PainPhase 1/2NCT03035578
Development of a Morphine Pharmacokinetic and Pharmacodynamic Model for the Neonatal Population
A Phase 1/2 study testing Morphine in people with Pain and Drug Effect, run by The Hospital for Sick Children.
Trial summary
This research aims to study what the baby's body does with morphine and how morphine works in the baby's body. One hundred newborn babies will be enrolled in this study. With a better understanding of the drug doctors and nurses will have more information and better administer the drug in case of pain, stress or… Read more about this study
- Who is it for?
- Ages 24 to 42 weeksHealthy volunteers can take part
- Conditions the study is for
- Pain, Drug Effect
- What is being tested?
- Morphine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- 1 Dec 2017to 1 Jun 2019
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 24 to 42 weeks
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- Gestational age > 24 completed weeks.
- Clinically prescribed to commence a continuous morphine infusion.
Who cannot join
- Gestational age < 24 completed weeks.
- Critically ill infant unlikely to survive for more than 72 hours.
- Prolonged fetal exposure to morphine, any other narcotic, or methadone, as a consequence of maternal use of the drug.
- Any postnatal exposure to morphine during the 72 hours prior to the commencement of the second morphine infusion.
- Neonates with impaired cardiac, hepatic or renal functioning as defined by clinical signs of impaired perfusion, abnormal liver function tests, or an elevated serum creatinine.
- Neonates with seizures.
- The attending neonatologist considers that participation in the study is contraindicated.
About this study
This research aims to study what the baby's body does with morphine and how morphine works in the baby's body. One hundred newborn babies will be enrolled in this study. With a better understanding of the drug doctors and nurses will have more information and better administer the drug in case of pain, stress or discomfort.
Read the detailed description
Critically ill immature preterm infants experience multiple noxious stimuli while receiving care in the Neonatal Intensive Care Unit (NICU). These noxious stimuli include, but are not limited to: venipuncture; insertion of intravenous and arterial catheters; suctioning of the nose, mouth and oropharynx; endotracheal intubation for mechanical ventilation; insertion of chest drains; repositioning and other types of patient manipulation. The delivery of optimal doses of analgesics for these noxious stimuli is a major challenge due to the lack of knowledge about drug disposition and its effects in this patient population.
Morphine is the commonest analgesic used in the NICU. The Premature Infant Pain Profile (PIPP) is used to quantify pain in the NICU1. This objective score, which combines physiological and behavioural variables defining levels of discomfort, is used as a guide for the use of morphine in newborn infants. Multidimensional pain assessment tools, such as PIPP, can easily identify behaviour in healthy infants undergoing painful events, however, its efficiency is questionable when applicable to critically ill premature infants with neurological impairment, where the pain processing and modulation may be altered. Pharmacokinetics/Pharmacodynamics (PKPD) models can be used to quantitatively describe and predict drug disposition in the blood and the target organ (e.g., brain) in relation to doses and patient characteristics. Although there has been a global effort to describe morphine plasma levels in this population using a pharmacokinetic modelling approach2-5, PKPD model development has not been reported. The study of morphine pharmacokinetics to determine the optimal dose for balancing analgesia/sedation together with the design of pharmacodynamic model for morphine may provide a better understanding of nociception/pain profile based on the physiological variables of immature infants. Moreover, the PKPD model may be used to achieve optimal therapeutic effects through individualised model-based dose selection. Objective: This study is composed by four main objectives:
- First: Define target morphine plasma and brain concentrations. To this end, we will develop a morphine PKPD model based on population PK characteristics and morphine effects captured by functional readout of central nervous system function;
- Second: Develop an opportunistic sampling method for fragile populations based on saliva sampling;
- Third: Compare pharmacokinetic parameters calculated from saliva with plasma sample;
- Fourth: Application of the morphine PKPD model for prediction of optimal morphine dosing in individual patients using the Bayesian framework of model refinement.
- Conditions
- Pain, Drug Effect
- Being tested
- Morphine
- Keywords
- Pharmacokinetics, Pharmacodynamics, Morphine, Neonatal
- Medical subject headings
- Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MorphineDrug
Sampling blood for development of Morphine Pharmacokinetic/Pharmacodynamic Model for Neonatal Population
MorphineDrug
Sampling saliva for development of Morphine Pharmacokinetic/Pharmacodynamic Model for Neonatal Population
| Study group | Role | What they receive |
|---|---|---|
| Morphine Blood and Saliva sampling | Experimental | The infants will receive a 50 mcg/kg loading dose of morphine followed by a constant infusion.Morphine Injection: 10mg/mL, 1mL ampoules.Two strengths of stock syringes:
a)patients <1.5kg, morphine 0.5mg/25mL; b)patients 1.5kg to <5kg, morphine 1mg/25mL.
Time blood samples will be collected for measurement of whole blood concentration of morphine in 24h. Total morphine, morphine-3-glucuronide and morphine-6-glucuronide concentrations; volume of blood required is 0.25 ml. Sparse sampling strategy will be used for those neonates < 1250; total volume of blood required is 0.50 ml. Frequent sampling strategy will be used for those neonates ≥ 1250 gm; total volume of blood required is 0.50 ml.Saliva samples will be collected at 10 and 30 minutes and at 6, 12 and 24h after morphine infusion started.100 uL of saliva, captured using a collection swab. Receives: Drug: Morphine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Target Morphine Plasma Concentration
Sparse sampling coupled with population (mixed effects) method will be used to design the morphine pharmacokinetics phase. This method captures pharmacokinetics data from many subjects (learning about population), which are based on a relatively few number of samples per patient (learning about individual characteristics considering the large number of samples).Population pharmacokinetic parameters will be estimated using a non-linear mixed effects modelling with NONMEM software.
Measured: 12 months (blood sampling and modeling)
Secondary outcomes (1)
Brain Morphine Concentrations
The drug effect will be design using the sigmoid modelling. The effect of drugs modeled by relating drug effect to the drug concentration (obtain in the primary outcome). The pain scores and amplitude-integrated electroencephalography (aEEG) will be used as markers of drug effect on the central nervous system for the development of the pharmacodynamic model. The effect-site concentration will be validated by comparing the predicted time of peak effect with the time of peak effect of aEEG effect. Heart rate, respiratory rate, blood oxygen saturation, and blood pressure will be captured continuously through neonatal computational platform with the intent to investigate, other pharmacodynamic relationship using the sigmoid modelling.
Measured: 12 months (a-eeg collection and modeling)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jan 2017 (estimated)
- Study start1 Dec 2017 (estimated)
- Primary completion1 Jun 2018 (estimated)
- Study completion1 Jun 2019 (estimated)
Why it stopped: research project has been abandoned primarily because of the excessive delays associated with past challenges in obtaining approval from Health Canada
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for PainStudies of the same condition, open and under way.
- More trials run by The Hospital for Sick ChildrenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Hospital for Sick Children
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Andrew James, The Hospital for Sick Children
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03035578
- Sponsor's protocol ID
- 1000053067
- Status last verified
- Feb 2020
- First submitted
- 24 Jan 2017
- Last updated
- 25 Feb 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 25 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Development of a Morphine Pharmacokinetic and Pharmacodynamic Model for the Neonatal Population
- ClinicalTrials.gov ID
- NCT03035578
- Acronym / sponsor ID
- 1000053067
- Conditions
- Pain, Drug Effect
- Keywords
- Pharmacokinetics, Pharmacodynamics, Morphine, Neonatal
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: research project has been abandoned primarily because of the excessive delays associated with past challenges in obtaining approval from Health Canada
- Enrolment
- 0 participants (actual)
- Lead sponsor
- The Hospital for Sick ChildrenUniversity, hospital or other
- Study start
- 1 Dec 2017 (estimated)
- Primary completion
- 1 Jun 2018 (estimated)
- Study completion
- 1 Jun 2019 (estimated)
- First posted
- 30 Jan 2017 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This research aims to study what the baby's body does with morphine and how morphine works in the baby's body. One hundred newborn babies will be enrolled in this study. With a better understanding of the drug doctors and nurses will have more information and better administer the drug in case of pain, stress or discomfort.
Detailed description
Critically ill immature preterm infants experience multiple noxious stimuli while receiving care in the Neonatal Intensive Care Unit (NICU). These noxious stimuli include, but are not limited to: venipuncture; insertion of intravenous and arterial catheters; suctioning of the nose, mouth and oropharynx; endotracheal intubation for mechanical ventilation; insertion of chest drains; repositioning and other types of patient manipulation. The delivery of optimal doses of analgesics for these noxious stimuli is a major challenge due to the lack of knowledge about drug disposition and its effects in this patient population.
Morphine is the commonest analgesic used in the NICU. The Premature Infant Pain Profile (PIPP) is used to quantify pain in the NICU1. This objective score, which combines physiological and behavioural variables defining levels of discomfort, is used as a guide for the use of morphine in newborn infants. Multidimensional pain assessment tools, such as PIPP, can easily identify behaviour in healthy infants undergoing painful events, however, its efficiency is questionable when applicable to critically ill premature infants with neurological impairment, where the pain processing and modulation may be altered. Pharmacokinetics/Pharmacodynamics (PKPD) models can be used to quantitatively describe and predict drug disposition in the blood and the target organ (e.g., brain) in relation to doses and patient characteristics. Although there has been a global effort to describe morphine plasma levels in this population using a pharmacokinetic modelling approach2-5, PKPD model development has not been reported. The study of morphine pharmacokinetics to determine the optimal dose for balancing analgesia/sedation together with the design of pharmacodynamic model for morphine may provide a better understanding of nociception/pain profile based on the physiological variables of immature infants. Moreover, the PKPD model may be used to achieve optimal therapeutic effects through individualised model-based dose selection. Objective: This study is composed by four main objectives:
- First: Define target morphine plasma and brain concentrations. To this end, we will develop a morphine PKPD model based on population PK characteristics and morphine effects captured by functional readout of central nervous system function;
- Second: Develop an opportunistic sampling method for fragile populations based on saliva sampling;
- Third: Compare pharmacokinetic parameters calculated from saliva with plasma sample;
- Fourth: Application of the morphine PKPD model for prediction of optimal morphine dosing in individual patients using the Bayesian framework of model refinement.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Morphine Blood and Saliva sampling | Experimental | Drug: MorphineThe infants will receive a 50 mcg/kg loading dose of morphine followed by a constant infusion.Morphine Injection: 10mg/mL, 1mL ampoules.Two strengths of stock syringes: a)patients <1.5kg, morphine 0.5mg/25mL; b)patients 1.5kg to <5kg, morphine 1mg/25mL. Time blood samples will be collected for measurement of whole blood concentration of morphine in 24h. Total morphine, morphine-3-glucuronide and morphine-6-glucuronide concentrations; volume of blood required is 0.25 ml. Sparse sampling strategy will be used for those neonates < 1250; total volume of blood required is 0.50 ml. Frequent sampling strategy will be used for those neonates ≥ 1250 gm; total volume of blood required is 0.50 ml.Saliva samples will be collected at 10 and 30 minutes and at 6, 12 and 24h after morphine infusion started.100 uL of saliva, captured using a collection swab. |
Who may qualify
- Ages
- 24 to 42 weeks
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (2 listed)
- Gestational age > 24 completed weeks.
- Clinically prescribed to commence a continuous morphine infusion.
Key exclusion criteria (7 listed)
- Gestational age < 24 completed weeks.
- Critically ill infant unlikely to survive for more than 72 hours.
- Prolonged fetal exposure to morphine, any other narcotic, or methadone, as a consequence of maternal use of the drug.
- Any postnatal exposure to morphine during the 72 hours prior to the commencement of the second morphine infusion.
- Neonates with impaired cardiac, hepatic or renal functioning as defined by clinical signs of impaired perfusion, abnormal liver function tests, or an elevated serum creatinine.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MorphineSampling blood for development of Morphine Pharmacokinetic/Pharmacodynamic Model for Neonatal Population | Drug | Morphine Blood and Saliva sampling |
| MorphineSampling saliva for development of Morphine Pharmacokinetic/Pharmacodynamic Model for Neonatal Population | Drug | Morphine Blood and Saliva sampling |
Primary outcome
Target Morphine Plasma Concentration
Time frame: 12 months (blood sampling and modeling)
Sparse sampling coupled with population (mixed effects) method will be used to design the morphine pharmacokinetics phase. This method captures pharmacokinetics data from many subjects (learning about population), which are based on a relatively few number of samples per patient (learning about individual characteristics considering the large number of samples).Population pharmacokinetic parameters will be estimated using a non-linear mixed effects modelling with NONMEM software.
1 secondary outcome
Brain Morphine Concentrations
Time frame: 12 months (a-eeg collection and modeling)
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2020.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Morphine in people with Pain and Drug Effect, run by The Hospital for Sick Children.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 25 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Target Morphine Plasma Concentration (time frame: 12 months (blood sampling and modeling)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2020.