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Trial record 1 of 1 for:    NCT01958476
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Improving Outcomes in Neonatal Abstinence Syndrome

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ClinicalTrials.gov Identifier: NCT01958476
Recruitment Status : Completed
First Posted : October 9, 2013
Results First Posted : October 15, 2019
Last Update Posted : October 15, 2019
Sponsor:
Information provided by (Responsible Party):
Tufts Medical Center

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Neonatal Abstinence Syndrome
Neonatal Opioid Withdrawal
Interventions Drug: Neonatal Morphine Solution
Drug: Methadone
Drug: Phenobarbital
Enrollment 117
Recruitment Details 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.
Pre-assignment Details 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.
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description

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.

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.

Period Title: Overall Study
Started 59 58
Completed 58 58
Not Completed 1 0
Reason Not Completed
Parent requested exclusion from analysis             1             0
Arm/Group Title Randomized: Methadone Randomized: Neonatal Morphine Solution Total
Hide Arm/Group Description

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.

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 of all reporting groups
Overall Number of Baseline Participants 58 58 116
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized   [1] 
Mean (Standard Deviation)
Unit of measure:  Days
Number Analyzed 58 participants 58 participants 116 participants
3.2  (1.3) 3.5  (1.6) 3.4  (1.6)
[1]
Measure Description: Infant mean age upon starting treatment;
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Female
29
  50.0%
29
  50.0%
58
  50.0%
Male
29
  50.0%
29
  50.0%
58
  50.0%
[1]
Measure Description: N (%)
Race/Ethnicity, Customized   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Infant Race/Ethnicity Number Analyzed 58 participants 58 participants 116 participants
White
46
  79.3%
42
  72.4%
88
  75.9%
Hispanic
6
  10.3%
6
  10.3%
12
  10.3%
Other
6
  10.3%
10
  17.2%
16
  13.8%
[1]
Measure Description: N (%)
Maternal opioid use   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Buprenorphine
20
  34.5%
19
  32.8%
39
  33.6%
Methadone
38
  65.5%
35
  60.3%
73
  62.9%
Prescription opioids for pain
0
   0.0%
4
   6.9%
4
   3.4%
[1]
Measure Description: N (%)
Maternal Smoking Frequency during Pregnancy   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Smoked >5 cigarettes per day
33
  56.9%
15
  25.9%
48
  41.4%
Unknown/Data Missing
25
  43.1%
43
  74.1%
68
  58.6%
[1]
Measure Description: N (%)
Maternal urine toxicology   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Positive urine toxicology
13
  22.4%
16
  27.6%
29
  25.0%
Negative urine toxicology
41
  70.7%
33
  56.9%
74
  63.8%
Data Missing
4
   6.9%
9
  15.5%
13
  11.2%
[1]
Measure Description: Positive for at least one illicit substance, N (%)
Maternal psychiatric diagnoses   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Psychiatric diagnoses
42
  72.4%
37
  63.8%
79
  68.1%
No psychiatric diagnoses/Unknown
16
  27.6%
21
  36.2%
37
  31.9%
[1]
Measure Description: N (%)
Maternal psychiatric medication during pregnancy   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Psychiatric medication during pregnancy
20
  34.5%
16
  27.6%
36
  31.0%
No psychiatric medication during pregnancy/Unknown
38
  65.5%
42
  72.4%
80
  69.0%
[1]
Measure Description: N (%)
Infant mean gestational age  
Mean (Standard Deviation)
Unit of measure:  Weeks
Number Analyzed 58 participants 58 participants 116 participants
39.2  (1.2) 39.1  (1.1) 39.2  (1.2)
Infant birth weight  
Mean (Standard Deviation)
Unit of measure:  Grams
Number Analyzed 58 participants 58 participants 116 participants
3186  (488) 3128  (487) 3146  (486)
Infant APGAR score at 1 minute   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Score ≥7
54
  93.1%
53
  91.4%
107
  92.2%
Score <7/Data missing
4
   6.9%
5
   8.6%
9
   7.8%
[1]
Measure Description: Appearance, Pulse, Grimace, Activity, and Respiration (APGAR), a 5-criteria assessment used to summarize the health of the newborn against infant mortality, scored at 1 minute after birth. Each assessment (Appearance, Pulse, Grimace, Activity, Respiration) is scored on a categorical scale of 0, 1 or 2 based on given criteria. All assessment scores are summarized to create the APGAR score (min = 0, max = 10). An APGAR score ≥7 generally indicates a newborn with normal health; An APGAR score ≤3 is generally considered critically low and cause for resuscitation efforts and critical care.
Infant mean head circumference  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 58 participants 58 participants 116 participants
33.9  (1.7) 33.7  (1.8) 33.8  (1.7)
Infant urine toxicology   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Positive
41
  70.7%
42
  72.4%
83
  71.6%
Negative
14
  24.1%
14
  24.1%
28
  24.1%
Missing
3
   5.2%
2
   3.4%
5
   4.3%
[1]
Measure Description: N (%)
Site of initial care before treatment   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
NICU
3
   5.2%
10
  17.2%
13
  11.2%
Newborn Nursery
55
  94.8%
48
  82.8%
103
  88.8%
Other
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: by type of care unit
Single dose of morphine prior to randomization   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Single dose of morphine prior to randomization
23
  39.7%
17
  29.3%
40
  34.5%
No dose of morphine prior to randomization
35
  60.3%
41
  70.7%
76
  65.5%
[1]
Measure Description: N (%)
Initial site of NAS care   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
NICU
17
  29.3%
17
  29.3%
34
  29.3%
Special Care Nursery
9
  15.5%
7
  12.1%
16
  13.8%
General Pediatric Unit
16
  27.6%
18
  31.0%
34
  29.3%
Newborn Unit
16
  27.6%
16
  27.6%
32
  27.6%
[1]
Measure Description: N (%)
Starting dose of study drug   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Level I: 0.3 mg/kg/day
26
  44.8%
32
  55.2%
58
  50.0%
Level II: 0.5 mg/kg/day
25
  43.1%
21
  36.2%
46
  39.7%
Level I: 0.7 mg/kg/day
7
  12.1%
5
   8.6%
12
  10.3%
[1]
Measure Description: N (%)
Maximum Finnegan score prior to starting treatment   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 58 participants 58 participants 116 participants
12.9  (2.9) 12.6  (2.8) NA [2]   (NA)
[1]
Measure Description: Finnegan Scoring Tool, a 25-item assessment of infants for Neonatal Abstinence Syndrome (NAS), is used within 24 hrs after birth and subsequently every 4 hours. Each item is scored on varying categorical subscales, scored depending on severity of each sign/symptom (ex. Generalized seizure Yes=8 No=0; Poor feeding Yes=2 No=0). Individually scored items are added to create the total Finnegan score. One score ≥12 or two consecutive scores ≥8 affirms the requirement for pharmacological treatment or increasing treatment dosage. A higher Finnegan score indicates greater NAS severity (min 0 max 50)
[2]
Baseline assessment for randomized cohorts only.
Primary feeding during hospitalization   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Formula only
22
  37.9%
32
  55.2%
54
  46.6%
Breast milk (exclusive or with formula supplement)
36
  62.1%
26
  44.8%
62
  53.4%
[1]
Measure Description: N (%)
Maternal Smoking Status during Pregnancy  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Smoked during pregnancy
49
  84.5%
44
  75.9%
93
  80.2%
Did not smoke during pregancy/Data missing
9
  15.5%
14
  24.1%
23
  19.8%
Infant APGAR Score at 5 minutes   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants 58 participants 116 participants
Score ≥7
57
  98.3%
57
  98.3%
114
  98.3%
Score <7/Data missing
1
   1.7%
1
   1.7%
2
   1.7%
[1]
Measure Description: Appearance, Pulse, Grimace, Activity, and Respiration (APGAR), a 5-criteria assessment used to summarize the health of the newborn against infant mortality, scored at 5 minutes after birth. Each assessment (Appearance, Pulse, Grimace, Activity, Respiration) is scored on a categorical scale of 0, 1 or 2 based on given criteria. All assessment scores are summarized to create the APGAR score (min = 0, max = 10). An APGAR score ≥7 generally indicates a newborn with normal health; An APGAR score ≤3 is generally considered critically low and cause for resuscitation efforts and critical care.
1.Primary Outcome
Title Length of Hospital Stay (LOS)
Hide Description Participants were monitored for the duration of their hospitalization, an expected mean of 22 days.
Time Frame Participants will be monitored during their entire hospitalization, expected mean 22 days.
Hide Outcome Measure Data
Hide Analysis Population Description
Includes infants requiring treatment for NAS who were randomized to either methadone or morphine study intervention. Analysis does not include Standard Clinical Care cohort.
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 58 58
Mean (Standard Deviation)
Unit of Measure: days
21.8  (15) 23.2  (8.8)
2.Secondary Outcome
Title Length of Hospital Stay (LOS) Due to Neonatal Abstinence Syndrome (NAS)
Hide Description Participants were monitored for the duration of their hospitalization attributable to NAS only.
Time Frame Participants were monitored for the duration of their hospitalization, expected mean 22 days.
Hide Outcome Measure Data
Hide Analysis Population Description
Includes infants requiring treatment for NAS who were randomized to either methadone or morphine study intervention. Analysis does not include Standard Clinical Care cohort.
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 58 58
Mean (Standard Deviation)
Unit of Measure: days
18.9  (7.9) 21.1  (6.9)
3.Secondary Outcome
Title Length of Treatment (LOT)
Hide Description Total number of days infant treated with replacement opioids while admitted to the hospital.
Time Frame Participants were monitored for the duration of their hospitalization.
Hide Outcome Measure Data
Hide Analysis Population Description
Includes infants requiring treatment for NAS who were randomized to either methadone or morphine study intervention. Analysis does not include Standard Clinical Care cohort.
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 58 58
Mean (Standard Deviation)
Unit of Measure: days
14.7  (8.0) 16.6  (6.9)
4.Secondary Outcome
Title Maximum Daily Dose of Replacement Opioid
Hide Description Maximum daily dose of neonatal morphine solution or methadone during the hospitalization
Time Frame Participants were monitored for the duration of their hospitalization.
Hide Outcome Measure Data
Hide Analysis Population Description
Data were not collected due to insufficient funding to carry out data collection.
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
5.Secondary Outcome
Title Mean Finnegan Score (FS)
Hide Description Mean Finnegan withdrawal score during the duration of hospitalization.
Time Frame Participants were monitored during their entire hospitalization
Hide Outcome Measure Data
Hide Analysis Population Description
Data were not collected due to insufficient funding to carry out data collection.
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
6.Secondary Outcome
Title Number of Infants Needing a Second NAS Medication
Hide Description 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).
Time Frame Participants were monitored for the duration of their hospitalization, an average of 22 days.
Hide Outcome Measure Data
Hide Analysis Population Description
Includes infants requiring treatment for NAS who were randomized to either methadone or morphine study intervention. Analysis does not include Standard Clinical Care cohort.
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 58 58
Measure Type: Count of Participants
Unit of Measure: Participants
10
  17.2%
17
  29.3%
7.Secondary Outcome
Title Growth Outcome: Weight Change From Birth to 18 Months
Hide Description 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.
Time Frame Birth to 18 month follow-up visit
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Hide Analysis Population Description
Participants who were continuously enrolled and attended the 18 month follow-up visit for developmental and growth measures.
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 46 36
Mean (Standard Deviation)
Unit of Measure: lbs
19.1  (2.5) 18.7  (2.8)
8.Secondary Outcome
Title Growth Outcome: Head Circumference at 18 Months
Hide Description Average head circumference growth outcome at 18 month follow-up visit.
Time Frame 18 month follow-up visit
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were continuously enrolled and attended the 18 month follow-up visit for developmental and growth measures.
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 46 36
Mean (Standard Deviation)
Unit of Measure: cm
47.8  (2.4) 48.2  (2.3)
9.Secondary Outcome
Title Maximum Finnegan Score
Hide Description Maximum Finnegan score during the hospitalization
Time Frame Participants monitored for the duration of their hospitalization.
Hide Outcome Measure Data
Hide Analysis Population Description
Data were not collected due to insufficient funding to carry out data collection.
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
10.Secondary Outcome
Title Growth Outcome: Length at 18 Months
Hide Description Average length (cm) at 18 month follow-up visit.
Time Frame 18 month follow-up visit
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were continuously enrolled and attended the 18 month follow-up visit for developmental and growth measures.
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 46 36
Mean (Standard Deviation)
Unit of Measure: cm
82.1  (4.6) 81.7  (5.2)
11.Other Pre-specified Outcome
Title Cognitive, Language, and Motor Development From 18 Month Bayley III Neurodevelopmental Assessment
Hide Description 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.
Time Frame Assessment at 18 month follow-up visit
Hide Outcome Measure Data
Hide Analysis Population Description
Includes subjects who were randomized and remained enrolled at 18 month follow-up visit.
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 46 36
Mean (Standard Deviation)
Unit of Measure: scores on a scale (Composite)
Cognitive Composite 100.1  (21.6) 98.1  (17.2)
Language Composite 96.0  (17.1) 94.2  (18.2)
Motor Composite 103.6  (17.3) 99.1  (17.2)
12.Post-Hoc Outcome
Title Number of Infants Needing a Dose Increase
Hide Description

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).

Time Frame Participants were monitored for the duration of their hospitalization, an average of 22 days.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 58 58
Measure Type: Count of Participants
Unit of Measure: Participants
22
  37.9%
28
  48.3%
Time Frame Participants were monitored for the duration of their hospitalization, an average of 22 days.
Adverse Event Reporting Description Adverse Events and Serious Adverse Events were reported according to standard definitions.
 
Arm/Group Title Methadone Neonatal Morphine Solution
Hide Arm/Group Description 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 (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.
All-Cause Mortality
Methadone Neonatal Morphine Solution
Affected / at Risk (%) Affected / at Risk (%)
Total   0/58 (0.00%)      0/58 (0.00%)    
Hide Serious Adverse Events
Methadone Neonatal Morphine Solution
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/58 (8.62%)      3/58 (5.17%)    
General disorders     
Hypothermia, apnea and lethargy  1  1/58 (1.72%)  1 0/58 (0.00%)  0
Surgical and medical procedures     
Medication Administration Error  1 [1]  4/58 (6.90%)  6 3/58 (5.17%)  3
1
Term from vocabulary, MedDRA
Indicates events were collected by systematic assessment
[1]
Includes "medication error by Registered Nurse (RN)", "missed dose by RN", "incorrect dose supplied by pharmacy", and "Delayed escalation doses by RN";
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Methadone Neonatal Morphine Solution
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   8/58 (13.79%)      6/58 (10.34%)    
Cardiac disorders     
Bradychardia  1  3/58 (5.17%)  3 1/58 (1.72%)  1
Gastrointestinal disorders     
Emesis  1  0/58 (0.00%)  0 1/58 (1.72%)  1
Investigations     
Excessive sleepiness/somnolence  1  4/58 (6.90%)  4 2/58 (3.45%)  2
Lethargy  1  0/58 (0.00%)  0 1/58 (1.72%)  1
Hypothermia  1  2/58 (3.45%)  2 0/58 (0.00%)  0
Poor feeding  1  0/58 (0.00%)  0 1/58 (1.72%)  1
Respiratory, thoracic and mediastinal disorders     
Apnea and shallow breathing episodes  1  1/58 (1.72%)  1 0/58 (0.00%)  0
Stridor/desaturation/shalllow breathing  1  2/58 (3.45%)  2 0/58 (0.00%)  0
1
Term from vocabulary, MedDRA
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT 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
Layout table for Results Point of Contact information
Name/Title: Jonathan M. Davis, MD
Organization: Tufts Medical Center Floating Hospital for Children
Phone: (617) 636-5322
EMail: jdavis@tuftsmedicalcenter.org
Publications:
Layout table for additonal information
Responsible Party: Tufts Medical Center
ClinicalTrials.gov Identifier: NCT01958476    
Other Study ID Numbers: 1R01DA032889-01A1 ( U.S. NIH Grant/Contract )
First Submitted: August 14, 2013
First Posted: October 9, 2013
Results First Submitted: July 1, 2019
Results First Posted: October 15, 2019
Last Update Posted: October 15, 2019