Pharmacologically-based Strategies for Opioid Substitution Therapy During Pregnancy

Pregnancy Clinical Trial

Official title:

Pharmacologically-based Strategies for Opioid Substitution Therapy During Pregnancy

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03831113
• Other study ID #: STUDY19100128
• Secondary ID: R01HD096796
• Status: Terminated
• Phase: Phase 2
• Start date: April 13, 2019
• Est. completion date: December 22, 2022

Study information

• Verified date: May 2024
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a pharmacodynamic study in pregnant women evaluating the relationship between buprenorphine concentration and outcome such as opioid withdrawal symptoms , NAS scores, neurodevelopmental and neuroanatomic outcomes. Strategies to reduce opioid exposure will be explored.

Description:

Opioid use has reached a staggering level and the associated deaths, neonatal consequences and economic impact are devastating. Buprenorphine and methadone are the two most commonly used medications for pregnant women in a Medication Assisted Treatment (MAT) program. Yet, the target concentration of these agents is not clearly identified. Furthermore, the relationship between drug exposure and adverse effects such as Neonatal Abstinence Syndrome and neurodevelopmental outcomes is unclear but contemporary thinking is that exposure (defined by maternal dose) is unrelated to adverse outcomes. The benefit of an MAT strategy is based on strong clinical data that demonstrates an improvement in perinatal outcomes in women participating in an MAT program. However, some women prefer to stop opioid medications entirely , but are not afforded this option in many MAT programs. The possibility that MAT is associated with some harms has received little attention but there are data that suggest that opioids adversely affect the fetal brain. If MAT is indeed associated with potential harms, then the option of Medically Assisted Withdrawal could be considered.

This study will define the plasma concentration of buprenorphine associated with maternal withdrawal . Additionally, the relationship between buprenorphine concentration in maternal and infant hair, placenta , meconium and cord and neonatal NAS markers will be assessed. That investigation will define exposure not by maternal dose but by the buprenorphine concentration in these matrices. Exposure will also be related to neurodevelopmental outcomes. Strategies for dose reduction or elimination will be assessed in a cohort of women who desire a reduction or elimination of their opioid exposure.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 10
• Est. completion date: December 22, 2022
• Est. primary completion date: December 22, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Specific Aim 1:

Inclusion Criteria:

1. Singleton gestation between 14-35 weeks

2. On a stable BUP dose (for at least 2 weeks) through a MAT program or just starting BUP therapy through a MAT program.

3. Willingness to consent to the study and for those on a stable BUP dose, willingness to experience mild, temporary withdrawal symptoms

Exclusion Criteria:

1. Multifetal gestation, major fetal malformation

2. Urine drug screen results positive for benzodiazepines, cocaine, heroin, barbiturates, phencyclidine (PCP), or opioids other than BUP

1. Subjects already enrolled in a MAT program must have negative urine drug screens at the Pre-Study Screening and again on the day of the PD study.

2. Subjects initiating BUP therapy will have a comprehensive drug screen performed on the day of the PD study. Results that are positive for the presence of cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP) or opioids other than BUP will be documented, but will not be used to determine eligibility for the study.

3. Currently taking more than one mental health medication

4. Active moderately severe depression (PHQ-9 score =15 or suicidal ideation)

5. Clinical signs of intoxication or mental disorientation at time of study

6. Uncontrolled hypertension

7. HIV or AIDS

8. Diagnosis of schizoaffective disorder or psychosis

Specific Aim 2:

Inclusion Criteria:

1. Singleton gestation greater than 37 0/7 weeks

2. Mother on BUP for at least 8 weeks prior to delivery.

3. Mother in a MAT program.

4. Infant with 5 minute Apgar scores >/= 6.

5. No maternal cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP), or opioids other than BUP in last 8 weeks of pregnancy, based on the urine drug screen results from the MAT clinic.

Exclusion Criteria:

1. Major fetal/neonatal malformation.

2. Delivery at non-study hospital.

3. Fetal growth restriction - BW < 10th percentile

4. Known fetal renal or hepatic disease that affects drug metabolism or elimination

5. Infant on ventilator support

6. HIV or AIDS

Specific Aim 3:

Part 1:

Inclusion Criteria:

1. Singleton gestation greater than 37 0/7 weeks

2. Mother on BUP for at least 12 weeks prior to delivery and compliant with clinic policies

3. Willingness to consent to the collection of biological samples; at a minimum, she must consent to a maternal hair sample, as well as a neonate hair sample and/or meconium.

4. Availability of prenatal records from Ob care provider and BUP dosing records

5. Infant with 5 minute Apgar scores = 6

Exclusion Criteria:

1. Multifetal gestation

2. Major fetal malformation

3. HIV or AIDS

4. Planned delivery at another institution

5. Medical or obstetrical complications in current pregnancy including: preeclampsia, poorly controlled diabetes or hypertension, or fetal growth restriction

6. Use of cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP), or opioids other than BUP in the last 12 weeks of pregnancy, based on urine drug screen results from the MAT clinic

7. Currently taking more than one mental health medication

8. Active moderately severe depression (PHQ-9 score =15 or suicidal ideation)

9. Alcohol abuse anytime during the current pregnancy

Specific Aim 3:

Part 2:

Inclusion Criteria

1. Single gestation between 35 0/7 and 38 0/7 weeks at the time of fetal imaging

2. Mother on BUP or methadone for at least 12 weeks prior to delivery and compliant with clinic policies

3. Willingness to consent to study requirements; at a minimum, she must consent to a fetal and neonatal MRI, maternal hair sample, as well as a neonate hair sample and/or meconium.

4. Availability of prenatal records from Ob care provider and BUP or methadone dosing records

Exclusion Criteria

1. Multifetal gestation

2. Major fetal malformation

3. HIV or AIDS

4. Medical or obstetrical complications in current pregnancy including: preeclampsia, poorly controlled diabetes or hypertension, or fetal growth restriction

5. Current use of cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP), or opioids other than BUP or methadone based on the comprehensive urine drug screen performed within 1-2 weeks prior to the fetal MRI exam.

Use of cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP), or opioids other than BUP or methadone in last 12 weeks prior to the fetal MRI exam, based on urine drug screen results from the MAT clinic

6. Currently taking more than one mental health medication

7. Active moderately severe depression (PHQ-9 score =15 or suicidal ideation)

8. Alcohol abuse anytime during the current pregnancy

9. Any contraindication to MRI such as a pacemaker, claustrophobia, or any metallic implant

10. Current or recent (last 2 years) history of incarceration

Specific Aim 4:

Inclusion Criteria:

1. On a stable BID, TID or QID dosing regimen of BUP for at least 2 weeks as part of an established medication- assisted treatment (MAT) program.

2. Willingness to undergo supervised dose reduction

3. Subjects on BID, TID or QID dosing, willingness to be assigned to either the Magnitude, Interval/Frequency, or Dosing group, depending on their current dosing.

4. Single gestation between 14-30 weeks at the initiation of the dose reduction

5. On a BUP dose between 6- 24 mg daily (lower doses will not provide sufficient data points)

6. Willingness to have urine samples tested for drugs of abuse and blood samples tested for BUP+M concentrations during the Medical Supervised Withdrawal (MSW) clinic appointments

7. Willingness to attend weekly or biweekly MSW clinic appointments and to have daily contact via text messaging and to complete daily logs of sleep quality, withdrawal symptoms and symptoms of craving.

8. Willingness to attend psychosocial support meetings as needed.

Exclusion Criteria:

1. Current use of cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP), or opioids other than BUP.

2. Currently taking more than two mental health medications

3. Active moderately severe depression (PHQ-9 score =15 or suicidal ideation)

4. Current incarceration

5. Lack of a phone or transportation to and from clinic

6. Major fetal malformation

7. Mother with significant vaginal bleeding or serious medical or obstetrical complication that could adversely affect the study

8. Planned delivery at another institution

9. HIV or AIDS

10. Diagnosis of schizoaffective disorder or psychosis

Related Conditions & MeSH terms

• Opiate Addiction
• Opioid-Related Disorders
• Pregnancy

Intervention

Drug:
• Buprenorphine: Magnitude Group
Dose reductions will continue until the subject is no longer taking buprenorphine or is at the lowest tolerable dose.
• Buprenorphine: Frequency Group
Dose reductions will continue until the subject is no longer taking buprenorphine or is at the lowest tolerable dose.
• Buprenorphine: Dosing Group
Dose reductions will continue until the subject is no longer taking buprenorphine or is at the lowest tolerable dose.

Locations

Country	Name	City	State
United States	High Risk Obstetrical Consultants	Knoxville	Tennessee
United States	Univerity of Pittsburgh Magee-Womens Hospital	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Steve N. Caritis, MD	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma levels of buprenorphine + metabolites, neurotransmitters (serotonin, dopamine and nor-adrenaline), and cotinine	Investigators will monitor plasma levels (ng/ml) of buprenorphine+metabolites (BUP+M), neurotransmitters, and cotinine levels during weekly clinic visits. The subject's weekly plasma concentrations will be compared to the VAS scores to determine the change in mu receptor sensitivity.	4.5 years
Primary	Visual Analog Scale (VAS) Scores	The VAS questionnaire consists of 4 questions related to cravings, withdrawal, sleep quality and sleep duration. Subjects will complete this questionnaire daily and at the weekly clinic visits. Subjects will grade each category on a scale of 0-100 in increments of 10. The VAS scores will be used within and across groups to evaluate the tolerance of the dose reductions (magnitude and frequency).	4.5 years
Primary	Clinical Opioid Withdrawal Scale (COWS) scores	The COWS questionnaire consists of 11 questions and will be completed at the weekly clinic visits. Responses to each question are graded on a scale of 0-4 and the total of all responses correlates to a particular withdrawal severity: mild (5-12), moderate (13-24), moderately severe (25-36), severe (>36). COWS scores will be used to assess the subject's tolerance to the dose reductions by measuring withdrawal and satiety.	4.5 years
Primary	Subjective Opioid Withdrawal Scale (SOWS) scores	The SOWS questionnaire consists of 16 questions and will be completed at the weekly clinic visits. Responses to each question are graded on a scale of 0-4 and the total of all responses correlates to a particular withdrawal severity: mild (1-10), moderate (11-20), severe (21-30). SOWS scores will be used to assess the current subjective symptoms of withdrawal and satiety.	4.5 years
Primary	Weekly Follow-up Form	The weekly follow-up form consists of 17 questions and will be completed at the weekly clinic visits. Subjects are asked to grade their cravings, withdrawal symptoms, and sleep quality on a scale of 1-10. The form also includes questions regarding which days were the best and worst for cravings, withdrawal and sleep and what the subject did to manage her symptoms.	4.5 years
Primary	Weekly Smoking and Alcohol Use Form	The weekly smoking and alcohol form consists of 4 questions concerning tobacco, alcohol, vaping, and marijuana use in the last week. If the subject answers "yes" to any questions, they are asked to quantify the amount used and indicate whether this habit has changed since starting the dose reduction.	4.5 years
Secondary	Urine toxicology screen	Urine toxicology screens will be performed during the weekly clinic visits to confirm that the subject is compliant with the study requirements.	4.5 years