Chronic Pancreatitis
Conditions
Keywords
Chronic Pancreatitis, Pancreatic Function, Reduced Exocrine Pancreatic Function, Pancreatic Insufficiency
Brief summary
The objective of this study is to evaluate the malabsorption blood test (MBT), stool coefficient of fat absorption (CFA) and stool bomb calorimetry (BC) methods as potential screening or diagnostic tests for reduced exocrine pancreatic function or pancreatic insufficiency (RPF/PI). A further objective is to determine the test responses before and after pancreatic enzyme medication administration (Creon36™) in the patients with chronic pancreatitis (CP).
Detailed description
Reduced exocrine pancreatic function or pancreatic insufficiency (RPF/PI) contributes to poor clinical outcome in a number of diseases and conditions. The incidence, mechanism and substantial adverse clinical outcomes of pancreatic insufficiency (PI) are well known in patients with cystic fibrosis (CF), and the life sustaining role of pancreatic enzyme medication in CF care is well established. Much less is known about the incidence and impact of RPF/PI in patients with chronic pancreatitis (CP). Reliable non-invasive screening or diagnostic tests with acceptable patient burden are not available for RPF/PI. This is a cohort study of subjects with CP who will be evaluated before and after pancreatic enzyme medication (Creon36™) administration. A cohort of healthy subjects will serve as a comparison group and will be evaluated only once. Subjects with CP will receive Creon36™, a pancreatic enzyme medication, and fat and energy absorption will be evaluated using three methods: MBT, CFA, and BC before and after administration of Creon36™. Many patients with CP are at risk for RPF/PI yet they rarely undergo diagnostic testing. Pancreatic enzyme medication will likely improve clinical outcomes and quality of life in some of those with RPF/PI. A cohort of healthy volunteers will be evaluated with the three methods to provide essential comparison data to optimize the understanding and interpretation of the findings from the three methods and the RPF/PI cohort with CP. There will be no intervention for the healthy cohort.
Interventions
DRUGCreon36™
Creon36™ delayed-release capsules, a pancreatic enzyme preparation, is an FDA approved medication. Subjects with chronic pancreatitis (CP) will take Creon36™ for nine days, at a daily dose of 72,000 lipase units per meal (two capsules) and 36,000 units per snack (one capsule), with each capsule containing 36,000 lipase units. Subjects will take Creon36™ for three days prior to Visit 2, the day of Visit 2 and then for five days after the visit until they have completed stool collections.
Sponsors
AbbVie
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Phoenix Indian Medical Center
Children's Hospital of Philadelphia
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
(CP): * Chronic pancreatitis diagnosis by gastroenterologist. Participants with CP will be characterized based on the TIGAR-O (toxic, genetic, autoimmune, recurrent, obstructive) etiology system, on pancreatic morphology (Cambridge criteria) when available, and on physiological state (exocrine and endocrine function) as recommended by the recent American Pancreatic Association Practice Guidelines4. * Age 30-70 years old * Evidence of at-risk for malabsorption including: 1) history of use of and response to pancreatic enzyme medication; 2) history of unintentional weight loss; 3) history of increased stools per week or fatty stools; and/or 4) other clinical signs or symptoms suggestive of fat malabsorption * In usual state of health for past two weeks including no change in medications * Able to consume a moderate fat diet for stool evaluations * Able to participate in the study for about four weeks with two study visits Inclusion Criteria (Healthy Volunteers): * Age 30-70 years old * No known chronic disease that would affect dietary intake or fat absorption * In usual state of health for past two weeks, with stable medications, diet and weight * BMI from 18-29 * Able to consume a moderate fat diet for stool evaluations * Able to participate in the study for about one week with one study visit
Exclusion criteria
(CP): * Evidence of normal fat absorption in medical record * Medications that alter fat absorption (i.e. orlistat, other weight loss medications, ursodeoxycholic acid) * Allergy to pork products * History of intestinal blockage or fibrosing colonopathy * History of gout, kidney disease, or high blood uric acid (hyperuricemia) * Pregnancy or breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Malabsorption Blood Test: Difference in Mean HA AUC Between Groups: Subjects With CP Compared to Healthy Subjects | 8 hours | The fat absorption pattern in CP subjects will be compared with healthy controls. Mean HA AUC will be calculated for the CP subjects and the healthy controls and compared to determine whether there is a difference in the fat absorption between the two groups. |
| Coefficient of Fat Absorption: Difference in Mean % Dietary Fat Absorption Between Groups: Subjects With CP Compared to Healthy Subjects | 72 hours | The fat absorption pattern in CP subjects will be compared with healthy controls. Mean coefficient of fat absorption (% dietary fat absorbed) will be calculated for the CP subjects and the healthy controls and compared to determine whether there is a difference in the fat absorption between the two groups. |
| Bomb Calorimetry: Difference in Mean Stool Energy Loss Between Groups: Subjects With CP Compared to Healthy Subjects | 72 hours | The energy absorption pattern in CP subjects will be compared with healthy controls. Mean calories per gram of stool will be calculated for the CP subjects and the healthy controls and compared to determine whether there is a difference in the stool energy loss between the two groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bomb Calorimetry: Difference in Mean Energy Loss Between Groups: Subjects With CP Before and After Creon36™ | 72 hours | The energy absorption pattern in CP subjects before and after treatment with Creon36™ will be compared. Calories per gram of stool will be calculated for the CP subjects before and after the medication and compared to determine whether there is a difference in the stool energy loss in the same subjects between the two time points. |
| Malabsorption Blood Test: Difference in Mean HA AUC Between Groups: Subjects With CP Before and After Creon36™ | 8 hours | The fat absorption pattern in CP subjects before and after treatment with Creon36™ will be compared. Mean HA AUC will be calculated for the CP subjects before and after the medication and compared to determine whether there is a difference in the fat absorption in the same subjects between the two time points. |
| Coefficient of Fat Absorption: Difference in Mean % Dietary Fat Absorption Between Groups: Subjects With CP Before and After Creon36™ | 72 hours | The fat absorption pattern in CP subjects before and after treatment with Creon36™ will be compared. The % of dietary fat absorbed will be calculated for the CP subjects before and after the medication and compared to determine whether there is a difference in the fat absorption in the same subjects between the two time points. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from academic medical centers in the Philadelphia region between August 2016 and November 2017. For the CP cohort, subjects were diagnosed with CP by a gastroenterologist based on criteria as recommended by the American Pancreatic Association (APA) Practice Guidelines.
Pre-assignment details
There were no events between enrollment and assignment in either group. All subjects enrolled were assigned to the appropriate arm.
Participants by arm
| Arm | Count |
|---|---|
| Chronic Pancreatitis (CP) Subjects CP subjects will fast for 12 hours prior to the malabsorption blood test (MBT) testing, consume the MBT breakfast meal following this fast, have blood drawn (MBT, vitamins A, D, E and K, zinc, selenium, and prealbumin) prior to MBT breakfast consumption and each hour for 8 hours after consumption, consume a low-fat study lunch, eat a moderate fat diet for 4 days during home diet and stool collection, maintain a 3-day food record, collect stool over 72 hours, have body size and composition assessment, complete quality of life questionnaires, home environment and health questionnaires, and adverse events diary. This visit will be repeated after initiation of Creon36™. | 24 |
| Healthy Controls Healthy controls will fast for 12 hours prior to the malabsorption blood test (MBT) testing, consume the MBT breakfast meal following this fast, have blood drawn (MBT, vitamins A, D, E and K, zinc, selenium, and prealbumin) prior to MBT breakfast consumption and each hour for 8 hours after consumption, consume a low-fat study lunch, eat a moderate fat diet for 4 days during home diet and stool collection, maintain a 3-day food record, collect stool over 72 hours, have body size and composition assessment, complete quality of life questionnaires, home environment and health questionnaires, and adverse events diary. Controls will only have 1 study visit and receive no intervention. | 24 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Assessment on PERT - CP Subj - 16 Days | Adverse Event | 1 | 0 |
| Assessment on PERT - CP Subj - 16 Days | Lost to Follow-up | 1 | 0 |
| Assessment on PERT - CP Subj - 16 Days | Unable to complete study procedures | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Healthy Controls | Chronic Pancreatitis (CP) Subjects |
|---|---|---|---|
| Age, Continuous | 47.1 years STANDARD_DEVIATION 10.4 | 43.4 years STANDARD_DEVIATION 10 | 50.7 years STANDARD_DEVIATION 9.6 |
| BMI | 24.7 kg/m^2 STANDARD_DEVIATION 4 | 25.6 kg/m^2 STANDARD_DEVIATION 4.4 | 23.9 kg/m^2 STANDARD_DEVIATION 3.6 |
| Bomb Calorimetry | 5463 cal/g stool STANDARD_DEVIATION 635 | 5171 cal/g stool STANDARD_DEVIATION 393 | 5728 cal/g stool STANDARD_DEVIATION 717 |
| Coefficient of Fat Absorption | 93.2 % of dietary fat absorbed STANDARD_DEVIATION 9.2 | 95.4 % of dietary fat absorbed STANDARD_DEVIATION 9.3 | 90.9 % of dietary fat absorbed STANDARD_DEVIATION 12.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 21 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Fecal Elastase | 169 ug/g stool STANDARD_DEVIATION 172 | — | 169 ug/g stool STANDARD_DEVIATION 172 |
| HA AUC | 12.7 mg*h/dL STANDARD_DEVIATION 9.1 | 17.7 mg*h/dL STANDARD_DEVIATION 10.3 | 8.3 mg*h/dL STANDARD_DEVIATION 4.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants | 9 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 12 Participants | 13 Participants |
| Sex: Female, Male Female | 26 Participants | 15 Participants | 11 Participants |
| Sex: Female, Male Male | 20 Participants | 7 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 7 / 24 | 3 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 |
Outcome results
Primary
Bomb Calorimetry: Difference in Mean Stool Energy Loss Between Groups: Subjects With CP Compared to Healthy Subjects
The energy absorption pattern in CP subjects will be compared with healthy controls. Mean calories per gram of stool will be calculated for the CP subjects and the healthy controls and compared to determine whether there is a difference in the stool energy loss between the two groups.
Time frame: 72 hours
Population: Three subjects with CP were excluded; two did not consume enough fat for a valid test, one subject did not have adequate stool for analysis. Of the 24 healthy controls, two were excluded from the analysis due to undisclosed chronic disease, one did not provide adequate stool for analysis, and two results failed internal the validation protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pancreatitis (CP) Subjects | Bomb Calorimetry: Difference in Mean Stool Energy Loss Between Groups: Subjects With CP Compared to Healthy Subjects | 5728 calories/gram of stool | Standard Deviation 717 |
| Healthy Controls | Bomb Calorimetry: Difference in Mean Stool Energy Loss Between Groups: Subjects With CP Compared to Healthy Subjects | 5171 calories/gram of stool | Standard Deviation 393 |
p-value: <0.01t-test, 2 sided
Primary
Coefficient of Fat Absorption: Difference in Mean % Dietary Fat Absorption Between Groups: Subjects With CP Compared to Healthy Subjects
The fat absorption pattern in CP subjects will be compared with healthy controls. Mean coefficient of fat absorption (% dietary fat absorbed) will be calculated for the CP subjects and the healthy controls and compared to determine whether there is a difference in the fat absorption between the two groups.
Time frame: 72 hours
Population: Four subjects with CP were excluded; two did not consume enough fat for a valid test, one subject did not have adequate stool for analysis, and one subject was excluded due to an error in the lab processing stool. Of the 24 healthy controls, two were excluded from the analysis due to undisclosed chronic disease.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pancreatitis (CP) Subjects | Coefficient of Fat Absorption: Difference in Mean % Dietary Fat Absorption Between Groups: Subjects With CP Compared to Healthy Subjects | 90.9 % of dietary fat intake | Standard Deviation 12.8 |
| Healthy Controls | Coefficient of Fat Absorption: Difference in Mean % Dietary Fat Absorption Between Groups: Subjects With CP Compared to Healthy Subjects | 95.4 % of dietary fat intake | Standard Deviation 9.3 |
p-value: >0.05t-test, 2 sided
Primary
Malabsorption Blood Test: Difference in Mean HA AUC Between Groups: Subjects With CP Compared to Healthy Subjects
The fat absorption pattern in CP subjects will be compared with healthy controls. Mean HA AUC will be calculated for the CP subjects and the healthy controls and compared to determine whether there is a difference in the fat absorption between the two groups.
Time frame: 8 hours
Population: Two subjects with CP were excluded; one did not complete the study meal for a valid test, and one was a significant outlier calling into question the validity of the test. Of the 24 healthy controls, two were excluded from the study due to undisclosed chronic disease, and two subjects did not complete the study meal for a valid test.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pancreatitis (CP) Subjects | Malabsorption Blood Test: Difference in Mean HA AUC Between Groups: Subjects With CP Compared to Healthy Subjects | 8.3 mg*h/dL | Standard Deviation 4.3 |
| Healthy Controls | Malabsorption Blood Test: Difference in Mean HA AUC Between Groups: Subjects With CP Compared to Healthy Subjects | 17.7 mg*h/dL | Standard Deviation 10.3 |
p-value: <0.001t-test, 2 sided
Secondary
Bomb Calorimetry: Difference in Mean Energy Loss Between Groups: Subjects With CP Before and After Creon36™
The energy absorption pattern in CP subjects before and after treatment with Creon36™ will be compared. Calories per gram of stool will be calculated for the CP subjects before and after the medication and compared to determine whether there is a difference in the stool energy loss in the same subjects between the two time points.
Time frame: 72 hours
Population: Two subjects were excluded from follow-up due to inadequate stool provision. Two subjects were excluded due to failing the internal validation protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pancreatitis (CP) Subjects | Bomb Calorimetry: Difference in Mean Energy Loss Between Groups: Subjects With CP Before and After Creon36™ | 5702 calories/gram of stool | Standard Deviation 691 |
p-value: >0.05t-test, 2 sided
Secondary
Coefficient of Fat Absorption: Difference in Mean % Dietary Fat Absorption Between Groups: Subjects With CP Before and After Creon36™
The fat absorption pattern in CP subjects before and after treatment with Creon36™ will be compared. The % of dietary fat absorbed will be calculated for the CP subjects before and after the medication and compared to determine whether there is a difference in the fat absorption in the same subjects between the two time points.
Time frame: 72 hours
Population: Two subjects were excluded from baseline due to inadequate dietary fat intake for a valid test, and one was excluded for inadequate stool provision. Three subjects were excluded at follow up for inadequate dietary information and stool provision. One subject was excluded from follow up due to lab error.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pancreatitis (CP) Subjects | Coefficient of Fat Absorption: Difference in Mean % Dietary Fat Absorption Between Groups: Subjects With CP Before and After Creon36™ | 93 % of dietary fat intake | Standard Deviation 8.8 |
p-value: >0.05t-test, 2 sided
Secondary
Malabsorption Blood Test: Difference in Mean HA AUC Between Groups: Subjects With CP Before and After Creon36™
The fat absorption pattern in CP subjects before and after treatment with Creon36™ will be compared. Mean HA AUC will be calculated for the CP subjects before and after the medication and compared to determine whether there is a difference in the fat absorption in the same subjects between the two time points.
Time frame: 8 hours
Population: For this paired analysis, twenty subjects had valid tests at both time points. Two subjects were excluded from baseline; one did not complete the study meal for a valid test, and one was a significant outlier calling into question the validity of the test. Two subjects were excluded from follow-up, as they did not complete the study meal or test.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pancreatitis (CP) Subjects | Malabsorption Blood Test: Difference in Mean HA AUC Between Groups: Subjects With CP Before and After Creon36™ | 9.4 mg*h/dL | Standard Deviation 4.2 |
p-value: <0.05t-test, 2 sided