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    Summary
    EudraCT Number:2017-000571-85
    Sponsor's Protocol Code Number:AN-EPI3333
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-05-08
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2017-000571-85
    A.3Full title of the trial
    A Phase 3, Randomized, Open-Label, Assessor-Blind, Non-Inferiority, Active-Comparator Study Evaluating the Efficacy and Safety of Liprotamase in Subjects with Cystic Fibrosis-Related Exocrine Pancreatic Insufficiency
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Oral Liprotamase Therapy Of Non-Porcine Origin
    A.3.2Name or abbreviated title of the trial where available
    RESULT: Reliable, Emergent Solution Using Liprotamase Treatment
    A.4.1Sponsor's protocol code numberAN-EPI3333
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03051490
    A.5.4Other Identifiers
    Name:BB-IND No. Number:062,037
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorANTHERA Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAnthera Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAnthera Pharmaceuticals
    B.5.2Functional name of contact pointMonica Gangal
    B.5.3 Address:
    B.5.3.1Street Address25801 Industrial Boulevard, Suite B
    B.5.3.2Town/ cityHayward, CA
    B.5.3.3Post code94545
    B.5.3.4CountryUnited States
    B.5.4Telephone number1510856-5600- 5574
    B.5.6E-mailmgangal@anthera.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/04/222
    D.3 Description of the IMP
    D.3.1Product nameliprotamase
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnot assigned
    D.3.9.1CAS number 9001-62-1
    D.3.9.3Other descriptive nameLIPASE
    D.3.9.4EV Substance CodeSUB14362MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10000 to 40000
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnot assigned
    D.3.9.1CAS number 9000-99-1
    D.3.9.3Other descriptive namePROTEASE
    D.3.9.4EV Substance CodeSUB15036MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10000 to 40000
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnot assigned
    D.3.9.3Other descriptive nameAMYLASE
    D.3.9.4EV Substance CodeSUB12892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1500 to 6000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name PANCREAZE®
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen Pharmaceuticals, Inc
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePANCREAZE®
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnot assigned
    D.3.9.1CAS number 8049-47-6
    D.3.9.3Other descriptive namePANCREATIN
    D.3.9.4EV Substance CodeSUB12545MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10500 to 21000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pancreatic Exocrine Insufficiency due to Cystic Fibrosis
    E.1.1.1Medical condition in easily understood language
    Maldigestion of diatery macronutients (pancreas not producing enough
    enzymes for digestion of fat, sugars and proteins) in Cystic Fibrosis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study No
    E.3Principal 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 ≥ 60 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.
    E.4Principal 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 ≥12 years of age, or 6,700 U lipase/kg/day in patients <12 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. Periodic abstinence (calendar, symptothermal, or post-ovulation
    methods) is not an acceptable method of contraception. The preferred and usual lifestyle of the subject must also be evaluated in determining if sexual abstinence is a reliable method of birth control.
    E.5 End points
    E.5.1Primary 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.5.1.1Timepoint(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.5.2Secondary 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, increased stool quantity, worsening of 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.
    E.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Israel
    United States
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 70
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 30
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 40
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 80
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    For minors, the parents will have to give their consent. The minors will
    also have to give their assent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 129
    F.4.2.2In the whole clinical trial 192
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Pancreaze: The patient will return to a commercially-available PERT therapy.
    Liprotamase: Patients receiving ≤ 10,000 U lipase-CLEC/kg/day will return to a commercially-available PERT therapy. Patients receiving >10,000 U lipase-CLEC/kg/day may have the option to participate in a separate clinical study to evaluate the long-term effects of liprotamase. If patient choose not to participate in that study, therapy with a commercially-available PERT will be resumed.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-07-28
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-03-26
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