| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pancreatic Exocrine Insufficiency due to Cystic Fibrosis |
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| E.1.1.1 | Medical condition in easily understood language |
Maldigestion of diatery macronutients (pancreas not producing enough
enzymes for digestion of fat, sugars and proteins) in Cystic Fibrosis |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10073392 |
| E.1.2 | Term | Pancreatic exocrine insufficiency |
| E.1.2 | System Organ Class | 100000173123 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011762 |
| E.1.2 | Term | Cystic fibrosis |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to demonstrate the non-inferiority of the non-porcine enzyme product, liprotamase, when administered at an individually-optimized dose, to Pancreaze for the change in coefficient of fat absorption (CFA) from screening to the end of the Primary Treatment Period in subjects ≥7 years of age with Exocrine Pancreatic Insufficiency (EPI) due to cystic fibrosis (CF). |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to evaluate and compare effects of liprotamase and Pancreaze on other measures of digestion including the coefficient of nitrogen absorption (CNA), stool weight, and symptoms of malabsorption. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Cystic Fibrosis based on the disease diagnostic criteria:
• Two clinical features consistent with CF, and
• Either:
a. genotype with 2 identifiable mutations consistent with CF, or
b. sweat chloride ≥ mEq/L (≥60 mmol/L) by quantitative pilocarpine iontophoresis.
Diagnostic evidence of CF disease may be measured during screening unless previously documented.
2. Age ≥ 7 years at the time of screening.
3. Fecal elastase <100 mcg/g stool measured during screening.
4. CFA during screening of ≥80% while receiving PERT therapy. Subjects who meet all enrollment criteria except CFA may be re screened for CFA after an increase in pre-enrollment PERT dose for at least 1 week if this is deemed to be safe and appropriate by the Investigator. Such rescreening of CFA should occur within 30 days of the result of the first CFA measurement.
5. Clinically stable with no evidence of acute upper or lower respiratory tract infection in the last 10 days prior to Visit 1.
6. Fair or better nutritional status as defined by:
• BMI ≥16.0 kg/m2 for female subjects ≥18 years of age, or
• BMI ≥16.5 kg/m2 for male subjects ≥18 years of age, or
• BMI ≥25th percentile for subjects 7 to <18 years of age based on growth charts published by the World Health Organization (WHO).
• Weight for all age groups has remained stable (no more than a 5% decline) during the 90 days prior to screening.
7. Able to take pancreatic enzyme supplementation in the form of capsules.
8. Using the same pancreatic enzyme treatment for the past 30 days without change in dosing regimen unless the change in regimen occurs during CFA rescreening as described in Inclusion Criterion #4.
9. Subjects receiving gastric acid suppression therapy (proton pump inhibitor or histamine 2 antagonist) must have been on a stable dose for at least 30 days prior to Visit 2.
10. Able to perform testing and procedures required for the study, as judged by the Investigator.
11. If adult, have given written informed consent or assent as required by Anthera or its designee and the Institutional Review Board/Independent Ethic Committee (IRB/IEC). If not adult, have parent or legal guardian who has given written informed consent approved by Anthera or its designee and the IRB/IEC governing the site.
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| E.4 | Principal exclusion criteria |
1. Presently using Pancreaze as enzyme preparation for treatment of EPI. Patients are not required to be Pancreaze naïve but should not have received Pancreaze within 30 days of screening.
2. Treatment with liprotamase in a previous clinical trial including Study TC-2A, Study 726, Study 767, the SIMPLICITY study (AN-EPI3332), and the SOLUTION trial (AN EPI3331).
3. Women who are breast-feeding during the study.
4. A history or diagnosis of fibrosing colonopathy (FC).
5. History of distal intestinal obstruction syndrome (DIOS) in the 6 months prior to the screening visit.
6. Any chronic diarrheal illness unrelated to pancreatic insufficiency (e.g., infectious gastroenteritis, sprue or inflammatory bowel disease).
7. A history of solid organ transplant, or significant surgical resection of the bowel. Significant resection of the bowel is defined as any resection of the terminal ileum or ileocecal valve. Subjects who have had qualitative, long term changes in nutritional status after any other bowel resection (e.g., increased or new need for pancreatic enzyme supplementation compared to pre operative status in order to maintain the same nutritional status) should also be excluded.
8. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥5 times upper limit of normal (ULN), or total bilirubin level ≥1.5 times ULN at the screening visit, unless due to Gilbert’s syndrome. Cases of suspected or confirmed Gilbert’s syndrome should be discussed with the Medical Monitor.
9. Signs and/or symptoms of liver cirrhosis or portal hypertension (e.g., splenomegaly, ascites, esophageal varices), or documented liver disease unrelated to CF.
10. Forced expiratory volume in 1 second (FEV1) <30% of the predicted value.
11. Use of an enzyme preparation at screening in excess of 10,000 U lipase/kg/day or 2,500 U lipase/kg per meal in patients ≥17 years of age, or 6,700 U lipase/kg/day in patients <17 years of age.
12. Known hypersensitivity to food additives or Pancreaze.
13. Uncontrolled hyperglycemia or uncontrolled CF-related diabetes.
14. Uncontrolled hyperuricemia or hyperuricosuria as determined by the principal Investigator (PI).
15. Feeding via an enteral tube during 6 months prior to screening.
16. Routine use of anti-diarrheals, anti-spasmodics, or cathartic laxatives, or a change in chronic osmotic laxative (e.g., polyethylene glycol) regimen in the previous 3 months.
17. Any condition that the Investigator believes would interfere with the intent of this study or would make participation not in the best interests of the subject.
18. Unlikely to complete the study, as determined by the Investigator.
19. Currently enrolled in, or have discontinued within the last 30 days (prior to the screening visit) from a clinical trial involving use of an investigational drug, biologic or device, or are currently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
20. Female who is nursing, pregnant, intending to become pregnant or intending to nurse during the time of the study, or who have a positive pregnancy test at baseline. All sexually-active subjects of reproductive potential are required to use a reliable method of birth control. Females and males are required to use or start using a reliable method of birth control at least 2 weeks prior to randomization, throughout the study, and for at least 3 months following completion of study therapy. A reliable method of birth control is defined as one of the following: oral or injectable contraceptives, intrauterine device, contraceptive implants, tubal ligation, hysterectomy, or a double-barrier method (diaphragm with spermicidal foam or jelly, or a condom), abstinence or vasectomy.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective of this study is to demonstrate the non-inferiority of liprotamase, administered at an individually-optimized dose, to Pancreaze for the change in coefficient of fat absorption (CFA) from screening to the end of the Primary Treatment Period (end of Week 4) in subjects ≥7 years of age with EPI due to cystic fibrosis (CF). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The values at the end of the primary treatment period of liprotamase, and of the
active control Pancreaze® will be compared. |
|
| E.5.2 | Secondary end point(s) |
• To demonstrate non-inferiority of liprotamase to the active comparator for the change in coefficient of nitrogen absorption (CNA) from screening to the end of the Primary Treatment Period using the same non-inferiority criteria as for CFA.
• To evaluate change in stool weight from screening to the end of the Primary Treatment Period (measured during the marker-to-marker stool collection).
• To demonstrate non-inferiority of liprotamase to Pancreaze in the change in CFA from screening to end of the Primary Treatment Period in the subgroup of subjects receiving gastric acid suppression.
• To evaluate signs and symptoms of malabsorption (abdominal pain, bloating, steatorrhea, flatulence, stool consistency, stool frequency, stool quantity, overall bowel habit) at baseline, during the Primary Treatment Period, and the Extension Period.
• To evaluate the change from baseline in height, weight, and body mass index (BMI) to the end of the Primary Treatment Period and the Extension Period.
• To evaluate the change in total cholesterol, vitamin (A, D, E, and K) levels, albumin, and prealbumin from baseline to the end of the Primary Treatment Period and the Extension Period.
Safety will be evaluated throughout the study based on adverse events (AEs) including serious AEs (SAEs), blood chemistry, hematology, urinalysis, physical examinations, vital signs, and measurement of total cholesterol, albumin, prealbumin and fat-soluble vitamin levels. Height, weight, BMI, and signs and symptoms of malabsorption will be evaluated during the Extension Period.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The values at the end of the primary treatment period of liprotamase, and of the
active control Pancreaze® will be compared. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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