A Study to Compare US Marketed Creon Manufactured With a Modernized Process at an Alternate Manufacturing Site and Manufactured With the Approved Manufacturing Process at an Alternate Active Pharmaceutical Ingredient Site, in Participants With Exocrine Pancreatic Insufficiency Due to Cystic Fibrosis

Study Overview
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Brief Summary
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Part 1 is a study to demonstrate that Creon (pancrelipase) delayed release (DR) capsules manufactured with a modernized process (MP) is non-inferior to currently marketed pancrelipase DR capsules in participants with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF), as measured by coefficient of fat absorption (CFA). Part 2 is a study to demonstrate that Creon (pancrelipase) manufactured with an alternate active pharmaceutical ingredient site (AAPIS) is non-inferior to currently marketed active control (Creon®) in participants with EPI due to CF, as measured by CFA. Safety is evaluated in each part.

Official Title
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A Phase 4 Study to Compare US Marketed Creon Drug Product With Drug Product Manufactured With a Modernized Process at an Alternate Manufacturing Site and With Drug Product Manufactured With the Approved Manufacturing Process at an Alternate Active Pharmaceutical Ingredient Site, in Subjects With EPI Due to Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Pancrelipase
* Drug: Pancrelipase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has a documented diagnosis of Cystic Fibrosis (CF) confirmed by: a sweat chloride test >= 60 mmol/L, and/or documented CF-causing cystic fibrosis transmembrane conductance regulator (CFTR) mutations and clinical features of CF. Participant has diagnosis of moderate to severe Exocrine Pancreatic Insufficiency (EPI), as determined by Fecal Elastase 1 (FE-1) < 15 μg/g at screening. Participant has EPI that is currently clinically controlled (no clinically overt steatorrhea or diarrhea) under treatment with a commercially available Pancreatic Enzyme Replacement Therapy (PERT), on an individually established dose regimen for more than 3 months prior to Screening, with a daily dose not exceeding 4,000 Lipase Units (LU)/g fat/day or 10,000 LU/kg/day. Participant is available for two (if participating in one of the parts) or four (if participating in both parts) hospitalization/confinement periods of 6 to 8 days each during the expected study window. Participant is able to consume a diet with 100 g fat/day, a minimum of 1 g/kg of protein/day and normal to low fiber content. Exclusion Criteria: BMI percentile for age less than 10% in participants less than 18 years of age. Participant has a history of any of the following gastrointestinal disorders (acute pancreatitis within 6 months prior to Visit 2, chronic pancreatitis, fibrosing colonopathy, distal intestinal obstruction syndrome (DIOS) within 6 months prior to Visit 2, C. difficile infection within 6 months prior to Visit 2, celiac disease, gastric bypass or partial/total gastrectomy, Crohn's disease or other inflammatory bowel disease, small bowel surgery (other than minor resection due to meconium ileus without resultant malabsorption syndrome), or any type of malignancy involving the digestive tract in the last 5 years). Participant has a history of any clinically significant endocrine, respiratory (except mild asthma or CF related lung disease), neurological, cardiac, renal, hepatic (including Hepatitis B or C), hematologic or psychiatric disease or disorder, or any other uncontrolled medical illness which might limit participation in or completion of the study. Participant requires concomitant treatment with any medication not allowed by the protocol or a prohibited medication is expected to be needed during the study. Participant is currently receiving nutritional supplementation via tube feeding (nasogastric, gastrostomy, jejunostomy). Participant has clinically significant (as per Investigator's judgment) abnormalities in clinical chemistry, hematology, or urinalysis (excluding findings that are associated with CF) such as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >= 3 times the upper limit of normal values, or clinically significant (investigator opinion) elevation of uric acid.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Double-Blind Creon MP / Creon<br>After receiving open-label currently marketed Creon delayed release (Creon DR) capsules during a pre-randomization period, participants receive double-blind Creon DR capsules manufactured by modernized process pellets (Creon MP) in treatment period 1, followed by double-blind Creon DR capsules in treatment period 2. Participants also receive open-label currently marketed Creon DR for an interval of up to 28 days between periods 1 and 2, and during a 30-day follow-up period after period 2. | Drug: Pancrelipase<br>* Delayed release capsules<br>* Other names: Creon MP;|
| Experimental: Part 1 Double-Blind Creon / Creon MP<br>After receiving open-label currently marketed Creon DR capsules during a pre-randomization period, participants receive double-blind Creon DR capsules in treatment period 1, followed by double-blind Creon MP in treatment period 2. Participants also receive open-label currently marketed Creon DR for an interval of up to 28 days between periods 1 and 2, and during a 30-day follow-up period after period 2. | Drug: Pancrelipase<br>* Delayed release capsules<br>* Other names: Creon MP;|
| Experimental: Part 2 Double-Blind Creon AAPIS / Creon<br>After receiving open-label currently marketed Creon DR capsules during a pre-randomization period, participants receive double-blind Creon DR capsules manufactured at an alternate active pharmaceutical ingredient site (Creon AAPIS) in treatment period 1, followed by double-blind Creon DR capsules in treatment period 2. Participants also receive open-label currently marketed Creon DR for an interval of up to 28 days between periods 1 and 2, and during a 30-day follow-up period after period 2. | Drug: Pancrelipase<br>* Delayed release capsules<br>* Other names: Creon AAPIS;|
| Experimental: Part 2 Double-Blind Creon / Creon AAPIS<br>After receiving open-label currently marketed Creon DR capsules during a pre-randomization period, participants receive double-blind Creon DR capsules in treatment period 1, followed by double-blind Creon AAPIS in treatment period 2. Participants also receive open-label currently marketed Creon DR for an interval of up to 28 days between periods 1 and 2, and during a 30-day follow-up period after period 2. | Drug: Pancrelipase<br>* Delayed release capsules<br>* Other names: Creon AAPIS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 Coefficient of Fat Absorption (CFA) | CFA is calculated as 100*[fat intake - fat excretion]/fat intake. Fat intake was determined from fat content of food consumed on Day 3, 4, 5 of each treatment period. Fat excretion was determined from the content in the stool(s) collected after the first blue dyed stool (exclusive) following administration of the first blue dye marker (day 2) and until the first dyed stool (inclusive) following administration of the second blue dye marker (day 5) during each treatment period. | Up to Day 8 of each DB treatment period | 
| Part 2 Coefficient of Fat Absorption (CFA) | CFA is calculated as 100*[fat intake - fat excretion]/fat intake. Fat intake was determined from fat content of food consumed on Day 3, 4, 5 of each treatment period. Fat excretion was determined from the content in the stool(s) collected after the first blue dyed stool (exclusive) following administration of the first blue dye marker (day 2) and until the first dyed stool (inclusive) following administration of the second blue dye marker (day 5) during each treatment period. | Up to Day 8 of each DB treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coefficient of Nitrogen Absorption (CNA) | The CNA is calculated as 100*[nitrogen intake - nitrogen excretion]/nitrogen intake. Nitrogen intake was determined from protein content of food consumed on Day 3, 4, 5 of each treatment period. Nitrogen excretion was determined from the content in the stool(s) collected after the first blue dyed stool (exclusive) following administration of the first blue dye marker (day 2) and until the first dyed stool (inclusive) following administration of the second blue dye marker (day 5) during each treatment period. | Up to Day 8 of each DB treatment period | 
| Stool Fat | Total amount of fat excreted during the stool collection period. Stool fat was determined from the stool fat in the stool(s) collected after the first blue dyed stool (exclusive) following administration of the first blue dye marker (day 2) and until the first dyed stool (inclusive) following administration of the second blue dye marker (day 5) during each treatment period. | Up to Day 8 of each DB treatment period | 
| Stool Weight | Stool weight was determined from the net weight of the stool samples collected after the first blue dyed stool (exclusive) following administration of the first blue dye marker (day 2) and until the first dyed stool (inclusive) following administration of the second blue dye marker (day 5) during each treatment period. | Up to Day 8 of each DB treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis, Creon, Pancrelipase, ABT-SLV-245, Exocrine Pancreatic Insufficiency (EPI)