Neonatal Abstinence SyndromePhase 2/3NCT01360450
Clonidine to Treat Iatrogenic-induced Opioid Dependence in Infants
A Phase 2/3 study testing Clonidine HCL and saline in people with Neonatal Abstinence Syndrome, run by Johns Hopkins University at 1 site in United States.
Trial summary
Thousands of critically ill infants (and children) are exposed to opioids and benzodiazepines to achieve sedation and analgesia as part of routine care in neonatal and pediatric intensive care units. Read more about this study
- Who is it for?
- Ages 5 to 90 days
- Conditions the study is for
- Neonatal Abstinence Syndrome
- What is being tested?
- Clonidine HCL and saline
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2011to Dec 2014
- Phase
- Phase 2/3
- 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 5 to 90 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- >35 week Gestational Age (GA) at birth
- <3 months (90 days) old chronological age at the time of enrollment
- Exposed to a minimum five days of continuous narcotic infusion
Who cannot join
- Neurologic abnormality which would make Neonatal Abstinence Score (NAS) scoring inaccurate
- Major chromosomal abnormality (with the exception of Trisomy 21)
- Infant already enrolled in another randomized, controlled clinical trial
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Efficacy of Clonidine in Reducing Iatrogenic-induced Opioid Dependence in Infants:
Thousands of critically ill infants (and children) are exposed to opioids and benzodiazepines to achieve sedation and analgesia as part of routine care in neonatal and pediatric intensive care units. While the use of these agents are undisputedly beneficial in reducing pain and anxiety, improving ventilation, reducing pulmonary vascular resistance and improving outcomes; the consequence is often the development of tolerance and physiologic dependence - similar to prenatal exposure from these same classes of drugs. The investigators have recently reported the results of randomized placebo control trial showing that the addition of clonidine (central alpha 2 agonist) to tapering doses of opioids was efficacious and safe in treating opioid dependence in infants who had moderate to severe neonatal abstinence syndrome from prenatal drug exposure to opioids. Currently, the investigators propose to perform a double-blind, randomized placebo control trial in a cohort of critically ill infants without prenatal drug exposure at Johns Hopkins Hospital to test the overall hypothesis that early addition of clonidine to a cohort of critically ill neonates on mechanical ventilation who are receiving opioids and benzodiazepines for analgesia and sedation will be efficacious and safe in reducing both the incidence and severity of withdrawal symptoms (NICU-NAS); as well as, reducing the time to complete sedative and analgesic drug detoxification. The hypothesis will be tested by addressing 2 specific aims that will determine: 1) the efficacy and safety of clonidine in critically ill infants, and 2) pharmacokinetics and pharmacodynamics using population-based pharmacokinetics in this vulnerable infant population who have only been exposed to these drugs as part of their routine care. Many "standard of care practices" are incorporated in neonatal and pediatric care prior to evidence based studies. This proposal will fill a much needed gap in translating what the investigators have learned about basic mechanisms mediating dependence and withdrawal to proven therapies for vulnerable pediatric populations.
Read the detailed description
The study will test the following 2 specific aims:
Specific Aim 1
To determine the efficacy and short-term safety of clonidine in reducing the severity of iatrogenic neonatal abstinence syndrome (NAS) by decreasing the time required for complete sedative and analgesic drug detoxification. The investigators will enroll 88 neonates at risk for having moderate to severe NAS in a randomized, double-blinded placebo controlled trial comparing opioid/benzodiazepine administration combined with a placebo (control) vs. opioid/benzodiazepine combined with clonidine. Principal outcome measure will be the difference in length of treatment for complete detoxification. Early safety of clonidine will be determined by monitoring for cardiorespiratory side effects that might be associated with clonidine use in this high risk population.
Specific Aim 2
To determine the pharmacokinetics and pharmacodynamics of clonidine in this critically ill infant population. The investigators will estimate the dose-exposure-response relationship of clonidine in neonates at risk for developing iatrogenic by using nonlinear mixed-effects population pharmacokinetic (PK)-pharmacodynamic (PD) analysis.
- Conditions
- Neonatal Abstinence Syndrome
- Being tested
- Clonidine HCL, saline
- Keywords
- opioid withdrawal, Neonatal Pain, Agitation, and Sedation Scale (NPASS), duraclon
- Medical subject headings
- Neonatal Abstinence Syndrome, Psychomotor Agitation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Clonidine HCLDrug
Also called Duraclon
At day 5 on opioid and/or benzodiazepine (BZD), the infant will be randomized to receive either placebo (normal saline) or clonidine 1μg/kg/q 4 hrs to a maximum dose of 2μg/kg/q 4. Weaning from the study drug: When the opioid is no longer required, 24 hrs later the study drug (placebo or study drug) will be reduced by 50% and then discontinued 24 hours later provided that the Modified Finnegan scores remain between < 9.
salineDrug
Also called placebo, sterile water, saline
Infants randomized to placebo will be administered IV saline or oral sterile water in the same volume as study drug. The placebo will be give every 4 hrs as outlined in the algorithm for the study.
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Experimental | Interventions: Infants will receive intravenous or oral clonidine(Duraclon) for the treatment of pain and sedation: Duration: (Clonidine HCL) 1 mcg/kg/dose q4 either iv or po. Receives: Drug: Clonidine HCL |
| Control | Placebo comparator | Intervention: Infants will receive place (saline) (if receiving it IV) or orally (sterile water) if receiving it orally Receives: Drug: saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to Complete Detoxification
Time to complete detoxification is defined as 48 hrs off all opioids/benzodiazepines and study drug with acceptable withdrawal scores of <9 (on average we expect the infant to be enrolled in the study for 2-4 weeks). The scale used to assess withdrawal was the Modified Finnegan Neonatal Withdrawal Scale, which ranges from 0-41, 0 represents no withdrawal and 41 represent maximum withdrawal.
Measured: up to 4 weeks
Secondary outcomes (2)
Cardiovascular Side-effects Changes HR and BP
Changes in Heart Rate (HR) and BP for 48 hrs after starting study drug and for 48hrs after stopping study drug
Measured: 48 hrs after starting study drug and for 48hrs after stopping study drug
Cumulative Dose of Opioid and Benzodiazepine
We will determine the total amount of opioid and benzodiazepine needed from the start of detoxification to the end of the the detoxification.
Measured: 2-4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 May 2011 (estimated)
- Study startJul 2011
- Primary completionJul 2011
- Study completionDec 2014
Why it stopped: The study was treminated because of low accural
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 (3)Papers the sponsor has linked to this study.
- Other trials for Neonatal Abstinence SyndromeStudies of the same condition, open and under way.
- More trials run by Johns Hopkins 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 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Drug Abuse (NIDA)
- Responsible party
- Sponsor
- Investigators
- Estelle B Gauda, MD, Principal investigator, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01360450
- Sponsor's protocol ID
- Clonidine NICU-NAS
- Other IDs
- R21DA029295-01
- Status last verified
- Aug 2017
- First submitted
- 13 Oct 2010
- Last updated
- 13 Sep 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Agthe AG, Kim GR, Mathias KB, Hendrix CW, Chavez-Valdez R, Jansson L, Lewis TR, Yaster M, Gauda EB. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized, controlled trial. Pediatrics. 2009 May;123(5):e849-56. doi: 10.1542/peds.2008-0978. Epub 2009 Apr 27.
PubMed 19398463Leikin JB, Mackendrick WP, Maloney GE, Rhee JW, Farrell E, Wahl M, Kelly K. Use of clonidine in the prevention and management of neonatal abstinence syndrome. Clin Toxicol (Phila). 2009 Jul;47(6):551-5. doi: 10.1080/15563650902980019.
PubMed 19566381Pohl-Schickinger A, Lemmer J, Hubler M, Alexi-Meskishvili V, Redlin M, Berger F, Stiller B. Intravenous clonidine infusion in infants after cardiovascular surgery. Paediatr Anaesth. 2008 Mar;18(3):217-22. doi: 10.1111/j.1460-9592.2008.02413.x.
PubMed 18230064
Study at a glance
From the registry record, last updated by the sponsor on 13 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy of Clonidine in Reducing Iatrogenic-induced Opioid Dependence in Infants:
- ClinicalTrials.gov ID
- NCT01360450
- Acronym / sponsor ID
- Clonidine NICU-NAS
- Conditions
- Neonatal Abstinence Syndrome
- Keywords
- opioid withdrawal, Neonatal Pain, Agitation, and Sedation Scale (NPASS), duraclon
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study was treminated because of low accural
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Johns Hopkins UniversityUniversity, hospital or other
- Collaborators
- National Institute on Drug Abuse (NIDA)
- Study start
- Jul 2011
- Primary completion
- Jul 2011 (actual)
- Study completion
- Dec 2014 (actual)
- First posted
- 25 May 2011 (estimated)
- Results
- Posted 13 Sep 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Thousands of critically ill infants (and children) are exposed to opioids and benzodiazepines to achieve sedation and analgesia as part of routine care in neonatal and pediatric intensive care units. While the use of these agents are undisputedly beneficial in reducing pain and anxiety, improving ventilation, reducing pulmonary vascular resistance and improving outcomes; the consequence is often the development of tolerance and physiologic dependence - similar to prenatal exposure from these same classes of drugs. The investigators have recently reported the results of randomized placebo control trial showing that the addition of clonidine (central alpha 2 agonist) to tapering doses of opioids was efficacious and safe in treating opioid dependence in infants who had moderate to severe neonatal abstinence syndrome from prenatal drug exposure to opioids. Currently, the investigators propose to perform a double-blind, randomized placebo control trial in a cohort of critically ill infants without prenatal drug exposure at Johns Hopkins Hospital to test the overall hypothesis that early addition of clonidine to a cohort of critically ill neonates on mechanical ventilation who are receiving opioids and benzodiazepines for analgesia and sedation will be efficacious and safe in reducing both the incidence and severity of withdrawal symptoms (NICU-NAS); as well as, reducing the time to complete sedative and analgesic drug detoxification. The hypothesis will be tested by addressing 2 specific aims that will determine: 1) the efficacy and safety of clonidine in critically ill infants, and 2) pharmacokinetics and pharmacodynamics using population-based pharmacokinetics in this vulnerable infant population who have only been exposed to these drugs as part of their routine care. Many "standard of care practices" are incorporated in neonatal and pediatric care prior to evidence based studies. This proposal will fill a much needed gap in translating what the investigators have learned about basic mechanisms mediating dependence and withdrawal to proven therapies for vulnerable pediatric populations.
Detailed description
The study will test the following 2 specific aims:
Specific Aim 1
To determine the efficacy and short-term safety of clonidine in reducing the severity of iatrogenic neonatal abstinence syndrome (NAS) by decreasing the time required for complete sedative and analgesic drug detoxification. The investigators will enroll 88 neonates at risk for having moderate to severe NAS in a randomized, double-blinded placebo controlled trial comparing opioid/benzodiazepine administration combined with a placebo (control) vs. opioid/benzodiazepine combined with clonidine. Principal outcome measure will be the difference in length of treatment for complete detoxification. Early safety of clonidine will be determined by monitoring for cardiorespiratory side effects that might be associated with clonidine use in this high risk population.
Specific Aim 2
To determine the pharmacokinetics and pharmacodynamics of clonidine in this critically ill infant population. The investigators will estimate the dose-exposure-response relationship of clonidine in neonates at risk for developing iatrogenic by using nonlinear mixed-effects population pharmacokinetic (PK)-pharmacodynamic (PD) analysis.
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 |
|---|---|---|
| Treatment | Experimental | Drug: Clonidine HCLInterventions: Infants will receive intravenous or oral clonidine(Duraclon) for the treatment of pain and sedation: Duration: (Clonidine HCL) 1 mcg/kg/dose q4 either iv or po. |
| Control | Placebo comparator | Drug: salineIntervention: Infants will receive place (saline) (if receiving it IV) or orally (sterile water) if receiving it orally |
Who may qualify
- Ages
- 5 to 90 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- >35 week Gestational Age (GA) at birth
- <3 months (90 days) old chronological age at the time of enrollment
- Exposed to a minimum five days of continuous narcotic infusion
Key exclusion criteria (3 listed)
- Neurologic abnormality which would make Neonatal Abstinence Score (NAS) scoring inaccurate
- Major chromosomal abnormality (with the exception of Trisomy 21)
- Infant already enrolled in another randomized, controlled clinical trial
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 |
|---|---|---|
| Clonidine HCLAlso: DuraclonAt day 5 on opioid and/or benzodiazepine (BZD), the infant will be randomized to receive either placebo (normal saline) or clonidine 1μg/kg/q 4 hrs to a maximum dose of 2μg/kg/q 4. Weaning from the study drug: When the opioid is no longer required, 24 hrs later the study drug (placebo or study drug) will be reduced by 50% and then discontinued 24 hours later provided that the Modified Finnegan scores remain between < 9. | Drug | Treatment |
| salineAlso: placebo, sterile water, salineInfants randomized to placebo will be administered IV saline or oral sterile water in the same volume as study drug. The placebo will be give every 4 hrs as outlined in the algorithm for the study. | Drug | Control |
Primary outcome
Time to Complete Detoxification
Time frame: up to 4 weeks
Time to complete detoxification is defined as 48 hrs off all opioids/benzodiazepines and study drug with acceptable withdrawal scores of <9 (on average we expect the infant to be enrolled in the study for 2-4 weeks). The scale used to assess withdrawal was the Modified Finnegan Neonatal Withdrawal Scale, which ranges from 0-41, 0 represents no withdrawal and 41 represent maximum withdrawal.
2 secondary outcomes
Cardiovascular Side-effects Changes HR and BP
Time frame: 48 hrs after starting study drug and for 48hrs after stopping study drug
Cumulative Dose of Opioid and Benzodiazepine
Time frame: 2-4 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Sep 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19398463Agthe AG, Kim GR, Mathias KB, Hendrix CW, Chavez-Valdez R, Jansson L, Lewis TR, Yaster M, Gauda EB. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized, controlled trial. Pediatrics. 2009 May;123(5):e849-56. doi: 10.1542/peds.2008-0978. Epub 2009 Apr 27.
- Background: PubMed 19566381Leikin JB, Mackendrick WP, Maloney GE, Rhee JW, Farrell E, Wahl M, Kelly K. Use of clonidine in the prevention and management of neonatal abstinence syndrome. Clin Toxicol (Phila). 2009 Jul;47(6):551-5. doi: 10.1080/15563650902980019.
- Background: PubMed 18230064Pohl-Schickinger A, Lemmer J, Hubler M, Alexi-Meskishvili V, Redlin M, Berger F, Stiller B. Intravenous clonidine infusion in infants after cardiovascular surgery. Paediatr Anaesth. 2008 Mar;18(3):217-22. doi: 10.1111/j.1460-9592.2008.02413.x.
- 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.
Estelle B Gauda, MD principal investigator
Johns Hopkins University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Clonidine HCL and saline in people with Neonatal Abstinence Syndrome, run by Johns Hopkins University at 1 site 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 3 inclusion and 3 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: stopped early, as of the sponsor's last update on 13 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 1 site 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. Some participants in this study may receive a placebo. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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 13 Sep 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?
Time to Complete Detoxification (time frame: up to 4 weeks). 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 NCT01360450, which also lists 3 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 13 Sep 2017.