Exocrine Pancreatic Insufficiency in Subjects With Cystic Fibrosis
Conditions
Keywords
Exocrine Pancreatic Insufficiency
Brief summary
The objective of this study is to assess the efficacy and safety of different doses of Creon Immediate Release (IR) in comparison to Creon® 25,000 Delayed Release/Gastro-Resistant (DR/GR) in subjects with Pancreatic Exocrine Insufficiency (PEI) due to Cystis Fibrosis (CF).
Detailed description
This study is a Phase II, randomized, parallel-group, active-controlled, double-blind, dose ranging, multicenter study with 4 different doses of Creon IR and one dose of the active control Creon® (DR/GR), administered in subjects of 12 years or older with PEI due to CF. The study is divided into two periods: a screening period of 14 days and a double-blind treatment period of 6 to 7 days.
Interventions
DRUGCreon IR
DRUGCreon® (DR/GR)
Sponsors
AbbVie
LKF Laboratorium für Klinische Forschung GmbH
Analytical Biochemical Laboratory
Parexel
Datamap
Linical Co., Ltd.
Abbott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject has voluntarily signed and dated the Informed Consent Form (ICF). For subjects aged less than 18 years, the parents, or a legally acceptable representative, must sign consent and, as required by the Independent Ethics Committee (IEC), assent will be given by the subject. 2. Subject is 12 years old or older at the time of consent signature. 3. Subject has a diagnosis of CF previously confirmed by: * a sweat chloride test \> or equal to 60 mmol/Ls and/or * two CF causing Cystic Fibrosis trans membrane conductance regulator (CFTR) mutations and * CF clinical features 4. Subject has a documented clinically confirmed diagnosis of pancreatic exocrine insufficiency. 5. Subject has human fecal elastase \< 100 µg/g stool at screening 6. Subject has PEI 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, with a daily dose not exceeding 10,000 U lipase/kg/day. 7. Females of child-bearing potential and sexually active with men should agree to continue using a medically acceptable method of birth control throughout the study and for 7 days immediately after the last dose of study drug. Medically acceptable methods of birth control include bilateral tubal ligation or the use of either a contraceptive implant, a contraceptive injection (e.g., Depo Provera™), an intrauterine device, or an oral contraceptive taken continually within the past three months and which the subject agrees to continue using during the study or to adopt another birth control method, or a double-barrier method which consists of a combination of any two of the following: diaphragm, cervical cap, condom, or spermicide.
Exclusion criteria
1. Subject is \< 18 years of age and has a Body Mass Index (BMI) Z-Score below -1.5 (minus 1.5) 2. Subject has a history of any of the following gastrointestinal disorders: * pancreatitis within 6 months prior to study entry; * fibrosing colonopathy; * distal ileal obstruction syndrome (DIOS) within 6 months prior to study entry; * celiac disease; * gastric bypass or partial/total gastrectomy; * Crohn's disease; * small bowel surgery (other than minor resection due to meconium ileus without resulting in malabsorption syndrome). * Any type of malignancy involving the digestive tract in the last 5 years. 3. Subjects with diabetes mellitus, for which the study specific dietary requirements may not be appropriate. 4. Subject has a history of other endocrine or respiratory (except mild asthma) medical illness non-related to CF, which might limit participation in or completion of the study. 5. Subject has a history of any clinically significant neurological, cardiac, renal, hepatic (including Hepatitis B or C), hematologic or psychiatric disease or disorder, or any other uncontrolled medical illness (except cystic fibrosis) which might limit participation in or completion of the study. 6. Subjects requiring concomitant treatment with any medication not allowed by the protocol or is expected to be needed. 7. Subjects requiring Naso-gastric, G-tubes or J-tubes. 8. Subject is currently participating in any other interventional clinical study or has taken any experimental drug within 30 days prior to Screening. 9. Subject is known to be HIV-positive. 10. Subject has a history of allergic reaction or significant sensitivity to pancreatin or inactive ingredients (excipients) of Creon® (DR/GR) or Creon IR
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Coefficient of Fat Absorption (CFA) | End of the 6 to 7 days double-blind treatment period | CFA is calculated from fat intake and fat excretion, according to the formula: CFA (%) = 100 \[fat intake - fat excretion\] / fat intake |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Coefficient of Nitrogen Absorption (CNA) | End of the 6 to 7 days double-blind treatment period | CNA is calculated from nitrogen intake and nitrogen excretion, according to the formula: CNA (%) = 100 \[nitrogen intake - nitrogen excretion\] / nitrogen intake) |
| Stool Fat Content | End of the 6 to 7 days double-blind treatment period | Total amount of fat excreted during the stool collection period in grams. |
| Stool Weight | End of the 6 to 7 days double-blind treatment period | Total amount of stool weight during the collection period in grams |
Other
| Measure | Time frame | Description |
|---|---|---|
| Treatment Emergent Adverse Events | From randomization to end of Double Blind period plus 1 day, i.e. up to 7/8 days | Treatment emergent adverse events will be summarized per treatment group |
Countries
Czechia, Hungary, Poland, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Creon IR Low Dose Creon IR 300 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 30,000 lipase units)
Creon IR | 14 |
| Creon IR Medium Dose Creon IR 1,200 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 120,000 lipase units)
Creon IR | 14 |
| Creon IR High Dose Creon IR 2,400 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 240,000 lipase units)
Creon IR | 14 |
| Creon IR Maximum Dose Creon IR 4,000 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 400,000 lipase units)
Creon IR | 14 |
| Creon® (DR/GR) Creon® (DR/GR) 4,000 Ph. Eur. U lipase/g fat, proportionally administered five times daily (during 3 meals and 2 snacks) for 6 to 7 days (target total daily dose of 400,000 lipase units)
Creon® (DR/GR) | 14 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Creon IR Low Dose | Creon IR Medium Dose | Creon IR High Dose | Creon IR Maximum Dose | Creon® (DR/GR) | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 4 Participants | 5 Participants | 5 Participants | 8 Participants | 4 Participants | 26 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 9 Participants | 9 Participants | 6 Participants | 10 Participants | 44 Participants |
| Age, Continuous | 24.7 years STANDARD_DEVIATION 7.6 | 22.9 years STANDARD_DEVIATION 8.5 | 22.0 years STANDARD_DEVIATION 7.3 | 19.7 years STANDARD_DEVIATION 8.4 | 22.6 years STANDARD_DEVIATION 7.1 | 22.4 years STANDARD_DEVIATION 7.7 |
| Region of Enrollment Czech Republic | 1 participants | 1 participants | 1 participants | 1 participants | 1 participants | 5 participants |
| Region of Enrollment Hungary | 3 participants | 3 participants | 3 participants | 3 participants | 3 participants | 15 participants |
| Region of Enrollment Poland | 6 participants | 6 participants | 6 participants | 6 participants | 6 participants | 30 participants |
| Region of Enrollment Spain | 4 participants | 4 participants | 4 participants | 4 participants | 4 participants | 20 participants |
| Sex: Female, Male Female | 6 Participants | 9 Participants | 7 Participants | 5 Participants | 6 Participants | 33 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 7 Participants | 9 Participants | 8 Participants | 37 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 14 | 9 / 14 | 7 / 14 | 9 / 14 | 7 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 1 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Coefficient of Fat Absorption (CFA)
CFA is calculated from fat intake and fat excretion, according to the formula: CFA (%) = 100 \[fat intake - fat excretion\] / fat intake
Time frame: End of the 6 to 7 days double-blind treatment period
Population: Full Analysis set. Four randomized subjects excluded because no post-baseline efficacy data (two non-completers and two subjects whose stools were mixed-up with each other at the analytical laboratory).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Creon IR Low Dose | Coefficient of Fat Absorption (CFA) | 71.0 percentage of fat intake | Standard Deviation 12.4 |
| Creon IR Medium Dose | Coefficient of Fat Absorption (CFA) | 70.9 percentage of fat intake | Standard Deviation 13.9 |
| Creon IR High Dose | Coefficient of Fat Absorption (CFA) | 71.8 percentage of fat intake | Standard Deviation 15.2 |
| Creon IR Maximum Dose | Coefficient of Fat Absorption (CFA) | 75.9 percentage of fat intake | Standard Deviation 9.2 |
| Creon® (DR/GR) | Coefficient of Fat Absorption (CFA) | 92.3 percentage of fat intake | Standard Deviation 3.7 |
Secondary
Coefficient of Nitrogen Absorption (CNA)
CNA is calculated from nitrogen intake and nitrogen excretion, according to the formula: CNA (%) = 100 \[nitrogen intake - nitrogen excretion\] / nitrogen intake)
Time frame: End of the 6 to 7 days double-blind treatment period
Population: Full Analysis set. Four randomized subjects excluded because no post-baseline efficacy data (two non-completers and two subjects whose stools were mixed-up with each other at the analytical laboratory).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Creon IR Low Dose | Coefficient of Nitrogen Absorption (CNA) | 71.0 percentage of nitrogen intake | Standard Deviation 10 |
| Creon IR Medium Dose | Coefficient of Nitrogen Absorption (CNA) | 73.2 percentage of nitrogen intake | Standard Deviation 6.4 |
| Creon IR High Dose | Coefficient of Nitrogen Absorption (CNA) | 76.2 percentage of nitrogen intake | Standard Deviation 8.1 |
| Creon IR Maximum Dose | Coefficient of Nitrogen Absorption (CNA) | 79.9 percentage of nitrogen intake | Standard Deviation 7.3 |
| Creon® (DR/GR) | Coefficient of Nitrogen Absorption (CNA) | 84.8 percentage of nitrogen intake | Standard Deviation 4.3 |
Secondary
Stool Fat Content
Total amount of fat excreted during the stool collection period in grams.
Time frame: End of the 6 to 7 days double-blind treatment period
Population: Full Analysis set. Four randomized subjects excluded because no post-baseline efficacy data (two non-completers and two subjects whose stools were mixed-up with each other at the analytical laboratory).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Creon IR Low Dose | Stool Fat Content | 87.5 gram per 72 hours | Standard Deviation 37.5 |
| Creon IR Medium Dose | Stool Fat Content | 87.1 gram per 72 hours | Standard Deviation 41 |
| Creon IR High Dose | Stool Fat Content | 84.1 gram per 72 hours | Standard Deviation 44.9 |
| Creon IR Maximum Dose | Stool Fat Content | 73.0 gram per 72 hours | Standard Deviation 28.2 |
| Creon® (DR/GR) | Stool Fat Content | 23.5 gram per 72 hours | Standard Deviation 11.3 |
Secondary
Stool Weight
Total amount of stool weight during the collection period in grams
Time frame: End of the 6 to 7 days double-blind treatment period
Population: Full Analysis set. Four randomized subjects excluded because no post-baseline efficacy data (two non-completers and two subjects whose stools were mixed-up with each other at the analytical laboratory).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Creon IR Low Dose | Stool Weight | 889.0 gram per 72 hours | Standard Deviation 294.2 |
| Creon IR Medium Dose | Stool Weight | 905.3 gram per 72 hours | Standard Deviation 225.7 |
| Creon IR High Dose | Stool Weight | 793.8 gram per 72 hours | Standard Deviation 279.8 |
| Creon IR Maximum Dose | Stool Weight | 755.7 gram per 72 hours | Standard Deviation 383.2 |
| Creon® (DR/GR) | Stool Weight | 545.7 gram per 72 hours | Standard Deviation 256.3 |
Other Pre-specified
Treatment Emergent Adverse Events
Treatment emergent adverse events will be summarized per treatment group
Time frame: From randomization to end of Double Blind period plus 1 day, i.e. up to 7/8 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Creon IR Low Dose | Treatment Emergent Adverse Events | 10 participants |
| Creon IR Medium Dose | Treatment Emergent Adverse Events | 9 participants |
| Creon IR High Dose | Treatment Emergent Adverse Events | 7 participants |
| Creon IR Maximum Dose | Treatment Emergent Adverse Events | 9 participants |
| Creon® (DR/GR) | Treatment Emergent Adverse Events | 7 participants |