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

Phase 2

Completed

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

Interventions: Drug: Placebo
Drug: Pioglitazone

Registration Number: NCT00782795

Lead Sponsor: University of Michigan

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 64

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
sugar pill (placebo)	Placebo	1 sugar pill (placebo) taken once daily for 48 weeks.
Pioglitazone	Pioglitazone	30 mg pioglitazone (Actos) tablet taken once daily for 48 weeks.

Primary Outcome Measures

Name	Time	Method
Insulin Sensitivity Index for Glycemia at 48 Weeks.	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.
Glucose Tolerance at 48 Weeks	48 weeks	1. Normal = normal plasma glucose and normal glucose tolerance (OGTT). 2. 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. 3. Diabetes = fasting plasma glucose \>126 mg/dl 2-hour (OGTT) plasma glucose \>200 mg/dl.
Glucose Tolerance at 24 Weeks	24 weeks	1. Normal = normal plasma glucose and normal glucose tolerance (OGTT). 2. 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. 3. Diabetes = fasting plasma glucose \>126 mg/dl 2-hour (OGTT) plasma glucose \>200 mg/dl.
Insulin Sensitivity Index for Glycemia at 24 Weeks	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.

Secondary Outcome Measures

Name	Time	Method
Beta-cell Function	24, 48 weeks	Homeostasis model assessment (HOMA 2) values generated using calculator at https://www.dtu.ox.ac.uk/homacalculator/
Hospitalizations	12, 24, 36, 48 and 60 weeks	Mean number of hospitalizations within the prior 12 weeks
Insulin Resistance at 24 and 48 Weeks	24, 48 weeks	Homeostasis model assessment (HOMA 2) values generated using calculator at https://www.dtu.ox.ac.uk/homacalculator/
Insulin Sensitivity (%S)	24 and 48 weeks	Homeostasis model assessment (HOMA 2) values generated using calculator at https://www.dtu.ox.ac.uk/homacalculator/;
Pancreas Ultrasound Appearance	48 weeks	Mean score on a scale of 0 - 10: count of positive Endoscopic Ultrasound(EUS) features: Parenchymal Features - Only Body and Tail 1. Calcification (\>3 hyperechoic foci \>2 mm length \& width with shadowing) 2. Lobularity (\>3 well-circumscribed, \>5mm structures) 3. 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 4. Cyst (\>2 mm diameter anechoic round or oval structure) 5. Hyperechoic foci (\>3 reflectors, \>3 mm long \& wide, no shadowing) Ductal Features - Only Body and Tail 6. Side Branch Dilation (\>3 tubular, anechoic, \>1 mm structures,Main pancreatic duct (MPD) connects) 7. Irregular MPD contour (uneven and ectatic in its course) 8. Hyperechoic MPD margin (hyperechoic in \>50% of MPD) 9. Dilation MPD (\>3.5 mm body, \>1.5 mm tail\*) Ductal Features - Head, Body and Tail 10. MPD calculi (hyperechoic foci with shadowing contained within MPD)
Number and Percentage of Participants With Steatorrhea	48 weeks	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
Body Mass Index (BMI)	12, 24, 36, 48 and 60 weeks	standard BMI defined as mass in kilograms divided by height in meters squared
Quality of Life	24, 48 weeks	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.
Pain	12, 24, 36, 48 and 60 weeks	Pain is reported as the mean of four Visual analogue scales, ranging from 0 points (no pain) to 100 points (severe pain) 1. What is your pain right now? 2. What is your typical or average pain in the last 12 weeks? 3. What is your pain level at its best in the last 12 weeks (how close to "0" does your pain get at its best)? 4. What is your pain level at its worst in the last 12 weeks (how close to "0" does your pain get at its worst)?
Missed Work	12, 24, 36, 48, 60 weeks	Mean days of missed work reported by participants in response to question asking about missed work since the last visit (12 weeks)