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    Summary
    EudraCT Number:2017-000571-85
    Sponsor's Protocol Code Number:AN-EPI3333
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-04-21
    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 ConcernedSpain - AEMPS
    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
    Estudio en fase III aleatorizado, abierto, con evaluador enmascarado, de no inferioridad y con comparador activo para evaluar la eficacia y la seguridad de liprotamasa en sujetos con insuficiencia pancreática exocrina debida a fibrosis quística.
    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
    Estudio de la terapia con lipotramasa oral de origen no porcino
    A.3.2Name or abbreviated title of the trial where available
    RESULT: Reliable, Emergent Solution Using Liprotamase Treatment
    RESULT
    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 organisationLinical Spain, S.L.U.
    B.5.2Functional name of contact pointMar Torre Gómez
    B.5.3 Address:
    B.5.3.1Street AddressCalle Rosa de Lima, 1-bis. Edificio Alba
    B.5.3.2Town/ cityLas Matas / Madrid
    B.5.3.3Post code28290
    B.5.3.4CountrySpain
    B.5.4Telephone number+34913726059
    B.5.5Fax number+34913726060
    B.5.6E-mailupmmadrid@linical.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
    Insuficiencia Pancreática Exocrina debida a Fibrosis Quística
    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
    Mala digestión de los macronutrientes alimenticios (el páncreas no produce las suficientes enzimas para la digestión de la grasa, azúcares y proteínas) en la Fibrosis Cística.
    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).
    El objetivo principal de este estudio consiste en demostrar la no inferioridad del producto enzimático no porcino, liprotamasa, administrado a una dosis optimizada individualmente, con respecto a Pancreaze en cuanto al cambio en el coeficiente de absorción de grasas (CAG) desde la selección hasta el final del periodo de tratamiento principal en sujetos ≥7 años de edad con insuficiencia pancreática exocrina (IPE) debida a fibrosis quística (FQ).
    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.
    Los objetivos secundarios del estudio son evaluar y comparar los efectos de liprotamasa y Pancreaze sobre otras medidas de la digestión, incluido el coeficiente de absorción de nitrógeno (CAN), el peso de las deposiciones y los síntomas de malabsorción.
    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 ≥ 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 of age 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.
    1. Fibrosis quística según los criterios diagnósticos de la enfermedad:
    • Dos características clínicas indicativas de FQ y
    • O bien:
    a. Genotipo con 2 mutaciones identificables indicativas de FQ, o
    b. Cloruro en el sudor ≥mEq/l (≥60 mmol/l) mediante iontoforesis cuantitativa con pilocarpina.
    Las pruebas del diagnóstico de FQ se pueden obtener durante la selección, a menos que se hayan documentado previamente.
    2. Edad ≥7 años en el momento de la selección.
    3. Valor de elastasa fecal <100 mcg/g de heces obtenido durante la selección.
    4. Valor de CAG en la selección de ≥80 % durante el tratamiento con TREP. A los sujetos que reúnan todos los criterios de inclusión excepto el CAG se les podrá repetir el análisis del CAG después de haber experimentado un aumento en la dosis de TREP previa a la inclusión durante al menos 1 semana si el investigador considera que es seguro y adecuado. Este nuevo análisis del CAG debe realizarse dentro de los 30 días siguientes a la obtención del resultado de la primera medición del CAG.
    5. Clínicamente estables y sin indicios de infección aguda de las vías respiratorias altas o bajas en los 10 días anteriores a la visita 1.
    6. Estado nutricional aceptable o mejor, definido según lo siguiente:
    • IMC ≥16,0 kg/m2 para los sujetos de sexo femenino ≥18 años, o
    • IMC ≥16,5 kg/m2 para los sujetos de sexo masculino ≥18 años, o
    • IMC ≥percentil 25 en los sujetos de 7 a <18 años basado en las gráficas de crecimiento publicadas por la Organización Mundial de la Salud (OMS).
    • Peso que haya permanecido estable en todos los grupos de edad (descenso no superior al 5 %) durante los 90 días anteriores a la selección.
    7. Ser capaces de tomar un suplemento de enzimas pancreáticas en forma de cápsulas.
    8. Usando el mismo tratamiento de enzimas pancreáticas durante los últimos 30 días sin cambios en la pauta, a menos que el cambio de pauta se haya producido durante una repetición del análisis de CAG según lo descrito en el criterio de inclusión n.º 4.
    9. Los sujetos que reciban un tratamiento de supresión de ácidos gástricos (inhibidor de la bomba de protones o antagonista de los receptores de histamina 2) deben haber recibido una dosis estable durante al menos los 30 días anteriores a la visita 2.
    10. Capaces de realizar las pruebas y procedimientos necesarios para el estudio, según el criterio del investigador.
    11. Si se trata de un adulto, haber otorgado su consentimiento informado o su asentimiento por escrito según lo establecido por Anthera o por su representante y por el Comité de Revisión Institucional / Comité Ético Independiente (IRB/CEI). Si no es adulto, tener un progenitor o tutor legal que haya otorgado su consentimiento informado por escrito aprobado por Anthera o por su representante y por el CEI supervisor del centro.
    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 ≥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.
    1. Uso en curso de Pancreaze como preparado enzimático para el tratamiento de la IPE. Pueden haber utilizado Pancreaze previamente, pero no durante los 30 días anteriores a la selección.
    2. Tratamiento con liprotamasa en un ensayo clínico anterior, como los estudios TC-2A, 726 y 767, en el estudio SIMPLICITY (AN-EPI3332) y el ensayo SOLUTION (AN-EPI3331).
    3. Mujeres en periodo de lactancia durante el estudio.
    4. Antecedentes o diagnóstico de colonopatía fibrosante (CF).
    5. Antecedentes de síndrome de obstrucción intestinal distal (SOID) en los 6 meses previos a la visita de selección.
    6. Cualquier enfermedad diarreica crónica sin relación con la insuficiencia pancreática (p. ej., gastroenteritis infecciosa, esprúe o enfermedad intestinal inflamatoria).
    7. Antecedentes de trasplante de órganos sólidos o de resección quirúrgica intestinal importante. La resección intestinal importante se define como cualquier resección de la porción terminal del íleon o de la válvula ileocecal. También debe excluirse a los sujetos que hayan experimentado cambios cualitativos prolongados en su estado nutricional después de cualquier otra resección intestinal (p. ej., aumento o nueva necesidad de suplementos de enzimas pancreáticas en comparación con el estado prequirúrgico para mantener el mismo estado nutricional).
    8. Nivel de alanina aminotransferasa (ALT) o de aspartato aminotransferasa (AST) ≥5 veces el límite superior normal (LSN), o nivel de bilirrubina total ≥1,5 veces el LSN en la visita de selección, a menos que se deba a Síndrome de Gilbert. Los casos de sospecha o confirmación del Síndrome de Gilbert, deben ser discutidos con el monitor médico.
    9. Signos y/o síntomas de cirrosis hepática o de hipertensión portal (p. ej., esplenomegalia, ascitis, varices esofágicas), o hepatopatía documentada sin relación con la FQ.
    10. Volumen de espiración forzada en 1 segundo (FEV1 por sus siglas en inglés) <30 % del valor previsto.
    11. Uso de un preparado enzimático en la selección superior a 10 000 U de lipasa/kg/día o 2 500 U de lipasa/kg por comida en pacientes ≥17 años de edad, o 6 700 U de lipasa/kg/día en pacientes <17 años de edad.
    12. Hipersensibilidad conocida a los aditivos alimentarios o a Pancreaze.
    13. Hiperglucemia o diabetes relacionada con la FQ no controladas.
    14. Hiperuricemia o hiperuricosuria no controladas según el criterio del investigador principal (IP).
    15. Alimentación mediante sonda enteral durante los 6 meses previos a la selección.
    16. Uso rutinario de antidiarreicos, antiespasmódicos o purgantes laxantes, o cambio de la pauta de laxante osmótico crónico (p. ej., polietilenglicol) en los 3 meses anteriores.
    17. Cualquier afección que el investigador considere que pueda interferir en la intención de este estudio o hacer que la participación en él no sea lo que más interese al sujeto.
    18. Mostrar escasas probabilidades de finalizar el estudio, según el criterio del investigador.
    19. Estar participando en o haber abandonado dentro de los 30 días anteriores (antes de la visita de selección) un ensayo clínico donde se haya utilizado un fármaco, sustancia biológica o dispositivo en investigación, o participando actualmente en cualquier otro tipo de investigación médica que se considere incompatible desde el punto de vista científico o médico con este estudio.
    20. Mujer en periodo de lactancia, embarazada o que pretenda quedarse embarazada o amamantar durante el periodo del estudio, o bien que tenga un resultado positivo en una prueba de embarazo al inicio. Todos los sujetos sexualmente activos con capacidad reproductiva deberán utilizar un método anticonceptivo fiable. Las mujeres y los hombres deben utilizar o empezar a usar un método anticonceptivo fiable al menos 2 semanas antes de la aleatorización, a lo largo del estudio y durante al menos 3 meses después de finalizar el tratamiento del estudio. Un método anticonceptivo fiable se define como alguno de los siguientes: anticonceptivos por vía oral o inyectables, dispositivo intrauterino, implantes anticonceptivos, ligadura de trompas, histerectomía o un método de doble barrera (diafragma con espuma o gel espermicida, o preservativo), abstinencia o vasectomía.
    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).
    El objetivo principal de este estudio consiste en demostrar la no inferioridad de la liprotamasa, administrada a una dosis optimizada individualmente, con respecto a Pancreaze en cuanto al cambio en el coeficiente de absorción de grasas (CAG) desde la selección hasta el final del periodo de tratamiento principal (final de la semana 4) en sujetos ≥7 años de edad con IPE debida a fibrosis quística (FQ).
    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.
    Se compararán los valores al final del período de tratamiento principal de liprotamasa, y del control activo Pancreaze®.
    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, 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.
    • Demostrar la no inferioridad de la liprotamasa con respecto al comparador activo en cuanto al cambio en el coeficiente de absorción de nitrógeno (CAN) desde la selección hasta el final del periodo de tratamiento principal utilizando los mismos criterios de no inferioridad que para el CAG.
    • Evaluar el cambio en el peso de las heces desde la selección hasta el final del periodo de tratamiento principal (medido durante la recogida de heces de marcador a marcador).
    • Demostrar la no inferioridad de la liprotamasa con respecto a Pancreaze en cuanto al cambio en el CAG desde la selección hasta el final del periodo de tratamiento principal en el subgrupo de sujetos que reciban supresores de los ácidos gástricos.
    • Evaluar los signos y síntomas de malabsorción (dolor abdominal, meteorismo, esteatorrea, flatulencia, consistencia de las deposiciones, frecuencia de las deposiciones, cantidad de las deposiciones, hábitos intestinales en general) al inicio, durante el periodo de tratamiento principal y en el periodo de extensión.
    • Evaluar el cambio producido desde el inicio en la estatura, el peso y el índice de masa corporal (IMC) hasta el final del periodo de tratamiento principal y el periodo de extensión.
    • Evaluar el cambio producido en los niveles de colesterol total, vitaminas (A, D, E y K), albúmina y prealbúmina desde el inicio hasta el final del periodo de tratamiento principal y el periodo de extensión.

    La seguridad se evaluará a lo largo del estudio de acuerdo con los acontecimientos adversos (AA), incluidos los AA graves (AAG), la bioquímica sanguínea, la hematología, el análisis de orina, las exploraciones físicas, las constantes vitales y la medición de los niveles de colesterol total, albúmina, prealbúmina y vitaminas liposolubles. Durante el periodo de extensión se evaluarán la estatura, el peso, el IMC y los signos y síntomas de malabsorción.
    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.
    Se compararán los valores al final del período de tratamiento principal de liprotamasa, y del control activo Pancreaze®.
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    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.
    Para los menores, los padres tendrán que dar su consentimiento. Los menores también tendrán que dar su asentimiento.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 150
    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: the patient 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.
    Pancreaze: El paciente volverá a un tratamiento TREP comercialmente disponible.
    Liprotamasa: El paciente puede tener la opción de participar en un estudio clínico separado para evaluar los efectos a largo plazo de liprotamasa. Si el paciente decide no participar en ese estudio, se reanudará su tratamiento TREP comercialmente disponible.
    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 Decision2017-06-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-04-25
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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