Chronic Pancreatitis, Exocrine Pancreatic Insufficiency
Conditions
Keywords
Chronic Pancreatitis, Exocrine Pancreatic Insufficiency
Brief summary
The primary efficacy objective of this study is to evaluate the difference in coefficient of fat absorption (CFA) of participants treated with high dose EUR-1008 (APT-1008) versus low dose of EUR-1008 (APT-1008) in the treatment of signs and symptoms of malabsorption in participants with EPI associated with CP. This study is sponsored by Aptalis Pharma (formerly Eurand).
Detailed description
After screening, eligible participants will start the placebo baseline ambulatory phase (4 days). On day 5, they will be hospitalized for three to five days, to undergo a baseline 72-hour CFA determination under a controlled diet and using a stool marker to indicate the beginning and end of the controlled diet period, while they continue receiving placebo treatment. At the end of the placebo baseline phase, participants will be randomized to a high dose followed by a low dose or to a low dose followed by a high dose EUR-1008 (APT-1008) dose sequence and proceed to the first crossover (treatment) phase. Each crossover (treatment) phase will consist of a stabilization period for six days at home, followed by a hospitalization of three to five days to undergo a 72-hour CFA determination using a controlled diet and using a stool marker to indicate the beginning and end of the controlled diet period. Participants will immediately proceed from the first crossover (treatment) phase to the second without a washout period or return-to-baseline period in between phases. Participants will be stabilized at home for 6 days. Any residual lipase from the prior treatment phase is likely to be a negligible influence on the subsequent CFA determination because participants will be taking the new dose level (high or low) for six days before the beginning of sample collection for a new CFA. This interval is more than enough time for the CFA to be reflective of only the new dose.
Interventions
DRUGPlacebo
Placebo matching to EUR-1008 (APT-1008) capsules orally daily for 4 days home treatment and 3 to 5 days hospital treatment in the baseline run-in phase, which will then be randomized to either high dose or low dose of EUR-1008 (APT-1008).
DRUGEUR-1008 (APT-1008) High Dose
EUR-1008 (APT-1008) total high dose 140,000 lipase USP Lipase units will be given as 7 capsules containing 20,000 USP Lipase units each, orally daily, distributed over the day per gram of fat in diet (possible example: 2 capsules with breakfast, 2 capsules with lunch, 2 capsules with dinner and 1 capsule with a snack) for 6 days home treatment and 3 to 5 days hospital treatment in either first intervention period or second intervention period.
DRUGEUR-1008 (APT-1008) Low Dose
EUR-1008 (APT-1008) total low dose 35,000 lipase USP Lipase units will be given as 7 capsules containing 5,000 USP Lipase units each, orally daily, distributed over the day per gram of fat in diet (possible example: 2 capsules with breakfast, 2 capsules with lunch, 2 capsules with dinner and 1 capsule with a snack) for 6 days home treatment and 3 to 5 days hospital treatment in either first intervention period or second intervention period.
Sponsors
Forest Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants are male or female * Participants with age over 18 years * Participants who have written, legally valid informed consent * Women of childbearing potential must be using a medically acceptable form of birth control for the 30 days prior to the beginning of the study and agree to maintain adequate birth control measures during the whole duration of the study plus an additional 30 days as well as have a negative pregnancy test at screening Visit 3 and Visit 7 * Participants with documented diagnosis of CP by medical history and it is preferred that it is supported by imaging evidence confirming CP which include: abnormal endoscopic retrograde cholangio-pancreatography (ERCP) (Cambridge Class 4), abnormal computed tomography (CT) scan (dilated main pancreatic duct, atrophy of the pancreas or calcification), abnormal ultrasound, or endoscopic ultrasound with at least 5 abnormalities noted * In the case of pancreatic surgery, the participant can be included with partial or distal resection of the pancreas (not due to cancer) * Participants with documented EPI with target fecal elastase (FE) less than or equal to 100 microgram per gram (mcg/g) of stool using the monoclonal test (pancreatic elastase 1 \[PE1\] by Genova Diagnostics) performed at the screening visit. The mean coefficient of variation (CV) for the FE test is 20 percent (%)
Exclusion criteria
* Participants known to the investigator to have a significant medical and/or mental disease that would compromise the participant's welfare, pose an unacceptable risk to him/her or confound the study results * Participants who participated in a clinical trial within 30 days of randomization or per specific country regulations/guidelines * Participants with cystic fibrosis * Participants with excessive alcohol consumption * Participants with drug abuse * Participants with contraindicated medications or who are unable to discontinue prohibited concomitant medication * Participants with uncontrolled diabetes mellitus * Participants allergic to pork protein/unwilling to ingest pork products * Participants with atopic predisposition such as multiple drug hypersensitivity, allergic asthma, urticaria, or other relevant allergic diathesis * Participants who are pregnant or lactating * Participants with acute pancreatitis or acute exacerbation in chronic pancreatitis * Participants with acute biliary disease * Participants with malabsorption syndrome caused by a metabolic disease or by surgery, not related to exocrine pancreatic insufficiency * Participants with any resection of the stomach or the gastrointestinal tract that will affect transit time and/or gastric emptying. * Participants with evidence of active gastric or duodenal ulcer * Participants with chronic inflammatory bowel disease * Participants with any history of pancreatic cancer and other non-cutaneous malignancies (except basal cell and squamous cell carcinoma of the skin in situ that have been removed and not reoccurred in 5 years) * Participants with viral hepatitis with infectious virions in blood and/or body fluids (any etiology) * Participants with human immunodeficiency virus (HIV) infection * Participants with hyperuricemia ( greater than \[\>\] 1.5 times upper normal value for lab) * Participants with any acute or chronic disease, which in the opinion of the investigator could influence study results or pose a risk to the participants' safety
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Coefficient of Fat Absorption (CFA) of Participants Treated With High Dose EUR-1008 and Low Dose EUR-1008 | 3 to 5 days of hospital treatment in first and second intervention periods | Percent CFA was calculated as (\[fat intake - fat excretion\]/fat intake)\*100, determined in the stools collected during the 72-hour CFA determination period. Mean percent CFA was calculated for the 3 to 5 days of hospital treatment in first and second intervention periods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Placebo Baseline in Percent Coefficient of Fat Absorption (CFA) in High Dose EUR-1008 and Low Dose EUR-1008 During Hospital Treatment | Baseline, 3 to 5 days of hospital treatment in first and second intervention periods | Percent CFA was calculated as (\[fat intake - fat excretion\]/fat intake)\*100, determined in the stools collected during the 72-hour CFA determination period. Mean percent CFA was calculated for 3 to 5 days of hospital treatment in first and second intervention periods. |
| Change From Placebo Baseline in Percent Coefficient of Nitrogen Absorption (CNA) During Hospital Treatment | Baseline, 3 to 5 days of hospital treatment in first and second intervention periods | Percent CNA was calculated as \[(nitrogen intake - nitrogen excretion)/nitrogen intake\]\*100 , determined in the stools collected during the 72-hour CNA determination period. Nitrogen intake was calculated as protein intake/6.2. Nitrogen excretion was measured as total fecal nitrogen. Mean percent CNA was calculated for 3 to 5 days of hospital treatment in first and second intervention periods. |
| Change From Placebo Baseline in Weight at End of Each Treatment Period | Baseline, end of treatment (6 days home treatment and 3-5 days hospital treatment in first and second intervention periods) | Mean change from baseline in weight was calculated for end of treatment (6 days home treatment and 3-5 days hospital treatment) in first and second intervention periods. |
| Change From Placebo Baseline in Body Mass Index (BMI) at End of Treatment | Baseline, end of treatment (6 days home treatment and 3-5 days hospital treatment in first and second intervention periods) | BMI was calculated by weight divided by height squared and measured as kilogram per square meter (kg/m\^2). Mean change from baseline in BMI was calculated for end of treatment (6 days home treatment and 3-5 days hospital treatment) in first and second intervention periods. |
Countries
Italy, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes participants who received placebo, EUR-1008 (APT-1008) high dose first and EUR-1008 (APT-1008) low dose first. | 82 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| First Intervention Period | Adverse Event | 0 | 1 | 0 |
| Placebo Run-in Phase | Adverse Event | 2 | 0 | 0 |
| Placebo Run-in Phase | Protocol Violation | 2 | 0 | 0 |
| Placebo Run-in Phase | Withdrawal by Subject | 2 | 0 | 0 |
| Second Intervention Period | Lost to Follow-up | 0 | 1 | 0 |
| Second Intervention Period | Other | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 51.91 years STANDARD_DEVIATION 12.08 |
| Body Mass Index (BMI) | 23.36 kg/m^2 STANDARD_DEVIATION 4.44 |
| Body Weight | 68.75 kilogram (kg) STANDARD_DEVIATION 14.12 |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 53 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 | 34 / 82 | 28 / 74 | 31 / 75 |
| serious Total, serious adverse events | 2 / 82 | 2 / 74 | 2 / 75 |
Outcome results
Primary
Percent Coefficient of Fat Absorption (CFA) of Participants Treated With High Dose EUR-1008 and Low Dose EUR-1008
Percent CFA was calculated as (\[fat intake - fat excretion\]/fat intake)\*100, determined in the stools collected during the 72-hour CFA determination period. Mean percent CFA was calculated for the 3 to 5 days of hospital treatment in first and second intervention periods.
Time frame: 3 to 5 days of hospital treatment in first and second intervention periods
Population: FAS included all participants who received at least 1 dose of the study medication. Here N (number of participants analyzed) signifies those participants for whom the CFA values were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EUR-1008 (APT-1008) Low Dose | Percent Coefficient of Fat Absorption (CFA) of Participants Treated With High Dose EUR-1008 and Low Dose EUR-1008 | 88.87 percent CFA | Standard Deviation 12.44 |
| EUR-1008 (APT-1008) High Dose | Percent Coefficient of Fat Absorption (CFA) of Participants Treated With High Dose EUR-1008 and Low Dose EUR-1008 | 89.86 percent CFA | Standard Deviation 8.77 |
Comparison: Treatment difference and 95 percent (%) confidence interval (CI) was based on LS mean from analysis of covariance (ANCOVA) which included participant as random effect, treatment, period and sequence as fixed effects, and placebo baseline CFA value as covariate.p-value: 0.22895% CI: [-0.656, 2.701]ANCOVA
Secondary
Change From Placebo Baseline in Body Mass Index (BMI) at End of Treatment
BMI was calculated by weight divided by height squared and measured as kilogram per square meter (kg/m\^2). Mean change from baseline in BMI was calculated for end of treatment (6 days home treatment and 3-5 days hospital treatment) in first and second intervention periods.
Time frame: Baseline, end of treatment (6 days home treatment and 3-5 days hospital treatment in first and second intervention periods)
Population: FAS included all participants who received at least one dose of the study medication. Here N (number of participants analyzed) represents number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EUR-1008 (APT-1008) Low Dose | Change From Placebo Baseline in Body Mass Index (BMI) at End of Treatment | 0.13 kg/m^2 | Standard Deviation 0.39 |
| EUR-1008 (APT-1008) High Dose | Change From Placebo Baseline in Body Mass Index (BMI) at End of Treatment | 0.16 kg/m^2 | Standard Deviation 0.42 |
Secondary
Change From Placebo Baseline in Percent Coefficient of Fat Absorption (CFA) in High Dose EUR-1008 and Low Dose EUR-1008 During Hospital Treatment
Percent CFA was calculated as (\[fat intake - fat excretion\]/fat intake)\*100, determined in the stools collected during the 72-hour CFA determination period. Mean percent CFA was calculated for 3 to 5 days of hospital treatment in first and second intervention periods.
Time frame: Baseline, 3 to 5 days of hospital treatment in first and second intervention periods
Population: FAS included all participants who received at least 1 dose of the study medication. Here N (number of participants analyzed) signifies those participants for whom the CFA values were available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EUR-1008 (APT-1008) Low Dose | Change From Placebo Baseline in Percent Coefficient of Fat Absorption (CFA) in High Dose EUR-1008 and Low Dose EUR-1008 During Hospital Treatment | Baseline | 81.68 percent CFA | Standard Deviation 22.13 |
| EUR-1008 (APT-1008) Low Dose | Change From Placebo Baseline in Percent Coefficient of Fat Absorption (CFA) in High Dose EUR-1008 and Low Dose EUR-1008 During Hospital Treatment | Change During Hospital Period | NA percent CFA | — |
| EUR-1008 (APT-1008) High Dose | Change From Placebo Baseline in Percent Coefficient of Fat Absorption (CFA) in High Dose EUR-1008 and Low Dose EUR-1008 During Hospital Treatment | Baseline | NA percent CFA | — |
| EUR-1008 (APT-1008) High Dose | Change From Placebo Baseline in Percent Coefficient of Fat Absorption (CFA) in High Dose EUR-1008 and Low Dose EUR-1008 During Hospital Treatment | Change During Hospital Period | 7.19 percent CFA | Standard Deviation 14.49 |
| EUR-1008 (APT-1008) High Dose | Change From Placebo Baseline in Percent Coefficient of Fat Absorption (CFA) in High Dose EUR-1008 and Low Dose EUR-1008 During Hospital Treatment | Baseline | NA percent CFA | — |
| EUR-1008 (APT-1008) High Dose | Change From Placebo Baseline in Percent Coefficient of Fat Absorption (CFA) in High Dose EUR-1008 and Low Dose EUR-1008 During Hospital Treatment | Change During Hospital Period | 8.18 percent CFA | Standard Deviation 17.35 |
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
Secondary
Change From Placebo Baseline in Percent Coefficient of Nitrogen Absorption (CNA) During Hospital Treatment
Percent CNA was calculated as \[(nitrogen intake - nitrogen excretion)/nitrogen intake\]\*100 , determined in the stools collected during the 72-hour CNA determination period. Nitrogen intake was calculated as protein intake/6.2. Nitrogen excretion was measured as total fecal nitrogen. Mean percent CNA was calculated for 3 to 5 days of hospital treatment in first and second intervention periods.
Time frame: Baseline, 3 to 5 days of hospital treatment in first and second intervention periods
Population: FAS included all participants who received at least one dose of the study drug. Here N (number of participants analyzed) represents number of participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EUR-1008 (APT-1008) Low Dose | Change From Placebo Baseline in Percent Coefficient of Nitrogen Absorption (CNA) During Hospital Treatment | Baseline | 78.05 percent CNA | Standard Deviation 18.64 |
| EUR-1008 (APT-1008) Low Dose | Change From Placebo Baseline in Percent Coefficient of Nitrogen Absorption (CNA) During Hospital Treatment | Change During Hospital Period | NA percent CNA | — |
| EUR-1008 (APT-1008) High Dose | Change From Placebo Baseline in Percent Coefficient of Nitrogen Absorption (CNA) During Hospital Treatment | Baseline | NA percent CNA | — |
| EUR-1008 (APT-1008) High Dose | Change From Placebo Baseline in Percent Coefficient of Nitrogen Absorption (CNA) During Hospital Treatment | Change During Hospital Period | 5.33 percent CNA | Standard Deviation 10.38 |
| EUR-1008 (APT-1008) High Dose | Change From Placebo Baseline in Percent Coefficient of Nitrogen Absorption (CNA) During Hospital Treatment | Baseline | NA percent CNA | — |
| EUR-1008 (APT-1008) High Dose | Change From Placebo Baseline in Percent Coefficient of Nitrogen Absorption (CNA) During Hospital Treatment | Change During Hospital Period | 7.62 percent CNA | Standard Deviation 15.55 |
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
Secondary
Change From Placebo Baseline in Weight at End of Each Treatment Period
Mean change from baseline in weight was calculated for end of treatment (6 days home treatment and 3-5 days hospital treatment) in first and second intervention periods.
Time frame: Baseline, end of treatment (6 days home treatment and 3-5 days hospital treatment in first and second intervention periods)
Population: FAS included all participants who received at least one dose of the study medication. Here N (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EUR-1008 (APT-1008) Low Dose | Change From Placebo Baseline in Weight at End of Each Treatment Period | 0.38 kilogram (kg) | Standard Deviation 1.18 |
| EUR-1008 (APT-1008) High Dose | Change From Placebo Baseline in Weight at End of Each Treatment Period | 0.50 kilogram (kg) | Standard Deviation 1.31 |