Trial Outcomes & Findings for Improving Outcomes in Neonatal Abstinence Syndrome (NCT NCT01958476)
NCT ID: NCT01958476
Last Updated: 2019-10-15
Results Overview
Participants were monitored for the duration of their hospitalization, an expected mean of 22 days.
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
117 participants
Primary outcome timeframe
Participants will be monitored during their entire hospitalization, expected mean 22 days.
Results posted on
2019-10-15
Participant Flow
Recruitment took place at Tufts Medical Center, Baystate Children's Hospital, Boston Medical Center, Maine Medical Center, Shands Jacksonville Medical Center, University of Pittsburgh Medical Center, Vanderbilt University Medical Center, and Women \& Infants Hospital of Rhode Island.
If infant was diagnosed with NAS (Finnegan score ≥8 on two consecutive occasions, or ≥12 on single assessment) and research pharmacy staff were unavailable for preparation of trial drug, infant could receive one dose of morphine prior to randomization. Dosing was based on weight and Finnegan scores.
Participant milestones
| Measure |
Methadone
First line therapy: 0.4mg/mL oral solution, based on weight and symptoms.
Clinical monitoring: Infants scored using standardized Finnegan system;
Regimen: Initiated treatment w/ 2 consec. scores ≥8, or 1 score ≥12. Starting doses range 0.3mg/kg/day - 0.9mg/kg/day, divided every 8hrs depending on the severity of Finnegan scores. Doses were increased to max of 0.9mg/kg/day for contd. scores generally \>8 caused primarily by worsening NAS, as needed. Weaned by 10% of max dose every 24-48 hours; Medication discontinued once at 25% of max dose.
Second Line Therapy: Phenobarbital (20mg/kg) was added once infant reached max methadone doses for contd. scores generally \>8. Option to re-load w/ 10mg/kg q8-12 hours for 2 more doses if needed for contd. high scores. Maintenance therapy of 5mg/kg/day was initiated 12 - 24hrs after last loading dose. Phenobarbital trough levels monitored, w/ goal levels 20 - 30 mcg/mL. Weaning procedure outlined in protocol.
|
Neonatal Morphine Solution
First line therapy: 0.2mg/mL solution, based on weight and symptoms.
Clinical monitoring: Infants scored using standardized Finnegan system;
Regimen: Initiated treatment w/ 2 consec. scores ≥8, or 1 score ≥12. Starting doses range 0.3mg/kg/day - 0.9mg/kg/day, divided every 4hrs depending on the severity of Finnegan scores. Doses were increased to max of 0.9mg/kg/day for contd. scores generally \>8 caused primarily by worsening NAS, as needed. Weaned by 10% of max dose every 24 - 48 hours; Medication discontinued once at 25% of max dose.
Second Line Therapy: Phenobarbital (20mg/kg) was added once infant reached max morphine doses for contd. scores generally \>8. Option to re-load w/ 10mg/kg q8-12 hours for 2 more doses if needed for contd. high scores. Maintenance therapy of 5mg/kg/day was initiated 12 - 24hrs after last loading dose. Phenobarbital trough levels monitored, w/ goal levels 20 - 30 mcg/mL. Weaning procedure outlined in protocol.
|
|---|---|---|
|
Overall Study
STARTED
|
59
|
58
|
|
Overall Study
COMPLETED
|
58
|
58
|
|
Overall Study
NOT COMPLETED
|
1
|
0
|
Reasons for withdrawal
| Measure |
Methadone
First line therapy: 0.4mg/mL oral solution, based on weight and symptoms.
Clinical monitoring: Infants scored using standardized Finnegan system;
Regimen: Initiated treatment w/ 2 consec. scores ≥8, or 1 score ≥12. Starting doses range 0.3mg/kg/day - 0.9mg/kg/day, divided every 8hrs depending on the severity of Finnegan scores. Doses were increased to max of 0.9mg/kg/day for contd. scores generally \>8 caused primarily by worsening NAS, as needed. Weaned by 10% of max dose every 24-48 hours; Medication discontinued once at 25% of max dose.
Second Line Therapy: Phenobarbital (20mg/kg) was added once infant reached max methadone doses for contd. scores generally \>8. Option to re-load w/ 10mg/kg q8-12 hours for 2 more doses if needed for contd. high scores. Maintenance therapy of 5mg/kg/day was initiated 12 - 24hrs after last loading dose. Phenobarbital trough levels monitored, w/ goal levels 20 - 30 mcg/mL. Weaning procedure outlined in protocol.
|
Neonatal Morphine Solution
First line therapy: 0.2mg/mL solution, based on weight and symptoms.
Clinical monitoring: Infants scored using standardized Finnegan system;
Regimen: Initiated treatment w/ 2 consec. scores ≥8, or 1 score ≥12. Starting doses range 0.3mg/kg/day - 0.9mg/kg/day, divided every 4hrs depending on the severity of Finnegan scores. Doses were increased to max of 0.9mg/kg/day for contd. scores generally \>8 caused primarily by worsening NAS, as needed. Weaned by 10% of max dose every 24 - 48 hours; Medication discontinued once at 25% of max dose.
Second Line Therapy: Phenobarbital (20mg/kg) was added once infant reached max morphine doses for contd. scores generally \>8. Option to re-load w/ 10mg/kg q8-12 hours for 2 more doses if needed for contd. high scores. Maintenance therapy of 5mg/kg/day was initiated 12 - 24hrs after last loading dose. Phenobarbital trough levels monitored, w/ goal levels 20 - 30 mcg/mL. Weaning procedure outlined in protocol.
|
|---|---|---|
|
Overall Study
Parent requested exclusion from analysis
|
1
|
0
|
Baseline Characteristics
Improving Outcomes in Neonatal Abstinence Syndrome
Baseline characteristics by cohort
| Measure |
Randomized: Methadone
n=58 Participants
First line therapy: 0.4mg/mL oral solution, based on weight and symptoms.
Clinical monitoring: Infants scored using standardized Finnegan system;
Regimen: Initiated treatment w/ 2 consec. scores ≥8, or 1 score ≥12. Starting doses range 0.3mg/kg/day - 0.9mg/kg/day, divided every 8hrs depending on the severity of Finnegan scores. Doses were increased to max of 0.9mg/kg/day for contd. scores generally \>8 caused primarily by worsening NAS, as needed. Weaned by 10% of max dose every 24-48 hours; Medication discontinued once at 25% of max dose.
Second Line Therapy: Phenobarbital (20mg/kg) was added once infant reached max methadone doses for contd. scores generally \>8. Option to re-load w/ 10mg/kg q8-12 hours for 2 more doses if needed for contd. high scores. Maintenance therapy of 5mg/kg/day was initiated 12 - 24hrs after last loading dose. Phenobarbital trough levels monitored, w/ goal levels 20 - 30 mcg/mL. Weaning procedure outlined in protocol.
|
Randomized: Neonatal Morphine Solution
n=58 Participants
First line therapy: 0.2mg/mL solution, based on weight and symptoms.
Clinical monitoring: Infants scored using standardized Finnegan system;
Regimen: Initiated treatment w/ 2 consec. scores ≥8, or 1 score ≥12. Starting doses range 0.3mg/kg/day - 0.9mg/kg/day, divided every 4hrs depending on the severity of Finnegan scores. Doses were increased to max of 0.9mg/kg/day for contd. scores generally \>8 caused primarily by worsening NAS, as needed. Weaned by 10% of max dose every 24 - 48 hours; Medication discontinued once at 25% of max dose.
Second Line Therapy: Phenobarbital (20mg/kg) was added once infant reached max morphine doses for contd. scores generally \>8. Option to re-load w/ 10mg/kg q8-12 hours for 2 more doses if needed for contd. high scores. Maintenance therapy of 5mg/kg/day was initiated 12 - 24hrs after last loading dose. Phenobarbital trough levels monitored, w/ goal levels 20 - 30 mcg/mL. Weaning procedure outlined in protocol.
|
Total
n=116 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Customized
|
3.2 days
STANDARD_DEVIATION 1.3 • n=5 Participants
|
3.5 days
STANDARD_DEVIATION 1.6 • n=7 Participants
|
3.4 days
STANDARD_DEVIATION 1.6 • n=5 Participants
|
|
Sex: Female, Male
Female
|
29 Participants
n=5 Participants
|
29 Participants
n=7 Participants
|
58 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
29 Participants
n=5 Participants
|
29 Participants
n=7 Participants
|
58 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Infant Race/Ethnicity · White
|
46 Participants
n=5 Participants
|
42 Participants
n=7 Participants
|
88 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Infant Race/Ethnicity · Hispanic
|
6 Participants
n=5 Participants
|
6 Participants
n=7 Participants
|
12 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Infant Race/Ethnicity · Other
|
6 Participants
n=5 Participants
|
10 Participants
n=7 Participants
|
16 Participants
n=5 Participants
|
|
Maternal opioid use
Buprenorphine
|
20 Participants
n=5 Participants
|
19 Participants
n=7 Participants
|
39 Participants
n=5 Participants
|
|
Maternal opioid use
Methadone
|
38 Participants
n=5 Participants
|
35 Participants
n=7 Participants
|
73 Participants
n=5 Participants
|
|
Maternal opioid use
Prescription opioids for pain
|
0 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
4 Participants
n=5 Participants
|
|
Maternal Smoking Frequency during Pregnancy
Smoked >5 cigarettes per day
|
33 Participants
n=5 Participants
|
15 Participants
n=7 Participants
|
48 Participants
n=5 Participants
|
|
Maternal Smoking Frequency during Pregnancy
Unknown/Data Missing
|
25 Participants
n=5 Participants
|
43 Participants
n=7 Participants
|
68 Participants
n=5 Participants
|
|
Maternal urine toxicology
Positive urine toxicology
|
13 Participants
n=5 Participants
|
16 Participants
n=7 Participants
|
29 Participants
n=5 Participants
|
|
Maternal urine toxicology
Negative urine toxicology
|
41 Participants
n=5 Participants
|
33 Participants
n=7 Participants
|
74 Participants
n=5 Participants
|
|
Maternal urine toxicology
Data Missing
|
4 Participants
n=5 Participants
|
9 Participants
n=7 Participants
|
13 Participants
n=5 Participants
|
|
Maternal psychiatric diagnoses
Psychiatric diagnoses
|
42 Participants
n=5 Participants
|
37 Participants
n=7 Participants
|
79 Participants
n=5 Participants
|
|
Maternal psychiatric diagnoses
No psychiatric diagnoses/Unknown
|
16 Participants
n=5 Participants
|
21 Participants
n=7 Participants
|
37 Participants
n=5 Participants
|
|
Maternal psychiatric medication during pregnancy
Psychiatric medication during pregnancy
|
20 Participants
n=5 Participants
|
16 Participants
n=7 Participants
|
36 Participants
n=5 Participants
|
|
Maternal psychiatric medication during pregnancy
No psychiatric medication during pregnancy/Unknown
|
38 Participants
n=5 Participants
|
42 Participants
n=7 Participants
|
80 Participants
n=5 Participants
|
|
Infant mean gestational age
|
39.2 weeks
STANDARD_DEVIATION 1.2 • n=5 Participants
|
39.1 weeks
STANDARD_DEVIATION 1.1 • n=7 Participants
|
39.2 weeks
STANDARD_DEVIATION 1.2 • n=5 Participants
|
|
Infant birth weight
|
3186 grams
STANDARD_DEVIATION 488 • n=5 Participants
|
3128 grams
STANDARD_DEVIATION 487 • n=7 Participants
|
3146 grams
STANDARD_DEVIATION 486 • n=5 Participants
|
|
Infant APGAR score at 1 minute
Score ≥7
|
54 Participants
n=5 Participants
|
53 Participants
n=7 Participants
|
107 Participants
n=5 Participants
|
|
Infant APGAR score at 1 minute
Score <7/Data missing
|
4 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
9 Participants
n=5 Participants
|
|
Infant mean head circumference
|
33.9 cm
STANDARD_DEVIATION 1.7 • n=5 Participants
|
33.7 cm
STANDARD_DEVIATION 1.8 • n=7 Participants
|
33.8 cm
STANDARD_DEVIATION 1.7 • n=5 Participants
|
|
Infant urine toxicology
Positive
|
41 Participants
n=5 Participants
|
42 Participants
n=7 Participants
|
83 Participants
n=5 Participants
|
|
Infant urine toxicology
Negative
|
14 Participants
n=5 Participants
|
14 Participants
n=7 Participants
|
28 Participants
n=5 Participants
|
|
Infant urine toxicology
Missing
|
3 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
5 Participants
n=5 Participants
|
|
Site of initial care before treatment
NICU
|
3 Participants
n=5 Participants
|
10 Participants
n=7 Participants
|
13 Participants
n=5 Participants
|
|
Site of initial care before treatment
Newborn Nursery
|
55 Participants
n=5 Participants
|
48 Participants
n=7 Participants
|
103 Participants
n=5 Participants
|
|
Site of initial care before treatment
Other
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Single dose of morphine prior to randomization
Single dose of morphine prior to randomization
|
23 Participants
n=5 Participants
|
17 Participants
n=7 Participants
|
40 Participants
n=5 Participants
|
|
Single dose of morphine prior to randomization
No dose of morphine prior to randomization
|
35 Participants
n=5 Participants
|
41 Participants
n=7 Participants
|
76 Participants
n=5 Participants
|
|
Initial site of NAS care
NICU
|
17 Participants
n=5 Participants
|
17 Participants
n=7 Participants
|
34 Participants
n=5 Participants
|
|
Initial site of NAS care
Special Care Nursery
|
9 Participants
n=5 Participants
|
7 Participants
n=7 Participants
|
16 Participants
n=5 Participants
|
|
Initial site of NAS care
General Pediatric Unit
|
16 Participants
n=5 Participants
|
18 Participants
n=7 Participants
|
34 Participants
n=5 Participants
|
|
Initial site of NAS care
Newborn Unit
|
16 Participants
n=5 Participants
|
16 Participants
n=7 Participants
|
32 Participants
n=5 Participants
|
|
Starting dose of study drug
Level I: 0.3 mg/kg/day
|
26 Participants
n=5 Participants
|
32 Participants
n=7 Participants
|
58 Participants
n=5 Participants
|
|
Starting dose of study drug
Level II: 0.5 mg/kg/day
|
25 Participants
n=5 Participants
|
21 Participants
n=7 Participants
|
46 Participants
n=5 Participants
|
|
Starting dose of study drug
Level I: 0.7 mg/kg/day
|
7 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
12 Participants
n=5 Participants
|
|
Maximum Finnegan score prior to starting treatment
|
12.9 units on a scale
STANDARD_DEVIATION 2.9 • n=5 Participants
|
12.6 units on a scale
STANDARD_DEVIATION 2.8 • n=7 Participants
|
NA units on a scale
STANDARD_DEVIATION NA • n=5 Participants
|
|
Primary feeding during hospitalization
Formula only
|
22 Participants
n=5 Participants
|
32 Participants
n=7 Participants
|
54 Participants
n=5 Participants
|
|
Primary feeding during hospitalization
Breast milk (exclusive or with formula supplement)
|
36 Participants
n=5 Participants
|
26 Participants
n=7 Participants
|
62 Participants
n=5 Participants
|
|
Maternal Smoking Status during Pregnancy
Smoked during pregnancy
|
49 Participants
n=5 Participants
|
44 Participants
n=7 Participants
|
93 Participants
n=5 Participants
|
|
Maternal Smoking Status during Pregnancy
Did not smoke during pregancy/Data missing
|
9 Participants
n=5 Participants
|
14 Participants
n=7 Participants
|
23 Participants
n=5 Participants
|
|
Infant APGAR Score at 5 minutes
Score ≥7
|
57 Participants
n=5 Participants
|
57 Participants
n=7 Participants
|
114 Participants
n=5 Participants
|
|
Infant APGAR Score at 5 minutes
Score <7/Data missing
|
1 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Participants will be monitored during their entire hospitalization, expected mean 22 days.Population: Includes infants requiring treatment for NAS who were randomized to either methadone or morphine study intervention. Analysis does not include Standard Clinical Care cohort.
Participants were monitored for the duration of their hospitalization, an expected mean of 22 days.
Outcome measures
| Measure |
Methadone
n=58 Participants
Infants randomized to this group will receive methadone oral solution (0.4mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 8 hours depending on the severity of the Finnegan scores. To maintain blinding of the two study arms, a "double dummy" design will be used - each infant will receive both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS as needed. Infants will be weaned by 10% of the maximum dose once every 24-48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
Neonatal Morphine Solution
n=58 Participants
Infants randomized to this arm will receive neonatal morphine solution (0.2mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. A "double dummy" design will be used - each infant will be ordered for both a methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 4 hours depending on the severity of the Finnegan scores. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS. Infants will be weaned by 10% of the maximum dose once every 24 - 48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
|---|---|---|
|
Length of Hospital Stay (LOS)
|
21.8 days
Standard Deviation 15
|
23.2 days
Standard Deviation 8.8
|
SECONDARY outcome
Timeframe: Participants were monitored for the duration of their hospitalization, expected mean 22 days.Population: Includes infants requiring treatment for NAS who were randomized to either methadone or morphine study intervention. Analysis does not include Standard Clinical Care cohort.
Participants were monitored for the duration of their hospitalization attributable to NAS only.
Outcome measures
| Measure |
Methadone
n=58 Participants
Infants randomized to this group will receive methadone oral solution (0.4mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 8 hours depending on the severity of the Finnegan scores. To maintain blinding of the two study arms, a "double dummy" design will be used - each infant will receive both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS as needed. Infants will be weaned by 10% of the maximum dose once every 24-48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
Neonatal Morphine Solution
n=58 Participants
Infants randomized to this arm will receive neonatal morphine solution (0.2mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. A "double dummy" design will be used - each infant will be ordered for both a methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 4 hours depending on the severity of the Finnegan scores. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS. Infants will be weaned by 10% of the maximum dose once every 24 - 48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
|---|---|---|
|
Length of Hospital Stay (LOS) Due to Neonatal Abstinence Syndrome (NAS)
|
18.9 days
Standard Deviation 7.9
|
21.1 days
Standard Deviation 6.9
|
SECONDARY outcome
Timeframe: Participants were monitored for the duration of their hospitalization.Population: Includes infants requiring treatment for NAS who were randomized to either methadone or morphine study intervention. Analysis does not include Standard Clinical Care cohort.
Total number of days infant treated with replacement opioids while admitted to the hospital.
Outcome measures
| Measure |
Methadone
n=58 Participants
Infants randomized to this group will receive methadone oral solution (0.4mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 8 hours depending on the severity of the Finnegan scores. To maintain blinding of the two study arms, a "double dummy" design will be used - each infant will receive both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS as needed. Infants will be weaned by 10% of the maximum dose once every 24-48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
Neonatal Morphine Solution
n=58 Participants
Infants randomized to this arm will receive neonatal morphine solution (0.2mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. A "double dummy" design will be used - each infant will be ordered for both a methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 4 hours depending on the severity of the Finnegan scores. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS. Infants will be weaned by 10% of the maximum dose once every 24 - 48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
|---|---|---|
|
Length of Treatment (LOT)
|
14.7 days
Standard Deviation 8.0
|
16.6 days
Standard Deviation 6.9
|
SECONDARY outcome
Timeframe: Participants were monitored for the duration of their hospitalization.Population: Data were not collected due to insufficient funding to carry out data collection.
Maximum daily dose of neonatal morphine solution or methadone during the hospitalization
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Participants were monitored during their entire hospitalizationPopulation: Data were not collected due to insufficient funding to carry out data collection.
Mean Finnegan withdrawal score during the duration of hospitalization.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Participants were monitored for the duration of their hospitalization, an average of 22 days.Population: Includes infants requiring treatment for NAS who were randomized to either methadone or morphine study intervention. Analysis does not include Standard Clinical Care cohort.
Number of infants treated with a second medication following protocol, phenobarbital. If the Finnegan Score remained elevated (still scored ≥8 two times consecutively, or still scored once ≥12) despite increasing to a predetermined maximal opioid dose (methadone or morphine), phenobarbital was administered (20-mg/kg loading dose followed by 4-5 mg/kg daily).
Outcome measures
| Measure |
Methadone
n=58 Participants
Infants randomized to this group will receive methadone oral solution (0.4mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 8 hours depending on the severity of the Finnegan scores. To maintain blinding of the two study arms, a "double dummy" design will be used - each infant will receive both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS as needed. Infants will be weaned by 10% of the maximum dose once every 24-48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
Neonatal Morphine Solution
n=58 Participants
Infants randomized to this arm will receive neonatal morphine solution (0.2mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. A "double dummy" design will be used - each infant will be ordered for both a methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 4 hours depending on the severity of the Finnegan scores. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS. Infants will be weaned by 10% of the maximum dose once every 24 - 48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
|---|---|---|
|
Number of Infants Needing a Second NAS Medication
|
10 Participants
|
17 Participants
|
SECONDARY outcome
Timeframe: Birth to 18 month follow-up visitPopulation: Participants who were continuously enrolled and attended the 18 month follow-up visit for developmental and growth measures.
Growth outcome weight (lbs) depicted as difference in averaged weights from birth to 18 month follow-up visit. Standard deviations were averaged between birth and 18 mo time points.
Outcome measures
| Measure |
Methadone
n=46 Participants
Infants randomized to this group will receive methadone oral solution (0.4mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 8 hours depending on the severity of the Finnegan scores. To maintain blinding of the two study arms, a "double dummy" design will be used - each infant will receive both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS as needed. Infants will be weaned by 10% of the maximum dose once every 24-48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
Neonatal Morphine Solution
n=36 Participants
Infants randomized to this arm will receive neonatal morphine solution (0.2mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. A "double dummy" design will be used - each infant will be ordered for both a methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 4 hours depending on the severity of the Finnegan scores. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS. Infants will be weaned by 10% of the maximum dose once every 24 - 48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
|---|---|---|
|
Growth Outcome: Weight Change From Birth to 18 Months
|
19.1 lbs
Standard Deviation 2.5
|
18.7 lbs
Standard Deviation 2.8
|
SECONDARY outcome
Timeframe: 18 month follow-up visitPopulation: Participants who were continuously enrolled and attended the 18 month follow-up visit for developmental and growth measures.
Average head circumference growth outcome at 18 month follow-up visit.
Outcome measures
| Measure |
Methadone
n=46 Participants
Infants randomized to this group will receive methadone oral solution (0.4mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 8 hours depending on the severity of the Finnegan scores. To maintain blinding of the two study arms, a "double dummy" design will be used - each infant will receive both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS as needed. Infants will be weaned by 10% of the maximum dose once every 24-48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
Neonatal Morphine Solution
n=36 Participants
Infants randomized to this arm will receive neonatal morphine solution (0.2mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. A "double dummy" design will be used - each infant will be ordered for both a methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 4 hours depending on the severity of the Finnegan scores. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS. Infants will be weaned by 10% of the maximum dose once every 24 - 48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
|---|---|---|
|
Growth Outcome: Head Circumference at 18 Months
|
47.8 cm
Standard Deviation 2.4
|
48.2 cm
Standard Deviation 2.3
|
SECONDARY outcome
Timeframe: Participants monitored for the duration of their hospitalization.Population: Data were not collected due to insufficient funding to carry out data collection.
Maximum Finnegan score during the hospitalization
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: 18 month follow-up visitPopulation: Participants who were continuously enrolled and attended the 18 month follow-up visit for developmental and growth measures.
Average length (cm) at 18 month follow-up visit.
Outcome measures
| Measure |
Methadone
n=46 Participants
Infants randomized to this group will receive methadone oral solution (0.4mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 8 hours depending on the severity of the Finnegan scores. To maintain blinding of the two study arms, a "double dummy" design will be used - each infant will receive both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS as needed. Infants will be weaned by 10% of the maximum dose once every 24-48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
Neonatal Morphine Solution
n=36 Participants
Infants randomized to this arm will receive neonatal morphine solution (0.2mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. A "double dummy" design will be used - each infant will be ordered for both a methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 4 hours depending on the severity of the Finnegan scores. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS. Infants will be weaned by 10% of the maximum dose once every 24 - 48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
|---|---|---|
|
Growth Outcome: Length at 18 Months
|
82.1 cm
Standard Deviation 4.6
|
81.7 cm
Standard Deviation 5.2
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Assessment at 18 month follow-up visitPopulation: Includes subjects who were randomized and remained enrolled at 18 month follow-up visit.
The Bayley Scales of Infant and Toddler Development (BSID-III) assesses the development of infants and children (1-42 months) through a series of developmental play tasks, identifying children with developmental delay. Raw scores of completed items are summarized within three distinct scale scores (Cognitive Scale, Language Scale, Motor Scale). Scale scores are each converted to composite scores to determine the child's performance compared with scores of age-matched children of typical development (percentile rank). A higher composite score indicates more ideal developmental outcome (range 40-160). At 18 month follow-up visit, participants were assessed using the BSID-III for cognitive, language and motor scale composite score outcomes.
Outcome measures
| Measure |
Methadone
n=46 Participants
Infants randomized to this group will receive methadone oral solution (0.4mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 8 hours depending on the severity of the Finnegan scores. To maintain blinding of the two study arms, a "double dummy" design will be used - each infant will receive both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS as needed. Infants will be weaned by 10% of the maximum dose once every 24-48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
Neonatal Morphine Solution
n=36 Participants
Infants randomized to this arm will receive neonatal morphine solution (0.2mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. A "double dummy" design will be used - each infant will be ordered for both a methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 4 hours depending on the severity of the Finnegan scores. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS. Infants will be weaned by 10% of the maximum dose once every 24 - 48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
|---|---|---|
|
Cognitive, Language, and Motor Development From 18 Month Bayley III Neurodevelopmental Assessment
Cognitive Composite
|
100.1 scores on a scale (Composite)
Standard Deviation 21.6
|
98.1 scores on a scale (Composite)
Standard Deviation 17.2
|
|
Cognitive, Language, and Motor Development From 18 Month Bayley III Neurodevelopmental Assessment
Language Composite
|
96.0 scores on a scale (Composite)
Standard Deviation 17.1
|
94.2 scores on a scale (Composite)
Standard Deviation 18.2
|
|
Cognitive, Language, and Motor Development From 18 Month Bayley III Neurodevelopmental Assessment
Motor Composite
|
103.6 scores on a scale (Composite)
Standard Deviation 17.3
|
99.1 scores on a scale (Composite)
Standard Deviation 17.2
|
POST_HOC outcome
Timeframe: Participants were monitored for the duration of their hospitalization, an average of 22 days.One Finnegan score ≥12, or two consecutive scores ≥8 affirms the requirement for pharmacological treatment or increasing treatment dosage. If the infant continued to have two consecutive Finnegan Scores ≥8 two times consecutively, or one ≥12, the dose was increased to the next level. (Level I: 0.3 mg/kg/day) (Level II: 0.5 mg/kg/day) (Level III: 0.7 mg/kg/day) A higher Finnegan score indicates greater severity of NAS (min 0, max 50).
Outcome measures
| Measure |
Methadone
n=58 Participants
Infants randomized to this group will receive methadone oral solution (0.4mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 8 hours depending on the severity of the Finnegan scores. To maintain blinding of the two study arms, a "double dummy" design will be used - each infant will receive both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS as needed. Infants will be weaned by 10% of the maximum dose once every 24-48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
Neonatal Morphine Solution
n=58 Participants
Infants randomized to this arm will receive neonatal morphine solution (0.2mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. A "double dummy" design will be used - each infant will be ordered for both a methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 4 hours depending on the severity of the Finnegan scores. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS. Infants will be weaned by 10% of the maximum dose once every 24 - 48 hours and the medication will be discontinued once at 25% of the maximum dose.
|
|---|---|---|
|
Number of Infants Needing a Dose Increase
|
22 Participants
|
28 Participants
|
Adverse Events
Methadone
Serious events: 5 serious events
Other events: 8 other events
Deaths: 0 deaths
Neonatal Morphine Solution
Serious events: 3 serious events
Other events: 6 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Methadone
n=58 participants at risk
Methadone oral solution (0.4mg/mL) for first line therapy. Infants were scored using the standardized Finnegan Scoring Tool and were initiated on treatment with 2 consecutive scores ≥8 or 1 score ≥12. Dosing was weight and symptom based. Starting doses range from 0.3mg/kg/day - 0.9mg/kg/day divided every 8 hours, depending on the severity of the Finnegan scores. To maintain blinding, a "double dummy" design was used - each infant received both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses were increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS, as needed. Infants were weaned by 10% of the maximum dose every 24-48 hours and the medication was discontinued once at 25% of the maximum dose.
|
Neonatal Morphine Solution
n=58 participants at risk
Neonatal morphine solution (0.2mg/mL) for first line therapy. Infants were scored using the standardized Finnegan Scoring Tool and were initiated on treatment with 2 consecutive scores ≥8 or 1 score ≥12. Dosing was weight and symptom based. Starting doses range from 0.3mg/kg/day - 0.9mg/kg/day divided every 4 hrs, depending on the severity of the Finnegan scores. To maintain blinding, a "double dummy" design was used - each infant received both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses were increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS, as needed. Infants were weaned by 10% of the maximum dose every 24-48 hours and the medication was discontinued once at 25% of the maximum dose.
|
|---|---|---|
|
General disorders
Hypothermia, apnea and lethargy
|
1.7%
1/58 • Number of events 1 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
0.00%
0/58 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
|
Surgical and medical procedures
Medication Administration Error
|
6.9%
4/58 • Number of events 6 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
5.2%
3/58 • Number of events 3 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
Other adverse events
| Measure |
Methadone
n=58 participants at risk
Methadone oral solution (0.4mg/mL) for first line therapy. Infants were scored using the standardized Finnegan Scoring Tool and were initiated on treatment with 2 consecutive scores ≥8 or 1 score ≥12. Dosing was weight and symptom based. Starting doses range from 0.3mg/kg/day - 0.9mg/kg/day divided every 8 hours, depending on the severity of the Finnegan scores. To maintain blinding, a "double dummy" design was used - each infant received both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses were increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS, as needed. Infants were weaned by 10% of the maximum dose every 24-48 hours and the medication was discontinued once at 25% of the maximum dose.
|
Neonatal Morphine Solution
n=58 participants at risk
Neonatal morphine solution (0.2mg/mL) for first line therapy. Infants were scored using the standardized Finnegan Scoring Tool and were initiated on treatment with 2 consecutive scores ≥8 or 1 score ≥12. Dosing was weight and symptom based. Starting doses range from 0.3mg/kg/day - 0.9mg/kg/day divided every 4 hrs, depending on the severity of the Finnegan scores. To maintain blinding, a "double dummy" design was used - each infant received both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses were increased to a maximum of 0.9mg/kg/day for continued scores generally \>8 caused primarily by worsening NAS, as needed. Infants were weaned by 10% of the maximum dose every 24-48 hours and the medication was discontinued once at 25% of the maximum dose.
|
|---|---|---|
|
Respiratory, thoracic and mediastinal disorders
Apnea and shallow breathing episodes
|
1.7%
1/58 • Number of events 1 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
0.00%
0/58 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
|
Investigations
Excessive sleepiness/somnolence
|
6.9%
4/58 • Number of events 4 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
3.4%
2/58 • Number of events 2 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
|
Investigations
Lethargy
|
0.00%
0/58 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
1.7%
1/58 • Number of events 1 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
|
Investigations
Hypothermia
|
3.4%
2/58 • Number of events 2 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
0.00%
0/58 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
|
Respiratory, thoracic and mediastinal disorders
Stridor/desaturation/shalllow breathing
|
3.4%
2/58 • Number of events 2 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
0.00%
0/58 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
|
Cardiac disorders
Bradychardia
|
5.2%
3/58 • Number of events 3 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
1.7%
1/58 • Number of events 1 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
|
Investigations
Poor feeding
|
0.00%
0/58 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
1.7%
1/58 • Number of events 1 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
|
Gastrointestinal disorders
Emesis
|
0.00%
0/58 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
1.7%
1/58 • Number of events 1 • Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Events and Serious Adverse Events were reported according to standard definitions.
|
Additional Information
Jonathan M. Davis, MD
Tufts Medical Center Floating Hospital for Children
Phone: (617) 636-5322
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place