Clonidine for Analgesia to Preterm Infants During Neonatal Intensive Care

Study Overview
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Brief Summary
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A prospective pharmacokinetic (PK), pharmacodynamic (PD) and pharmacogenetic (PG) observation study, including the PK/PD/PG relationship, in clonidine administered for analgesia and sedation to preterm newborn infants receiving neonatal intensive care. Phase 3 - therapeutic confirmatory study

Detailed Description
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All preterm infants that are admitted to the study neonatal intensive care units (NICUs) for neonatal intensive care are potential study patients, and their parents will be asked for consent. The patient will be treated according to clinical guidelines and will be included in the study if in need for clonidine according to clinical judgment (pain scores) and as decided by the responsible clinical doctor. The dosing and administration of the drug will be implemented according to an algorithm based on pain scoring results. Apart from extra blood sampling, the bedside monitoring, investigations (electroencephalography, EEG, echocardiography, ECG, ultrasound of the brain) and follow-up (neurologic examination and magnetic resonance imaging, MRI) are the same as for all preterm infants according to local and national guidelines. In total 100 infants will be included.

Official Title
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Clonidine for Analgesia to Preterm Infants During Neonatal Intensive Care - a Prospective Pharmacokinetic/Pharmacodynamic/Pharmacogenetic Observational Study. Cohort 2 in The SANNI Project

Conditions
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Analgesia, Intensive Care, Neonatal, Hypnotics and Sedatives

Intervention / Treatment
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* Drug: Clonidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm infants (< gw 37+0) who are in need for analgesic or sedative medication according to clinical judgment (scoring with pain assessment scales; ALPS-Neo and Comfort-Neo) Existing arterial or venous cannulas/catheters for repeated non-traumatic blood sampling Informed and written parental consent Exclusion Criteria: Hemodynamic instability (same as in clinical routine). Cardiac malformations in need for postnatal surgery. Any serious medical condition or ethical issues that could, in the Investigators opinion, interfere with the study procedures.

Ages Eligible for Study
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Maximum Age: 37 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Clonidine<br>Preterm infants (< gw 37+0) who are in need for analgesic or sedative medication will receive treatment with clonidine according to an algorithm based on pain and sedative scoring results | Drug: Clonidine<br>* Clonidine will be administered to preterm infants in need of analgesia and sedation; either as the primary drug for comfort and light sedation or as an add-on drug to opioids according to an algorithm based on pain and sedative scoring results. Opioids are mostly given to postoperative patients. These drugs (morphine or fentanyl) will not be studied, but a baseline PK sample will be taken to correlate to the baseline aEEG.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of clonidine; S-concentration | Clonidine analyses will be performed with LC-MS standard assay on a Waters ultra-pressure liquid chromatography (UPLC)-MS/MS system and then statistically analysed with NONMEM (Non-linear Mixed Effect Modelling) populationbased PK statistics | Repeated blood samples (5 minutes after the loading dose, just before start of the clonidine infusion and at 1 hour, 24 hours, 48 hours and 72 hours after start of the infusion | 
| Pharmacokinetics (PK) of clonidine; elimination half-time | Statistical analyses will be performed with NONMEM (Non-linear Mixed Effect Modelling) populationbased PK statistics | Data from repeated blood samples (5 minutes after the loading dose, just before start of the clonidine infusion and at 1 hour, 24 hours, 48 hours and 72 hours after start of the infusion | 
| Pharmacokinetics (PK) of clonidine; clearance | Statistical analyses will be performed with NONMEM (Non-linear Mixed Effect Modelling) populationbased PK statistics | Data from repeated blood samples (5 minutes after the loading dose, just before start of the clonidine infusion and at 1 hour, 24 hours, 48 hours and 72 hours after start of the infusion | 
| Pharmacokinetics (PK) of clonidine; volume of distribution | Statistical analyses will be performed with NONMEM (Non-linear Mixed Effect Modelling) populationbased PK statistics | Data from repeated blood samples (5 minutes after the loading dose, just before start of the clonidine infusion and at 1 hour, 24 hours, 48 hours and 72 hours after start of the infusion | 
| Neurophysiologic amplitude-integrated EEG response in relation to PK | Analyse of single cortical events and their dynamics, based on burst detection and measuring features of individual bursts as well as their mass statistical behaviour over time. | From 30 minutes before start of treatment until 72 hours after start of treatment. | 
| Neurophysiologic amplitude-integrated EEG response; longer term brain function in relation to PK | Assessment of longer term brain function using measures of long range correlation and brain activity cycling. | From 30 minutes before start of treatment until 72 hours after start of treatment. | 
| Neurophysiologic amplitude-integrated EEG response; assessment of global brain network function in relation to PK | Assessment of global brain network function will be based on Activation Synchrony Index. | From 30 minutes before start of treatment until 72 hours after start of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in/association between heart rate in relation to PK . | The heart rate will be monitored 1/second according to clinical routine in the neonatal intensive care, and concomitantly downloaded into the aEEG (amplitude integrated electroencephalography) monitor. The change will be described as percentage increase/decrease | From 30 minutes before start of treatment until 72 hours. | 
| Change in/association between blood pressure (systolic, diastolic and mean arterial blood pressure) in relation to PK . | The blood pressure will be monitored 1/second according to clinical routine in the neonatal intensive care, and concomitantly downloaded into the aEEG (amplitude integrated electroencephalography) monitor. The change will be described as percentage increase/decrease | From 30 minutes before start of treatment until 72 hours. | 
| Change in/association between peripheral oxygen saturation in relation to PK . | The peripheral oxygenation will be monitored 1/second according to clinical routine in the neonatal intensive care, and concomitantly downloaded into the aEEG (amplitude integrated electroencephalography) monitor. The change will be described as percentage increase/decrease | From 30 minutes before start of treatment until 72 hours. | 
| Change in NIRS (near-infrared spectroscopy) response in relation to PK . | The NIRS registration will be sampled into a USB and downloaded and analysed. The change will be described as percentage increase/decrease | From 30 minutes before start of treatment until 72 hours. | 
| Change in pain, stress and behavioral state as assessed with a pain scale for continuous pain/stress (Astrid Lindgrens and Lund childrens hospitals Pain and stress assessment scale for Preterm and Sick newborn infants, ALPS-Neo) in relation to PK. | Change in pain responses as measured by pain assessment scores for continuous pain/stress, The Astrid Lindgren and Lund Children's Hospitals Pain and Stress Assessment Scale for Preterm and sick Newborn Infants (ALPS-Neo) in relation to PK. This scale evaluates facial expression, breathing pattern, tone of extremities, hand/foot activity and level of activity, rated 0-2. Will be assessed hourly according to clinical routine. The relation to PK will be analysed with the help of NONMEM statistics | From 30 minutes before start of treatment until 72 hours. | 
| Change in pain, stress and behavioral state as assessed with a pain scale for continuous pain/stress (The COMFORT-Neo scale) in relation to PK | Change in pain responses as measured by pain assessment scores for continuous pain/stress, the Comfort Neo, in relation to PK. This scale evaluates alertness, calmness/agitation, respiratory response, crying, body movement, facial tension and muscle tone, rated 0-5. Will be assessed hourly according to clinical routine. The relation to PK will be analysed with the help of NONMEM statistics | From 30 minutes before start of treatment until 72 hours. | 
| Procedural pain response in relation to PK: assessed with change in galvanic skin response | Procedural pain response at a short standardized pain stimulation; as assessed with change in galvanic skin response in relation to PK. The change will be described as percentage increase/decrease | At one occasion during the study period (72 hours) when the analgesic treatment has not been changed the last six hours. | 
| Procedural pain response in relation to PK: change in serum-cortisol | Procedural pain response at a short standardized pain stimulation; change in serum-cortisol in relation to PK. The relation to PK will be analysed with NONMEM statistics. | At one occasion during the study period (72 hours) when the analgesic treatment has not been changed the last six hours. | 
| Procedural pain response in relation to PK as assessed with the Premature Infant Pain Profile - revised, PIPP-R, a scale for assessment of procedural pain. | Procedural pain response at a short standardized pain stimulation; as scored by a procedural pain assessment scale (Premature Infant Pain Profile - revised, PIPP-R) in relation to PK. The relation to PK will be analysed with NONMEM statistics. | At one occasion during the study period (72 hours) when the analgesic treatment has not been changed the last six hours. | 
| Pharmacogenetic profile in relation to PK results how PK phenotypes depend on pharmacogenetic (PG) profiles. | Whole exome sequencing will be conducted, specific pain related genes investigated and related to PK | One blood sample during the study period of 72 hours | 
| Pharmacogenetic profile in relation to PD results | Whole exome sequencing will be conducted, specific pain related genes investigated and related to pain response as assessed with scores, serum cortisol and skin conductance. | One blood sample during the study period of 72 hours |