PainPhase 1/2NCT01094522
Measuring the Amount of Methadone or Morphine in the Blood of Neonates, Infants & Children After Cardiac Surgery.
A Phase 1/2 study testing Methadone and Morphine in people with Pain, run by Stanford University at 3 sites in United States.
Trial summary
Study Population: Neonates, infants and children from birth to 5 years of age undergoing cardiac surgery with CPB. The use of methadone to provide analgesia may be increasing due to advantages compared to other commonly used opioid analgesic drugs. Read more about this study
- Who is it for?
- Ages Up to 5 years
- Conditions the study is for
- Pain
- What is being tested?
- Methadone and Morphine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 47 participants
- Where
- 3 sitesUnited States
- Study dates
- Mar 2010to Jun 2012
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 Up to 5 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Neonates, infants and children from birth through 5 years of age undergoing mechanical ventilation following cardiac surgery for congenital heart disease. Congenital heart lesions include "two ventricle repairs", including tetralogy of Fallot, transposition of the great arteries, "unobstructed" total anomalous pulmonary venous return, truncus arteriosus, atrioventricular canal defect and ventricular septal defect.
Who cannot join
- Subjects will be excluded from the study because of prematurity (gestational age < 37 weeks), weight < 3.0 kg, severe hepatic dysfunction (elevation of conjugated bilirubin > 2, AST/ALT > 200 IU/L), significant renal dysfunction (serum Cr > 1.5 mg/dL), participation within 30 days of study entry or within 5 times the half-life, whichever is longer, in another investigational drug study, or previous participation in this study. Patients will be excluded if they have received opioids for more than 12 hours of the 48-hour period prior to surgery. In addition, patients will be excluded if they have a history of other clinically significant medical problems, which, in the opinion of the investigator, would interfere with study participation.
Trial locations and contacts
3 sites in 1 country.
United States3 sites
University of Colorado
Denver, Colorado
Oregon Health & Sciences University
Portland, Oregon, 97239
Stanford University School of Medicine
Stanford, California, 94305
About this study
Official title: A Randomized, Double-blind, Controlled, Multi-site Study of the Pharmacokinetics and Pharmacodynamics of Methadone vs. Morphine During Mechanical Ventilation Following Cardiac Surgery in Neonates, Infants and Children
Study Population:
Neonates, infants and children from birth to 5 years of age undergoing cardiac surgery with CPB.
The use of methadone to provide analgesia may be increasing due to advantages compared to other commonly used opioid analgesic drugs. While efficacy of methadone has been reported in adults, there is a paucity of information in neonates and infants. In the latter population, fentanyl and morphine are most commonly used for opioid analgesia following major surgery, while methadone is frequently used for weaning of opioid dependent and tolerant patients, in spite of the paucity of knowledge of methadone pharmacology in this population. There are several clinical problems associated with fentanyl and morphine, and methadone may offer superior efficacy with fewer side effects than these agents. We propose to study the pharmacokinetics (PK) and pharmacodynamics (PD) of methadone in neonates and infants in the intensive care unit following cardiac surgery.
Read the detailed description
Treatment:
Fentanyl will be administered for intraoperative analgesia by the treating anesthesiologist in a dose range of 25 - 50 mcg/kg. No other intraoperative opioids will be given.
Subjects will receive intravenous methadone or morphine ("study drug") delivered by an initial IV "bolus" injection followed by a nurse-administered patient controlled analgesia (PCA) device for postoperative pain for a period of 24 hours. The initial dose of study drug will be 0.2 mg/kg IV administered following admission to the ICU after surgery. The study drug will then be given at a dose of 0.035 mg/kg IV as needed q30min via PCA. The study drug may be increased or decreased in increments of 20-25% according to the discretion of the investigator as needed to maintain a FLACC pain assessment tool < 4. Subjects will also receive lorazepam 0.025 mg/kg IV q2hr as needed for agitation as indicated by specific criteria. The study drug will be discontinued after 24 hours to facilitate "wash out" sampling and determination of elimination half-life. Beginning at 24 hours, fentanyl will be used for analgesia at an equianalgesic dose to be determined by the investigator based upon the current PCA "study drug" dose.
Measurements and Monitoring:
- Blood samples will be obtained for measurement of concentrations of methadone (methadone group) and morphine and its metabolites, morphine-3-glucuronide and morphine-6-glucuronide (morphine group), prior to administration of initial bolus dose (t = 0) and t = 5 min, 15 min, 30 min, 60 min, 2 hrs, 4 hrs and 6 hrs; thereafter, blood samples will be obtained for measurement every 6 hrs for up to 90 hrs according to availability of vascular access for phlebotomy.
- Continuous monitoring: temperature (rectal), electrocardiogram, heart rate, systemic arterial blood pressure, central venous blood pressure, respiratory rate, oxygen saturation (pulse oximetry)
- Intermittent recording (q1hr): urine output
- Lab Tests (at baseline[prior to study procedures] and 24 hours after initial dose of study medication): arterial blood gas tensions, arterial lactate, Hb/Hct, BUN/Cr, glucose, AST, ALT
- 12 lead ECG at hour 24 for determination of QTc.
- The Faces, Legs, Activity, Cry, Consolability (FLACC) Scale recoded every hour, and preceding every study medication PCA dose for 24 hours.
- Subject follow up at 90 hours to record time of extubation, re-intubation if necessary, and reason for re-intubation.
Primary Endpoints: Pharmacokinetics of methadone and morphine, including its metabolites (morphine-3-glucuronide and morphine-6-glucuronide)
Secondary Endpoints:
- Pain scores (FLACC) during the 24 hours study period
- Amount of study drug administered during the 24-hour dosing period
- Changes in heart rate, systemic arterial blood pressure and laboratory test values
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethadoneDrug
0.2 mg/kg (IV) for the Initial Loading Dose; followed by PRN ("as needed") doses (given by the ICU Nurses) starting at 0.035 mg/kg (IV) every 30 minutes, for postoperative pain. The PRN dose of methadone may be increased by the ICU doctors until the dose is adequate to relieve the patient's pain.
MorphineDrug
Also called MS
0.2 mg/kg (IV) for the Initial Loading Dose; followed by PRN ("as needed") doses (given by the ICU Nurses) starting at 0.035 mg/kg (IV) every 30 minutes, for postoperative pain. The PRN dose of morphine may be increased by the ICU doctors until the dose is adequate to relieve the patient's pain.
| Study group | Role | What they receive |
|---|---|---|
| Methadone | Experimental | One half the Study patients will be randomized to receive a loading dose of IV methadone, followed by IV doses (given by the ICU nurse), on a PRN basis, for pain control for up to 24 hours during their postoperative course while they are intubated. Receives: Drug: Methadone |
| Morphine | Active comparator | One half the Study patients will be randomized to receive a loading dose of IV morphine, followed by IV doses (given by the ICU nurse), on a PRN basis, for pain control for up to 24 hours during their postoperative course while they are intubated. Receives: Drug: Morphine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Concentration of Morphine Including Its Metabolites (Morphine-3-glucuronide and Morphine-6-glucuronide)
Measured: 0, 15, 30 minutes, 1, 2, 4, 6 hrs, every 6 hrs up to 24 hrs
Maximum Concentration of Methadone Including Its Metabolites (EDDP and EMDP)
Measured: 0, 15, 30 minutes, 1, 2, 4, 6 hrs, every 6 hrs up to 24 hrs
Secondary outcomes (2)
•Pain Scores (FLACC) During the 24 Hours Study Period
Average of hourly FLACC score for each subject over 24 hours was calculated, followed by median and full range for total subjects in each arm.
FLACC (Face, Leg, Activity, Cry, Consolability) score ranges from 0-10 with 0 representing no pain
Measured: 24 hours
•Amount of Study Drug Administered During the 24-hour Dosing Period
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Mar 2010 (estimated)
- Study startMar 2010
- Primary completionJun 2012
- Study completionJun 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for PainStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe 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
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 47 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Gregory Hammer, Stanford University
- Investigators
- Gregory Hammer, Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01094522
- Sponsor's protocol ID
- SU-03012010-5083
- Other IDs
- IRB Protocol # 16739
- Status last verified
- Aug 2017
- First submitted
- 25 Mar 2010
- Last updated
- 18 Sep 2017
- Results posted
- Yes, on ClinicalTrials.gov
Publications
Ward RM, Drover DR, Hammer GB, Stemland CJ, Kern S, Tristani-Firouzi M, Lugo RA, Satterfield K, Anderson BJ. The pharmacokinetics of methadone and its metabolites in neonates, infants, and children. Paediatr Anaesth. 2014 Jun;24(6):591-601. doi: 10.1111/pan.12385. Epub 2014 Mar 26.
PubMed 24666686Elkomy MH, Drover DR, Glotzbach KL, Galinkin JL, Frymoyer A, Su F, Hammer GB. Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery. AAPS J. 2016 Jan;18(1):124-33. doi: 10.1208/s12248-015-9826-5. Epub 2015 Sep 9.
PubMed 26349564
Study at a glance
From the registry record, last updated by the sponsor on 18 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Double-blind, Controlled, Multi-site Study of the Pharmacokinetics and Pharmacodynamics of Methadone vs. Morphine During Mechanical Ventilation Following Cardiac Surgery in Neonates, Infants and Children
- ClinicalTrials.gov ID
- NCT01094522
- Acronym / sponsor ID
- SU-03012010-5083
- Conditions
- Pain
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 47 participants (actual)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Collaborators
- University of Colorado, Denver, Oregon Health and Science University
- Study start
- Mar 2010
- Primary completion
- Jun 2012 (actual)
- Study completion
- Jun 2012 (actual)
- First posted
- 29 Mar 2010 (estimated)
- Results
- Posted 9 Aug 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Study Population:
Neonates, infants and children from birth to 5 years of age undergoing cardiac surgery with CPB.
The use of methadone to provide analgesia may be increasing due to advantages compared to other commonly used opioid analgesic drugs. While efficacy of methadone has been reported in adults, there is a paucity of information in neonates and infants. In the latter population, fentanyl and morphine are most commonly used for opioid analgesia following major surgery, while methadone is frequently used for weaning of opioid dependent and tolerant patients, in spite of the paucity of knowledge of methadone pharmacology in this population. There are several clinical problems associated with fentanyl and morphine, and methadone may offer superior efficacy with fewer side effects than these agents. We propose to study the pharmacokinetics (PK) and pharmacodynamics (PD) of methadone in neonates and infants in the intensive care unit following cardiac surgery.
Detailed description
Treatment:
Fentanyl will be administered for intraoperative analgesia by the treating anesthesiologist in a dose range of 25 - 50 mcg/kg. No other intraoperative opioids will be given.
Subjects will receive intravenous methadone or morphine ("study drug") delivered by an initial IV "bolus" injection followed by a nurse-administered patient controlled analgesia (PCA) device for postoperative pain for a period of 24 hours. The initial dose of study drug will be 0.2 mg/kg IV administered following admission to the ICU after surgery. The study drug will then be given at a dose of 0.035 mg/kg IV as needed q30min via PCA. The study drug may be increased or decreased in increments of 20-25% according to the discretion of the investigator as needed to maintain a FLACC pain assessment tool < 4. Subjects will also receive lorazepam 0.025 mg/kg IV q2hr as needed for agitation as indicated by specific criteria. The study drug will be discontinued after 24 hours to facilitate "wash out" sampling and determination of elimination half-life. Beginning at 24 hours, fentanyl will be used for analgesia at an equianalgesic dose to be determined by the investigator based upon the current PCA "study drug" dose.
Measurements and Monitoring:
- Blood samples will be obtained for measurement of concentrations of methadone (methadone group) and morphine and its metabolites, morphine-3-glucuronide and morphine-6-glucuronide (morphine group), prior to administration of initial bolus dose (t = 0) and t = 5 min, 15 min, 30 min, 60 min, 2 hrs, 4 hrs and 6 hrs; thereafter, blood samples will be obtained for measurement every 6 hrs for up to 90 hrs according to availability of vascular access for phlebotomy.
- Continuous monitoring: temperature (rectal), electrocardiogram, heart rate, systemic arterial blood pressure, central venous blood pressure, respiratory rate, oxygen saturation (pulse oximetry)
- Intermittent recording (q1hr): urine output
- Lab Tests (at baseline[prior to study procedures] and 24 hours after initial dose of study medication): arterial blood gas tensions, arterial lactate, Hb/Hct, BUN/Cr, glucose, AST, ALT
- 12 lead ECG at hour 24 for determination of QTc.
- The Faces, Legs, Activity, Cry, Consolability (FLACC) Scale recoded every hour, and preceding every study medication PCA dose for 24 hours.
- Subject follow up at 90 hours to record time of extubation, re-intubation if necessary, and reason for re-intubation.
Primary Endpoints: Pharmacokinetics of methadone and morphine, including its metabolites (morphine-3-glucuronide and morphine-6-glucuronide)
Secondary Endpoints:
- Pain scores (FLACC) during the 24 hours study period
- Amount of study drug administered during the 24-hour dosing period
- Changes in heart rate, systemic arterial blood pressure and laboratory test values
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Methadone | Experimental | Drug: MethadoneOne half the Study patients will be randomized to receive a loading dose of IV methadone, followed by IV doses (given by the ICU nurse), on a PRN basis, for pain control for up to 24 hours during their postoperative course while they are intubated. |
| Morphine | Active comparator | Drug: MorphineOne half the Study patients will be randomized to receive a loading dose of IV morphine, followed by IV doses (given by the ICU nurse), on a PRN basis, for pain control for up to 24 hours during their postoperative course while they are intubated. |
Who may qualify
- Ages
- Up to 5 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (1 listed)
- Neonates, infants and children from birth through 5 years of age undergoing mechanical ventilation following cardiac surgery for congenital heart disease. Congenital heart lesions include "two ventricle repairs", including tetralogy of Fallot, transposition of the great arteries, "unobstructed" total anomalous pulmonary venous return, truncus arteriosus, atrioventricular canal defect and ventricular septal defect.
Key exclusion criteria (1 listed)
- Subjects will be excluded from the study because of prematurity (gestational age < 37 weeks), weight < 3.0 kg, severe hepatic dysfunction (elevation of conjugated bilirubin > 2, AST/ALT > 200 IU/L), significant renal dysfunction (serum Cr > 1.5 mg/dL), participation within 30 days of study entry or within 5 times the half-life, whichever is longer, in another investigational drug study, or previous participation in this study. Patients will be excluded if they have received opioids for more than 12 hours of the 48-hour period prior to surgery. In addition, patients will be excluded if they have a history of other clinically significant medical problems, which, in the opinion of the investigator, would interfere with study participation.
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 |
|---|---|---|
| Methadone0.2 mg/kg (IV) for the Initial Loading Dose; followed by PRN ("as needed") doses (given by the ICU Nurses) starting at 0.035 mg/kg (IV) every 30 minutes, for postoperative pain. The PRN dose of methadone may be increased by the ICU doctors until the dose is adequate to relieve the patient's pain. | Drug | Methadone |
| MorphineAlso: MS0.2 mg/kg (IV) for the Initial Loading Dose; followed by PRN ("as needed") doses (given by the ICU Nurses) starting at 0.035 mg/kg (IV) every 30 minutes, for postoperative pain. The PRN dose of morphine may be increased by the ICU doctors until the dose is adequate to relieve the patient's pain. | Drug | Morphine |
Primary outcome
Maximum Concentration of Morphine Including Its Metabolites (Morphine-3-glucuronide and Morphine-6-glucuronide)
Time frame: 0, 15, 30 minutes, 1, 2, 4, 6 hrs, every 6 hrs up to 24 hrs
Maximum Concentration of Methadone Including Its Metabolites (EDDP and EMDP)
Time frame: 0, 15, 30 minutes, 1, 2, 4, 6 hrs, every 6 hrs up to 24 hrs
2 secondary outcomes
•Pain Scores (FLACC) During the 24 Hours Study Period
Time frame: 24 hours
•Amount of Study Drug Administered During the 24-hour Dosing Period
Time frame: 24 hours
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Sep 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 24666686Ward RM, Drover DR, Hammer GB, Stemland CJ, Kern S, Tristani-Firouzi M, Lugo RA, Satterfield K, Anderson BJ. The pharmacokinetics of methadone and its metabolites in neonates, infants, and children. Paediatr Anaesth. 2014 Jun;24(6):591-601. doi: 10.1111/pan.12385. Epub 2014 Mar 26.
- Results publication: PubMed 26349564Elkomy MH, Drover DR, Glotzbach KL, Galinkin JL, Frymoyer A, Su F, Hammer GB. Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery. AAPS J. 2016 Jan;18(1):124-33. doi: 10.1208/s12248-015-9826-5. Epub 2015 Sep 9.
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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.
Gregory Hammer principal investigator
Stanford University
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Methadone and Morphine in people with Pain, run by Stanford University at 3 sites in United States.
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 1 inclusion and 1 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: finished, as of the sponsor's last update on 18 Sep 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
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?
Yes. Results are posted in the registry (first posted 9 Aug 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Maximum Concentration of Morphine Including Its Metabolites (Morphine-3-glucuronide and Morphine-6-glucuronide) (time frame: 0, 15, 30 minutes, 1, 2, 4, 6 hrs, every 6 hrs up to 24 hrs). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01094522, which also lists 2 linked publications.
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 18 Sep 2017.