Condition category
Signs and Symptoms
Date applied
29/07/2015
Date assigned
29/07/2015
Last edited
02/09/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Pain in babies has negative consequences, both immediately and in the longer term. As babies cannot describe their pain the measurement and treatment of pain is difficult and, compared to adults and older children, pain is undertreated in this group. Given that a baby requiring intensive care will experience an average of 12 painful procedures per day and, the youngest and sickest babies may experience 50 procedures per day, this is a serious clinical issue that urgently needs to be addressed. The aim of this study is to test whether morphine can provide effective pain relief in babies during invasive medical procedures. While morphine is frequently given to adults when they experience pain, it is not known whether morphine provides effective pain relief for acute pain in babies. An example of a painful procedure that is frequently and regularly performed on premature babies is an eye exam that tests for Retinopathy of Prematurity – this is a disease which if untreated can lead to permanent blindness. Although the exam is considered to be painful and can result in unstable breathing and heartbeat for up to 24 hours after the exam, the pain relief currently provided during this procedure has limited efficacy. Here, we want to see if morphine can provide effective pain relief for babies undergoing this exam.

Who can participate?
Infants that were born at less than 32 weeks gestation or with a birth weight or less than 1501g. They must be in-patients at the John Radcliffe Hospital in Oxford and be between 34-42 weeks gestational age when undergoing the test.

What does the study involve?
Participants are randomly allocated into one of two groups. Those in group 1 are given morphine during an eye exam testing for Retinopathy of Prematurity. Those in group 2 are given a placebo during the same procedure. Clinical pain assessment tools are used to measure pain experienced. Newly developed brain imaging techniques are also used to see how morphine can affect pain related brain activity.

What are the possible benefits and risks of participating?
We cannot guarantee any direct benefits. At present we don’t know whether giving a pain relieving medication (morphine) reduces the pain and discomfort caused by eye exams and blood tests. We are carrying out this study to help doctors make the right decisions about the care of preterm babies in the future. Morphine is a pain-relieving drug that is routinely used in children and adults to treat acute pain. Morphine is routinely used in the neonatal unit to sedate babies when they are ventilated, although to-date few studies have been carried out where morphine has been administered to babies to provide pain relief prior to invasive procedures. The dose of morphine (100 μg/kg) will be administered by mouth and has been approved by the neonatal pharmacist. Although morphine can have effects on breathing rate and blood pressure, a study that used twice this dose did not report any adverse side effects. We do not anticipate that the babies will experience these side effects and they will be monitored very closely by the staff on the neonatal unit

Where is the study run from?
John Radcliffe Hospital, Department of Paediatrics (UK)

When is the study starting and how long is it expected to run for?
January 2015 to November 2019

Who is funding the study?
1. National Institute for Health Research, EME (UK)
2. Wellcome Trust (UK)

Who is the main contact?
Dr Rebeccah Slater

Trial website

Contact information

Type

Public

Primary contact

Dr Rebeccah Slater

ORCID ID

Contact details

John Radcliffe Hospital
Department of Paediatrics
University of Oxford
Level 2
Children's Hospital
Oxford
OX3 9DU
United Kingdom

Additional identifiers

EudraCT number

2014-003237-25

ClinicalTrials.gov number

Protocol/serial number

19317

Study information

Scientific title

A blinded randomised placebo controlled trial investigating the efficacy of morphine analgesia for procedural pain in infants

Acronym

POPPI: procedural pain in premature infants

Study hypothesis

The aim of this study is to test whether morphine can provide effective pain relief in babies during invasive medical procedures.

Ethics approval

The Northampton Research Ethics Committee, 23/07/2015, ref.: 15/EM/0310

Study design

Blinded, placebo-controlled, parallel-group randomised clinical trial

Primary study design

Interventional

Secondary study design

Clinical trial of an investigational medicinal product (CTIMP)

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Topic: Children; Subtopic: Pain

Intervention

As of 02/09/2016:
1: Morphine Sulphate: 10ml of the IMP will be supplied in amber glass bottle at a concentration of 200 μg/ml. This will provide a dose of 100 μg/kg which will be administered orally by sterile oral/enteral 3ml syringe.
2: Placebo (inactive solution): The placebo (inactive solution) will be supplied in identical packaging but will contain only the carrier solution.
Study Entry: Single Randomisation only

Initial:
1. Morphine Sulphate: 2 ml of the IMP will be supplied at a concentration of 200 µg/ml. This will provide a dose of 100 µg/kg which will be administered orally by syringe
2. Placebo (inactive solution): The placebo (inactive solution) will be supplied in identical syringes but will contain only the carrier solution
Study Entry : Single Randomisation only

Intervention type

Other

Phase

Phase II

Drug names

Primary outcome measures

Current as of 04/02/2016:
1. Clinical pain score measured using the Premature Infant Pain Profile-revised (PIPP-R) 30 seconds after ROP screening
2. Magnitude of nociceptive-specific brain activity evoked by heel lance

Previous:
1. Clinical pain score measured using the Premature Infant Pain Profile (PIPP) 1 minute after ROP screening
2. Magnitude of nociceptive-specific brain activity evoked by heel lance

Secondary outcome measures

Current as of 04/02/2016:
1. Clinical stability in the 6-hour and 24-hour period following the start of the clinical intervention. The clinical intervention is defined as the heel lance followed by rhe ROP screening.
2. Premature infant pain profile-revised (PIPP-R) score and amplitude of nociceptive reflex withdrawal activity following heel lance
3. Drug safety will be assessed by calculating the number of incidences of apnoea that require intervention using NeoPuff or ‘bag and mask’ and the number of incidences of hypotension that require treatment with inotropes in the 24-hour period following the administration of the IMP or placebo.following ROP screening

Previous:
1. Clinical stability in the 6-hour and 24-hour period after ROP screening
2. Premature infant pain profile (PIPP) score and amplitude of nociceptive reflex withdrawal activity following heel lance
3. Drug safety will be assessed by calculating the number of incidences of apnoea that require intervention using NeoPuff or ‘bag and mask’ and the number of incidences of hypotension that require treatment with inotropes in the 24-hour period following ROP screening

Overall trial start date

01/01/2015

Overall trial end date

01/11/2019

Reason abandoned

Eligibility

Participant inclusion criteria

1. Participants will be in-patients on the neonatal unit at the John Radcliffe Hospital, Oxford
2. Infants born less than 32 weeks’ gestation or birth weight <1501 g
3. At the time of study, infants will be between 34 and 42 weeks gestational age (GA) and will be studied if they require a clinical heel lance and retinopathy of prematurity (ROP) screening on the same test occasion. We will study infants during a single ROP examination when they are greater than or equal to 34 weeks’ gestation
4. Infants for whom parents/guardians have consented to inclusion in the trial.; Upper Age Limit 42 weeks
Lower Age Limit 34 weeks
5. Senior clinician considers inclusion in trial to be medically appropriate (added 04/02/2016)

Participant type

Patient

Age group

Child

Gender

Both

Target number of participants

Planned Sample Size: 156; UK Sample Size: 156

Participant exclusion criteria

1. Intraventricular haemorrhage > grade II
2. Short bowel syndrome
3. Receiving nil by mouth due to documented gut pathology
4. Received opiates in the last 72 hours
5. Received other analgesics or sedatives in the last 24 hours
6. Previously documented episode of morphine sensitivity
7. Congenital malformation or genetic condition known to affect neurological development
8. Senior clinician considers inclusion in trial to be medically appropriate
9. Born to mothers who regularly use opiates during pregnancy or while breastfeeding or expressing breast milk

Recruitment start date

01/09/2016

Recruitment end date

01/06/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

John Radcliffe Hospital
Department of Paediatrics University of Oxford Level 2, Children's Hospital
Oxford
OX3 9DU
United Kingdom

Sponsor information

Organisation

Research Services, University of Oxford

Sponsor details

Joint Research Office
Churchill Hospital
Oxford
OX3 7LE
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

National Institute for Health Research, EME

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Funder name

Wellcome Trust

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

international

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The plan to publish the results of the study in a peer-reviewed medical journal after we have acquired and analysed the data.

Intention to publish date

01/11/2019

Participant level data

Not expected to be available

Results - basic reporting

Publication summary

2016 protocol: http://www.thelancet.com/doi/story/10.1016/html.2016.01.19.2536

Publication citations

Additional files

Editorial Notes

02/09/2016: Interventions have been amended (see changes in interventions field). Overall study end date has changed from 01/06/2019 to 01/11/2019. Recruitment start date has changed from 01/05/2016 to 01/09/2016. Recruitment end date has changed from 01/07/2018 to 01/06/2019. Intention to publish date changed from 31/10/2019 to 01/11/2019. 04/02/2016: Please note that as of 04/02/2016 this trial record was extensively amended. Most of the changes to this record can be found in the relevant field, under the date on which the amendment was made. The following changes have also taken place: 1. The overall end date was changed from 01/07/2018 to 01/06/2019 2. The recruitment start date was changed from 01/10/2015 to 01/05/2016 and the recruitment end date was changed from 01/07/2018 to 01/02/2019 3. The funder name was changed from "National Institute for Health Research" to "National Institute for Health Research, EME" 4. Date of ethics approval was added. 5. Expected date of publication was added