Symptom-Based Dosing for Neonatal Abstinence Syndrome

(OPTimize NOW Trial)

Recruiting at 22 trial locations

Overseen By HELP for NOWS Consortium

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: HELP for NOWS Consortium

Disqualifiers: Major birth defects, Neonatal encephalopathy, Respiratory support, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

480 Participants Needed

Trial Summary

What is the purpose of this trial?

This clinical trial will help us learn more about how to best care for babies with Neonatal Opioid Withdrawal Syndrome, also called NOWS. Babies with NOWS often have tremors, a hard time sleeping, excessive crying, and trouble feeding. Some babies that have NOWS need medicine. Doctors have two ways of providing medicine that are widely used today: 1. Scheduled opioid taper approach. The baby gets medicine at regular times. As symptoms get better, the amount of medicine the baby gets decreases until the baby no longer needs medicine. This is called a medicine taper. 2. Symptom-based approach. The baby will only get medicine when they show signs of NOWS, instead of at regular times. If the baby is showing no signs of NOWS, no medicine will be given. We are doing the OPTimize NOW study to figure out the best way to give medicine to babies with NOWS.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications. However, there is a mention of a 'washout period' (time without taking certain medications) for the study site, but it is unclear if this applies to individual participants.

What data supports the effectiveness of the symptom-based dosing approach for treating neonatal abstinence syndrome?

Research comparing a symptom-triggered methadone approach to a fixed-schedule methadone taper for neonatal opioid withdrawal syndrome (NOWS) suggests that adjusting methadone based on symptoms may improve hospitalization outcomes for infants. ^{1 2 3 4 5}

Is methadone safe for treating neonatal abstinence syndrome?

Research suggests that methadone is generally safe for treating neonatal abstinence syndrome (NAS) in newborns, although it may require more medication and longer hospital stays compared to buprenorphine. Studies have shown that methadone does not increase the severity of NAS when used in pregnant women with opioid dependence. ^{2 3 4 6 7}

How does the symptom-based dosing approach for neonatal abstinence syndrome differ from other treatments?

The symptom-based dosing approach for neonatal abstinence syndrome (NOWS) is unique because it adjusts the methadone dosage based on the infant's symptoms rather than following a fixed schedule. This personalized method aims to better manage withdrawal symptoms by providing medication only when needed, potentially reducing the total amount of medication used and the length of hospital stay compared to standard fixed-schedule treatments. ^{2 3 4 8 9}

Research Team

Lori Devlin, MD

Principal Investigator

University of Louisville

Eligibility Criteria

This trial is for babies at risk of Neonatal Opioid Withdrawal Syndrome (NOWS) who are 36 weeks gestation or older, with prenatal opioid exposure. Babies must not need respiratory support at 48 hours old, have no major birth defects, and cannot have started treatment elsewhere.

Inclusion Criteria

My baby was exposed to opioids before birth.

The infant is greater than or equal to 36 weeks gestation

My infant is being treated for opioid withdrawal at a qualified study location.

Exclusion Criteria

My infant needed breathing support at 48 hours old.

My infant was exposed to opioids before starting treatment for withdrawal.

My infant has been diagnosed with a brain condition like encephalopathy or meningitis before starting any drug treatment.

Timeline

Run-in Period

A three-week run-in period to prepare for the treatment phase

3 weeks

Treatment Period 1

Infants receive either a scheduled opioid taper approach or a symptom-based dosing approach for five months

5 months

Washout Period

A three-week washout period between treatment phases

3 weeks

Treatment Period 2

Infants receive the alternate treatment approach (either scheduled opioid taper or symptom-based dosing) for five months

5 months

Follow-up

Participants are monitored for safety and effectiveness after treatment until hospital discharge or up to 1 year

Up to 1 year

Treatment Details

Interventions

• Scheduled Opioid Taper Approach
• Symptom-based Dosing Approach

Trial Overview The study compares two methods to treat NOWS in infants: a scheduled opioid taper approach where medicine is reduced over time, and a symptom-based dosing approach that administers medication only when withdrawal symptoms appear.

Participant Groups

Group I: Sequence 2 Experimental Treatment 2 Interventions

This sequence will assign eligible participants to a three-week run-in period followed by a symptom-based dosing approach for five months followed by a three-week washout period followed by scheduled opioid taper approach for five months.

Group II: Sequence 1 Experimental Treatment 2 Interventions

This sequence will assign eligible participants to a three-week run-in period followed by a scheduled opioid taper approach for five months followed by a three-week washout period followed by symptom-based dosing approach for five months.

Scheduled Opioid Taper Approach is already approved in United States, European Union for the following indications:

Approved in United States as Methadose for:

• Detoxification and maintenance treatment of opioid addiction
• Relief of moderate to severe pain

Approved in European Union as Methadone for:

• Treatment of opioid dependence
• Severe chronic pain

Who Is Running the Clinical Trial?

HELP for NOWS Consortium

Lead Sponsor

Trials

1

Recruited

480+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Findings from Research

The Medication Taper Complexity Score (MTCS) was validated as a reliable tool for assessing the complexity of methadone tapers in children with opioid abstinence syndrome, achieving a high reliability coefficient of 0.9949.

The MTCS effectively distinguished between 'easy,' 'medium,' and 'difficult' tapers, indicating its potential usefulness in clinical practice and research for managing methadone treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

External validation of the medication taper complexity score for methadone tapers in children with opioid abstinence syndrome. Johnson, PN., Miller, JL., Hagemann, TM., et al.[2019]

In a study of 174 pregnant women on methadone maintenance, the incidence of clinically significant neonatal abstinence syndrome (NAS) was similar across different maternal methadone dosing groups, indicating that higher doses do not increase the risk of NAS.

The study found no significant differences in birth weight, preterm birth rates, or neonatal morbidities based on methadone dosage, suggesting that concerns about NAS should not limit methadone dosing during pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher maternal doses of methadone does not increase neonatal abstinence syndrome. Pizarro, D., Habli, M., Grier, M., et al.[2021]

In a study comparing neonates of opioid-dependent women treated with buprenorphine versus methadone, buprenorphine-exposed neonates required less opioid medication for neonatal abstinence syndrome (NAS) and had shorter hospital stays, indicating a potential safety and efficacy advantage.

The study found that 20% of buprenorphine-exposed neonates were treated for NAS compared to 45.5% of methadone-exposed neonates, suggesting that buprenorphine may be as effective as methadone in managing NAS outcomes when treatment begins in the second trimester.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. Jones, HE., Johnson, RE., Jasinski, DR., et al.[2022]

Infants with neonatal opioid withdrawal syndrome (NOWS) treated with a novel symptom-triggered methadone approach (STMA) had a significantly shorter median hospital length of stay (10.5 days) compared to those treated with a fixed-schedule methadone taper (FSMT) (17.0 days), indicating improved hospitalization outcomes.

The STMA also resulted in fewer methadone treatment days (2.5 days) compared to FSMT (11.7 days), suggesting that this approach not only reduces hospital time but also minimizes medication exposure for infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Standard Fixed-Schedule Methadone Taper Versus Symptom-Triggered Methadone Approach for Treatment of Neonatal Opioid Withdrawal Syndrome. Wachman, EM., Minear, S., Hirashima, M., et al.[2020]

In a study of 156 infants with neonatal abstinence syndrome (NAS) due to in utero methadone exposure, those treated with buprenorphine had significantly shorter treatment lengths (8 days) and hospital stays (13 days) compared to those treated with methadone (15 days and 20 days, respectively).

Buprenorphine-treated infants also had lower cumulative opioid exposure (0.6 mg/kg) compared to methadone-treated infants (1.05 mg/kg), and fewer required ongoing therapy after discharge, suggesting that buprenorphine may be a more effective first-line treatment for NAS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine pharmacotherapy for the management of neonatal abstinence syndrome in methadone-exposed neonates. Taleghani, AA., Isemann, BT., Rice, WR., et al.[2022]

In a study of 117 pregnant women on methadone maintenance treatment, 40.4% had their methadone dose decreased during pregnancy, but this change did not affect the incidence of neonatal abstinence syndrome (NAS) in their newborns.

The study also found that a significant number of women were prescribed additional medications, such as antidepressants (25.7%) and benzodiazepines (38.0%), during pregnancy, indicating the complexity of managing opioid dependence in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methadone dosing and prescribed medication use in a prospective cohort of opioid-dependent pregnant women. Cleary, BJ., Reynolds, K., Eogan, M., et al.[2013]

Buprenorphine shows better or similar safety outcomes compared to methadone for treating neonatal abstinence syndrome (NAS), with fewer infants requiring treatment and shorter hospital stays, based on a review of 5 critical studies.

Both medications are effective for pregnant women with opioid dependence, but buprenorphine may be a preferable option due to its improved outcomes, although more extensive studies are needed to confirm its safety and advantages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine Versus Methadone for Opioid Dependence in Pregnancy. Noormohammadi, A., Forinash, A., Yancey, A., et al.[2018]

The study reviewed 49 articles on managing opioid abstinence syndrome in critically ill pediatric patients, highlighting the importance of methadone for preventing withdrawal symptoms during opioid tapering.

It was found that using a standardized tapering protocol for methadone significantly reduced the incidence of abstinence symptoms, and the Withdrawal Assessment Tool - 1 was effective for monitoring withdrawal signs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Opioid tapering and weaning protocols in pediatric critical care units: a systematic review. Bichaff, P., Setani, KT., Motta, EHG., et al.[2019]

In a unique case series involving three women from the MOTHER study, both methadone and buprenorphine were found to be effective and safe for treating opioid dependence during pregnancy, with methadone leading to higher neonatal birth weights.

Buprenorphine exposure was associated with lower neonatal abstinence syndrome (NAS) scores compared to methadone, suggesting it could be a viable alternative treatment for pregnant women with opioid dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized controlled trials in pregnancy: scientific and ethical aspects. Exposure to different opioid medications during pregnancy in an intra-individual comparison. Unger, A., Jagsch, R., Jones, H., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

External validation of the medication taper complexity score for methadone tapers in children with opioid abstinence syndrome. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Higher maternal doses of methadone does not increase neonatal abstinence syndrome. [2021]

3. Ireland pubmed.ncbi.nlm.nih.gov

Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Standard Fixed-Schedule Methadone Taper Versus Symptom-Triggered Methadone Approach for Treatment of Neonatal Opioid Withdrawal Syndrome. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Buprenorphine pharmacotherapy for the management of neonatal abstinence syndrome in methadone-exposed neonates. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Methadone dosing and prescribed medication use in a prospective cohort of opioid-dependent pregnant women. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Buprenorphine Versus Methadone for Opioid Dependence in Pregnancy. [2018]

8. Brazil pubmed.ncbi.nlm.nih.gov

Opioid tapering and weaning protocols in pediatric critical care units: a systematic review. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Randomized controlled trials in pregnancy: scientific and ethical aspects. Exposure to different opioid medications during pregnancy in an intra-individual comparison. [2021]