Chronic Pancreatitis, Pancreatectomy, Pancreatic Exocrine Insufficiency
Conditions
Keywords
Chronic Pancreatitis, Pancreatectomy, Pancreatic Exocrine Insufficiency
Brief summary
This study assessed the effect of pancrelipase delayed release capsules on fat and nitrogen absorption in subjects with PEI due to Chronic Pancreatitis and Pancreatectomy. There was a run-in with a 5-day of single-blind placebo treatment, followed by a 7-day Double-blind period and a 6-month Open-Label Follow-up.
Interventions
DRUGPancrelipase delayed release capsule
24,000 unit capsule
DRUGPlacebo Comparator
Placebo
Sponsors
Solvay Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Pancreatic exocrine insufficiency has to be proven (in medical history) by the following criteria: * Direct or indirect pancreatic function test (except stool fat excretion) or Clinical signs of severe steatorrhoea that resolved upon administration of pancreatic supplementation. * Total stool fat \> 40 g over 4 days (using Van De Kamer method) * Proven chronic pancreatitis * Females of child-bearing potential must agree to continue using a medically acceptable method of birth control
Exclusion criteria
* Ileus or acute abdomen * Any type of malignancy involving the digestive tract in the last 5 years * Presence of pseudo-pancreatic cyst ≥ 4 * Continued excessive intake of alcohol or drug abuse * Known infection with HIV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Coefficient of Fat Absorption (CFA) (%) Between Baseline and End of Double-blind (DB) Period. | End of double-blind period (5-7 days) | The CFA is calculated from fat intake and fat excretion : 100\*\[fat intake-fat excretion\]/fat intake. Higher values indicated a better response. Change is calculated as (DB CFA-Baseline CFA). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of Coefficient of Nitrogen Absorption (CNA) (%) Between Baseline and End of Double-blind (DB) Period. | End of double-blind period (5-7 days) | The CNA is calculated from nitrogen intake and nitrogen excretion : 100\*\[nitrogen intake-nitrogen excretion\]/nitrogen intake. Higher values indicated a better response. Change is calculated as (DB CNA-Baseline CNA). |
| Change From Baseline of Stool Fat (g) Between Baseline and End of Double-blind (DB) Period. | End of double-blind period (5-7 days) | Total amount of fat excreted during the stool collection period. Lower values indicate a better response. Change was calculated as (DB Stool fat - Baseline stool fat). |
| Change From Baseline of Stool Nitrogen (g) Between Baseline and End of Double-blind (DB) Period. | End of double-period (5-7 days) | Total amount of nitrogen excreted during the stool collection period. Lower values indicate a better response. Change was calculated as (DB Stool nitrogen - Baseline stool nitrogen). |
| Abdominal Pain at the End of the Double-blind Period. | End of double-period (5-7 days) | 4- point ordinal scale on this symptom from 0 (No Abdominal pain) to 3 (Severe abdominal pain). |
| Stool Consistency at the End of the Double-blind Period | End of double-period (5-7 days) | 4- point ordinal scale on this symptom from 0 (Hard) to 3 (Watery). |
| Flatulence at the End of Double-blind Period | End of double-period (5-7 days) | 4- point ordinal scale on this symptom from 0 (None) to 3 (Severe). |
| Change of Stool Frequency Between Baseline and End of Double-blind (DB) Period | End of double-period (5-7 days) | Stool frequency is the average of the daily number of stools recorded during the treatment period. Lower values indicate a better response. Change was calculated as (DB stool frequency - Baseline Stool frequency). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change of Stool Frequency Between Original Baseline and End of Open-label Period (OL) | 27 weeks | Stool frequency is the average of the daily number of stools recorded during the OL period. Lower values indicate a better response. Change was calculated as (OL stool frequency - Baseline stool frequency). |
Countries
Bulgaria, Poland, Puerto Rico, Russia, Serbia, South Africa, Ukraine, United States
Participant flow
Recruitment details
Subjects were recruited in centers in Bulgaria, Poland, Russia, Serbia, Ukraine and US between April 2007 and August 2008. This report presents the double-blind (DB) period of the study as well as the Open Label (OL) results.
Pre-assignment details
There was a run-in with a 5-day of single-blind placebo treatment. One hundred and eighty subjects were consented and 179 entered the run-in. A total of 54 subjects were randomly allocated to treatment. Only two subjects did not complete the DB period of the treatment because of protocol violation. Fifty one patients entered the OL period.
Participants by arm
| Arm | Count |
|---|---|
| Pancrelipase (DB) Pancrelipase delayed release capsules given during the Double-Blind period | 24 |
| Placebo (DB) Placebo group given during the Double-Blind period | 28 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 1 |
Baseline characteristics
| Characteristic | Pancrelipase (DB) | Placebo (DB) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 27 Participants | 50 Participants |
| Age Continuous | 51.7 years STANDARD_DEVIATION 9.7 | 50.4 years STANDARD_DEVIATION 7.8 | 51.0 years STANDARD_DEVIATION 8.7 |
| Region of Enrollment Bulgaria | 5 participants | 6 participants | 11 participants |
| Region of Enrollment Poland | 7 participants | 7 participants | 14 participants |
| Region of Enrollment Russian Federation | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Serbia | 1 participants | 3 participants | 4 participants |
| Region of Enrollment Ukraine | 3 participants | 4 participants | 7 participants |
| Region of Enrollment United States | 6 participants | 6 participants | 12 participants |
| Sex: Female, Male Female | 6 Participants | 9 Participants | 15 Participants |
| Sex: Female, Male Male | 18 Participants | 19 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 24 | 2 / 28 | 4 / 51 |
| serious Total, serious adverse events | 0 / 24 | 0 / 28 | 7 / 51 |
Outcome results
Primary
Change of Coefficient of Fat Absorption (CFA) (%) Between Baseline and End of Double-blind (DB) Period.
The CFA is calculated from fat intake and fat excretion : 100\*\[fat intake-fat excretion\]/fat intake. Higher values indicated a better response. Change is calculated as (DB CFA-Baseline CFA).
Time frame: End of double-blind period (5-7 days)
Population: The analysis was done on the Full Analysis sample. Full Analysis Population consists of all subjects who were allocated to the treatment and had data for at least one post-baseline assessment of any efficacy measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pancrelipase (DB) | Change of Coefficient of Fat Absorption (CFA) (%) Between Baseline and End of Double-blind (DB) Period. | 31.93 Percentage | Standard Deviation 18.57 |
| Placebo (DB) | Change of Coefficient of Fat Absorption (CFA) (%) Between Baseline and End of Double-blind (DB) Period. | 8.72 Percentage | Standard Deviation 12.44 |
Comparison: The following null hypothesis was tested (μ0 and μ1 denote the treatment group means respectively in the placebo and pancrelipase delayed release capsules group): H0: μ0 = μ1 (i.e., placebo and pancrelipase delayed release capsules are equal). The hypothesis corresponded to the primary objective to show superior efficacy of pancrelipase delayed release capsules over placebo. A non-parametric ANCOVA was used because the necessary assumptions were not met for the parametric ANCOVA.p-value: <0.0001Non parametric ANCOVA
Secondary
Abdominal Pain at the End of the Double-blind Period.
4- point ordinal scale on this symptom from 0 (No Abdominal pain) to 3 (Severe abdominal pain).
Time frame: End of double-period (5-7 days)
Population: The analysis was done on the Full Analysis sample. Full Analysis Population consists of all subjects who were allocated to the treatment and had data for at least one post-baseline assessment of any efficacy measurement.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pancrelipase (DB) | Abdominal Pain at the End of the Double-blind Period. | 0 (None) | 12 Participants |
| Pancrelipase (DB) | Abdominal Pain at the End of the Double-blind Period. | 1 (Mild) | 7 Participants |
| Pancrelipase (DB) | Abdominal Pain at the End of the Double-blind Period. | 2 (Moderate) | 4 Participants |
| Pancrelipase (DB) | Abdominal Pain at the End of the Double-blind Period. | 3 (Severe) | 0 Participants |
| Placebo (DB) | Abdominal Pain at the End of the Double-blind Period. | 3 (Severe) | 1 Participants |
| Placebo (DB) | Abdominal Pain at the End of the Double-blind Period. | 0 (None) | 8 Participants |
| Placebo (DB) | Abdominal Pain at the End of the Double-blind Period. | 2 (Moderate) | 7 Participants |
| Placebo (DB) | Abdominal Pain at the End of the Double-blind Period. | 1 (Mild) | 12 Participants |
Secondary
Change From Baseline of Stool Fat (g) Between Baseline and End of Double-blind (DB) Period.
Total amount of fat excreted during the stool collection period. Lower values indicate a better response. Change was calculated as (DB Stool fat - Baseline stool fat).
Time frame: End of double-blind period (5-7 days)
Population: The analysis was done on the Full Analysis sample. Full Analysis Population consists of all subjects who were allocated to the treatment and had data for at least one post-baseline assessment of any efficacy measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pancrelipase (DB) | Change From Baseline of Stool Fat (g) Between Baseline and End of Double-blind (DB) Period. | -147.08 Grammes | Standard Error 12.71 |
| Placebo (DB) | Change From Baseline of Stool Fat (g) Between Baseline and End of Double-blind (DB) Period. | -34.62 Grammes | Standard Error 11.47 |
Comparison: The following null hypothesis was tested (μ0 and μ1 denote the treatment group means in the placebo and pancrelipase delayed release capsules group): H0: μ0 = μ1 (i.e., placebo and pancrelipase capsules are equal).~The hypothesis was to show superior efficacy of pancrelipase delayed release capsules over placebo.~For this secondary efficacy variable, an analysis of covariance (ANCOVA) model was assumed with the treatment group as a fixed factor and the Stool fat at baseline as a covariate.p-value: <0.000195% CI: [-147.04, -77.87]ANCOVA
Secondary
Change From Baseline of Stool Nitrogen (g) Between Baseline and End of Double-blind (DB) Period.
Total amount of nitrogen excreted during the stool collection period. Lower values indicate a better response. Change was calculated as (DB Stool nitrogen - Baseline stool nitrogen).
Time frame: End of double-period (5-7 days)
Population: The analysis was done on the Full Analysis sample. Full Analysis Population consists of all subjects who were allocated to the treatment and had data for at least one post-baseline assessment of any efficacy measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pancrelipase (DB) | Change From Baseline of Stool Nitrogen (g) Between Baseline and End of Double-blind (DB) Period. | -17.55 Grammes | Standard Error 2.06 |
| Placebo (DB) | Change From Baseline of Stool Nitrogen (g) Between Baseline and End of Double-blind (DB) Period. | -5.87 Grammes | Standard Error 1.85 |
Comparison: The following null hypothesis was tested (μ0 and μ1 denote the treatment group means in the placebo and pancrelipase delayed release capsules group): H0: μ0 = μ1 (i.e., placebo and pancrelipase capsules are equal).~The hypothesis was to show superior efficacy of pancrelipase delayed release capsules over placebo. For this secondary efficacy variable, an analysis of covariance (ANCOVA) model was assumed with the treatment group as a fixed factor and the Stool nitrogen at baseline as a covariate.p-value: <0.000195% CI: [-17.3, -6.06]ANCOVA
Secondary
Change of Coefficient of Nitrogen Absorption (CNA) (%) Between Baseline and End of Double-blind (DB) Period.
The CNA is calculated from nitrogen intake and nitrogen excretion : 100\*\[nitrogen intake-nitrogen excretion\]/nitrogen intake. Higher values indicated a better response. Change is calculated as (DB CNA-Baseline CNA).
Time frame: End of double-blind period (5-7 days)
Population: The analysis was done on the Full Analysis sample. Full Analysis Population consists of all subjects who were allocated to the treatment and had data for at least one post-baseline assessment of any efficacy measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pancrelipase (DB) | Change of Coefficient of Nitrogen Absorption (CNA) (%) Between Baseline and End of Double-blind (DB) Period. | 35.23 Percentage | Standard Deviation 29.05 |
| Placebo (DB) | Change of Coefficient of Nitrogen Absorption (CNA) (%) Between Baseline and End of Double-blind (DB) Period. | 8.85 Percentage | Standard Deviation 28.04 |
Comparison: The following null hypothesis was tested (μ0 and μ1 denote the treatment group means respectively in the placebo and pancrelipase delayed release capsules group): H0: μ0 = μ1 (i.e., placebo and pancrelipase delayed release capsules are equal). The hypothesis corresponded to the primary objective to show superior efficacy of pancrelipase delayed release capsules over placebo. A non-parametric ANCOVA was used because the necessary assumptions were not met for the parametric ANCOVA.p-value: 0.0002Non parametric ANCOVA
Secondary
Change of Stool Frequency Between Baseline and End of Double-blind (DB) Period
Stool frequency is the average of the daily number of stools recorded during the treatment period. Lower values indicate a better response. Change was calculated as (DB stool frequency - Baseline Stool frequency).
Time frame: End of double-period (5-7 days)
Population: The analysis was done on the Full Analysis sample. Full Analysis Population consists of all subjects who were allocated to the treatment and had data for at least one post-baseline assessment of any efficacy measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pancrelipase (DB) | Change of Stool Frequency Between Baseline and End of Double-blind (DB) Period | -0.55 Number | Standard Error 0.19 |
| Placebo (DB) | Change of Stool Frequency Between Baseline and End of Double-blind (DB) Period | 0.20 Number | Standard Error 0.17 |
Comparison: The following null hypothesis was tested (μ0 and μ1 denote the treatment group means in the placebo and pancrelipase delayed release capsules group): H0: μ0 = μ1 (i.e., placebo and pancrelipase capsules are equal). The hypothesis was to show superior efficacy of pancrelipase capsules over placebo.~For this secondary efficacy variable, an analysis of covariance (ANCOVA) model was assumed with the treatment group as a fixed factor and the Stool frequency at baseline as a covariate.p-value: 0.00595% CI: [-1.27, -0.24]ANCOVA
Secondary
Flatulence at the End of Double-blind Period
4- point ordinal scale on this symptom from 0 (None) to 3 (Severe).
Time frame: End of double-period (5-7 days)
Population: The analysis was done on the Full Analysis sample. Full Analysis Population consists of all subjects who were allocated to the treatment and had data for at least one post-baseline assessment of any efficacy measurement.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pancrelipase (DB) | Flatulence at the End of Double-blind Period | 0 (None) | 6 Participants |
| Pancrelipase (DB) | Flatulence at the End of Double-blind Period | 1 (Mild) | 13 Participants |
| Pancrelipase (DB) | Flatulence at the End of Double-blind Period | 2 (Moderate) | 4 Participants |
| Pancrelipase (DB) | Flatulence at the End of Double-blind Period | 3 (Severe) | 0 Participants |
| Placebo (DB) | Flatulence at the End of Double-blind Period | 3 (Severe) | 1 Participants |
| Placebo (DB) | Flatulence at the End of Double-blind Period | 0 (None) | 0 Participants |
| Placebo (DB) | Flatulence at the End of Double-blind Period | 2 (Moderate) | 12 Participants |
| Placebo (DB) | Flatulence at the End of Double-blind Period | 1 (Mild) | 15 Participants |
Secondary
Stool Consistency at the End of the Double-blind Period
4- point ordinal scale on this symptom from 0 (Hard) to 3 (Watery).
Time frame: End of double-period (5-7 days)
Population: The analysis was done on the Full Analysis sample. Full Analysis Population consists of all subjects who were allocated to the treatment and had data for at least one post-baseline assessment of any efficacy measurement.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pancrelipase (DB) | Stool Consistency at the End of the Double-blind Period | 0 (Hard) | 0 Participants |
| Pancrelipase (DB) | Stool Consistency at the End of the Double-blind Period | 1 (Formed/Normal) | 11 Participants |
| Pancrelipase (DB) | Stool Consistency at the End of the Double-blind Period | 2 (Soft) | 12 Participants |
| Pancrelipase (DB) | Stool Consistency at the End of the Double-blind Period | 3 (Watery) | 0 Participants |
| Placebo (DB) | Stool Consistency at the End of the Double-blind Period | 3 (Watery) | 3 Participants |
| Placebo (DB) | Stool Consistency at the End of the Double-blind Period | 0 (Hard) | 0 Participants |
| Placebo (DB) | Stool Consistency at the End of the Double-blind Period | 2 (Soft) | 20 Participants |
| Placebo (DB) | Stool Consistency at the End of the Double-blind Period | 1 (Formed/Normal) | 5 Participants |
Other Pre-specified
Change of Stool Frequency Between Original Baseline and End of Open-label Period (OL)
Stool frequency is the average of the daily number of stools recorded during the OL period. Lower values indicate a better response. Change was calculated as (OL stool frequency - Baseline stool frequency).
Time frame: 27 weeks
Population: This analysis is done on the Open-Label period of 6 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pancrelipase (DB) | Change of Stool Frequency Between Original Baseline and End of Open-label Period (OL) | -0.98 Number | Standard Deviation 1.26 |
p-value: <0.001Paired t-test