Ignite Creation Date:
2024-05-05 @ 4:48 PM
Last Modification Date:
2024-10-26 @ 9:24 AM
Study NCT ID:
NCT00319358
Status:
COMPLETED
Last Update Posted:
2009-01-29
First Post:
2006-04-26
Brief Title:
Role of Antioxidants Supplementation in Chronic Pancreatitis
Sponsor:
All India Institute of Medical Sciences New Delhi
Organization:
All India Institute of Medical Sciences New Delhi
Study Overview
Official Title:
Effect of Antioxidant Supplementation on Pain Antioxidant Profile and Oxidative Stress in Patients With Chronic Pancreatitis
Status:
COMPLETED
Status Verified Date:
2009-01
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:
None
Brief Summary:
Chronic pancreatitis is a progressive inflammatory disease of the pancreas that presents with abdominal pain and in late stages may cause diabetes and malnutrition The pain may be incapacitating and may affect patients physically mentally and socially Pain due to chronic pancreatitis is difficult to treat Oxidative stress and free radical mediated injury has been shown to cause pancreatic inflammation It has been shown that patients with chronic pancreatitis are deficient in micronutrients and natural antioxidants such as b-carotene vitamin E and C etc Studies have suggested that antioxidant supplementation may help to combat pain in these patients Antioxidant supplementation may decrease the oxidative stress and boost the antioxidant status thereby resulting in pain relief The investigators have planned to perform a trial to study the effect of antioxidant supplementation on pain relief in patients with chronic pancreatitis
Detailed Description:
INTRODUCTION Chronic pancreatitis CP is a progressive inflammatory disease of the pancreas accompanied by abdominal pain and in late stages by exocrine and endocrine insufficiency The etiology of CP include alcohol abuse hereditary ductal obstruction tropical pancreatitis systemic diseases systemic lupus erythematosus and cystic fibrosis etc and idiopathic Alcohol abuse accounts for 70-80 of cases of chronic pancreatitis in the West and about 40 in India The intensity of injury depends on the duration and amount of alcohol consumed Hereditary pancreatitis transmitted as an autosomal dominant trait accounts for a small subset of all cases of CP and occurs due to mutation in cationic trypsinogen gene Pancreatic duct obstruction may be secondary to trauma pseudocysts calcific stones or tumors and leads to obstructive CP 1 Tropical pancreatitis is a condition of unknown etiology that is seen predominantly in south India and other tropical areas of the World Young patients are commonly affected with this disease Cassava consumption had been proposed as an etiological factor due to its cyanogenic glycoside content however no epidemiological study has proved this hypothesis 2 Malnutrition has been suggested as an etiological factor in tropical pancreatitis Idiopathic pancreatitis accounts for a substantial number of cases
Many recent studies have emphasized a role for Reactive Oxygen Radicals ROR in the development of oxidative stress and hence inflammation in the pathogenesis of chronic pancreatitis Increased oxidative stress probably results from increased exposure to xenobiotics Xenobiotics are chemical substances present in the environment to which human beings are constantly exposed It is conceivable that many of these xenobiotics are metabolized in pancreas that contains cytochrome P450 CYP450 enzymatic system The metabolism of xenobiotics occurs through two phases Phase I and Phase II Phase I metabolism may result in bioactivation of the xenobiotics in turn activating CYP system Phase II involves attachment of biotransformed compound to a biological molecule that makes it more polar and thus easier to excrete The metabolism of xenobiotics places an oxidative stress and can overwhelm the natural antioxidant defense of the body The resultant production of the free radicals may play an important role in the pathogenesis of CP 2 Over induction of this enzyme can cause increased utilization of glutathione GSH which causes irreversible loss of glutathione Moreover glutathione serves as a reservoir for cysteinecystine required for disulphide synthesis for pancreatic digestive proteins This further aggravates the situation Three types of cytochrome enzymes are induced through xenobiotics CYP2E1 has been specifically examined in the context of liver injury CYP1A metabolizes smoke constituents and potent carcinogens such as benzoapyrene Cytochrome 3A is inducible by reactive oxygen species generated from aflatoxin B1 Alcohol nicotine from cigarette smoke and other forms of tobacco consumption and industrial pollutants all are considered as xenobiotics and overwhelm the detoxification capacity of cytochrome CYP450 system 3 The CYP induction increases heme and heme-oxygenase thus buttressing the antioxidant defenses The free radical peroxidation products may act as second messengers and block exocytosis leading to increased autophagy and crinophagy thus diverting the pancreatic enzymes into interstitium This leads to degranulation of mast cells inducing inflammation mediated by chemotaxis The synthesis of enzyme proteins in pancreas also produces H2O2 which also induces free radical production Furthermore the depressed methionine trans-sulphuration pathway induces CYP as well The free radicals generated from all these processes induce oxidative stress which is implicated in damage to cell membranes due to lipid peroxidation Above all if the antioxidant levels of an individual are may be low due to either low intake or depletion during oxidative stress Some studies also indicate that free radicals cause disintegration of antioxidative enzymes if over exposed to them
However the role of oxidative stress still not fully explained in that whether the oxidative stress is the cause of chronic pancreatitis or a consequence of it This can be established by two observations 1 If the oxidative stress is noted before the onset of disease and 2 If the disease symptoms are relieved by supplementation with antioxidants Patients with alcoholic pancreatitis have been shown to have an increased oxidative stress Supplementation with antioxidants hence decreases the production of such free radicals and may be beneficial to patients with CP 4
A study by Braganza et al has shown that CP involves oxidative stress in-patients with CP 5 This was the first study to indicate the role of free radicals in the pathogenesis of chronic pancreatitis However the mechanism by which it occurs is still unclear The preliminary studies show that malondialdehyde MDA a marker of peroxidation secondary to oxidative stress increases during CP
In the present proposed study the aim is to find out if there is increased oxidative stress in patients with CP and if supplementation with antioxidants relieves pain in them in order to establish a relationship between oxidant stress and pathophysiology of chronic pancreatitis
Objectives
1 To evaluate the effect of antioxidant supplementation given daily on pain relief in chronic pancreatitis during the 6 months of therapy as compared to a placebo
2 To assess the improvement in oxidative stress and antioxidant profile in these patients during 6 months of antioxidant supplementation by measuring markers of oxidative stress and blood antioxidant levels
Material and methods Study Design Double blind randomized controlled trial Patients All consecutive patients with chronic pancreatitis attending the pancreas clinic at AIIMS will be included in the study as per the inclusion criteria The diagnosis of CP will be made if there is evidence of CP on imaging studies including plain film of the abdomen Ultrasonography Computerized tomography CT scan endoscopic retrograde cholangiopancreatography ERCP and magnetic resonance imaging MRI scan Also hematological tests biochemical investigations will be done as part of diagnostic work-up
All patients will undergo detailed clinical evaluation including detailed family history of pancreatic diseases and diabetes The WHO criteria will be used to diagnose diabetes The patients will also be inquired about their dietary history and addiction to tobacco or alcohol Patients will be explained the purpose of study clearly and consent forms will be duly signed by them The patients will be regularly followed up in pancreas clinic at All India Institute of Medical Sciences New Delhi All the patients will be treated in the standard manner including medical endoscopic and surgical treatment as and when indicated
Inclusion criteria
CP with significant pain ie at least one episode of pain in a month requiring oral analgesic or one episode of severe pain in last three months requiring hospitalization
Sample size calculation Sample size is calculated on the basis of probability sampling methods For 80 power at a significance level of 5 a 005 a sample size of 100 in each arm would be required
Randomization and blinding Randomization of treatment allocation largely ensures unbiased treatment comparison A simple randomization scheme for treatment allocation will be done using a table of random numbers by a Statistician Epidemiologist not associated with conduct of the study Heshe will label the boxes of treatment with individual patient numbers from 1-200 according to the randomization scheme This person will keep the assignment code at a safe place the code will be available to the investigator only at the end of the trial These will be serially opened as new patients are recruited into the study Double blinding will be done to ensure minimum bias ie blinding of researcher and clinician attending patients to the randomization process so that allocation and outcome evaluation are not affected and blinding of patients to the identity of the drug or intervention they are receiving The inert placebo which will be identical to the active drug in packaging appearance and schedule of administration
Intervention One group will be given antioxidant supplementation and the other group will be placebo The antioxidant intervention will be daily doses of 600 mg organic selenium 054 g vitamin C 9000 IU B-carotene 270 IU vitamin E and 2 g methionine Both the groups will be supplemented with the pancreatic enzymes The enzyme will be administered as capsules each containing 10000 units Three capsules 30000 units will be required per meal thereby making it to 90000 units per day
Follow up assessment during study period
Clinical
Assessment of painful days and requirement of oral IV analgesic or hospitalization in a month will be done The patients will be provided with a pain diary so as to get the correct data
Any other symptoms either due to primary disease ie CP or considered due to the intervention will be duly recorded
Pain assessment and clinical examination will be done at each visit of patient to the clinic while USG ERCP CT or X-ray will be done as and when required
Markers of oxidative stress
MDA Marker of antioxidant capacity or defense
Superoxide dismutase SOD Total glutathione Ferric Reducing Assay of Plasma FRAP Markers of intervention compliance
Vitamins A E C All the biochemical investigations will be done at baseline 1 and 6 months of intervention
All the samples will be light protected and purged with nitrogen to retard deterioration from oxidation of substrates during storage
Statistics Descriptive statistics ie mean standard deviation and frequency distribution will be calculated for each variable in the study To compare the two groups Student t test quantitative and chi square test qualitative wherever applicable will be applied To see trend within the variable 2-way analysis of variance parametric as well as non-parametric whichever is applicable will be done post-hoc analysis P value 005 will be considered as statistical significant Statistic software SPSS 75 for Windows will be used for statistical analysis
Study Outcome Primary Outcome
1 Reduction in the number of painful days per month due to chronic pancreatitis
Secondary Outcome
1 Decrease in no of severe attacks requiring hospitalization
2 Percentage of patients who are pain-free
3 Increase in markers of antioxidant defense in the intervention group compared to placebo group and decrease in oxidative stress parameters in patients after intervention compared to placebo
References
1 Pitchumoni CS Mohan AT Pancreatic stones Gastroenterol Clin North Amer 1990 19 873-893
2 Walling MA Xenobiotic metabolism oxidant stress and chronic pancreatitis Focus on glutathione Digestion 59 Suppl4 13-24 1998
3 Lin Y Tamakoshi A et al 2000 Cigarette smoke as a risk factor for chronic pancreatitis A case control study in Japan Pancreas 21 2 109-114
4 Uden S Schofield D Miller PF Day JP Bottiglier T and Braganza JM 1992 Aliment Pharmacol Ther 6 229-240
5 Braganza JM A framework for etiogenesis of chronic pancreatitis Digestion 1998 59 suppl 4 1-12
Many recent studies have emphasized a role for Reactive Oxygen Radicals ROR in the development of oxidative stress and hence inflammation in the pathogenesis of chronic pancreatitis Increased oxidative stress probably results from increased exposure to xenobiotics Xenobiotics are chemical substances present in the environment to which human beings are constantly exposed It is conceivable that many of these xenobiotics are metabolized in pancreas that contains cytochrome P450 CYP450 enzymatic system The metabolism of xenobiotics occurs through two phases Phase I and Phase II Phase I metabolism may result in bioactivation of the xenobiotics in turn activating CYP system Phase II involves attachment of biotransformed compound to a biological molecule that makes it more polar and thus easier to excrete The metabolism of xenobiotics places an oxidative stress and can overwhelm the natural antioxidant defense of the body The resultant production of the free radicals may play an important role in the pathogenesis of CP 2 Over induction of this enzyme can cause increased utilization of glutathione GSH which causes irreversible loss of glutathione Moreover glutathione serves as a reservoir for cysteinecystine required for disulphide synthesis for pancreatic digestive proteins This further aggravates the situation Three types of cytochrome enzymes are induced through xenobiotics CYP2E1 has been specifically examined in the context of liver injury CYP1A metabolizes smoke constituents and potent carcinogens such as benzoapyrene Cytochrome 3A is inducible by reactive oxygen species generated from aflatoxin B1 Alcohol nicotine from cigarette smoke and other forms of tobacco consumption and industrial pollutants all are considered as xenobiotics and overwhelm the detoxification capacity of cytochrome CYP450 system 3 The CYP induction increases heme and heme-oxygenase thus buttressing the antioxidant defenses The free radical peroxidation products may act as second messengers and block exocytosis leading to increased autophagy and crinophagy thus diverting the pancreatic enzymes into interstitium This leads to degranulation of mast cells inducing inflammation mediated by chemotaxis The synthesis of enzyme proteins in pancreas also produces H2O2 which also induces free radical production Furthermore the depressed methionine trans-sulphuration pathway induces CYP as well The free radicals generated from all these processes induce oxidative stress which is implicated in damage to cell membranes due to lipid peroxidation Above all if the antioxidant levels of an individual are may be low due to either low intake or depletion during oxidative stress Some studies also indicate that free radicals cause disintegration of antioxidative enzymes if over exposed to them
However the role of oxidative stress still not fully explained in that whether the oxidative stress is the cause of chronic pancreatitis or a consequence of it This can be established by two observations 1 If the oxidative stress is noted before the onset of disease and 2 If the disease symptoms are relieved by supplementation with antioxidants Patients with alcoholic pancreatitis have been shown to have an increased oxidative stress Supplementation with antioxidants hence decreases the production of such free radicals and may be beneficial to patients with CP 4
A study by Braganza et al has shown that CP involves oxidative stress in-patients with CP 5 This was the first study to indicate the role of free radicals in the pathogenesis of chronic pancreatitis However the mechanism by which it occurs is still unclear The preliminary studies show that malondialdehyde MDA a marker of peroxidation secondary to oxidative stress increases during CP
In the present proposed study the aim is to find out if there is increased oxidative stress in patients with CP and if supplementation with antioxidants relieves pain in them in order to establish a relationship between oxidant stress and pathophysiology of chronic pancreatitis
Objectives
1 To evaluate the effect of antioxidant supplementation given daily on pain relief in chronic pancreatitis during the 6 months of therapy as compared to a placebo
2 To assess the improvement in oxidative stress and antioxidant profile in these patients during 6 months of antioxidant supplementation by measuring markers of oxidative stress and blood antioxidant levels
Material and methods Study Design Double blind randomized controlled trial Patients All consecutive patients with chronic pancreatitis attending the pancreas clinic at AIIMS will be included in the study as per the inclusion criteria The diagnosis of CP will be made if there is evidence of CP on imaging studies including plain film of the abdomen Ultrasonography Computerized tomography CT scan endoscopic retrograde cholangiopancreatography ERCP and magnetic resonance imaging MRI scan Also hematological tests biochemical investigations will be done as part of diagnostic work-up
All patients will undergo detailed clinical evaluation including detailed family history of pancreatic diseases and diabetes The WHO criteria will be used to diagnose diabetes The patients will also be inquired about their dietary history and addiction to tobacco or alcohol Patients will be explained the purpose of study clearly and consent forms will be duly signed by them The patients will be regularly followed up in pancreas clinic at All India Institute of Medical Sciences New Delhi All the patients will be treated in the standard manner including medical endoscopic and surgical treatment as and when indicated
Inclusion criteria
CP with significant pain ie at least one episode of pain in a month requiring oral analgesic or one episode of severe pain in last three months requiring hospitalization
Sample size calculation Sample size is calculated on the basis of probability sampling methods For 80 power at a significance level of 5 a 005 a sample size of 100 in each arm would be required
Randomization and blinding Randomization of treatment allocation largely ensures unbiased treatment comparison A simple randomization scheme for treatment allocation will be done using a table of random numbers by a Statistician Epidemiologist not associated with conduct of the study Heshe will label the boxes of treatment with individual patient numbers from 1-200 according to the randomization scheme This person will keep the assignment code at a safe place the code will be available to the investigator only at the end of the trial These will be serially opened as new patients are recruited into the study Double blinding will be done to ensure minimum bias ie blinding of researcher and clinician attending patients to the randomization process so that allocation and outcome evaluation are not affected and blinding of patients to the identity of the drug or intervention they are receiving The inert placebo which will be identical to the active drug in packaging appearance and schedule of administration
Intervention One group will be given antioxidant supplementation and the other group will be placebo The antioxidant intervention will be daily doses of 600 mg organic selenium 054 g vitamin C 9000 IU B-carotene 270 IU vitamin E and 2 g methionine Both the groups will be supplemented with the pancreatic enzymes The enzyme will be administered as capsules each containing 10000 units Three capsules 30000 units will be required per meal thereby making it to 90000 units per day
Follow up assessment during study period
Clinical
Assessment of painful days and requirement of oral IV analgesic or hospitalization in a month will be done The patients will be provided with a pain diary so as to get the correct data
Any other symptoms either due to primary disease ie CP or considered due to the intervention will be duly recorded
Pain assessment and clinical examination will be done at each visit of patient to the clinic while USG ERCP CT or X-ray will be done as and when required
Markers of oxidative stress
MDA Marker of antioxidant capacity or defense
Superoxide dismutase SOD Total glutathione Ferric Reducing Assay of Plasma FRAP Markers of intervention compliance
Vitamins A E C All the biochemical investigations will be done at baseline 1 and 6 months of intervention
All the samples will be light protected and purged with nitrogen to retard deterioration from oxidation of substrates during storage
Statistics Descriptive statistics ie mean standard deviation and frequency distribution will be calculated for each variable in the study To compare the two groups Student t test quantitative and chi square test qualitative wherever applicable will be applied To see trend within the variable 2-way analysis of variance parametric as well as non-parametric whichever is applicable will be done post-hoc analysis P value 005 will be considered as statistical significant Statistic software SPSS 75 for Windows will be used for statistical analysis
Study Outcome Primary Outcome
1 Reduction in the number of painful days per month due to chronic pancreatitis
Secondary Outcome
1 Decrease in no of severe attacks requiring hospitalization
2 Percentage of patients who are pain-free
3 Increase in markers of antioxidant defense in the intervention group compared to placebo group and decrease in oxidative stress parameters in patients after intervention compared to placebo
References
1 Pitchumoni CS Mohan AT Pancreatic stones Gastroenterol Clin North Amer 1990 19 873-893
2 Walling MA Xenobiotic metabolism oxidant stress and chronic pancreatitis Focus on glutathione Digestion 59 Suppl4 13-24 1998
3 Lin Y Tamakoshi A et al 2000 Cigarette smoke as a risk factor for chronic pancreatitis A case control study in Japan Pancreas 21 2 109-114
4 Uden S Schofield D Miller PF Day JP Bottiglier T and Braganza JM 1992 Aliment Pharmacol Ther 6 229-240
5 Braganza JM A framework for etiogenesis of chronic pancreatitis Digestion 1998 59 suppl 4 1-12
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