Cystic Fibrosis
Conditions
Keywords
Cystic Fibrosis, Creon, Pancrelipase, ABT-SLV-245, Exocrine Pancreatic Insufficiency (EPI)
Brief summary
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.
Interventions
DRUGPancrelipase
Delayed release capsules
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 Coefficient of Fat Absorption (CFA) | Up to Day 8 of each DB treatment period | 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. |
| Part 2 Coefficient of Fat Absorption (CFA) | Up to Day 8 of each DB treatment period | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Coefficient of Nitrogen Absorption (CNA) | Up to Day 8 of each DB treatment period | 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. |
| Stool Fat | Up to Day 8 of each DB treatment period | 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. |
| Stool Weight | Up to Day 8 of each DB treatment period | 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. |
Countries
United States
Participant flow
Recruitment details
This study was conducted in 2 independent parts, and gave participants the option to participate in both. The screening period for each Part included an Open Label (OL) Pre-Randomization Period during which participants were expected to receive OL study drug while they were evaluated for eligibility. Therefore, some participants received treatment in the study who were not enrolled per the protocol definition of enrollment (i.e. randomized).
Pre-assignment details
A total of 36 unique participants enrolled in the study, with 13 participants enrolling in both parts. Participants who decided to participate in Parts 1 or 2 within ≤ 30 days since completion of the other Part did not need to repeat all screening procedures for the second study Part (including the OL Pre-Randomization Period) before beginning in that Part's Double-Blind (DB) Treatment Period.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 DB Creon MP / Creon Participants received DB Creon MP in treatment period 1, followed by DB currently marketed Creon DR capsules in treatment period 2. Participants also received OL 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. | 13 |
| Part 1 DB Creon / Creon MP Participants received DB currently marketed Creon DR capsules in treatment period 1, followed by DB Creon MP in treatment period 2. Participants also received OL 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. | 13 |
| Part 2 DB Creon AAPIS / Creon Participants received DB Creon DR capsules manufactured at an alternate active pharmaceutical ingredient site (Creon AAPIS) in treatment period 1, followed by DB currently marketed Creon DR Capsules in treatment period 2. Participants also received OL 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. | 11 |
| Part 2 DB Creon / Creon AAPIS Participants received DB currently marketed Creon DR capsules in treatment period 1, followed by DB Creon AAPIS in treatment period 2. Participants also received OL 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. | 12 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part 1: Double Blind Period 1 | Other, Not Specified | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1 DB Creon MP / Creon | Part 1 DB Creon / Creon MP | Total | Part 2 DB Creon AAPIS / Creon | Part 2 DB Creon / Creon AAPIS |
|---|---|---|---|---|---|
| Age, Customized Part 1 12 - 18 years | 2 Participants | 1 Participants | 3 Participants | — | — |
| Age, Customized Part 1 > 18 years | 11 Participants | 12 Participants | 23 Participants | — | — |
| Age, Customized Part 2 12 - 18 years | — | — | 1 Participants | 1 Participants | 0 Participants |
| Age, Customized Part 2 > 18 years | — | — | 22 Participants | 10 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Part 1 Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | — | — |
| Ethnicity (NIH/OMB) Part 1 Not Hispanic or Latino | 12 Participants | 13 Participants | 25 Participants | — | — |
| Ethnicity (NIH/OMB) Part 1 Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | — | — |
| Ethnicity (NIH/OMB) Part 2 Hispanic or Latino | — | — | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Part 2 Not Hispanic or Latino | — | — | 22 Participants | 11 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Part 2 Unknown or Not Reported | — | — | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Part 1: White | 13 Participants | 13 Participants | 26 Participants | — | — |
| Race/Ethnicity, Customized Part 2: White | — | — | 23 Participants | 11 Participants | 12 Participants |
| Sex: Female, Male Part 1 Female | 7 Participants | 6 Participants | 13 Participants | — | — |
| Sex: Female, Male Part 1 Male | 6 Participants | 7 Participants | 13 Participants | — | — |
| Sex: Female, Male Part 2 Female | — | — | 9 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Part 2 Male | — | — | 14 Participants | 5 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 26 | 0 / 25 | 0 / 26 | 0 / 27 | 0 / 23 | 0 / 23 | 0 / 23 |
| other Total, other adverse events | 4 / 31 | 1 / 26 | 0 / 25 | 0 / 26 | 0 / 27 | 3 / 23 | 1 / 23 | 2 / 23 |
| serious Total, serious adverse events | 1 / 31 | 1 / 26 | 0 / 25 | 0 / 26 | 0 / 27 | 0 / 23 | 0 / 23 | 1 / 23 |
Outcome results
Primary
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.
Time frame: Up to Day 8 of each DB treatment period
Population: Evaluable Set: participants who completed both treatment periods and had 100% of stool samples collected and analyzed by the laboratory in both treatment periods
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 DB Creon | Part 1 Coefficient of Fat Absorption (CFA) | 85.53 percentage of fat intake absorbed | Standard Error 1.898 |
| Part 1 DB Creon MP | Part 1 Coefficient of Fat Absorption (CFA) | 84.59 percentage of fat intake absorbed | Standard Error 1.898 |
Comparison: Double Blind Creon - Double Blind Creon MP99% CI: [-2.37, 4.259]
Primary
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.
Time frame: Up to Day 8 of each DB treatment period
Population: Evaluable Set: participants who completed both treatment periods and had 100% of stool samples collected and analyzed by the laboratory in both treatment periods
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 DB Creon | Part 2 Coefficient of Fat Absorption (CFA) | 87.74 percentage of fat intake absorbed | Standard Error 1.554 |
| Part 1 DB Creon MP | Part 2 Coefficient of Fat Absorption (CFA) | 88.88 percentage of fat intake absorbed | Standard Error 1.554 |
Comparison: Double Blind Creon - Double Blind Creon AAPIS99% CI: [-4.892, 2.602]
Secondary
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.
Time frame: Up to Day 8 of each DB treatment period
Population: Evaluable Set: participants who completed both treatment periods and had 100% of stool samples collected and analyzed by the laboratory in both treatment periods
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 DB Creon | Coefficient of Nitrogen Absorption (CNA) | 85.01 percentage of nitrogen absorbed | Standard Error 1.058 |
| Part 1 DB Creon MP | Coefficient of Nitrogen Absorption (CNA) | 85.04 percentage of nitrogen absorbed | Standard Error 1.058 |
| Part 2 DB Creon | Coefficient of Nitrogen Absorption (CNA) | 85.67 percentage of nitrogen absorbed | Standard Error 1.223 |
| Part 2 Double-Blind Creon AAPIS | Coefficient of Nitrogen Absorption (CNA) | 86.50 percentage of nitrogen absorbed | Standard Error 1.223 |
Comparison: Creon - Creon MP95% CI: [-2.456, 2.392]
Comparison: Creon - Creon AAPIS95% CI: [-3.005, 1.345]
Secondary
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.
Time frame: Up to Day 8 of each DB treatment period
Population: Evaluable Set: participants who completed both treatment periods and had 100% of stool samples collected and analyzed by the laboratory in both treatment periods
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 DB Creon | Stool Fat | 44.52 grams | Standard Error 5.848 |
| Part 1 DB Creon MP | Stool Fat | 47.88 grams | Standard Error 5.848 |
| Part 2 DB Creon | Stool Fat | 37.46 grams | Standard Error 4.734 |
| Part 2 Double-Blind Creon AAPIS | Stool Fat | 34.19 grams | Standard Error 4.734 |
Comparison: Creon - Creon MP95% CI: [-10.699, 3.987]
Comparison: DB Creon - DB Creon AAPIS95% CI: [-5.172, 11.702]
Secondary
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.
Time frame: Up to Day 8 of each DB treatment period
Population: Evaluable Set: participants who completed both treatment periods and had 100% of stool samples collected and analyzed by the laboratory in both treatment periods
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 DB Creon | Stool Weight | 861.04 grams | Standard Error 66.63 |
| Part 1 DB Creon MP | Stool Weight | 826.36 grams | Standard Error 66.63 |
| Part 2 DB Creon | Stool Weight | 754.91 grams | Standard Error 87.307 |
| Part 2 Double-Blind Creon AAPIS | Stool Weight | 771.47 grams | Standard Error 87.307 |
Comparison: Creon - Creon MP95% CI: [-94.424, 163.786]
Comparison: DB Creon - DB Creon AAPIS95% CI: [-144.418, 111.298]