Ignite Creation Date:
2024-05-05 @ 11:55 AM
Last Modification Date:
2024-10-26 @ 9:16 AM
Study NCT ID:
NCT00175305
Status:
TERMINATED
Last Update Posted:
2007-10-31
First Post:
2005-09-09
Brief Title:
Prader-Willi Syndrome and Appetite
Sponsor:
University of British Columbia
Organization:
University of British Columbia
Study Overview
Official Title:
Effect of Somatostatin on Ghrelin Concentrations Food Seeking Behaviour and Weight in Patients With Prader-Willi Syndrome
Status:
TERMINATED
Status Verified Date:
2007-10
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:
None
Brief Summary:
Excessive weight gain is a cardinal feature of Prader-Willi syndrome PWS for which there is presently no effective treatment It is caused by increased appetite decreased perception of satiety and obsessive and compulsive behaviour towards food Ghrelin is a powerful appetite-stimulating hormone Patients with PWS have markedly elevated ghrelin levels suggesting that it may be responsible for the increased food intake The goal of the study is to determine whether treatment with somatostatin Sandostatin a hormone that inhibits ghrelin is an effective treatment for the prevention and treatment of weight excess in patients with PWS
Detailed Description:
Prader-Willi Syndrome and Obesity
Prader-Willi syndrome PWS is a genetic disorder occurring in 110000 to 115000 live births Clinical characteristics include neonatal and infantile central hypotonia with feeding problems and poor weight gain followed after 1-3 years by hyperphagia and excessive weight gain Patients also have characteristic facial features short stature possibly due to growth hormone GH deficiency of hypothalamic origin hypogonadism increased pain threshold global developmental delay and variable mental retardation
Obesity is clearly one of the cardinal features of PWS It can result in tremendous distress for both the parents and the affected child and is a significant health problem with complications that include hypertension sleep apneas and diabetes More than 13 of patients with PWS weigh more than 200 of their ideal body weight Obesity is thought to result mainly from hyperphagia persistent hunger with increased caloric intake decreased perception of satiety and obsessive and compulsive behaviours that are primarily food related Decreased physical activity associated with hypotonia andor decreased energy expenditure is also thought to play a role in the pathophysiology of obesity
The treatment of obesity in PWS is very difficult and requires constant involvement of the parents or caregivers with establishment of rigid structures around the young patient increased physical activity hiding food locking fridges etc Recently studies on the effects of growth hormone GH treatment now an approved indication in most patients with PWS in the US irrespective of their GH status on body composition in PWS have been performed While GH among other favourable effects significantly improves body composition increased lean mass and decreased fat mass the long-term effects on body mass index are modest and variable
Thus obesity is clearly one of the greatest challenges faced by parents of patients with PWS and treatment modalities are presently not successful
Ghrelin
Ghrelin is a recently discovered peptide that stimulates appetite and GH secretion Ghrelin increases with fasting and decreases following a meal and is thought to play a role in meal initiation in humans In obese adult and young patients without PWS ghrelin is decreased compared to control lean subjects suggesting that it does not play a causal role in the development of obesity In contrast PWS patients are characterized by extremely high circulating ghrelin levels 3 to 10 times higher compared to controls The mechanisms underlying ghrelin increase in PWS are unclear The gene encoding ghrelin is located on chromosome 3 in humans while PWS is associated with the functional loss of paternally expressed genes located on chromosome 15 most patients affected with PWS present with a deletion in the area of 15q11-13 70 or a uniparental disomy for maternal chromosome 15 30 A logical hypothesis is that these missing genes may be part of a pathway regulating ghrelin expression
Thus the elevated ghrelin concentrations observed in PWS at the very least raise the possibility that ghrelin may play an etiological role in the food-seeking behaviour reported in these patients In support of this hypothesis a significant correlation between hunger sensation and ghrelin concentrations has recently been reported in a combined group of 6 lean controls and 7 patients with PWS
Somatostatin and Somatostatin Analogues
Somatostatin is a hormone that circulates under 2 main forms a 14 amino acid peptide SST-14 mainly in the brain including the hypothalamus and a 28 amino acid peptide SST-28 mainly in the gastrointestinal tract Somatostatin inhibits GH and insulin secretion Somatostatin is also a powerful regulator of gastric activity that decreases gastrin release acid output and gastric motility
The somatostatin analogue octreotide Sandostatin Novartis contains 8 amino acids and is very similar to SST-14 It is an effective treatment of neonatal hyperinsulinism a condition characterized by excessive and inappropriate secretion of insulin that causes severe hypoglycemia in infants and acromegaly a condition characterized by excessive GH production by the pituitary Sandostatin LAR is a recent long-acting analogue of somatostatin that is used for the treatment of acromegaly and less often in childrens hyperinsulinism
Sandostatin LAR therapy may be associated with significant side-effects
Reduction of bile production and gallbladder contractility and increased risk of cholesterol gallstones However these tend to resolve either spontaneously when therapy is discontinued or with ursodiol despite remaining on therapy Therefore gallbladder ultrasound is part of the routine follow-up of all patients receiving octreotide for prolonged periods
Decreased height velocity secondary to inhibition of GH secretion This effect is variable in intensity but present and will need to be taken into account in case of prolonged octreotide treatment In the proposed study 12 weeks of octreotide treatment are not expected to have a significant long-term effect on longitudinal growth Octreotide should not interfere with GH action in PWS subjects receiving concomitant exogenous human GH
Glucose intolerance Prolonged octreotide treatment has been associated with impaired glucose tolerance secondary to a decrease in insulin secretion However when octreotide treatment results in weight loss an improvement in glucose tolerance is observed Therefore parameters reflecting glucose tolerance must be followed as part of Sandostatin LAR therapy
Other side effects include nausea abdominal cramps diarrhea and flatulence that usually subside after 2 weeks of treatment
Effect of Somatostatin Analogues on Ghrelin and Weight Gain
Somatostatin has been shown to decrease ghrelin concentrations in normal subjects as well as in patients with PWS and with acromegaly In nine lean young men continuous SC infusion of octreotide 600 microg24 hours caused a 50 decrease in ghrelin concentrations In patients with PWS using the dose of 5 microg Sandostatinkg body weight SC three times a day Hacqq et al observed a 67 drop in ghrelin concentrations The study was of short duration 1 week but the results suggest that somatostatin may indeed be helpful in decreasing ghrelin concentrations in patients with PWS There were no complications In adults with acromegaly aged 25-59 years mean BMI 289 kgm2 fasting ghrelin concentrations decreased in all patients mean 54 range 30-74 following treatment with Sandostatin LAR 10 to 30 mg4-6 weeks for 3-29 months Finally Lustig et al reported the effects of daily injections of octreotide for 6 months in a group of children with severe hypothalamic obesity due to brain tumor treatment andor cranial irradiation They observed that the weight gain in octreotide-treated patients was minimal 12 kg6 mo compared to the placebo group 92 kg6 mo Bile sludging andor gallstones were observed in 44 of the patients but resolved with ursodiol therapy Ghrelin concentrations were not measured in that study
Thus somatostatin analogues cause a marked decrease in ghrelin concentrations in control subjects as well as in patients with PWS Whether they are associated with a sustained decrease in ghrelin concentrations and whether the decrease in ghrelin is associated with a decrease in appetite is unknown and will be studied in the present project
Prader-Willi syndrome PWS is a genetic disorder occurring in 110000 to 115000 live births Clinical characteristics include neonatal and infantile central hypotonia with feeding problems and poor weight gain followed after 1-3 years by hyperphagia and excessive weight gain Patients also have characteristic facial features short stature possibly due to growth hormone GH deficiency of hypothalamic origin hypogonadism increased pain threshold global developmental delay and variable mental retardation
Obesity is clearly one of the cardinal features of PWS It can result in tremendous distress for both the parents and the affected child and is a significant health problem with complications that include hypertension sleep apneas and diabetes More than 13 of patients with PWS weigh more than 200 of their ideal body weight Obesity is thought to result mainly from hyperphagia persistent hunger with increased caloric intake decreased perception of satiety and obsessive and compulsive behaviours that are primarily food related Decreased physical activity associated with hypotonia andor decreased energy expenditure is also thought to play a role in the pathophysiology of obesity
The treatment of obesity in PWS is very difficult and requires constant involvement of the parents or caregivers with establishment of rigid structures around the young patient increased physical activity hiding food locking fridges etc Recently studies on the effects of growth hormone GH treatment now an approved indication in most patients with PWS in the US irrespective of their GH status on body composition in PWS have been performed While GH among other favourable effects significantly improves body composition increased lean mass and decreased fat mass the long-term effects on body mass index are modest and variable
Thus obesity is clearly one of the greatest challenges faced by parents of patients with PWS and treatment modalities are presently not successful
Ghrelin
Ghrelin is a recently discovered peptide that stimulates appetite and GH secretion Ghrelin increases with fasting and decreases following a meal and is thought to play a role in meal initiation in humans In obese adult and young patients without PWS ghrelin is decreased compared to control lean subjects suggesting that it does not play a causal role in the development of obesity In contrast PWS patients are characterized by extremely high circulating ghrelin levels 3 to 10 times higher compared to controls The mechanisms underlying ghrelin increase in PWS are unclear The gene encoding ghrelin is located on chromosome 3 in humans while PWS is associated with the functional loss of paternally expressed genes located on chromosome 15 most patients affected with PWS present with a deletion in the area of 15q11-13 70 or a uniparental disomy for maternal chromosome 15 30 A logical hypothesis is that these missing genes may be part of a pathway regulating ghrelin expression
Thus the elevated ghrelin concentrations observed in PWS at the very least raise the possibility that ghrelin may play an etiological role in the food-seeking behaviour reported in these patients In support of this hypothesis a significant correlation between hunger sensation and ghrelin concentrations has recently been reported in a combined group of 6 lean controls and 7 patients with PWS
Somatostatin and Somatostatin Analogues
Somatostatin is a hormone that circulates under 2 main forms a 14 amino acid peptide SST-14 mainly in the brain including the hypothalamus and a 28 amino acid peptide SST-28 mainly in the gastrointestinal tract Somatostatin inhibits GH and insulin secretion Somatostatin is also a powerful regulator of gastric activity that decreases gastrin release acid output and gastric motility
The somatostatin analogue octreotide Sandostatin Novartis contains 8 amino acids and is very similar to SST-14 It is an effective treatment of neonatal hyperinsulinism a condition characterized by excessive and inappropriate secretion of insulin that causes severe hypoglycemia in infants and acromegaly a condition characterized by excessive GH production by the pituitary Sandostatin LAR is a recent long-acting analogue of somatostatin that is used for the treatment of acromegaly and less often in childrens hyperinsulinism
Sandostatin LAR therapy may be associated with significant side-effects
Reduction of bile production and gallbladder contractility and increased risk of cholesterol gallstones However these tend to resolve either spontaneously when therapy is discontinued or with ursodiol despite remaining on therapy Therefore gallbladder ultrasound is part of the routine follow-up of all patients receiving octreotide for prolonged periods
Decreased height velocity secondary to inhibition of GH secretion This effect is variable in intensity but present and will need to be taken into account in case of prolonged octreotide treatment In the proposed study 12 weeks of octreotide treatment are not expected to have a significant long-term effect on longitudinal growth Octreotide should not interfere with GH action in PWS subjects receiving concomitant exogenous human GH
Glucose intolerance Prolonged octreotide treatment has been associated with impaired glucose tolerance secondary to a decrease in insulin secretion However when octreotide treatment results in weight loss an improvement in glucose tolerance is observed Therefore parameters reflecting glucose tolerance must be followed as part of Sandostatin LAR therapy
Other side effects include nausea abdominal cramps diarrhea and flatulence that usually subside after 2 weeks of treatment
Effect of Somatostatin Analogues on Ghrelin and Weight Gain
Somatostatin has been shown to decrease ghrelin concentrations in normal subjects as well as in patients with PWS and with acromegaly In nine lean young men continuous SC infusion of octreotide 600 microg24 hours caused a 50 decrease in ghrelin concentrations In patients with PWS using the dose of 5 microg Sandostatinkg body weight SC three times a day Hacqq et al observed a 67 drop in ghrelin concentrations The study was of short duration 1 week but the results suggest that somatostatin may indeed be helpful in decreasing ghrelin concentrations in patients with PWS There were no complications In adults with acromegaly aged 25-59 years mean BMI 289 kgm2 fasting ghrelin concentrations decreased in all patients mean 54 range 30-74 following treatment with Sandostatin LAR 10 to 30 mg4-6 weeks for 3-29 months Finally Lustig et al reported the effects of daily injections of octreotide for 6 months in a group of children with severe hypothalamic obesity due to brain tumor treatment andor cranial irradiation They observed that the weight gain in octreotide-treated patients was minimal 12 kg6 mo compared to the placebo group 92 kg6 mo Bile sludging andor gallstones were observed in 44 of the patients but resolved with ursodiol therapy Ghrelin concentrations were not measured in that study
Thus somatostatin analogues cause a marked decrease in ghrelin concentrations in control subjects as well as in patients with PWS Whether they are associated with a sustained decrease in ghrelin concentrations and whether the decrease in ghrelin is associated with a decrease in appetite is unknown and will be studied in the present project
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| W04-0007 | None | None | None |