E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Exocrine Pancreatic Insufficiency due to Cystic Fibrosis |
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E.1.1.1 | Medical condition in easily understood language |
Maldigestion of dietary macronutrients (pancreas not producing enough enzymes for digestion of fat, sugars and proteins) in Cistic Fibrosis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
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 | 100000004856 |
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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 |
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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 |
Primary efficacy objective: To determine the efficacy of escalating doses of MS1819-SD on top of a stable dose of Porcine Pancreatic Extracts (PPEs) on triglyceride digestion assessed by coefficient of fat absorption (CFA) in patients with severe Exocrine Pancreatic Insufficiency (EPI) caused by cystic fibrosis (CF) and not fully compensated with only PPEs.
Primary safety objective: To assess the safety and tolerability of escalating doses of MS1819-SD on top of a stable dose of PPEs in patients with severe EPI caused by CF. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed and dated informed consent form.
2. Age ≥ 12 years at the time of screening
3. Male or female.
4. Under stable dose of PPE ≥ 1 month. Stable dose is defined as dose of medication not changed during this time period and the medication must be commercially available and be administered in the recommended dose range.
5. A nutritional status as defined by:
a. BMI < or = 22.0 kg/m2 for female patients
b. BMI < or = 23.0 kg/m2 for male patients
c. BMI < or = 50th percentile for patients 12 to < 18 years of age.
6. Cystic fibrosis (CF), based on at least 2 clinical features consistent with CF in the opinion of the investigator and a sweat chloride concentration > 60 mmol/L by pilocarpine iontophoresis.
7. Fecal pancreatic elastase-1 < 100 µg/g of stools at screening.
8. Baseline CFA < 80% with a maximum daily dose of 10,000 lipase units/kg/day.
9. Clinically stable with no documented evidence of significant respiratory symptoms that would require administration of intravenous antibiotics, oxygen supplementation, or hospitalization within the 30 days of screening.
10. Male and female patients, if of childbearing potential, must use a reliable method of contraception during the study. 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. Periodic abstinence (calendar, symptom-thermal, or post-ovulation methods) is not an acceptable method of contraception. The preferred and usual lifestyle of the patient must also be evaluated in determining if sexual abstinence is a reliable method of birth control.
11. Be considered as reliable and capable of adhering to the protocol, according to the judgment of the investigator. |
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E.4 | Principal exclusion criteria |
1. Established or suspected fibrosing colonopathy.
2. Total or partial gastrectomy.
3. 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. Patients who have had qualitative, long-term changes in nutritional status after any other bowel resection (eg, increased of new need for pancreatic enzyme supplementation compared with preoperative status to maintain the same nutritional status) should also be excluded.
4. Any chronic diarrheal illness unrelated to pancreatic insufficiency (eg, infectious gastroenteritis, sprue, inflammatory bowel disease)
5. Known hypersensitivity or other severe reaction to any ingredient of the investigational medicinal product (IMP).
6. Bilirubin > 1.5 times upper limit normal (ULN).
7. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times ULN.
8. Alkaline phosphatase (ALP) > 5 times ULN.
9. Gamma glutamyltransferase (GGT) > 5 times ULN.
10. Signs and/or symptoms of liver cirrhosis or portal hypertension (eg, splenomegaly, ascites, esophageal varices), or documented liver disease unrelated to CF
11. Known allergy to the stool marker.
12. Feeding via an enteral tube during 6 months before screening
13. Routine use of anti-diarrheals, anti-spasmodics, or cathartic laxatives, or a change in chronic osmotic laxatives (eg, polyethylene glycol) regimen in the previous laxative therapy within the last 12 months before screening
14. History of severe constipation with < 1 evacuation/week under appropriate laxative therapy within the last 12 months before screening.
15. Documentation of distal intestinal pseudo-obstruction syndrome within the last 12 months before screening.
16. Forced Expiratory Volume < or = 30% at the screening visit.
17. Lactation or known pregnancy or positive pregnancy test at both screening and baseline for women of childbearing potential.
18. Participation in another clinical study involving an IMP within 30 days before inclusion or concomitantly with this study.
19. Poorly controlled diabetes according the investigator’s judgement. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
• Change in CFA from baseline (V2) to visits of phase C (V4, V5 and V6).
Primary Safety Endpoints:
Safety data, including all observed AEs with a particular focus on immunoallergic events and digestive symptomatology. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
Key secondary endpoints:
• Change from Phase B in the mean number of daily evacuations during the days of the stool collection period in each cycle in Phase C.
• Change from Phase B in the mean consistency of stools assessed by the Bristol scale during the stool collection period in each cycle in Phase C.
Secondary Safety Endpoints
In addition to primary safety endpoints, laboratory test results will be summarized:
• Fasting glucose.
• Urinalysis
• Hematology: Hematocrit, Hemoglobin, Erythrocyte count (RBC), Leukocytes (WBC), Absolute counts of: Neutrophils (segmented), Neutrophils juvenile (bands), Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets.
• Biochemistry: Serum concentration of: Sodium, Potassium, Chloride, Bicarbonate, Blood urea nitrogen (BUN), Total Calcium, Phosphorus, Magnesium, Albumin, Prealbumin, Total protein, Creatinine, Alkaline phosphatase, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Lactate deshydrogenase (LDH), Total bilirubin, Direct bilirubin, Uric Acid.
• Fasting Lipid Profile: Total cholesterol, Triglycerides, Low Density Lipoprotein (LDL), High Density Lipoprotein (HDL) and Very Low Density Lipoprotein (VLDL)
• Serum vitamins A, D, E and K.
• Activated partial thromboplastin time (aPTT), Prothrombin time/International normalized ratio (PT/INR)
• Immunogenic assessment for circulating levels of LIP2 lipase.
• Antibodies against LIP2. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 |
Hungary |
Poland |
Spain |
Turkey |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 11 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |