Ignite Creation Date:
2024-05-05 @ 4:37 PM
Last Modification Date:
2024-10-26 @ 9:22 AM
Study NCT ID:
NCT00287053
Status:
COMPLETED
Last Update Posted:
2016-02-08
First Post:
2006-02-02
Brief Title:
Effects of Divalproex Sodium on Food Intake Energy Expenditure and Posture Allocation
Sponsor:
Pennington Biomedical Research Center
Organization:
Pennington Biomedical Research Center
Study Overview
Official Title:
Phase IV Study of the Effects of Divalproex Sodium on Food Intake and Energy Expenditure
Status:
COMPLETED
Status Verified Date:
2016-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
VPA
Brief Summary:
The purpose of the proposed study is to identify the mechanisms responsible for the weight gain associated with Depakote treatment and to identify methods to prevent and treat weight gain in people taking Depakote Both sides of the energy balance equation will be measured in a sample of healthy lean and overweight adults Energy intake will be measured in the Pennington Centers Eating Laboratory and total daily energy expenditure TEE and posture allocation will be measured with the IDEEA Questionnaires that assess food cravings and eating attitudes and behaviors will be used to determine if a behavioral phenotype is associated with weight gain in response to Depakote treatment It is hypothesized that Depakote treatment will result in increased food intake It is also hypothesized that the time spent engaging in sedentary behavior will increase in response to Depakote treatment Time spent engaging in and the energy expended during physical activity is expected to decrease significantly Therefore it is hypothesized that TEE is expected to decrease significantly The results will be used to identify specific behavioral targets to prevent weight gain during treatment with Depakote Potential targets include interventions to modify food intake and physical activity The degree to which each behavior food intake or physical activity will be targeted is dependent on the results of this study For instance if the majority of the weight gain associated with Depakote treatment is due to changes in food intake stronger dietary interventions will be suggested Additionally changes in endocrine factors hormones and peptides will be evaluated during the study to determine if Depakote is associated with an altered endocrine response that affects satiety food intake or energy expenditure If an altered endocrine response is found these results will be used to identify adjunctive medications or compounds to correct the endocrine response and reduce weight gain Genomic studies will also be possible since gene sequencing and gene expression can be analyzed from archived buffy coat samples
Detailed Description:
Depakote Abbott Laboratories Abbott Park IL is an anti-convulsant medication used to treat epilepsy 1 and mania associated with bipolar disorder 2 3 Depakote also is used as a prophylaxis for migraine headache 4 One side effect of Depakote that negatively influences its appeal to health care professionals and consumers is weight gain It is unknown if changes in energy intake energy expenditure or a combination of both are responsible for this side effect The purpose of the proposed study is to 1 test if Depakote increases body weight by increasing food intake or decreasing energy expenditure possibly through changes in posture allocation and 2 identify methods to prevent and treat weight gain in people taking Depakote This randomized placebo-controlled trial will measure both sides of the energy balance equation energy intake and expenditure and posture allocation the time spent in active and sedentary behaviors and the energy cost of these behaviors Measurement of both total daily energy expenditure TEE and posture allocation provides a powerful tool to determine if Depakote decreases energy expenditure by increasing the time spent in sedentary behavior These data along with the food intake data provide a test of the mechanisms responsible for weight gain associated with Depakote and these data can identify methods to prevent or treat this weight gain
Divalproex sodium is a co-ordination compound consisting of sodium valproate and valproic acid The exact mechanism of action of Depakote is unknown but it is believed to increase brain concentrations of gamma aminobutyric acid GABA Similarly the mechanism by which Depakote increases body weight is not understood The balance between energy intake and expenditure influences body weight therefore Depakote likely alters energy intake energy expenditure or both Alterations in energy intake or expenditure can result from or be associated with changes in biological mechanisms including hormone and peptide levels To our knowledge only one study has tested the effects of a compound containing valproic acid on energy intake and expenditure but this study was small n 8 uncontrolled and used methods to measure energy intake food records and recall that were unlikely to detect changes in such a small sample 5 The study proposed herein is the first study to test the effects of Depakote on eating behavior measured in the laboratory and energy expenditure and posture allocation measured with the Intelligent Device for Energy Expenditure and Activity IDEEA MiniSun LLC Fresno CA
In vitro leptin secretion and mRNA levels in adipocytes decrease in response to valproic acid and it is believed that altered leptin levels might influence weight gain in people taking compounds containing valproic acid 6 Other researchers have reported that postprandial insulin and proinsulin levels increase in people taking valproic acid and BMI is positively related to two-hour postprandial levels of insulin proinsulin and C-peptide 7 Luef and colleagues indicate that treatment with valproic acid might increase glucose stimulated pancreatic section which could be related to higher body weight due to two factors that are related to pancreatic beta-cell regulation and insulin secretion First valproic acid is a free-fatty acid FFA derivative that competes with FFAs for albumin binding and second valproic acid is a GABA agonist Thus valproic acid treatment might increase glucose stimulated pancreatic secretion and contribute to weight gain Evidence from other laboratories suggests that valproic acid treatment in children increases insulin levels and decreases glucose levels which might stimulate appetite 8 Importantly Demir and Aysun note that carnitine levels did not correlate with weight gain suggesting that valproic acid induced weight gain is not due to impairments in beta-oxidation of fatty acids Carnitine is involved in the transfer of fatty acids into the mitochondria for beta-oxidation Due to the potential role of FFA and valproic acid in influencing pancreatic beta-cell regulation and insulin secretion FFA will be measured in the present study at baseline day 0 and day 21 ½ hour before and one hour after the food intake tests at lunch
Due to the likelihood that hormones and peptides influence the weight gain associated with Depakote blood samples will be archived for later analysis pending availability of funds Specifically a portion of the archives will be used to measure gastric inhibitory polypeptide GIP and oxyntomodulin Oxyntomodulin and GIP will not be assayed immediately because commercially available assay kits are not yet available Oxyntomodulin has been implicated in the control of food intake and satiety in both humans and animals 9 and GIP modulates insulin secretion and might provide new treatments for diabetes 10 Additionally levels of PYY3-36 glucagon-like peptide-1 GLP-1 leptin and ghrelin will be measured PYY3-36 and GLP-1 are distal gut hormones that have been found to reduce food intake 9 11 PYY3-36 decreases food intake by 30 when infused into humans 11 and obese humans and rodents have attenuated fasting and post-prandial PYY3-36 levels that are likely associated with their obesity 12 GLP-1 also decreases food intake in rodents and man and it works synergistically with PYY3-36 13 Leptin reduces food intake 14 and increases energy expenditure in humans 15 while ghrelin increases food intake and is likely an important regulator of food intake 16
The aforementioned hormones will be sampled ½ hour before and one hour after the start of the food intake tests at lunch on days 0 and 21 The timing of these samples is based on the finding that PYY3-36 and GLP-1 peak one hour after a meal 17 18 Therefore we will compare levels prior to meals and the change after the meals between the Depakote and placebo groups Different pre-meal levels of these hormones and peptides can be correlated with food intake between the groups and differential change in these hormones in response to the meal will be evaluated between the groups and correlated with food intake
Two factors that likely affect the amount of weight gain with Depakote treatment are gene sequencing and gene expression Although these analyses can be costly DNA material including RNA can be archived from whole blood samples and stored for later analysis This method allows cost to be controlled since analyses can be conducted on a sub-sample of the participants who displayed specific reactions to treatment during the study For example genomic studies can be conducted on participants who fall within the lower and upper quartiles of weight gain or a sub-sample of participants from the placebo and treatment groups This provides empirical tests of a priori stated hypothesis without the need to endure the costs of running genomic analyses on the entire sample of participants In the present study both gene sequencing and gene expression studies will be made possible by archiving blood samples as outlined in the Methods section These analyses will depend on the availability of funds and the development of specific testable hypotheses eg weight gain in the Depakote group will be associated with the peroxisome proliferator-activated receptor-gamma gene
Divalproex sodium is a co-ordination compound consisting of sodium valproate and valproic acid The exact mechanism of action of Depakote is unknown but it is believed to increase brain concentrations of gamma aminobutyric acid GABA Similarly the mechanism by which Depakote increases body weight is not understood The balance between energy intake and expenditure influences body weight therefore Depakote likely alters energy intake energy expenditure or both Alterations in energy intake or expenditure can result from or be associated with changes in biological mechanisms including hormone and peptide levels To our knowledge only one study has tested the effects of a compound containing valproic acid on energy intake and expenditure but this study was small n 8 uncontrolled and used methods to measure energy intake food records and recall that were unlikely to detect changes in such a small sample 5 The study proposed herein is the first study to test the effects of Depakote on eating behavior measured in the laboratory and energy expenditure and posture allocation measured with the Intelligent Device for Energy Expenditure and Activity IDEEA MiniSun LLC Fresno CA
In vitro leptin secretion and mRNA levels in adipocytes decrease in response to valproic acid and it is believed that altered leptin levels might influence weight gain in people taking compounds containing valproic acid 6 Other researchers have reported that postprandial insulin and proinsulin levels increase in people taking valproic acid and BMI is positively related to two-hour postprandial levels of insulin proinsulin and C-peptide 7 Luef and colleagues indicate that treatment with valproic acid might increase glucose stimulated pancreatic section which could be related to higher body weight due to two factors that are related to pancreatic beta-cell regulation and insulin secretion First valproic acid is a free-fatty acid FFA derivative that competes with FFAs for albumin binding and second valproic acid is a GABA agonist Thus valproic acid treatment might increase glucose stimulated pancreatic secretion and contribute to weight gain Evidence from other laboratories suggests that valproic acid treatment in children increases insulin levels and decreases glucose levels which might stimulate appetite 8 Importantly Demir and Aysun note that carnitine levels did not correlate with weight gain suggesting that valproic acid induced weight gain is not due to impairments in beta-oxidation of fatty acids Carnitine is involved in the transfer of fatty acids into the mitochondria for beta-oxidation Due to the potential role of FFA and valproic acid in influencing pancreatic beta-cell regulation and insulin secretion FFA will be measured in the present study at baseline day 0 and day 21 ½ hour before and one hour after the food intake tests at lunch
Due to the likelihood that hormones and peptides influence the weight gain associated with Depakote blood samples will be archived for later analysis pending availability of funds Specifically a portion of the archives will be used to measure gastric inhibitory polypeptide GIP and oxyntomodulin Oxyntomodulin and GIP will not be assayed immediately because commercially available assay kits are not yet available Oxyntomodulin has been implicated in the control of food intake and satiety in both humans and animals 9 and GIP modulates insulin secretion and might provide new treatments for diabetes 10 Additionally levels of PYY3-36 glucagon-like peptide-1 GLP-1 leptin and ghrelin will be measured PYY3-36 and GLP-1 are distal gut hormones that have been found to reduce food intake 9 11 PYY3-36 decreases food intake by 30 when infused into humans 11 and obese humans and rodents have attenuated fasting and post-prandial PYY3-36 levels that are likely associated with their obesity 12 GLP-1 also decreases food intake in rodents and man and it works synergistically with PYY3-36 13 Leptin reduces food intake 14 and increases energy expenditure in humans 15 while ghrelin increases food intake and is likely an important regulator of food intake 16
The aforementioned hormones will be sampled ½ hour before and one hour after the start of the food intake tests at lunch on days 0 and 21 The timing of these samples is based on the finding that PYY3-36 and GLP-1 peak one hour after a meal 17 18 Therefore we will compare levels prior to meals and the change after the meals between the Depakote and placebo groups Different pre-meal levels of these hormones and peptides can be correlated with food intake between the groups and differential change in these hormones in response to the meal will be evaluated between the groups and correlated with food intake
Two factors that likely affect the amount of weight gain with Depakote treatment are gene sequencing and gene expression Although these analyses can be costly DNA material including RNA can be archived from whole blood samples and stored for later analysis This method allows cost to be controlled since analyses can be conducted on a sub-sample of the participants who displayed specific reactions to treatment during the study For example genomic studies can be conducted on participants who fall within the lower and upper quartiles of weight gain or a sub-sample of participants from the placebo and treatment groups This provides empirical tests of a priori stated hypothesis without the need to endure the costs of running genomic analyses on the entire sample of participants In the present study both gene sequencing and gene expression studies will be made possible by archiving blood samples as outlined in the Methods section These analyses will depend on the availability of funds and the development of specific testable hypotheses eg weight gain in the Depakote group will be associated with the peroxisome proliferator-activated receptor-gamma gene
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None