Chronic Pancreatitis. Effect of Pioglitazone on Endocrine Function, Exocrine Function & Structure, Pain & Life Quality

Study Overview
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Brief Summary
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The purpose of this study is to determine if study drug (Pioglitazone) treatment will improve pre-diabetes (insulin resistance) or ealy diabetes and improve clinical symptoms (pain) or laboratory evidence of chronic pancreatitis. The goal of the investigators is to gather information from this study to help gain understanding of a potential therapy for chronic pancreatitis.

Detailed Description
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The pancreas is a digestive organ that secretes insulin (and other hormones) into the blood for regulating blood sugar (glucose) and digestive enzymes into the intestine for digesting and absorbing nutrients consumed in meals. Chronic pancreatitis is a progressive clinical disease of the pancreas, associated with swelling (inflammation), scarring (fibrosis) and loss of normal functioning tissue. Patients develop diabetes mellitus (elevated blood sugar), malabsorption of nutrients, weight loss and pain. Presently chronic pancreatitis is considered an irreversible condition because the mechanisms responsible for chronic pancreatitis are poorly understood and no therapy is proven. However, recent studies provide important clues that oral medications (Thiazolidinediones) used to treat diabetes mellitus might improve or reverse features of chronic pancreatitis, including elevated sugar or diabetes, reduced secretion of digestive enzymes, and pancreatic swelling and scarring. Note: Takeda Pharmaceuticals North America (TPNA) provided pioglitazone and placebo pills with identically appearance until June 28, 2010, approximately the middle of the study.

Official Title
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Phase II Study of Chronic Pancreatitis and the Effect of Pioglitazone on Endocrine Function, Exocrine Function & Structure, Pain & Life Quality

Conditions
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Chronic Pancreatitis, Insulin Resistance, Normal or Mildly Abnormal Stool Fat Levels

Intervention / Treatment
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* Drug: Pioglitazone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Insulin resistance or mild diabetes mellitus Symptoms of abdominal pain Xray test showing damage to the pancreas Normal or mildly abnormal stool fat levels Exclusion Criteria: Mentally disabled patients Women who are planning pregnancy, pregnant or lactating/nursing Chronic pancreatitis is due to other specific conditions Autosomal dominant pancreatitis Classic cystic fibrosis with lung involvement Autoimmune pancreatitis Pancreatic cancer Biliary obstruction (non-pancreatic cause) Abdominal trauma Hypercalcemia Hypertriglyceridemia Surgical resection of the head of the pancreas Alcohol consumption within prior 2 months Specific medical conditions Gastric surgery Celiac sprue Crohns disease Heart failure Kidney failure Cirrhosis or liver disease Osteoporosis Blood clotting disorder Visual problems Low albumin Low BMI Specific medications *Diabetes drug treatment is allowed except for short-acting insulin, long-acting insule more than 15 units daily, pioglitazone, rosiglitazone, orlistat, acarbose, miglitol or voglibose.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pioglitazone<br>30 mg pioglitazone (Actos) tablet taken once daily for 48 weeks. | Drug: Pioglitazone<br>* Participants randomized to pioglitazone receive 30 mg taken once daily for 48 weeks.<br>* Other names: Actos;|
| Placebo Comparator: sugar pill (placebo)<br>1 sugar pill (placebo) taken once daily for 48 weeks. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose Tolerance at 24 Weeks | Normal = normal plasma glucose and normal glucose tolerance (OGTT). Impaired category includes all non-diabetic participants with either a) Impaired fasting glucose = fasting plasma glucose >110 mg/dl and <126 mg/dl; or b) Impaired glucose intolerance = 2-hour plasma glucose (OGTT) >140 mg/dl and <200 mg/dl. Diabetes = fasting plasma glucose >126 mg/dl 2-hour (OGTT) plasma glucose >200 mg/dl. | 24 weeks | 
| Glucose Tolerance at 48 Weeks | Normal = normal plasma glucose and normal glucose tolerance (OGTT). Impaired category includes all non-diabetic participants with either a) Impaired fasting glucose = fasting plasma glucose >110 mg/dl and <126 mg/dl; or b) Impaired glucose intolerance = 2-hour plasma glucose (OGTT) >140 mg/dl and <200 mg/dl. Diabetes = fasting plasma glucose >126 mg/dl 2-hour (OGTT) plasma glucose >200 mg/dl. | 48 weeks | 
| Insulin Sensitivity Index for Glycemia at 24 Weeks | Insulin Sensitivity = Index for Glycemia (ISI gly) = 2 / ([INSp x GLYp] + 1). GLYp = Glycemic 0-2 hr area = sum of normalized (based on institutional values) 0 & 2 hr glucose. INSp = Insulinemic 0-2 hr area = sum of normalized (based on institutional values) 0 & 2 hr insulin. | 24 weeks | 
| Insulin Sensitivity Index for Glycemia at 48 Weeks. | Insulin Sensitivity = Index for Glycemia (ISI gly) = 2 / ([INSp x GLYp] + 1). GLYp = Glycemic 0-2 hr area = sum of normalized (based on institutional values) 0 & 2 hr glucose. INSp = Insulinemic 0-2 hr area = sum of normalized (based on institutional values) 0 & 2 hr insulin. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Beta-cell Function | Homeostasis model assessment (HOMA 2) values generated using calculator at https://www.dtu.ox.ac.uk/homacalculator/ | 24, 48 weeks | 
| Insulin Resistance at 24 and 48 Weeks | Homeostasis model assessment (HOMA 2) values generated using calculator at https://www.dtu.ox.ac.uk/homacalculator/ | 24, 48 weeks | 
| Pancreas Ultrasound Appearance | Mean score on a scale of 0 - 10: count of positive Endoscopic Ultrasound(EUS) features: Parenchymal Features - Only Body and Tail Calcification (>3 hyperechoic foci >2 mm length & width with shadowing) Lobularity (>3 well-circumscribed, >5mm structures) Hyperechoic stranding (>3 hyperechoic lines >3mm in length, seen in > 2 different directions with respect to the imaged plane Parenchymal Features - Head, Body and Tail Cyst (>2 mm diameter anechoic round or oval structure) Hyperechoic foci (>3 reflectors, >3 mm long & wide, no shadowing) Ductal Features - Only Body and Tail Side Branch Dilation (>3 tubular, anechoic, >1 mm structures,Main pancreatic duct (MPD) connects) Irregular MPD contour (uneven and ectatic in its course) Hyperechoic MPD margin (hyperechoic in >50% of MPD) Dilation MPD (>3.5 mm body, >1.5 mm tail*) Ductal Features - Head, Body and Tail MPD calculi (hyperechoic foci with shadowing contained within MPD) | 48 weeks | 
| Quality of Life | The SF36 (Short Form with 36 questions) QoL scoring system has 36 questions, comprising two main dimensions (Physical Health and Mental Health), further divided by 8 independent scales (Physical functioning, Role-Physical, Bodily pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health). The scales for general health and mental health overlap components of both the two main dimensions (Physical Health and Mental Health). The scales, including the total score and dimensions are scored as a number between 0 and 100, where 0 represents lower limits of functioning and 100 is best functioning possible. Data reported is the average total score. | 24, 48 weeks | 
| Number and Percentage of Participants With Steatorrhea | Participants were counted as having steatorrhea if they had either a) positive qualitative fecal fat; or b) 72 hour quantitative fecal fat result with >7g fat in stool in 24hours | 48 weeks | 
| Pain | Pain is reported as the mean of four Visual analogue scales, ranging from 0 points (no pain) to 100 points (severe pain) What is your pain right now? What is your typical or average pain in the last 12 weeks? What is your pain level at its best in the last 12 weeks (how close to 0 does your pain get at its best)? What is your pain level at its worst in the last 12 weeks (how close to 0 does your pain get at its worst)? | 12, 24, 36, 48 and 60 weeks | 
| Body Mass Index (BMI) | standard BMI defined as mass in kilograms divided by height in meters squared | 12, 24, 36, 48 and 60 weeks | 
| Hospitalizations | Mean number of hospitalizations within the prior 12 weeks | 12, 24, 36, 48 and 60 weeks | 
| Missed Work | Mean days of missed work reported by participants in response to question asking about missed work since the last visit (12 weeks) | 12, 24, 36, 48, 60 weeks | 
| Insulin Sensitivity (%S) | Homeostasis model assessment (HOMA 2) values generated using calculator at https://www.dtu.ox.ac.uk/homacalculator/; | 24 and 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic pancreatitis, Insulin resistance