Choline Supplementation for Fetal Alcohol Spectrum Disorders
(CHOLINE4 Trial)
Recruiting in Palo Alto (17 mi)
JR
Overseen byJeffrey R Wozniak, Ph.D.
Age: < 18
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Jeff Wozniak
Disqualifiers: Neurological condition, Neurodevelopmental disorder, others
No Placebo Group
Prior Safety Data
Approved in 3 Jurisdictions
Trial Summary
What is the purpose of this trial?
This trial is testing whether giving choline, a nutrient found in foods like eggs and meat, can help improve brain function in young children with Fetal Alcohol Spectrum Disorders (FASD). These children have cognitive issues due to alcohol exposure before birth. Choline might help their brains work better, especially for memory and thinking skills.
Will I have to stop taking my current medications?
The trial information does not specify whether participants need to stop taking their current medications.
What evidence supports the effectiveness of the treatment choline supplementation for fetal alcohol spectrum disorders?
Research shows that choline, an essential nutrient, can help improve memory and learning deficits in children with fetal alcohol spectrum disorders (FASD). Studies in both animals and humans suggest that choline supplementation can reduce some of the cognitive and behavioral problems caused by prenatal alcohol exposure.12345
Is choline supplementation safe for humans, especially in children with fetal alcohol spectrum disorders?
How does the drug Choline Bitartrate differ from other treatments for Fetal Alcohol Spectrum Disorders?
Choline Bitartrate is unique because it is an essential nutrient that directly supports brain development and has shown potential in improving cognitive and behavioral deficits associated with Fetal Alcohol Spectrum Disorders (FASD), unlike other treatments that may not target these specific brain functions.13478
Research Team
JR
Jeffrey R Wozniak, Ph.D.
Principal Investigator
University of Minnesota
Eligibility Criteria
This trial is for children aged between 2.5 and 5 years who have been exposed to alcohol before birth and have a guardian able to consent. It's not for kids with conditions affecting brain function, other neurodevelopmental disorders like autism or Down syndrome, epilepsy, traumatic brain injuries, or those born weighing less than 1500 grams.Inclusion Criteria
Prenatal alcohol exposure
I am between 2.5 and 5 years old.
Available parent or legal guardian capable of giving informed consent for participation
Exclusion Criteria
I have a history of a neurological condition.
I have a medical condition that affects my brain function.
Other neurodevelopmental disorder (e.g., autism, Down syndrome)
See 1 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive choline bitartrate or placebo for a total of 9 months, with two dosing regimens: 3 months choline and 6 months placebo, or 6 months choline and 3 months placebo
9 months
Follow-up
Participants are monitored for cognitive and behavioral outcomes using various tests
9 months
Treatment Details
Interventions
- Choline Bitartrate (Other)
Trial OverviewThe study tests if choline bitartrate supplements can help with cognitive development in kids with Fetal Alcohol Spectrum Disorders. It compares the effects of taking the supplement for either three months or six months in a randomized and double-blind setup.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: 6 months choline bitartrateExperimental Treatment1 Intervention
Over the 9-month study, participants will receive a total of 6 months of choline bitartrate (19 mg/kg) and a total of 3 months of placebo
Group II: 3 months choline bitartrateExperimental Treatment1 Intervention
Over the 9-month study, participants will receive a total of 3 months of choline bitartrate (19 mg/kg) and a total of 6 months of placebo
Choline Bitartrate is already approved in United States, Canada, European Union for the following indications:
🇺🇸 Approved in United States as Choline Bitartrate for:
- Dietary Supplement
- Neurodevelopmental Intervention in Fetal Alcohol Spectrum Disorders
🇨🇦 Approved in Canada as Choline Bitartrate for:
- Dietary Supplement
- Neurodevelopmental Intervention
🇪🇺 Approved in European Union as Choline Bitartrate for:
- Dietary Supplement
- Nutrient
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of MinnesotaMinneapolis, MN
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Who Is Running the Clinical Trial?
Jeff Wozniak
Lead Sponsor
Trials
1
Patients Recruited
60+
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Collaborator
Trials
865
Patients Recruited
1,091,000+
References
Prenatal and Postnatal Choline Supplementation in Fetal Alcohol Spectrum Disorder. [2022]Fetal alcohol spectrum disorder (FASD) is common and represents a significant public health burden, yet very few interventions have been tested in FASD. Cognitive deficits are core features of FASD, ranging from broad intellectual impairment to selective problems in attention, executive functioning, memory, visual-perceptual/motor skills, social cognition, and academics. One potential intervention for the cognitive impairments associated with FASD is the essential nutrient choline, which is known to have numerous direct effects on brain and cognition in both typical and atypical development. We provide a summary of the literature supporting the use of choline as a neurodevelopmental intervention in those affected by prenatal alcohol. We first discuss how alcohol interferes with normal brain development. We then provide a comprehensive overview of the nutrient choline and discuss its role in typical brain development and its application in the optimization of brain development following early insult. Next, we review the preclinical literature that provides evidence of choline's potential as an intervention following alcohol exposure. Then, we review a handful of existing human studies of choline supplementation in FASD. Lastly, we conclude with a review of practical considerations in choline supplementation, including dose, formulation, and feasibility in children.
Choline supplementation in children with fetal alcohol spectrum disorders has high feasibility and tolerability. [2021]There are no biological treatments for fetal alcohol spectrum disorders (FASDs), lifelong conditions associated with physical anomalies, brain damage, and neurocognitive abnormalities. In preclinical studies, choline partially ameliorates memory and learning deficits from prenatal alcohol exposure. This phase I pilot study evaluated the feasibility, tolerability, and potential adverse effects of choline supplementation in children with FASD. We hypothesized that choline would be well tolerated with minimal adverse events. The study design was a double-blind, randomized, placebo-controlled trial. Participants included 20 children aged 2.5 to 4.9 years with prenatal alcohol exposure and FASD diagnoses. Participants were randomly assigned to 500 mg choline or placebo daily for 9 months (10 active, 10 placebo). Primary outcome measures included feasibility, tolerability, adverse effects, and serum choline levels. Seventeen participants completed the study. Compliance was 82% to 87%, as evidenced by parent-completed log sheets and dose counts. Periodic 24-hour dietary recalls showed no evidence of dietary confounding. Adverse events were minimal and were equivalent in the active and placebo arms with the exception of fishy body odor, which occurred only in the active group. There were no serious adverse events to research participants. This phase I pilot study demonstrates that choline supplementation at 500 mg/d for 9 months in children aged 2 to 5 years is feasible and has high tolerability. Further examination of the efficacy of choline supplementation in FASD is currently underway.
Neurophysiological correlates of memory change in children with fetal alcohol spectrum disorders treated with choline. [2023]Prenatal and early postnatal choline supplementation reduces cognitive and behavioral deficits in animal models of Fetal Alcohol Spectrum Disorder (FASD). In a previously published 9-month clinical trial of choline supplementation in children with FASD, we reported that postnatal choline was associated with improved performance on a hippocampal-dependent recognition memory task. The current paper describes the neurophysiological correlates of that memory performance for trial completers.
Prenatal choline supplementation mitigates the adverse effects of prenatal alcohol exposure on development in rats. [2022]Prenatal alcohol exposure can lead to a range of physical, neurological, and behavioral alterations referred to as fetal alcohol spectrum disorders (FASD). Variability in outcome observed among children with FASD is likely related to various pre- and postnatal factors, including nutritional variables. Choline is an essential nutrient that influences brain and behavioral development. Recent animal research indicates that prenatal choline supplementation leads to long-lasting cognitive enhancement, as well as changes in brain morphology, electrophysiology and neurochemistry. The present study examined whether choline supplementation during ethanol exposure effectively reduces fetal alcohol effects. Pregnant dams were exposed to 6.0g/kg/day ethanol via intubation from gestational days (GD) 5-20; pair-fed and lab chow controls were included. During treatment, subjects from each group received choline chloride (250mg/kg/day) or vehicle. Physical development and behavioral development (righting reflex, geotactic reflex, cliff avoidance, reflex suspension and hindlimb coordination) were examined. Subjects prenatally exposed to alcohol exhibited reduced birth weight and brain weight, delays in eye opening and incisor emergence, and alterations in the development of all behaviors. Choline supplementation significantly attenuated ethanol's effects on birth and brain weight, incisor emergence, and most behavioral measures. In fact, behavioral performance of ethanol-exposed subjects treated with choline did not differ from that of controls. Importantly, choline supplementation did not influence peak blood alcohol level or metabolism, indicating that choline's effects were not due to differential alcohol exposure. These data indicate early dietary supplements may reduce the severity of some fetal alcohol effects, findings with important implications for children of women who drink alcohol during pregnancy.
Choline supplementation attenuates learning deficits associated with neonatal alcohol exposure in the rat: effects of varying the timing of choline administration. [2021]Despite the harmful effects of fetal alcohol exposure, some pregnant women continue to drink alcohol. Thus, it is imperative to pursue safe, effective treatments for children with fetal alcohol spectrum disorders. Using an animal model, our laboratory has demonstrated that choline, an essential nutrient, effectively reduces the severity of some fetal alcohol effects, even when administered after the ethanol insult is complete. The present study investigated whether there is a critical developmental period when choline is most effective in attenuating ethanol's teratogenic effects. Sprague-Dawley rats were exposed to 5.25 g/kg/day ethanol during the third trimester equivalent brain growth spurt (postnatal days (PD) 4-9) via intubation. A non-intubation control group and a sham intubation control group were included. Following ethanol exposure, pups received subcutaneous injections of saline vehicle or choline chloride (100 mg/kg/day) from PD 11-20, PD 21-30, or PD 11-30. Beginning on PD 45, subjects were tested on a Morris water maze spatial learning task. Performance of both the ethanol-exposed group that did not receive choline and the ethanol-exposed group treated with choline from PD 21-30 was significantly impaired compared to controls during acquisition of the Morris water maze task. Performance of ethanol-exposed groups treated with choline from PD 11-20 or PD 11-30 was intermediate, not differing significantly from any other groups. However, during the probe trial, ethanol exposure produced significant deficits in spatial memory which were mitigated by all choline treatments, regardless of the timing of administration. These findings suggest that choline's therapeutic window may be very large, or spans across the two developmental periods examined in this study. Importantly, these findings indicate that choline supplementation may effectively reduce some alcohol-related learning impairments, even when administered in later childhood.
Association between Maternal Choline, Fetal Brain Development, and Child Neurocognition: Systematic Review and Meta-Analysis of Human Studies. [2023]We studied associations between prenatal and early postnatal choline intake, brain development, and neurocognitive function of children. We conducted a systematic review followed by a meta-analysis and critical appraisal of human studies published from 1997 to 2021. Thirty publications were identified. The meta-analysis included 5 of 7 case-control studies studying neural tube defects (NTDs) in relation to maternal choline intakes/circulating concentrations. Low maternal choline intake/circulating concentrations were associated with a higher OR for NTDs among 1131 mothers of newborns with NTDs and 4439 control mothers (pooled estimate = 1.36; 95% CI: 1.11, 1.67). The 95% prediction intervals were 0.78, 2.36. Findings and critical evaluation of 10 publications with interventional designs showed that higher maternal choline intakes during the second half of pregnancy and early postnatal period (550 mg up to 1 g/d on top of the diet) or a child intake of 513 to 625 mg/d from supplements were safe and likely to demonstrate favorable effects on several domains of child neurocognition, such as memory, attention, and visuospatial learning versus the comparators. Findings from observational studies (n = 13) partly supported the association between maternal choline intake/serum concentrations and child neurocognition, but there was low confidence in the use of plasma choline concentrations as a choline intake marker. In conclusion, low maternal choline intakes were associated with a higher OR for NTDs. The risk could be up to 2.36-fold in some populations. Despite limitations of available trials and observational studies, higher maternal choline intake was likely to be associated with better child neurocognition/neurodevelopment. The results should be used to guide choline intake recommendations in pregnancy and lactation, especially because most young women are not achieving the reference intake of choline. This meta-analysis is registered at PROSPERO as CRD42021233790.
Effect of Choline Supplementation on Neurological, Cognitive, and Behavioral Outcomes in Offspring Arising from Alcohol Exposure During Development: A Quantitative Systematic Review of Clinical and Preclinical Studies. [2019]Prenatal alcohol exposure results in cognitive, behavioral, and neurological deficits in offspring. There is an urgent need for safe and effective treatments to overcome these effects. Maternal choline supplementation has been identified as a potential intervention. Our objective was to review preclinical and clinical studies using choline supplementation in known cases of fetal alcohol exposure to determine its effectiveness in ameliorating deficits in offspring. A systematic search of 6 electronic databases was conducted and studies selected by reviewing titles/abstracts against specific inclusion/exclusion criteria. Study characteristics, population demographics, alcohol exposure, and intervention methods were tabulated, and quality of reporting was assessed. Data on cognitive, behavioral, and neurological outcomes were extracted and tabulated. Quantitative analysis was performed to determine treatment effects for individual study outcomes. A total of 189 studies were retrieved following duplicate removal. Of these, 22 studies (2 randomized controlled trials, 2 prospective cohort studies, and 18 preclinical studies) met the full inclusion/exclusion criteria. Choline interventions were administered at different times relative to alcohol exposure, impacting on their success to prevent deficits for specific outcomes. Only 1 clinical study showed significant improvements in information processing in 6-month-old infants from mothers treated with choline during pregnancy. Preclinical studies showed significant amelioration of deficits due to prenatal alcohol exposure across a wide variety of outcomes, including epigenetic/molecular changes, gross motor, memory, and executive function. This review suggests that choline supplementation has the potential to ameliorate specific behavioral, neurological, and cognitive deficits in offspring caused by fetal alcohol exposure, at least in preclinical studies. As only 1 clinical study has shown benefit, we recommend more clinical trials be undertaken to assess the effectiveness of choline in preventing deficits across a wider range of cognitive domains in children.
Choline Ameliorates Deficits in Balance Caused by Acute Neonatal Ethanol Exposure. [2018]Fetal alcohol spectrum disorder (FASD) is estimated to occur in 1 % of all live births. The developing cerebellum is vulnerable to the toxic effects of alcohol. People with FASD have cerebellar hypoplasia and developmental deficits associated with cerebellar injury. Choline is an essential nutrient, but many diets in the USA are choline deficient. In rats, choline given with or following alcohol exposure reduces many alcohol-induced neurobehavioral deficits but not those associated with cerebellar function. Our objective was to determine if choline supplementation prior to alcohol exposure would ameliorate the impact of ethanol on a cerebellar-associated behavioral test in mice. Pregnant C57Bl6/J mice were maintained on a choline-deficient diet from embryonic day 4.5. On postnatal day 1 (P1), pups were assigned to one of eight treatment groups: choline (C) or saline (S) pre-treatment from P1 to P5, ethanol (6 g/kg) or Intralipid(®) on P5, C and or S post-treatment from P6 to P20. On P30, balance and coordination were tested using the dowel crossing test. Overall, there was a significant effect of treatment and females crossed longer distances than males. Ethanol exposure significantly reduced the total distance crossed. Choline pre-treatment increased the distance crossed by males, and both pre- and post-treatment with choline significantly increased total distance crossed for females and males. There was no effect of choline on Intralipid®-exposed animals. This is the first study to show that choline ameliorates ethanol-induced effects on balance and coordination when given before ethanol exposure. Choline fortification of common foodstuffs may reduce the effects of alcohol.