Premature Birth of NewbornPhase 1/2MethadoneNCT01327079
The Use of Methadone in Newborn Infants
A Phase 1/2 study testing Methadone in people with Premature Birth of Newborn and Critically Ill, run by John van den Anker at 2 sites in United States.
Trial summary
This proposed investigation will test the following hypotheses: 1) Enzymatic activity of CYP2B6 characterized by the formation clearance of methadone to EDDP (CLf,EDDP), is directly related to both gestational and postnatal age; 2) variations in the CYP2B6 gene (SNPs) are associated with variable activity of the… Read more about this study
- Who is it for?
- Ages 22 to 43 weeks
- Conditions the study is for
- Premature Birth of Newborn, Critically Ill
- What is being tested?
- Methadone
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 2 sitesUnited States
- Study dates
- Dec 2010to Dec 2017
- 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 22 to 43 weeks
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Newborn infants of both genders and all races who have:
- a postnatal age of less than 3 months
- an indwelling (peripheral or umbilical) arterial line, and
- already treated with an opioid (morphine or fentanyl) for clinical reasons
Who cannot join
- Neonates with severe asphyxia grade III or IV intraventricular hemorrhage,
- Neonates with major congenital malformations or facial malformations (e.g., cleft lip and palate), neurological disorders
- Neonates receiving continuous or intermittent neuromuscular blockers neonates will be excluded who have:
- clinical or biochemical evidence of hepatic and renal failure (including systemic hypoperfusion
- received drugs that are CYP2B6 substrates
- been exposed in utero to methadone, despite the fact that they indeed receive a CYP2B6 substrate through their mother, will not be excluded but will be analyzed as a subgroup
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Childrens Research Institute
Washington D.C., District of Columbia, 20010
Childrens's Research Institute
Washington D.C., District of Columbia, 20010
About this study
Official title: Optimizing the Use of Methadone in Newborn Infants
This proposed investigation will test the following hypotheses: 1) Enzymatic activity of CYP2B6 characterized by the formation clearance of methadone to EDDP (CLf,EDDP), is directly related to both gestational and postnatal age; 2) variations in the CYP2B6 gene (SNPs) are associated with variable activity of the CYP2B6 enzyme (as measured by the formation clearance, CLf,EDDP), and 3) the elimination rate of methadone and its major metabolite EDDP in neonates is dependent on the glomerular filtration rate and therefore on the stage of development (defined by both gestational and postnatal age). The investigators propose to develop a PK model for methadone dosing in neonates that takes into account both developmental stage and genetic variability. The long-term goal of the proposed investigations is to improve dosing of methadone in neonates exposed to opioids in utero or post-natally, leading to improved control of their withdrawal syndrome and decreased adverse drug reactions associated with the current use of methadone in these vulnerable patients. More immediately, the investigators will develop a PK model for methadone dosing based on relevant developmental and genetic characteristics. The acquired knowledge based on the proposed study will lead to a more efficacious treatment of pain or opiate withdrawal syndrome in newborn infants with a decreased chance of adverse drug reactions.
Read the detailed description
The investigators will identify and recruit from the NICU of CNMC 60 preterm neonates uniformly distributed with respect to gestational age and encompassing GA's of from 22 to less than 43 weeks.
- Stratified Selection by Gestational Age (GA): The study neonates will be selected to achieve balance in the following GA strata: (22-24 wks, 25-26 wks, 27-28 wks, 29-30 wks, 31-32 wks, 33-37 wks; 38-43 wks). Stratification will be done to ensure broad representation by GA. As described below, analyses will treat GA as a continuous variable.
- Randomization will assign a newborn infant to group 1 (n=30) or group 2 (n=30).
- Study medications: Methadone and inulin administration Blood and urine will be collected for the purposes of this research project. Blood will be drawn from the indwelling arterial catheter that already is in place for clinical purposes. The amount of blood obtained for all study related determinations will be minimized and kept at less than 3 mL/kg of blood per 48 hour period. The study will last 60 hours for group 1 and 72 hours for group.
- DNA study 0.3ml whole blood will be collected from each subject
- PK study Blood samples (0.2 mL per sample) will be taken in 30 newborn infants at t=0, 1, 4, 12, 36, 60 h (group 1) after the administration of one dose of methadone, and in 30 newborn infants at t=0, 2, 8, 24, 48, 72 hr (group 2) after the administration of methadone. A total of 1.5 ml of blood will be collected from each subject
- Urine Collection Urine samples will be collected from each infant's diaper (wood pulp based study diapers) every 3-4 hours over the first 24 hour period or alternatively, from an indwelling urinary catheter placed based on clinical indications unrelated to the study protocol.
- Conditions
- Premature Birth of Newborn, Critically Ill
- Being tested
- Methadone
- Keywords
- NICU, Methadone, neonates
- Medical subject headings
- Premature Birth, Critical Illness
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethadoneDrug
Also called inulin
If the infant has been treated with morphine than substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone.
Administration of inulin:
Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.
MethadoneDrug
Also called inulin (Sinistrin)
If the infant has been treated with morphine than substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone.
Administration of inulin:
Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.
| Study group | Role | What they receive |
|---|---|---|
| Group 1 | Experimental | Gestational age less than 29 weeks We will substitute for one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone.
Administration of inulin:
Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated. Receives: Drug: Methadone |
| Group 2 | Experimental | Gestational age greater then 29 weeks We will substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone.
Administration of inulin:
Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated. Receives: Drug: Methadone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Methadone PK and EDDP
Primary outcome: Plasma and urine levels of methadone and EDDP (2-ethylidene- 1,5-dimethyl-3,3-diphenylpyrrolidine, the main metabolite of methadone). Secondary endpoints: CYP2DB6 genetic variability.
Measured: 36 months
Secondary outcomes (1)
DNA
Secondary endpoints: CYP2DB6 genetic variability.
Measured: 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Apr 2011 (estimated)
- Study startDec 2010
- Primary completionDec 2017
- Study completionDec 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Premature Birth of NewbornStudies of the same condition, open and under way.
- 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
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- John van den Anker
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, John van den Anker, Children's National Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01327079
- Sponsor's protocol ID
- 4781
- Other IDs
- IV Methadone
- Acronym
- Methadone
- Status last verified
- Jul 2018
- First submitted
- 30 Mar 2011
- Last updated
- 26 Jul 2018
- Results posted
- No
- Data monitoring committee
- Yes
Publications
van Donge T, Samiee-Zafarghandy S, Pfister M, Koch G, Kalani M, Bordbar A, van den Anker J. Methadone dosing strategies in preterm neonates can be simplified. Br J Clin Pharmacol. 2019 Jun;85(6):1348-1356. doi: 10.1111/bcp.13906. Epub 2019 Apr 10.
PubMed 30805946
Study at a glance
From the registry record, last updated by the sponsor on 26 Jul 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimizing the Use of Methadone in Newborn Infants
- ClinicalTrials.gov ID
- NCT01327079
- Acronym / sponsor ID
- Methadone / 4781
- Conditions
- Premature Birth of Newborn, Critically Ill
- Keywords
- NICU, Methadone, neonates
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- John van den AnkerUniversity, hospital or other
- Study start
- Dec 2010
- Primary completion
- Dec 2017 (actual)
- Study completion
- Dec 2017 (actual)
- First posted
- 1 Apr 2011 (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 proposed investigation will test the following hypotheses: 1) Enzymatic activity of CYP2B6 characterized by the formation clearance of methadone to EDDP (CLf,EDDP), is directly related to both gestational and postnatal age; 2) variations in the CYP2B6 gene (SNPs) are associated with variable activity of the CYP2B6 enzyme (as measured by the formation clearance, CLf,EDDP), and 3) the elimination rate of methadone and its major metabolite EDDP in neonates is dependent on the glomerular filtration rate and therefore on the stage of development (defined by both gestational and postnatal age). The investigators propose to develop a PK model for methadone dosing in neonates that takes into account both developmental stage and genetic variability. The long-term goal of the proposed investigations is to improve dosing of methadone in neonates exposed to opioids in utero or post-natally, leading to improved control of their withdrawal syndrome and decreased adverse drug reactions associated with the current use of methadone in these vulnerable patients. More immediately, the investigators will develop a PK model for methadone dosing based on relevant developmental and genetic characteristics. The acquired knowledge based on the proposed study will lead to a more efficacious treatment of pain or opiate withdrawal syndrome in newborn infants with a decreased chance of adverse drug reactions.
Detailed description
The investigators will identify and recruit from the NICU of CNMC 60 preterm neonates uniformly distributed with respect to gestational age and encompassing GA's of from 22 to less than 43 weeks.
- Stratified Selection by Gestational Age (GA): The study neonates will be selected to achieve balance in the following GA strata: (22-24 wks, 25-26 wks, 27-28 wks, 29-30 wks, 31-32 wks, 33-37 wks; 38-43 wks). Stratification will be done to ensure broad representation by GA. As described below, analyses will treat GA as a continuous variable.
- Randomization will assign a newborn infant to group 1 (n=30) or group 2 (n=30).
- Study medications: Methadone and inulin administration Blood and urine will be collected for the purposes of this research project. Blood will be drawn from the indwelling arterial catheter that already is in place for clinical purposes. The amount of blood obtained for all study related determinations will be minimized and kept at less than 3 mL/kg of blood per 48 hour period. The study will last 60 hours for group 1 and 72 hours for group.
- DNA study 0.3ml whole blood will be collected from each subject
- PK study Blood samples (0.2 mL per sample) will be taken in 30 newborn infants at t=0, 1, 4, 12, 36, 60 h (group 1) after the administration of one dose of methadone, and in 30 newborn infants at t=0, 2, 8, 24, 48, 72 hr (group 2) after the administration of methadone. A total of 1.5 ml of blood will be collected from each subject
- Urine Collection Urine samples will be collected from each infant's diaper (wood pulp based study diapers) every 3-4 hours over the first 24 hour period or alternatively, from an indwelling urinary catheter placed based on clinical indications unrelated to the study protocol.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group 1 | Experimental | Drug: MethadoneGestational age less than 29 weeks We will substitute for one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone. Administration of inulin: Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated. |
| Group 2 | Experimental | Drug: MethadoneGestational age greater then 29 weeks We will substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone. Administration of inulin: Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated. |
Who may qualify
- Ages
- 22 to 43 weeks
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- Newborn infants of both genders and all races who have:
Key exclusion criteria (6 listed)
- Neonates with severe asphyxia grade III or IV intraventricular hemorrhage,
- Neonates with major congenital malformations or facial malformations (e.g., cleft lip and palate), neurological disorders
- Neonates receiving continuous or intermittent neuromuscular blockers neonates will be excluded who have:
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 |
|---|---|---|
| MethadoneAlso: inulinIf the infant has been treated with morphine than substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone. Administration of inulin: Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated. | Drug | Group 1 |
| MethadoneAlso: inulin (Sinistrin)If the infant has been treated with morphine than substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone. Administration of inulin: Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated. | Drug | Group 1, Group 2 |
Primary outcome
Methadone PK and EDDP
Time frame: 36 months
Primary outcome: Plasma and urine levels of methadone and EDDP (2-ethylidene- 1,5-dimethyl-3,3-diphenylpyrrolidine, the main metabolite of methadone). Secondary endpoints: CYP2DB6 genetic variability.
1 secondary outcome
DNA
Time frame: 36 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jul 2018.
- Derived from this study: PubMed 30805946van Donge T, Samiee-Zafarghandy S, Pfister M, Koch G, Kalani M, Bordbar A, van den Anker J. Methadone dosing strategies in preterm neonates can be simplified. Br J Clin Pharmacol. 2019 Jun;85(6):1348-1356. doi: 10.1111/bcp.13906. Epub 2019 Apr 10.
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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.
2 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 in people with Premature Birth of Newborn and Critically Ill, run by John van den Anker at 2 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 4 inclusion and 6 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 26 Jul 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Methadone PK and EDDP (time frame: 36 months). 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 NCT01327079, which also lists 1 linked publication.
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 26 Jul 2018.