Zofran_PK: How Pregnant Women and Their Babies Metabolize Ondansetron Compared to a Group of Non-pregnant Women

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01801475
• Collaborator: (none)
• Enrollment: 100
• Location: 1
• Arms: 3
• Duration (Months): 3.9
• Patients Per Site Per Month: 25.4

Study Details

Study Description

Brief Summary

This is called "Aim 1" of the investigators' NIH grant. Ondansetron (Zofran) is a safe and effective drug used in pregnant women to prevent nausea but the investigators do not know what effect pregnancy may have on the metabolism of Zofran in pregnant women or their babies. Therefore the investigators will enroll approximately 40 pregnant women and their babies and draw blood samples from the mother, the baby and the cord, to determine how much Zofran is in each sample of blood (called the pharmacokinetics or PK of Zofran). The pregnant women will receive Zofran, as a standard-of-care drug, for their scheduled Cesarean Section.

The investigators will also enroll about 20 non-pregnant women undergoing surgery who will receive Zofran as standard-of-care during surgery. In both the pregnant & the non-pregnant women, the investigators will draw blood samples at the same time points based on number of minutes from the time the Zofran is given. The blood data (PK of Zofran) will help the investigators move into Aim 2 of the study, which will be done in pregnant, narcotic-addicted mothers and their babies who are born addicted to narcotics. Aim 2 will be listed separately as it will be an interventional study.

Condition or Disease	Intervention/Treatment	Phase
Postoperative Nausea	Drug: Ondansetron	Phase 1/Phase 2

Detailed Description

This phase of the study is Aim 1 and it will lead to Aim 2, which specifically will address the Prevention of Neonatal Abstinence Syndrome (NAS).

NAS is a constellation of narcotic drug withdrawal symptoms that develops in 42-94% of the infants born to narcotic dependent mothers. This severe syndrome, of which there are no preventative treatments, can result in prolonged hospitalization, some of which may be in the neonatal intensive care unit (NICU). The investigators have shown that ondansetron can eliminate or alleviate the symptoms of narcotic drug withdrawal in experimental studies in mice and in humans. Based upon these results, it is quite possible that ondansetron administration to pregnant narcotic-using mothers just prior to delivery, followed by a 3-day period of ondansetron administration to the neonate, could reduce the incidence or severity of NAS symptoms.

AIM 1 is a pharmacokinetic (PK) study of intravenous (IV) ondansetron in three different groups of participants: Study Group #1 = non-pregnant women undergoing surgery; Study Group #2 = pregnant women scheduled for cesarean section delivery; Study Group #3 = viable, full term, singleton neonates born to study group #2 mothers. Group #1 will be given IV ondansetron prior to their surgery and up to 5 PK blood samples will be drawn from an indwelling IV line or by IV stick. The PK samples will be 2-5 ml each and will be drawn at baseline (prior to ondansetron) and then at 7, 15, and 40 min and 8 hours after the ondansetron. Group #2 will be given IV ondansetron prior to their cesarean section and up to 6 PK blood samples will be drawn from an indwelling IV line or by IV stick. The PK samples will be 2-5 ml each and will be drawn at baseline, 7, 15, 40 min and prior to delivery and 8 hours after the ondansetron is given. The Group #3 neonates will provide a section of the umbilical cord from which arterial and venous blood samples will be drawn (this section of cord would normally be thrown out and the parents are consenting to allow the Investigators to take these two samples). Each time the baby has a "Standard-of-Care" lab test ordered by heel stick or needle stick, the investigators will obtain a few drops of blood to place on the special research filter paper to determine how much ondansetron is in the baby's blood. If the parents will allow any extra heel sticks, the Investigators will try to obtain 1-2 samples of blood in the first 6 hours of life. If the parents only want their baby's blood taken at the standard-of-care lab draws, then the first scheduled lab draw is at 24 hours of life for the newborn screening which is a mandated by state law. All blood samples taken for this study are being processed by the investigator, not the Stanford Lab. Also, the investigators are doing the PK analysis of the dried blood spots on the filter paper and the analysis of the frozen plasma samples.

Aim 2 of this NIH grant will be entered separately into ClinicalTrials.gov. It will be a multi-center, randomized, double-blind, placebo-controlled trial to determine whether ondansetron treatment will reduce the incidence or severity of NAS in babies born to narcotic-using mothers.

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Official Title: Prevention of Neonatal Abstinence Syndrome
• Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Pregnant women Full term pregnant women scheduled for Cesarean section and will be given Ondansetron as standard-of-care prior to surgery.	Drug: Ondansetron; Pregnant & non-pregnant women will receive either 4mg or 8mg of Ondansetron (IV) once prior to surgical procedure (open-label). Women are in the study for 8 hours. Babies of pregnant women are not given Ondansetron but are in the study for 24-48 hours.; Other Names: Zofran
Active Comparator: Non-pregnant women Non-pregnant women scheduled for surgery at Stanford who will be given Ondansetron prior to their surgery as standard-of-care.	Drug: Ondansetron; Pregnant & non-pregnant women will receive either 4mg or 8mg of Ondansetron (IV) once prior to surgical procedure (open-label). Women are in the study for 8 hours. Babies of pregnant women are not given Ondansetron but are in the study for 24-48 hours.; Other Names: Zofran
No Intervention: Neonates Babies of the pregnant women enrolled in the study; no ondansetron is given to babies in this "Aim 1" of the study.

Outcome Measures

Primary Outcome Measures

1. Volume of Distribution Estimated Pharmacokinetic Parameter [8 hours for women; 48 hours for neonate.]

   This is an estimated pharmacokinetic parameter as calculated by NONMEM.

2. Metabolic Clearance of Ondasetron [8 hours for women; 48 hours for neonate.]

   This is a mathematical estimation of the clearance for ondasetron as calculated by NONMEM.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

For Non-pregnant Females (Group #1)

1. Age 18-45 yrs inclusive

2. Generally healthy

3. Undergoing any scheduled surgical procedure deemed suitable by the Investigator MD

4. Planned to receive the drug Ondansetron for the surgery

5. Able and willing to sign the informed consent

For Pregnant Females (Group #2)

1. Age 18-45 yrs inclusive

2. Term pregnancy (37 weeks through 41 wks + 6 days)

3. Generally healthy (not morbidly obese)

4. Undergoing a planned C-section or by an unplanned, non-urgent C-section

5. Planned to receive the drug Ondansetron for the surgery

6. Single birth

7. Able and willing to sign the informed consent for herself & the baby

For the Neonatal Participant (Group #3)

1. Male or female

2. Viable birth

3. Gestational age of 37 weeks through 41 weeks + 6 days

4. Mother gave written consent for baby to participate

Exclusion Criteria:

1. Medical condition that would effect the metabolism of ondansetron

2. Known allergy to ondansetron

3. Use of medications in the last 48 hours, by the pregnant or non-pregnant subjects, that might induce or inhibit the metabolism of ondansetron (such as CYP3A4 inhibitors or inducers)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lucile Packard Children's Hospital & Stanford Hospital	Palo Alto	California	United States	94305

Sponsors and Collaborators

• Stanford University

Investigators

• Principal Investigator: David R. Drover, MD, Stanford University School of Medicine, Department of Anesthesia

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: David R. Drover, Professor of Anesthesia, Stanford School of Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT01801475
• Other Study ID Numbers: 1R01HD070795-01A1; NAS Aim 1
• First Posted: Feb 28, 2013
• Last Update Posted: Jun 1, 2015
• Last Verified: May 1, 2015

• Keywords provided by David R. Drover, Professor of Anesthesia, Stanford School of Medicine, Stanford University: Pharmacokinetics of ondansetron in women; Pharmacokinetics of ondansetron in neonates; Term pregnancy; Cesarean section
• Additional relevant MeSH terms: Postoperative Nausea and Vomiting; Ondansetron

Study Results

Participant Flow

Arm/Group Title	Ondansetron 4 mg IV - Pregnant	Ondansetron 8 mg IV - Pregnant	Non-pregnant Women - 8 mg Ondansetron	Non-pregnant Women - 4 mg Ondansetron	Neonates
Arm/Group Description	Ondansetron 4 mg was given intravenously prior to delivery of the infant.	Ondansetron 8 mg was given intravenously prior to delivery of the infant.	As a comparison for pharmacokinetics, a non-pregnant group was enrolled and received ondansetron. 8 mg ondansetron	As a comparison for pharmacokinetics, a non-pregnant group was enrolled and received ondansetron. 4 mg ondansetron	The neonates became part of the subject population after birth. They were subsequently sampled for pharmacokinetic samples.
Period Title: Overall Study
STARTED	10	30	10	10	40
COMPLETED	10	30	10	10	39
NOT COMPLETED	0	0	0	0	1

Baseline Characteristics

Arm/Group Title	Pregnant Women	Non-pregnant Women	Neonates	Total
Arm/Group Description	Full term pregnant women scheduled for Cesarean section and will be given Ondansetron as standard-of-care prior to surgery. Ondansetron: Pregnant women will receive either 4mg or 8mg of Ondansetron (IV) once prior to surgical procedure (open-label). Women are in the study for 8 hours.	Non-pregnant women scheduled for surgery at Stanford who will be given Ondansetron prior to their surgery as standard-of-care. Ondansetron: non-pregnant women will receive either 4mg or 8mg of Ondansetron (IV) once prior to surgical procedure (open-label). Women are in the study for 8 hours.	Babies of the pregnant women enrolled in the study; no ondansetron is given to babies in this "Aim 1" of the study. Babies of pregnant women are not given Ondansetron but are in the study for 24-48 hours.	Total of all reporting groups
Overall Participants	40	20	39	99
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33 (5.2)	37.7 (5.7)	0.003 (0.001)	35 (5.3)
Sex: Female, Male (Count of Participants)
Female	40 100%	20 100%	20 51.3%	80 80.8%
Male	0 0%	0 0%	19 48.7%	19 19.2%
Region of Enrollment (participants) [Number]
United States	40 100%	20 100%	39 100%	99 100%

Outcome Measures

1. Primary Outcome

Title	Volume of Distribution Estimated Pharmacokinetic Parameter
Description	This is an estimated pharmacokinetic parameter as calculated by NONMEM.
Time Frame	8 hours for women; 48 hours for neonate.

Outcome Measure Data

Analysis Population Description

All subjects but not possible for neonates

Arm/Group Title	Women - Pregnant/Non-pregnant	Neonates
Arm/Group Description	Ondansetron 4 mg or 8mg was given intravenously prior to delivery of her baby in pregnant women and was given to age similar women in the non-pregnant group.	The neonates became part of the subject population after birth. They were subsequently sampled for pharmacokinetic samples.
Measure Participants	60	39
Mean (95% Confidence Interval) [Liters]	27.9	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Women - Pregnant/Non-pregnant
	Comments	The nonlinear mixed-effects modeling software program NONMEM (version VII; Icon Development Solutions, Ellicott City, MD) was used to estimate the pharmacokinetic parameters. The first-order conditional estimation (FOCE) with η-ε interaction was used for the estimation process. Volume and clearance in this model is computed as a mean of the study population (pregnant and non-pregnant women) with a log-normal distribution in the population.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Chi-squared
	Comments

2. Primary Outcome

Title	Metabolic Clearance of Ondasetron
Description	This is a mathematical estimation of the clearance for ondasetron as calculated by NONMEM.
Time Frame	8 hours for women; 48 hours for neonate.

Outcome Measure Data

Analysis Population Description

All patient data was used in the estimation process.

Arm/Group Title	Women - Pregnant/Non-pregnant	Neonates
Arm/Group Description	Ondansetron 4 mg or 8mg was given intravenously prior to delivery of her baby in pregnant women and was given to age similar women in the non-pregnant group.	The neonates became part of the subject population after birth. They were subsequently sampled for pharmacokinetic samples.
Measure Participants	60	39
Mean (95% Confidence Interval) [L/hr]	21.8	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Women - Pregnant/Non-pregnant
	Comments	The nonlinear mixed-effects modeling software program NONMEM (version VII; Icon Development Solutions, Ellicott City, MD) was used to estimate the pharmacokinetic parameters. The first-order conditional estimation (FOCE) with η-ε interaction was used for the estimation process. Volume and clearance in this model is computed as a mean of the study population (pregnant and non-pregnant women) with a log-normal distribution in the population.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	From time of administration of ondansetron until last sample of blood for pharmacokinetic analysis at 8 hours.
Arm/Group Title	Ondansetron 4 mg IV - Pregnant		Ondansetron 8 mg IV - Pregnant		Non-pregnant Women - 8 mg Ondansetron		Non-pregnant Women - 4 mg Ondansetron		Neonates
Arm/Group Description	Ondansetron 4 mg was given intravenously prior to delivery of the infant.		Ondansetron 8 mg was given intravenously prior to delivery of the infant.		As a comparison for pharmacokinetics, a non-pregnant group was enrolled and received ondansetron. 8 mg ondansetron		As a comparison for pharmacokinetics, a non-pregnant group was enrolled and received ondansetron. 4 mg ondansetron		The neonates became part of the subject population after birth. They were subsequently sampled for pharmacokinetic samples.
All Cause Mortality
	Ondansetron 4 mg IV - Pregnant		Ondansetron 8 mg IV - Pregnant		Non-pregnant Women - 8 mg Ondansetron		Non-pregnant Women - 4 mg Ondansetron		Neonates
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ondansetron 4 mg IV - Pregnant		Ondansetron 8 mg IV - Pregnant		Non-pregnant Women - 8 mg Ondansetron		Non-pregnant Women - 4 mg Ondansetron		Neonates
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/30 (0%)		0/10 (0%)		0/10 (0%)		0/40 (0%)
Other (Not Including Serious) Adverse Events
	Ondansetron 4 mg IV - Pregnant		Ondansetron 8 mg IV - Pregnant		Non-pregnant Women - 8 mg Ondansetron		Non-pregnant Women - 4 mg Ondansetron		Neonates
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/30 (0%)		0/10 (0%)		0/10 (0%)		0/40 (0%)

Limitations/Caveats

Since the neonate was not given a dose of study medication (ondansetron) directly it was not possible to estimate the volume of distribution in the neonate.

More Information

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.