure: Sustained uterine relaxation.
timeFrame: Within 24 hours of the time of delivery of the placenta.
measure: Mean costs for each treatment allocation group
timeFrame: 6 weeks.
Other outcomes:
Locations:
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh
state: Midlothian
Study officials:
affiliation: University of Edinburgh
name: Fiona C Denison, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Denison FC, Carruthers KF, Hudson J, McPherson G, Chua GN, Peace M, Brewin J, Hallowell N, Scotland G, Lawton J, Norrie J, Norman JE; GOT-IT investigator team. Nitroglycerin for treatment of retained placenta: A randomised, placebo-controlled, multicentre, double-blind trial in the UK. PLoS Med. 2019 Dec 30;16(12):e1003001. doi: 10.1371/journal.pmed.1003001. eCollection 2019 Dec.