Efficacy and Safety Study of Creon IR in Subjects With Pancreatic Exocrine Insufficiency Due to Cystic Fibrosis

A Phase II, Multicenter, Parallel-Group, Active-Controlled, Randomized, Double-blind, Dose-Ranging Study to Evaluate the Efficacy and Safety of Different Doses of Creon IR in Subjects With Pancreatic Exocrine Insufficiency Due to Cystic Fibrosis

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).

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.

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