Clonidine for Neonatal Abstinence Syndrome Study
Study Details
Study Description
Brief Summary
The study plans to compare the use of Clonidine versus Phenobarbital as an additional medication to neonatal morphine sulfate for treatment of newborn infants undergoing drug withdrawal symptoms due to mother's use of opioid drug use. The investigators hypothesis is that use of Clonidine will lead to shorter duration of treatment, hospital stay and thereby early discharge home.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| N/A |
Detailed Description
Introduction: Neonatal abstinence syndrome (NAS) is a symptom complex experienced by 55 to 94% of neonates who are exposed to intrauterine opioids. Recent studies have shown that combination therapies are superior to monotherapy with neonatal morphine sulfate (NMS). Phenobarbital has been shown to reduce the length of hospitalization, decrease severity of withdrawal, as well as decrease hospital costs and care giver demands. Similarly, clonidine, an α2-adrenergic receptor agonist, has also been shown to be safe, effective and reduces length of treatment.
Phenobarbital as an antiepileptic acts on the GABA (A) receptors and has been shown in animal models to inhibit neuronal cell proliferation, survival and neurogenesis. In human infants long term treatment with phenobarbital may result in neuro-developmental compromise. Due to these potentially harmful effects of Phenobarbital (P) alternative therapies should be explored more thoroughly including clonidine (C).
Our primary aim is to compare the length of NAS treatment with NMS in the two study groups - NMS/C versus NMS/P. Our secondary aims are to compare the total dosage of NMS, total length of hospital stay for NAS treatment, treatment failures and adverse effect profiles for the two study groups. We hypothesize that clonidine when compared to phenobarbital as an adjunct therapy, will have shorter length of stay, with fewer treatment failures and side effects.
Study design/Methods: This study will be a prospective, randomized, non-blinded clinical trial of NMS/C versus NMS/P for treatment of infants with NAS. Infants will be recruited from the Baystate Children's Hospital Neonatal Intensive Care Unit (NICU) and Neonatal Continuing Care Nursery (NCCN), a level III unit, over a 2 year study period. After randomization, infants will adhere to strict treatment initiation and withdrawal protocols. Maternal and infant descriptive data will be collected along with specific data regarding vital signs, drug dosages, length of treatment, treatment failures and adverse effects.
The primary outcome will be length of treatment with NMS in the two study arms. The secondary outcomes will be - a) total length of hospital stay for NAS treatment, b) mean total treatment dose and mean daily dose of NMS, c) total number of treatment failures,d) adverse effects such as bradycardia, hypotension, hypertension e) Total outpatient therapy days with Phenobarbital
Significance: This comparison study is potentially of great significance. If clonidine is proven to be equally effective in treatment of NAS many of the detrimental effects of phenobarbital therapy may be avoided for infants on long term pharmacotherapy for treatment of withdrawal with shorter length of hospital stay.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: NMS/Clonidine
|
Drug: Clonidine
This group of infants undergoing NAS will be treated with neonatal morphine sulfate and Clonidine as an adjunct medication to control the symptoms. Once stable Finnegan scores <8 for 24h, NMS will be weaned by 10% daily till off, then Clonidine will be weaned off in a stepwise manner. Infant will not go home on any medication for NAS. NMS will be dosed as mg/kd/day divided q3h and Clonidine will be dosed as microgm/kg/day divided q6h based upon the initial Finnegan scores.
|
| Active Comparator: NMS/Phenobarbital
|
Drug: Phenobarbital
Infants in this arm will be treated as current standard practice with NMS and Phenobarbital. NMS will be weaned by 10% daily to completely off during the hospital stay. Infants will be discharged home on Phenobarbital.
NMS will be dosed as mg/kg/day divided q3h and Phenobarbital will be dosed as mg/kg/day divided q8h based on the Finnegan scores.
|
Outcome Measures
Primary Outcome Measures
- Length of Treatment With Neonatal Morphine Sulfate [subjects were followed for the duration of treatment, up to 3 months]
Secondary Outcome Measures
- Total Dose of NMS Used [For the duration of treatment, upto 3 months]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
0 to 15 days of age
-
Prenatal exposure to opioids with development of moderate to severe NAS (2 consecutive abstinence scores of ≥ 8)
-
Medically stable
Exclusion Criteria:
-
Gestational age < 35 weeks
-
Intrauterine growth retardation (birth weight below the 5th percentile)
-
Congenital heart disease
-
Congenital anomalies
-
Medically unstable
Exposure to Benzodiazepines prenatally
-
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | NICU @ Baystate Children's Hospital | Springfield | Massachusetts | United States | 01199 |
Sponsors and Collaborators
- Baystate Medical Center
Investigators
- Principal Investigator: Rachana Singh, MD, MS, Baystate Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- BH-10-196
Study Results
Participant Flow
| Recruitment Details | The study was conducted at Baystate Children's Hospital Davis Neonatal Intensive Care Unit (NICU), a level III, regional perinatal referral center, for Western Massachusetts, from June 2010 to June 2012 |
|---|---|
| Pre-assignment Detail | Overall 82 infants were consented for the study but 14 were excluded either because they did not have continued high modified Finnegan Scores (n=13), or had Unstable clinical status (n=1) |
| Arm/Group Title | NMS/Clonidine | NMS/Phenobarbital |
|---|---|---|
| Arm/Group Description | Dosing was based on the Finnegan scores as below Finn Score 8-10 NMS 0.32mg/kg/day + Clonidine 6 mcg/kg/day 11-13 NMS 0.48 mg/kg/day + Clonidine 8 mcg/kg/day 14-16 NMS 0.64 mg/kg/day + Clonidine 10 mcg/kg/day ≥17 NMS 0.8 mg/kg/day* + Clonidine 12 mcg/kg/day Daily NMS dose was divided for q3h dosing interval Daily Clonidine dose was divided for q6h dosing interval Clonidine escalation may be limited by hypotension or bradycardia *If needing morphine sulfate > 0.8 mg/kg/day, increase dose in increments of 0.16 mg/kg/day until Finnegan score < 8 | Dosing was based on the Finnegan scores as below Finn Score 8-10 NMS 0.32mg/kg/day +Phenobarbital 6 mg/kg/day 11-13 NMS 0.48 mg/kg/day +Phenobarbital 8 mg/kg/day 14-16 NMS 0.64 mg/kg/day +Phenobarbital 10 mg/kg/day ≥17 NMS 0.8 mg/kg/day* + Phenobarbital 12 mg/kg/day Daily NMS dose was divided for q3h dosing interval Daily Phenobarbital dose was divided for q8h dosing interval *If needing morphine sulfate > 0.8 mg/kg/day, increase dose in increments of 0.16 mg/kg/day until Finnegan score < 8 |
| Period Title: Overall Study | ||
| STARTED | 34 | 34 |
| COMPLETED | 32 | 34 |
| NOT COMPLETED | 2 | 0 |
Baseline Characteristics
| Arm/Group Title | NMS/Clonidine | NMS/Phenobarbital | Total |
|---|---|---|---|
| Arm/Group Description | Total of all reporting groups | ||
| Overall Participants | 34 | 34 | 68 |
| Age (days) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [days] |
1.8
(0.9)
|
2.26
(1.60)
|
2.05
(1.32)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
19
55.9%
|
16
47.1%
|
35
51.5%
|
| Male |
15
44.1%
|
18
52.9%
|
33
48.5%
|
Outcome Measures
| Title | Length of Treatment With Neonatal Morphine Sulfate |
|---|---|
| Description | |
| Time Frame | subjects were followed for the duration of treatment, up to 3 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | NMS/Clonidine | NMS/Phenobarbital |
|---|---|---|
| Arm/Group Description | ||
| Measure Participants | 32 | 34 |
| Mean (95% Confidence Interval) [days] |
18.2
|
13.6
|
| Title | Total Dose of NMS Used |
|---|---|
| Description | |
| Time Frame | For the duration of treatment, upto 3 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | NMS/Clonidine | NMS/Phenobarbital |
|---|---|---|
| Arm/Group Description | ||
| Measure Participants | 32 | 34 |
| Mean (95% Confidence Interval) [mg/kg] |
5.7
|
4.6
|
Adverse Events
| Time Frame | During the hospital stay | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | In the phenobarbital group, 3 infants (8.8%), manifested over sedation signs (poor feeds, and mild respiratory depression). This prompted serum phenobarbital measurements which were noted to be supra-therapeutic (>40 mg/dL) and required dosage adjustment. | |||
| Arm/Group Title | NMS/Clonidine | NMS/Phenobarbital | ||
| Arm/Group Description | ||||
All Cause Mortality |
||||
| NMS/Clonidine | NMS/Phenobarbital | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| NMS/Clonidine | NMS/Phenobarbital | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/34 (0%) | 0/34 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| NMS/Clonidine | NMS/Phenobarbital | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/34 (0%) | 3/34 (8.8%) | ||
| Nervous system disorders | ||||
| Oversedation | 0/34 (0%) | 0 | 3/34 (8.8%) | 3 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Rachana Singh, MD |
|---|---|
| Organization | Baystate Medical Center |
| Phone | 413-794-2400 |
| rachana.singhmd@bhs.org |
- BH-10-196