CREON Clinical Efficacy

Clinical Trial Endpoints

CFA: In normal, healthy subjects,
CFA is approximately 90%2

CNA: In normal, healthy subjects,
CNA is approximately 88%6

Trapnell Study:
Children and adults with EPI due to CF1,8

TREATMENT PERIOD OF 5 DAYS

Treatment-Related Improvement in Fat Absorption

49%

89%

Mean CFA (%)

100

80

60

40

20

0

Placebo

CREON

n=29

Mean difference in CFA was 41% (P<0.001)

  • Significant improvement in CFA in patients with EPI due to cystic fibrosis aged 12 to 43 years
  • Patients received CREON at a dose of 4,000 lipase units per gram of fat per day or placebo and had a dietary fat intake ≥90 g per day
  • The most common adverse reactions reported in this study were gastrointestinal-related, dizziness, and cough
Randomized, double-blind, multicenter, placebo-controlled, 2-period crossover study of CREON in 32 patients aged 12 to 43 with confirmed diagnosis of EPI and CF. Patients were randomized to receive CREON 24,000 lipase unit capsules, at a dose of 4,000 lipase units per gram of fat per day, or matching placebo for 5 to 6 days, followed by crossover to the alternate treatment for 5 to 6 days. Patients consumed ≥90 grams of fat per day during treatment periods. A washout period of 3 to 14 days was included between crossover periods to return patients to baseline conditions. The primary endpoint was the coefficient of fat absorption (CFA) and the secondary endpoint was coefficient of nitrogen absorption (CNA). The final analysis population was limited to 29 patients; 3 patients were excluded due to protocol deviations.

Graff Study:
Children with EPI due to CF1,7

TREATMENT PERIOD OF 5 DAYS

Treatment-Related Improvement in Fat Absorption

47%

83%

Mean CFA (%)

100

80

60

40

20

0

Placebo

CREON

n=16

Mean difference in CFA was 35% (P<0.001)

  • Significant improvement in CFA in pediatric patients aged 7 to 11 with EPI due to cystic fibrosis (CF)
  • Patients received CREON at a dose of 4,000 lipase units per gram of fat per day or placebo and had a dietary fat intake ≥90 g per day
  • The most common adverse reactions reported in this study were vomiting and headache
Randomized, double-blind, multicenter, placebo-controlled, 2-period crossover study of CREON in children aged 7 to 11 with confirmed EPI and CF. A total of 17 patients were randomized to receive CREON 12,000 lipase unit capsules, at a dose of 4,000 lipase units per gram of fat per day, or matching placebo for 5 to 6 days, followed by crossover to the alternate treatment for 5 to 6 days. Patients consumed ≥90 grams of fat per day during treatment periods. A washout period of 3 to 14 days was included between crossover periods to return patients to baseline conditions. The primary endpoint was the coefficient of fat absorption (CFA) and the secondary endpoint was coefficient of nitrogen absorption (CNA). One patient in the pancrelipase/placebo treatment sequence withdrew and was not included in the efficacy analysis.

Whitcomb Study: Adults with EPI due
to CP or pancreatectomy1,9

TREATMENT PERIOD OF 7 DAYS

Treatment-Related Improvement in Fat Absorption

66%

86%

Mean CFA (%)

100

80

60

40

20

0

Placebo

CREON

n=16

Mean difference in CFA was 35% (P<0.001)

Placebo

n=28

CREON

n=24

Mean difference in CFA was 21% (P<0.0001)

  • Significant improvement in CFA in adult patients aged 32 to 75 with EPI due to chronic pancreatitis (CP) and pancreatectomy
  • Patients received CREON at a dose of 72,000 lipase units per meal (3 meals) and 36,000 lipase units per snack (2 snacks) or placebo and had a dietary fat intake ≥100 g per day
  • The most common adverse reactions reported in this study were related to glycemic control and were reported more commonly during CREON treatment than during placebo treatment
Randomized, double-blind, multicenter, placebo-controlled, parallel-group study of CREON in patients aged 32 to 75 years with EPI due to chronic pancreatitis or pancreatectomy. Patients entered a 5-day placebo run-in period, followed by pancreatic enzyme replacement therapy as directed by the investigator for 16 days. Only patients with a coefficient of fat absorption (CFA) <80% in the run-in period were randomized to the double-blind period. A total of 54 patients were randomized to receive CREON 12,000 lipase unit capsules, at 72,000 lipase units per main meal (3 main meals) and 36,000 lipase units per snack (2 snacks), or matching placebo for 7 days. Patients consumed ≥100 grams of fat per day during the treatment period. The primary endpoint was CFA and the secondary endpoint was the coefficient of nitrogen absorption (CNA). The final analysis population was limited to 52 patients; 2 patients were excluded due to protocol violations.

Trapnell Study:
Children and adults with EPI due to CF1,8

TREATMENT PERIOD OF 5 DAYS

Treatment-Related Improvement in Protein Absorption

49%

86%

Mean CNA (%)

100

80

60

40

20

0

Placebo

CREON

n=29

Mean difference in CNA was 37% (P<0.001)

  • Significant improvement in CNA in patients with EPI due to cystic fibrosis aged 12 to 43 years
  • The primary efficacy measurement was CFA. The secondary efficacy measurement was CNA
  • Patients received CREON at a dose of 4,000 lipase units per gram of fat per day or placebo and had a dietary fat intake ≥90 g per day
  • The most common adverse reactions reported in this study were gastrointestinal-related, dizziness, and cough
Randomized, double-blind, multicenter, placebo-controlled, 2-period crossover study of CREON in 32 patients aged 12 to 43 with confirmed diagnosis of EPI and CF. Patients were randomized to receive CREON 24,000 lipase unit capsules, at a dose of 4,000 lipase units per gram of fat per day, or matching placebo for 5 to 6 days, followed by crossover to the alternate treatment for 5 to 6 days. Patients consumed ≥90 grams of fat per day during treatment periods. A washout period of 3 to 14 days was included between crossover periods to return patients to baseline conditions. The primary endpoint was the coefficient of fat absorption (CFA) and the secondary endpoint was coefficient of nitrogen absorption (CNA). The final analysis population was limited to 29 patients; 3 patients were excluded due to protocol deviations.

Graff Study:
Children with EPI due to CF1,7

TREATMENT PERIOD OF 5 DAYS

Treatment-Related Improvement in Protein Absorption

45%

80%

Mean CNA (%)

100

80

60

40

20

0

Placebo

CREON

n=16

Mean difference in CNA was 35% (P<0.001)

  • Significant improvement in CNA in pediatric patients aged 7 to 11 with EPI due to cystic fibrosis (CF)
  • The primary efficacy measurement was CFA. The secondary efficacy measurement was CNA
  • Patients received CREON at a dose of 4,000 lipase units per gram of fat per day or placebo and had a dietary fat intake ≥90 g per day
  • The most common adverse reactions reported in this study were vomiting and headache
Randomized, double-blind, multicenter, placebo-controlled, 2-period crossover study of CREON in children aged 7 to 11 with confirmed EPI and CF. A total of 17 patients were randomized to receive CREON 12,000 lipase unit capsules, at a dose of 4,000 lipase units per gram of fat per day, or matching placebo for 5 to 6 days, followed by crossover to the alternate treatment for 5 to 6 days. Patients consumed ≥90 grams of fat per day during treatment periods. A washout period of 3 to 14 days was included between crossover periods to return patients to baseline conditions. The primary endpoint was the coefficient of fat absorption (CFA) and the secondary endpoint was coefficient of nitrogen absorption (CNA). One patient in the pancrelipase/placebo treatment sequence withdrew and was not included in the efficacy analysis.
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Indications and Important
Safety Information

Indications1

CREON® (pancrelipase) Delayed-Release Capsules is a pancrelipase which is a combination of porcine-derived lipases, proteases, and amylases indicated for the treatment of exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreatectomy, or other conditions.

Important Safety Information

  • Fibrosing colonopathy is associated with high-dose use of pancreatic enzyme replacement in the treatment
    of cystic fibrosis patients. Exercise caution when doses of CREON exceed 2,500 lipase units/kg of body weight
    per meal (or greater than 10,000 lipase units/kg of body weight per day).
  • To avoid irritation of oral mucosa, care should be taken to ensure that CREON is not crushed, chewed, or retained in the mouth. CREON should always be taken with food.
  • Porcine-derived pancreatic enzyme products contain purines. Caution should be exercised when prescribing CREON to patients with gout, renal impairment, or hyperuricemia.
  • There is theoretical risk of viral transmission with all pancreatic enzyme products including CREON.
  • Exercise caution when administering pancrelipase to a patient with a known allergy to proteins of porcine origin.
  • Adverse reactions that occurred in at least 2 cystic fibrosis patients (greater than or equal to 4%) receiving CREON were vomiting, dizziness, and cough.
  • Adverse reactions that occurred in at least 1 chronic pancreatitis or pancreatectomy patient (greater than or equal to 4%) receiving CREON were hyperglycemia, hypoglycemia, abdominal pain, abnormal feces, flatulence, frequent bowel movements, and nasopharyngitis.
  • CREON is not interchangeable with any other pancrelipase product.

Reference: 1. CREON [package insert]. North Chicago, IL: AbbVie Inc.

  1. References:
  2. CREON [package insert]. North Chicago, IL: AbbVie Inc.
  3. Augarten A, Ben Tov A, Madgar I, et al. The changing face of the exocrine pancreas in cystic fibrosis: the correlation between pancreatic status, pancreatitis and cystic fibrosis genotype. Eur J Gastroenterol Hepatol. 2008;20(3):164-168.
  4. Borowitz D, Durie PR, Clarke LL, et al. Gastrointestinal outcomes and confounders in cystic fibrosis. J Pediatr Gastroenterol Nutr. 2005;41(3):273-285.
  5. Nunes RR, Clemente EL, Pandini JA, et al. Reliability of the classification of nutritional status obtained through the BMI and three different methods of body fat percentage in patients with type 1 diabetes mellitus. Arq Bras Endocrinol Metabol. 2009;53(3):360-367.
  6. Wells JC, Fewtrell MS. Measuring body composition. Arch Dis Child. 2006;91(7):612-617.
  7. Borowitz D, Konstan MW, O’Rourke A, Cohen M, Hendeles L, Murray FT. Coefficients of fat and nitrogen absorption in healthy subjects and individuals with cystic fibrosis. J Pediatr Pharmacol Ther. 2007;12(1):47-52.
  8. Graff GR, Maguiness K, McNamara J, et al. Efficacy and tolerability of a new formulation of pancrelipase delayed-release capsules in children aged 7 to 11 years with exocrine pancreatic insufficiency and cystic fibrosis: a multicenter, randomized, double-blind, placebo-controlled, two-period crossover, superiority study. Clin Ther. 2010;32(1):89-103.
  9. Trapnell BC, Maguiness K, Graff GR, Boyd D, Beckmann K, Caras S. Efficacy and safety of CREON 24,000 in subjects with exocrine pancreatic insufficiency due to cystic fibrosis. J Cyst Fibros. 2009;8(6):370-377.
  10. Whitcomb DC, Lehman GA, Vasileva G, et al. Pancrelipase delayed-release capsules (CREON) for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery: a double-blind randomized trial. Am J Gastroenterol. 2010;105(10):2276-2286.

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