Narcotic Addiction, Neonatal Abstinence Syndrome
Conditions
Keywords
Narcotic addiction during pregnancy, Neonatal abstinence syndrome, NAS
Brief summary
The Investigators hope to learn if they can prevent or lessen the symptoms of neonatal abstinence syndrome (NAS) in babies born to narcotic-dependent mothers by using the drug ondansetron in the mothers prior to delivery and their babies after delivery. The study is a randomized, double-blind, placebo-controlled study with one half the mother-baby pairs to receive ondansetron and the other half of the mother-baby pairs to receive placebo. The pregnant narcotic-dependent mothers will receive an intravenous dose of study medication prior to delivery; the neonates, after their birth, will receive the same study medication the mother received every 24 hours for up to 5 days. The Investigators will follow up with the mother-baby pairs for 10 days after study drug has stopped and one last follow up, about 30 days after stopping study drug, to learn if the baby had any symptoms of NAS in that time period.
Detailed description
All neonates will have a screening 12-lead EKG prior to their first dose of study medication to determine if QTc prolongation is present. A repeat 12-lead EKG will be done after each dose of study medication, approximately 2-5 hours post dose; if a neonate has prolonged QTc the study drug will be stopped. Investigators may obtain up to 9 pharmacokinetic (PK) blood samples from the neonates over 5 days when standard of care blood samples are drawn. These samples will consist of 1 to 2 drops of blood collected on filter paper and sent to Stanford for PK analysis. The modified Finnegan scoring system will be used to evaluate neonates for symptoms of NAS at each site and it is considered standard-of-care for babies at risk of NAS. Morphine will be the first treatment choice before other treatment medication choices (opioid or non-opioid) for NAS symptoms. Each site involved has established guidelines for starting, advancing and weaning treatment for NAS. Any medication used to treat NAS will be recorded. Interim analysis: will be performed after the first 20 pregnant women and their neonates have been enrolled and dosed with study drug. (Interim Analysis was done on first 21 mother/baby pairs in May 2016). To protect the confidentiality of the patients (study subjects), the lead site, Stanford University, received a Certificate of Confidentiality from the NIH.
Interventions
DRUGOndansetron
Pregnant women may receive a second dose of IV ondansetron if they have not delivered within 4 hours of receiving the IV study medication. 50% of the 90 mother/baby pairs will receive ondansetron; the baby will always get the same study medication as the mother.
DRUGPlacebo
All doses of placebo, whether IV or oral, will mimic the same volume as the ondansetron group to maintain the blind. Pregnant women may receive a second dose of IV placebo if they have not delivered within 4 hours of being given the IV study medication. 50% of the 90 mother/baby pairs will receive placebo; the baby will always receive the same study medication as the mother.
Sponsors
Santa Clara Valley Medical Center
Thomas Jefferson University
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 45 Years
Healthy volunteers
No
Inclusion criteria
* adult female, opioid-dependent for at least 3 weeks prior to delivery. * adult female, otherwise healthy. * adult female, age 18-45 years inclusive. * adult female, signed consent to participate for self and neonate (maternal subject may decide not to receive the study drug but her neonate can still be included in the study). * neonate, gestational age 37 weeks through 41 weeks and 6 days at birth. * neonate, corrected QT interval (QTc) from 12-lead electrocardiogram (ECG) less than 480 milliseconds (ms).
Exclusion criteria
* adult female, any condition that, in the opinion of the investigator, would compromise the health of the participant (both mother and fetus) or the integrity of the data. * adult female, known allergy to study drug (ondansetron). * adult female, screening 12-lead ECG, if done, showing prolonged QTc will stop the mother from receiving any study drug but her neonate can still be included in the study. * adult female, not dependent on opioids for at least 3 weeks prior to delivery. * adult female, generally not healthy. * adult female, age 17 years or less or 46 years of age and older. * adult female and neonate, the maternal ingestion or administration of ondansetron within 24 hours prior to delivery, for reasons other than study purposes, will exclude the mother and the neonate. * neonate, preterm or post-term gestational age at delivery. * neonate, QTc showing results greater than or equal to 480ms on any 12-lead ECG post delivery will stop the dosing of the study drug, but safety follow up will be done if the mother or baby received at least one dose of study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Neonatal Abstinence Syndrome | 35 days | The incidence of neonatal abstinence syndrome (NAS) measured as the number of neonates who need for morphine treatment for the symptoms of neonatal opioid withdrawal syndrome (NOWS) while the neonates received study medication and for the 30 days after stopping the study medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Length of Hospital Stay | At Day 15 and up to 64 days | Severity of NAS will be measured by neonates' length of hospital stay (birth to discharge). Length of stay was calculated with 1) no maximum length, and 2) maximum length of stay capped at 15 days. All participants were included in both analyses. |
| Total Dose of Narcotic Required to Treat the Symptoms of NAS | 15 days | Median dose of morphine required by neonates within 15 days of delivery. |
| Number of Participants Requiring Adjunctive Medication to Treat NOWS | 15 days | Number of neonates requiring treatment with phenobarbital or clonidine. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ondansetron - Mothers Pregnant Women: ondansetron 8mg intravenously (IV) within 4 hours of delivery; may receive a second dose of IV ondansetron if they have not delivered within 4 hours of receiving the IV study medication. | 45 |
| Ondansetron - Neonates Neonates: ondansetron 0.07 mg/kg given orally every 24 hours starting 4-8 hours after delivery, for up to 5 days (if IV line available in neonate, ondansetron 0.04 mg/kg IV every 24 hours for up to 5 days). | 45 |
| Placebo - Mothers Pregnant Women: placebo given intravenously prior to delivery (volume to mimic the IV volume of the ondansetron group); may receive a second dose of IV placebo if they have not delivered within 4 hours of being given the IV study medication. | 41 |
| Placebo - Neonates Neonates: placebo given orally every 24 hours, starting 4-8 hours after delivery, for up to 5 days with volume to mimic the oral volume of the ondansetron group (if IV line available, placebo may be given IV). | 41 |
| Total | 172 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 |
| Overall Study | Delivered at home | 1 | 1 | 0 | 0 |
| Overall Study | Did not meet inclusion criteria | 0 | 0 | 1 | 1 |
| Overall Study | Experienced complications | 0 | 0 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | Ondansetron - Mothers | Ondansetron - Neonates | Placebo - Mothers | Placebo - Neonates | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 45 Participants | 0 Participants | 41 Participants | 86 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 0 Participants | 41 Participants | 0 Participants | 86 Participants |
| Gestational age at birth | — | 39 weeks | — | 39 weeks | 39 weeks |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 6 Participants | 4 Participants | 4 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 12 Participants |
| Race (NIH/OMB) White | 35 Participants | 35 Participants | 34 Participants | 34 Participants | 138 Participants |
| Region of Enrollment United States | 45 Participants | 45 Participants | 41 Participants | 41 Participants | 172 Participants |
| Sex: Female, Male Female | 45 Participants | 22 Participants | 41 Participants | 19 Participants | 127 Participants |
| Sex: Female, Male Male | 0 Participants | 23 Participants | 0 Participants | 22 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 48 | 0 / 50 | 0 / 50 |
| other Total, other adverse events | 1 / 48 | 18 / 48 | 1 / 50 | 15 / 50 |
| serious Total, serious adverse events | 1 / 48 | 2 / 48 | 1 / 50 | 4 / 50 |
Outcome results
Primary
Number of Participants With Neonatal Abstinence Syndrome
The incidence of neonatal abstinence syndrome (NAS) measured as the number of neonates who need for morphine treatment for the symptoms of neonatal opioid withdrawal syndrome (NOWS) while the neonates received study medication and for the 30 days after stopping the study medication.
Time frame: 35 days
Population: Neonates who completed the protocol and met all inclusion criteria are included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ondansetron - Neonates | Number of Participants With Neonatal Abstinence Syndrome | 22 Participants |
| Placebo - Neonates | Number of Participants With Neonatal Abstinence Syndrome | 26 Participants |
p-value: 0.2Fisher Exact
Secondary
Length of Hospital Stay
Severity of NAS will be measured by neonates' length of hospital stay (birth to discharge). Length of stay was calculated with 1) no maximum length, and 2) maximum length of stay capped at 15 days. All participants were included in both analyses.
Time frame: At Day 15 and up to 64 days
Population: Neonates who completed the protocol and met all inclusion criteria are included in the analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ondansetron - Neonates | Length of Hospital Stay | Mean hospital stay | 15.5 days |
| Ondansetron - Neonates | Length of Hospital Stay | Mean hospital stay with a 15-day maximum | 9.3 days |
| Placebo - Neonates | Length of Hospital Stay | Mean hospital stay with a 15-day maximum | 11.2 days |
| Placebo - Neonates | Length of Hospital Stay | Mean hospital stay | 17.4 days |
Comparison: Difference in overall length of stay.p-value: 0.5695% CI: [-8, 4.3]Wilcoxon Rank-Sum test
Comparison: Difference in length of stay as calculated with maximum length capped at 15 days.p-value: 0.0795% CI: [-4, 0.2]Wilcoxon Rank-Sum test
Secondary
Number of Participants Requiring Adjunctive Medication to Treat NOWS
Number of neonates requiring treatment with phenobarbital or clonidine.
Time frame: 15 days
Population: Neonates who completed the protocol and met all inclusion criteria are included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ondansetron - Neonates | Number of Participants Requiring Adjunctive Medication to Treat NOWS | 5 Participants |
| Placebo - Neonates | Number of Participants Requiring Adjunctive Medication to Treat NOWS | 5 Participants |
Secondary
Total Dose of Narcotic Required to Treat the Symptoms of NAS
Median dose of morphine required by neonates within 15 days of delivery.
Time frame: 15 days
Population: Neonates who completed the protocol and met all inclusion criteria are included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ondansetron - Neonates | Total Dose of Narcotic Required to Treat the Symptoms of NAS | 9.3 mg |
| Placebo - Neonates | Total Dose of Narcotic Required to Treat the Symptoms of NAS | 11.1 mg |
p-value: 0.3195% CI: [-8.8, 2.7]Wilcoxon Rank-Sum test