RCT Comparing Methadone and Buprenorphine in Pregnant Women

• ClinicalTrials.gov Identifier: NCT00271219
• Recruitment Status: Completed
• First Posted: December 30, 2005
• Results First Posted: August 5, 2015
• Last Update Posted: August 5, 2015
• Sponsor: Johns Hopkins University
• Collaborator: National Institute on Drug Abuse (NIDA)
• Information provided by (Responsible Party): Hendree E. Jones, Johns Hopkins University

Tracking Information

• First Submitted Date: December 28, 2005
• First Posted Date: December 30, 2005
• Results First Submitted Date: March 11, 2013
• Results First Posted Date: August 5, 2015
• Last Update Posted Date: August 5, 2015
• Study Start Date: July 2005
• Actual Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 30, 2015)

• Child's Head Circumference Measurement (Measured at Birth) [ Time Frame: birth ]
• Child's Length of Hospital Stay [ Time Frame: delivery until hospital discharge (min=2 days, max=79 days) ]
• Number of Children Requiring Treatment for Neonatal Abstinence Signs (NAS) [ Time Frame: From birth until hospital discharge (min=4 days, max=10, depending on site) ]
  Neonatal abstinence syndrome (NAS) characterized by hyperirritability of the central nervous system and dysfunction in the autonomic nervous system, gastrointestinal tract, and respiratory system.11 When left untreated, NAS can result in serious illness (e.g., diarrhea, feeding difficulties, weight loss, and seizures) and death.
• Child's Peak Daily Total NAS Score [ Time Frame: minimum twice daily from birth until NAS no longer measured (min=10 days) ]
  NAS was measured with the MOTHER NAS scale, which includes 28 items, 19 of which are used for scoring and medication decisions. Scores can range from 0 to 42, with higher scores indicating more severe withdrawal.
• Total Amount of Morphine Sulfate That a Neonate Receives to Treat NAS [ Time Frame: Start of NAS treatment until discontinuation of NAS treatment (min=0 days, max=76 days) ]
  Total amount in mg

Original Primary Outcome Measures (submitted: December 28, 2005)

• Child's head circumference measurement (measured at birth)
• Child's length of hospital stay
• Number of children requiring treament for Neonatal Abstinence Signs (NAS)
• Child's peak daily total NAS score
• Total amount of withdrawal medication child receives

Current Secondary Outcome Measures (submitted: July 30, 2015)

• Mother's Self-report of Drug Use (Measured Monthly by Time Line Follow Back) [ Time Frame: monthly from study entry until discontinuation or delivery (min=29 days, max=239 days) ]
• Mother's HIV Risk Behaviors (Measured Monthly by Risk Behavior Assessment) [ Time Frame: monthly from study entry until discontinuation or delivery (min=29 days, max=239 days) ]
• Mother's Measures of Dose Adequacy and Acceptance Over Time (Measured Weekly by Dose Adequacy Measure) [ Time Frame: from study entry until discontinuation or delivery (min=29 days, max=239 days) ]
  Pregnant women maintained on an opioid agonist medication may require upward adjustment to their medication during the course of pregnant. The Dose Adequacy Measure represented a recordation of dosing adjustments during the course of the study.
• Mother's Psychosocial Functioning at Delivery as Measured by the Addiction Severity Index Psychosocial Index Score [ Time Frame: at delivery ]
  The Addiction Severity Index is a structured clinical interview that assesses problem severity in 7 areas of functioning: alcohol use, drug use, medical, legal, employment, psychosocial, and psychiatric status. Each area of functioning yields a composite scale score between 0 and 1, with higher scores indicating greater problem severity in that area. Only the psychosocial index was examined in this study.

Original Secondary Outcome Measures (submitted: December 28, 2005)

• Mother's self-report of drug use (measured monthly by Time Line Follow Back)
• Mother's HIV risk behaviors (measured monthly by Risk Behavior Assessment)
• Mother's measures of dose adequacy and acceptance over time (measured weekly by Dose Adequacy Questionnaire)
• Mother's psychosocial functioning (measured monthly by Addiction Severity Index and SCID)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: RCT Comparing Methadone and Buprenorphine in Pregnant Women
• Official Title: Maternal Opioid Treatment: Human Experimental Research
• Brief Summary: Children born to women who abuse drugs have a high risk of being born with birth defects and developmental problems. Methadone is a drug that is commonly used for treating opioid dependence. However, its use by a pregnant woman can cause severe withdrawal symptoms in a newborn because of the prenatal exposure. The purpose of this study is to evaluate the effectiveness of buprenorphine, another drug, versus methadone in reducing withdrawal symptoms in children born to opioid-dependent women.

Detailed Description

Women who use drugs during pregnancy place their unborn children at high risk for being born addicted to drugs. Such children may also be born with birth defects and may experience learning and behavioral problems. Methadone, a synthetic narcotic, is commonly prescribed to treat opioid addiction. It may not be an optimal solution for opioid-dependent pregnant women, however, because a large percentage of children born to women taking methadone experience severe drug withdrawal symptoms at birth that often require medical treatment. Common opioid withdrawal symptoms, described as neonatal abstinence syndrome (NAS) in babies, include tremors, irritability, sleep problems, seizures, dehydration, and fever. Buprenorphine is a medication that has been approved to treat opioid dependence in individuals who are not pregnant but has not been approved for pregnant individuals. Past research has shown that use of buprenorphine in pregnant women results in improved birth outcomes over methadone. The purpose of this study is to evaluate the effectiveness of buprenorphine versus methadone at reducing opioid withdrawal symptoms in babies born to opioid-dependent women.

This study will enroll opioid-dependent pregnant women who are 13 to 30 weeks pregnant and will follow each woman and her child throughout the pregnancy until 6 weeks postpartum. All participants will undergo an initial screening that will last several hours. Participants will then be randomly assigned to receive either methadone or buprenorphine on a daily basis, and will be required to visit the clinic each day to receive their medication. Outcome measurements will be assessed at weekly study visits throughout the pregnancy, and will include drug use, HIV risk behaviors, medication dose adequacy and safety, treatment retention, and psychosocial functioning. Urine samples will be collected 3 times a week, and blood will be drawn throughout the pregnancy for safety monitoring. Outcome measurements related to the baby will include head circumference measurement, length of hospital stay, severity and frequency of withdrawal symptoms, and amount of medication needed to control withdrawal symptoms.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Opioid Related Disorders
• Pregnancy
• Opioid Dependence

Intervention

• Drug: Methadone
  daily oral dosing 20-140 mg
• Drug: Buprenorphine
  sl daily 2-32 mg

Study Arms

• Experimental: Buprenorphine
  Buprenorphine
  Intervention: Drug: Buprenorphine
• Active Comparator: Methadone
  Methadone
  Intervention: Drug: Methadone

Publications *

• Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR. Nonserious adverse events in randomized trials with opioid-dependent pregnant women: direct versus indirect measurement. Am J Addict. 2012 Nov;21 Suppl 1:S1-4. doi: 10.1111/j.1521-0391.2012.00289.x.
• Holbrook AM, Jones HE, Heil SH, Martin PR, Stine SM, Fischer G, Coyle MG, Kaltenbach K. Induction of pregnant women onto opioid-agonist maintenance medication: an analysis of withdrawal symptoms and study retention. Drug Alcohol Depend. 2013 Sep 1;132(1-2):329-34. doi: 10.1016/j.drugalcdep.2013.02.031. Epub 2013 Mar 21.
• Jones HE, Heil SH, Tuten M, Chisolm MS, Foster JM, O'Grady KE, Kaltenbach K. Cigarette smoking in opioid-dependent pregnant women: neonatal and maternal outcomes. Drug Alcohol Depend. 2013 Aug 1;131(3):271-7. doi: 10.1016/j.drugalcdep.2012.11.019. Epub 2012 Dec 29.
• McNicholas LF, Holbrook AM, O'Grady KE, Jones HE, Coyle MG, Martin PR, Heil SH, Stine SM, Kaltenbach K. Effect of hepatitis C virus status on liver enzymes in opioid-dependent pregnant women maintained on opioid-agonist medication. Addiction. 2012 Nov;107 Suppl 1(0 1):91-7. doi: 10.1111/j.1360-0443.2012.04043.x.
• Holbrook AM, Baxter JK, Jones HE, Heil SH, Coyle MG, Martin PR, Stine SM, Kaltenbach K. Infections and obstetric outcomes in opioid-dependent pregnant women maintained on methadone or buprenorphine. Addiction. 2012 Nov;107 Suppl 1(Suppl 1):83-90. doi: 10.1111/j.1360-0443.2012.04042.x.
• Benningfield MM, Dietrich MS, Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Fischer G, Martin PR. Opioid dependence during pregnancy: relationships of anxiety and depression symptoms to treatment outcomes. Addiction. 2012 Nov;107 Suppl 1(0 1):74-82. doi: 10.1111/j.1360-0443.2012.04041.x.
• Coyle MG, Salisbury AL, Lester BM, Jones HE, Lin H, Graf-Rohrmeister K, Fischer G. Neonatal neurobehavior effects following buprenorphine versus methadone exposure. Addiction. 2012 Nov;107 Suppl 1(0 1):63-73. doi: 10.1111/j.1360-0443.2012.04040.x.
• Gaalema DE, Scott TL, Heil SH, Coyle MG, Kaltenbach K, Badger GJ, Arria AM, Stine SM, Martin PR, Jones HE. Differences in the profile of neonatal abstinence syndrome signs in methadone- versus buprenorphine-exposed neonates. Addiction. 2012 Nov;107 Suppl 1(0 1):53-62. doi: 10.1111/j.1360-0443.2012.04039.x.
• Kaltenbach K, Holbrook AM, Coyle MG, Heil SH, Salisbury AL, Stine SM, Martin PR, Jones HE. Predicting treatment for neonatal abstinence syndrome in infants born to women maintained on opioid agonist medication. Addiction. 2012 Nov;107 Suppl 1(0 1):45-52. doi: 10.1111/j.1360-0443.2012.04038.x.
• Salisbury AL, Coyle MG, O'Grady KE, Heil SH, Martin PR, Stine SM, Kaltenbach K, Weninger M, Jones HE. Fetal assessment before and after dosing with buprenorphine or methadone. Addiction. 2012 Nov;107 Suppl 1(0 1):36-44. doi: 10.1111/j.1360-0443.2012.04037.x.
• Jones HE, Fischer G, Heil SH, Kaltenbach K, Martin PR, Coyle MG, Selby P, Stine SM, O'Grady KE, Arria AM. Maternal Opioid Treatment: Human Experimental Research (MOTHER)--approach, issues and lessons learned. Addiction. 2012 Nov;107 Suppl 1(0 1):28-35. doi: 10.1111/j.1360-0443.2012.04036.x.
• Jones HE, Heil SH, Baewert A, Arria AM, Kaltenbach K, Martin PR, Coyle MG, Selby P, Stine SM, Fischer G. Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review. Addiction. 2012 Nov;107 Suppl 1(0 1):5-27. doi: 10.1111/j.1360-0443.2012.04035.x.
• Unger A, Jagsch R, Bawert A, Winklbaur B, Rohrmeister K, Martin PR, Coyle M, Fischer G. Are male neonates more vulnerable to neonatal abstinence syndrome than female neonates? Gend Med. 2011 Dec;8(6):355-64. doi: 10.1016/j.genm.2011.10.001. Epub 2011 Nov 15.
• Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR, Fischer G. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010 Dec 9;363(24):2320-31. doi: 10.1056/NEJMoa1005359.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 19, 2012): 175
• Original Enrollment (submitted: December 28, 2005): 300
• Actual Study Completion Date: June 2010
• Actual Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Current opioid dependence
• Current opioid use, as determined by a urine drug test
• Pregnant with a single child with a gestational age of 6 to 30 weeks, as determined by a sonogram

Exclusion Criteria:

• Current medical condition that would make study participation dangerous, as determined by study physician
• Diagnosed with an acute, severe psychiatric illness
• Current SCID I-E module diagnosis of benzodiazepine or alcohol abuse
• Use of alcohol or benzodiazepines in the 30 days prior to study entry, as determined by the Addiction Severity Index
• Pending legal action that may prohibit or interfere with study participation

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 41 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Canada, United States

Administrative Information

• NCT Number: NCT00271219
• Other Study ID Numbers: R01DA15764-1; R01DA015764 ( U.S. NIH Grant/Contract ); R01DA15764-1; DPMC
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hendree E. Jones, Johns Hopkins University
• Original Responsible Party: Not Provided
• Current Study Sponsor: Johns Hopkins University
• Original Study Sponsor: National Institute on Drug Abuse (NIDA)
• Collaborators: National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Hendree E. Jones, PhD; Johns Hopkins University

• PRS Account: Johns Hopkins University
• Verification Date: July 2015