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    Summary
    EudraCT Number:2016-005141-23
    Sponsor's Protocol Code Number:021FSGS16010
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-06-21
    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 number2016-005141-23
    A.3Full title of the trial
    A Randomized, Multicenter, Double-blind, Parallel, Active-control Study of the Effects of Sparsentan, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, on Renal Outcomes in Patients with Primary Focal Segmental Glomerulosclerosis (FSGS)
    Estudio controlado con principio activo, aleatorizado, multicéntrico, doble ciego y paralelo de los efectos de esparsentán, un receptor dual de endotelina y un bloqueador del receptor de angiotensina, sobre los resultados renales en pacientes con glomeruloesclerosis segmentaria y focal (GESF) primaria
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effectiveness and Safety of Sparsentan as treatment for Primary Focal Segmental Glomerulosclerosis (FSGS)
    La eficacia y seguridad de esparsentán como tratamiento para la glomeruloesclerosis segmentaria y focal (GESF) primaria.
    A.4.1Sponsor's protocol code number021FSGS16010
    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 SponsorRetrophin, 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 supportRetrophin, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRetrophin, Inc.
    B.5.2Functional name of contact pointRetrophin Call Center
    B.5.3 Address:
    B.5.3.1Street Address3721 Valley Centre Drive, Suite 200
    B.5.3.2Town/ citySan Diego, CA
    B.5.3.3Post code92130
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34962339485
    B.5.6E-mailcallcenter@retrophin.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/3/15/1574
    D.3 Description of the IMP
    D.3.1Product nameSparsentan
    D.3.2Product code RE-021
    D.3.4Pharmaceutical form Capsule, hard
    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 INNSparsentan
    D.3.9.1CAS number 254740-64-2
    D.3.9.2Current sponsor codeRE-021
    D.3.9.3Other descriptive nameSPARSENTAN
    D.3.9.4EV Substance CodeSUB168607
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 Irbesartan tablets (Approved in the USA. Reference listed drug Avapro) NDC # 43547-0374-03
    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 nameover-encapsulated 75 mg Irbesartan Tablets
    D.3.4Pharmaceutical form Capsule, hard
    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 INNIrbesartan
    D.3.9.1CAS number 138402-11-6
    D.3.9.3Other descriptive nameIRBESARTAN
    D.3.9.4EV Substance CodeSUB08293MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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
    Focal segmental glomerulosclerosis (FSGS)
    Glomeruloesclerosis segmentaria y focal (GESF)
    E.1.1.1Medical condition in easily understood language
    Scarring of the tissue in the filtering unit of the kidney (glomerulus).
    E.1.1.2Therapeutic area Diseases [C] - Symptoms and general pathology [C23]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10067757
    E.1.2Term Focal segmental glomerulosclerosis
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The efficacy objective of the study is to determine the long-term nephroprotective potential of treatment with sparsentan as compared to an angiotensin receptor blocker in patients with primary FSGS.

    The safety objective of the study is to assess the safety and tolerability of sparsentan by double-blind monitoring of safety endpoints.
    Eficacia: Determinar el potencial nefroprotector a largo plazo del tratamiento con esparsentán en comparación con un bloqueador del receptor de angiotensina en pacientes con glomeruloesclerosis segmentaria y focal (GESF) primaria.

    Seguridad: Evaluar la seguridad y la tolerabilidad de esparsentán mediante la supervisión con doble ciego de los criterios de valoración de la seguridad.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The patient or parent/legal guardian (as appropriate) is willing and able to provide signed informed consent, and where required, the patient is willing to provide assent, prior to any screening procedures.
    2. The patient has biopsy-proven primary FSGS or documentation of a genetic mutation in a podocyte protein associated with FSGS. The biopsy may have been performed at any time in the past, but will preferably include electron microscopy (EM) and immunofluorescence (IF) characteristics consistent with primary FSGS. The patient may be enrolled based on light microscopy diagnosis of FSGS in the absence of EM and/or IF analysis, provided the history (nephrotic syndrome with hypoalbuminemia, treatment with immunosuppression) and the course of the disease are indicative of primary FSGS, and potential secondary causes captured by the exclusion criteria have been carefully ruled out.
    3. Sites within the US: The patient is male or female aged 8 to 75 years, inclusive.
    Sites outside the US: The patient is male or female aged 18 to 75 years, inclusive.
    4. The patient has a UP/C ≥1.5 g/g at screening.
    5. The patient has an eGFR ≥30 mL/min/1.73 m2 at screening.
    6. The patient has a mean seated blood pressure ≥100/60 mmHg (on a maximum of 2 antihypertensive treatments at screening, including RAAS inhibitors) and ≤160/100 mmHg (patients >18 years of age) or ≥90/60 mmHg and ≤ the 95th percentile for age, sex, and height (patients ≤18 years of age).
    7. Sexually active women of childbearing potential (WOCBP) must agree to the simultaneous use of 2 medically accepted methods of contraception from Day 1/Randomization until 90 days after the last dose of study medication. At least one method of contraception must be highly reliable (ie, can achieve a failure rate of <1% per year), such as stable oral, implanted, transdermal, or injected contraceptive hormones associated with inhibition of ovulation, or an intrauterine device (IUD) in place for at least 3 months. The other method of contraception must be a barrier method, such as a diaphragm with spermicide or male partner’s use of male condom with spermicide. WOCBP are defined as those who are fertile, following menarche and until becoming postmenopausal unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as amenorrhea for more than 24 consecutive months without an alternative medical cause; women on hormone replacement therapy must have a documented plasma follicle-stimulating hormone level >40 mIU/mL. All WOCBP must have a negative pregnancy test (urine, with positive results confirmed by serum) at Visits 1 and 3 (Screening and Day 1/Randomization).
    NOTE: Prior to menarche, pregnancy testing and contraceptive use is not required. However, the patient and their parent/guardian must be advised that, immediately upon menarche, the patient will be required to begin pregnancy testing and, if deemed necessary by the Investigator, initiate contraceptive use. This requirement cannot be avoided.
    8. Males must be surgically sterile (more than 3 months post-vasectomy) or must agree to the use of medically accepted methods of contraception that are considered highly reliable from Day 1/Randomization until 90 days after the last dose of study medication.
    1. El paciente o el progenitor/tutor legal (según proceda) debe estar dispuesto y ser capaz de otorgar el consentimiento informado firmado y, donde así se requiera, el paciente debe estar dispuesto a facilitar su acuerdo antes de someterse a cualquiera de los procedimientos de selección.
    2. El paciente tiene GESF primaria probada mediante biopsia o documentación de una mutación genética en una proteína podocito asociada a la GESF. La biopsia puede haberse realizado en cualquier momento del pasado, pero incluirá preferentemente características en microscopia electrónica (ME) y en inmunofluorescencia (IF) coherentes con la GESF. Se podría inscribir al paciente en función del diagnóstico de GESF por microscopia en ausencia de MA y/o análisis de IF, siempre y cuando los antecedentes (síndrome nefrótico con hipoalbuminemia, tratamiento con inmunodepresión) y la evolución de la enfermedad sean indicativos de GESF primaria y las posibles causas secundarias recogidas por los criterios de exclusión se hayan descartado cuidadosamente.
    3. Centros de los Estados Unidos (EE. UU.): Pacientes de ambos sexos de 8 a 75 años de edad (inclusive).
    Centros fuera de los EE. UU.: Pacientes de ambos sexos de 18 a 75 años de edad (inclusive)
    4. Pacientes con p/C urinaria ≥1,5 g/g en la selección.
    5. Pacientes con una FGe ≥30 ml/min/1,73 m2 en la selección.
    6. Pacientes con una tensión arterial media asentada de ≥100/60 mmHg (con un máximo de 2 tratamientos con antihipertensores en la selección, incluidos los inhibidores del SRAA) y ≤160/100 mmHg (pacientes >18 años de edad) o ≥90/60 mmHg y ≤ el percentil 95º por edad, sexo y estatura (pacientes ≤18 años de edad).
    7. Las mujeres en edad fértil (MEF) y activas sexualmente deben aceptar el uso de 2 métodos anticonceptivos médicamente aceptados desde el día 1/aleatorización hasta 90 días después de la última dosis de la medicación del estudio. Al menos uno de los métodos anticonceptivos debe ser altamente fiable (es decir, puede alcanzar un índice de fallo de <1 % al año), como anticonceptivos hormonales orales, implantables, transdérmicos o inyectados estables asociados a la inhibición de la ovulación, o un dispositivo intrauterino (DIU) colocado durante al menos 3 meses. El otro método anticonceptivo debe ser un método de barrera, como el diafragma con espermicida o el uso por parte de la pareja masculina de un preservativo con espermicida. Las MEF se definen como las mujeres fértiles, después de la menarquía y hasta que alcanzan la posmenopausia, a menos que sean estériles de forma permanente. Los métodos de esterilización permanente incluyen la histerectomía, la salpingectomía bilateral y la ovariectomía bilateral. El estado posmenopáusico se define como una amenorrea que supera los 24 meses consecutivos sin una causa médica alternativa; las mujeres con terapia de restitución hormonal deben tener un nivel de folitropina plasmático documentado de >40 mIU/ml. Todas las MEF deben obtener un resultado negativo en la prueba de embarazo (en orina, con resultados positivos confirmados en suero) en las visitas 1 y 3 (selección y día 1/aleatorización).
    NOTA: Antes de la menarquía no son necesarias las pruebas de embarazo y anticonceptivos. No obstante, se debe recomendar a la paciente y a sus padres/tutor legal que, inmediatamente después de la menarquía, a la paciente se le requerirá que se someta a una prueba de embarazo y, si el investigador lo considera necesario, que inicie el uso de anticonceptivos. Este requisito no puede eludirse.
    8. Los hombres deben estar esterilizados quirúrgicamente (más de 3 meses después de la vasectomía) o deben aceptar utilizar métodos anticonceptivos médicamente aceptados que se consideren altamente fiables desde el día 1/aleatorización hasta 90 días después de la última dosis.
    E.4Principal exclusion criteria
    1. The patient has FSGS secondary to another condition.
    2. The patient has positive findings on any of the following serological tests of primary or secondary glomerular injury: anti-nuclear antibody, anti-double stranded deoxyribonucleic acid (DNA) antibodies, anti-neutrophil cytoplasmic antibody, rheumatoid factor, anti-glomerular basement membrane antibodies, polyclonal antibodies identified by serum and urine protein electrophoresis, cryoglobulins, or kappa and lambda chains.
    3. The patient has an indicator of relapse from complete remission (ie, recurrence or new occurrence of proteinuria >3.5 g/24 hours or UP/C >3.5 g/g within 30 days prior to or during screening).
    4. The patient has a history of type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus (hemoglobin A1c [HbA1c] >8%), or nonfasting blood glucose >180 mg/dL at screening.
    5. The patient has undergone any organ transplantation, with the exception of corneal transplants.
    6. The patient requires any of the prohibited concomitant medications.
    7. The patient has been treated with rituximab, cyclophosphamide, or abatacept within ≤3 months prior to screening. If a patient is taking other chronic immunosuppressive medications, the dosage must be stable for ≥1 month prior to randomization.
    8. The patient has a documented history of heart failure (New York Heart Association Class II-IV) and/or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema.
    9. The patient has clinically significant cerebrovascular disease (transient ischemic attack or stroke) and/or coronary artery disease (hospitalization for myocardial infarction or unstable angina, new onset of angina with positive functional tests, coronary angiogram revealing stenosis, or a coronary revascularization procedure) within 6 months prior to screening.
    10. The patient has hemodynamically significant valvular disease.
    11. The patient has jaundice, hepatitis, or known hepatobiliary disease (including asymptomatic cholelithiasis), or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2 times the upper limit of the normal range at screening.
    12. The patient is positive at screening for the human immunodeficiency virus (HIV) or markers indicating acute or chronic hepatitis B (HBV) infection (acute HBV is defined as a positive hepatitis B surface antigen [HBsAg], hepatitis B “e” antigen [HBeAg], HBV DNA in blood or liver, or immunoglobulin M [IgM] hepatitis B core antibody; chronic HBV is defined as a positive HBsAg and/or HBeAg and/or HBV DNA) or hepatitis C virus (HCV) infection (defined as reactive anti-HCV antibody and/or HCV RNA).
    13. The patient has a history of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years.
    14. The patient has a screening hematocrit value <27% or hemoglobin value <9 g/dL.
    15. The patient has a screening potassium value of >5.5 mEq/L.
    16. The patient is >18 years of age with a body mass index (BMI) >40, or is ≤18 years of age with a BMI in the 99th percentile plus 5 units at screening.
    17. The patient has a history of alcohol or illicit drug use disorder (as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition), or a reported habitual alcohol intake greater than 21 units/week within 2 years prior to screening.
    18. The patient has a history of serious side effect or allergic response to any angiotensin II antagonist or endothelin receptor antagonist, including sparsentan or irbesartan, or has a hypersensitivity to any of the excipients in the study medication.
    19. The female patient is pregnant, plans to become pregnant during the course of the study, or is breastfeeding.
    20. The male patient plans to father a child during the course of the study.
    21. The patient has participated in a study of another investigational product within 28 days prior to screening, or plans to participate in such a study during the course of this study.
    22. The patient has had prior exposure to sparsentan.
    23. The patient, in the opinion of the Investigator, is unable to adhere to the requirements of the study, including the ability to swallow the study medication capsules whole.
    1. El paciente tiene GESF secundaria a otra afección.
    2. El paciente tiene hallazgos positivos en alguna de las siguientes pruebas de serología de lesión glomerular primaria o secundaria: anticuerpos antinucleares, anticuerpos contra el ácido desoxirribonucleico (ADN) de doble cadena, anticuerpos contra neutrófilos citoplasmáticos, factor reumatoide, anticuerpos contra la membrana de la base glomerular, anticuerpos policlonales identificados mediante electroforesis de proteínas, crioglobulinas o cadenas kappa y lambda en suero y en orina.
    3. El paciente tiene un indicador de recaída después de la remisión completa (es decir, recurrencia o nueva aparición de proteinuria >3,5 g/24 horas o p/C en orina >3,5 g/g en un periodo inferior a 30 días antes de la selección).
    4. El paciente tiene antecedentes de diabetes mellitus tipo 1, diabetes mellitus tipo 2 no controlada (hemoglobina A1c [HbA1c] >8 %) o glucemia en condición de no ayuno >180 mg/dl en la selección.
    5. El paciente se ha sometido a algún trasplante de órganos, a excepción de trasplantes de córnea o tratamiento con células madre para la artrosis de rodilla.
    6. El paciente necesita tomar alguna de la medicación concomitante prohibida.
    7. Al paciente se le ha tratado con rituximab, ciclofosfamida o abatacept en un periodo ≤3 meses antes de la selección. Si un paciente está tomando otra medicación inmunodepresora crónica, la dosis debe ser estable durante ≥1 mes antes de la aleatorización.
    8. El paciente tiene antecedentes documentados de insuficiencia cardíaca (clase II-IV de la Asociación del corazón de Nueva York [New York Heart Association]) o de hospitalización previa por insuficiencia cardíaca o disnea sin explicar, ortopnea, disnea paroxística nocturna, ascitis y/o edema periférico.
    9. El paciente tiene una enfermedad cerebrovascular clínicamente significativa (accidente isquémico transitorio o accidente cerebrovascular) y/o arteriopatía coronaria (hospitalización por infarto de miocardio o angina inestable, nueva aparición de angina con pruebas funcionales positivas, angiograma coronario que revela estenosis o un procedimiento de revascularización coronaria) en los 6 meses previos a la selección.
    10. El paciente tiene una valvulopatía significativa a nivel hemodinámico
    11. El paciente tiene ictericia, hepatitis o enfermedad hepatobiliar conocida (incluida la colelitiasis asintomática) o niveles de alanina aminotransferasa (ALT) y/o de aspartato aminotransferasa (AST) >2 veces el límite superior de la normalidad en la selección.
    12. El paciente tiene un resultado positivo de virus de inmunodeficiencia humana (VIH) en la selección o marcadores que indican una infección aguda o crónica por virus de la hepatitis B (VHB) (la infección aguda por VHB se define como resultado positivo para antígeno de superficie de la hepatitis B [HBsAg], antígeno “e” de la hepatitis B [HBeAg], ADN del VHB en sangre o en el hígado o anticuerpo central de la hepatitis B inmunoglobulina M [IgM]. El VHB crónico se define como un resultado positivo de HBsAg, HBeAg o ADN de VHB, o bien como infección por virus de la hepatitis C (VHC) (definida como anticuerpo reactivo frente al VHC y/o ARN del VHC).
    13. El paciente tiene antecedentes de neoplasia maligna diferente al carcinoma basocelular o epidermoide o carcinoma cervicouterino en los últimos 2 años.
    14. El paciente tiene un nivel de hematocrito en la selección de <27 % o de hemoglobina <9 g/dl.
    15. El paciente tiene un nivel de potasio en la selección de >5,5 mEq/l.
    16. El paciente es menor de 18 años con un índice de masa corporal (IMC) >40 o es mayor de 18 años con un IMC en el percentil 99º más 5 unidades en la selección.
    17. El paciente tiene antecedentes de trastorno por abuso de alcohol o de drogas ilegales (tal y como lo define el Manual diagnóstico y estadístico de trastornos mentales, 5.ª edición) o de una ingesta de alcohol habitual comunicada superior a 21 unidades/semana en los 2 años previos a la selección.
    18. El paciente tiene antecedentes de efecto secundario o respuesta alérgica graves a los antagonistas de angiotensina II o a los antagonistas del receptor de endotelina, incluidos esparsentán o irbesartán, o bien tiene hipersensibilidad a cualquiera de los excipientes de la medicación del estudio.
    19. La paciente de sexo femenino está embarazada, piensa quedarse embarazada o está en periodo de lactancia.
    20. El paciente de sexo masculino prevé engendrar un niño.
    21. El paciente ha participado en un estudio de otro producto en investigación en los 28 días previos a la selección o prevé participar en un estudio de ese tipo durante el transcurso de este estudio.
    22. El paciente se ha expuesto previamente a esparsentán.
    23. El paciente, en opinión del investigador, es incapaz de cumplir con los requisitos del estudio, incluida la capacidad para tragar las cápsulas de la medicación del estudio enteras.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy End points:
    The primary efficacy endpoint is the slope of eGFR assessed at the final analysis.
    The surrogate efficacy endpoint is the proportion of patients achieving a Up/C ≤1.5 g/g and a >40% reduction from baseline in Up/C at Week 36.

    Safety End points:
    • Changes from baseline in body weight, vital signs, physical examinations, peripheral edema, 12-lead electrocardiogram (ECG), and clinical laboratory parameters
    • Changes from baseline in lipid profile (total cholesterol and triglycerides, low density lipoprotein cholesterol [LDL-C], very low-density lipoprotein cholesterol [VLDL-C] and triglycerides [VLDL-TG], and high-density lipoprotein cholesterol [HDL])
    • Changes from baseline in serum albumin and serum potassium at each visit
    • The incidence of treatment-emergent adverse events (TEAEs)
    Criterio de valoración principal de la eficacia:
    El criterio de valoración principal de la eficacia es la curva de la FGe evaluada en el análisis final.
    El criterio de valoración indirecto de la eficacia es la proporción de los pacientes que logran una p/C en orina ≤1,5 g/g y una reducción de >40 % a partir del valor inicial en p/C en orina en la semana 36 evaluada en el análisis intermedio.

    Seguridad:
    Los criterios de valoración de la seguridad incluyen:
    • Cambios respecto al valor inicial del peso corporal, las constantes vitales, las exploraciones físicas, el edema periférico, el electrocardiograma (ECG) de 12 derivaciones y los parámetros de análisis clínicos
    • Cambios desde el valor inicial en el perfil lipídico (colesterol total y triglicéridos, colesterol de lipoproteínas de baja densidad [C-LDL], colesterol de lipoproteínas de muy baja densidad [C-VLDL] y triglicéridos y colesterol de lipoproteínas de alta densidad [C-HDL])
    • Cambios respecto al valor inicial de la albúmina sérica y el potasio sérico en cada visita
    • Incidencia de los acontecimientos adversos (AA)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary efficacy and safety endpoints will be evaluated at the final analysis (Week 108)
    Surrogate efficacy analysis at Week 36
    Los criterios de valoración principales de la eficacioa y de la seguridad se evaluarán en el análisis final (Semana 108)
    El análisis de valoración indirecto en la Semana 36
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints include:
    • The percent change from Week 6 in eGFR at Week 108
    • The percent change from baseline in Up/C at Week 36 assessed at the final analysis

    Other Efficacy Endpoints:
    • The absolute and percent change from baseline in eGFR at each visit
    • The percent change from Week 6 in eGFR at each visit
    • The proportion of patients achieving a Up/C ≤1.5 g/g and a >40% reduction from baseline in Up/C at each visit
    • The percent change from baseline in Up/C at each visit
    • The time to achieve the target reduction in Up/C (ie, ≤1.5 g/g and a >40% reduction)
    • The proportion of patients reaching a confirmed 40% change in eGFR, end-stage renal disease (ESRD), or death. (ESRD is defined as initiation of renal replacement therapy [RRT], kidney transplantation, or sustained eGFR <15 mL/min/1.73 m2 during the study
    • New occurrence of, or relapse back to, nephrotic-range proteinuria (ie, Up/C >3.5 g/g) in patients who have achieved the target reduction in Up/C (ie, ≤1.5 g/g and a >40% reduction) at any time during the study
    • Changes from baseline in blood pressure at each visit
    • The proportion of patients requiring intensification in immunosuppressive medication during the study
    • The proportion of patients undergoing reduction in immunosuppressive medication during the study
    • Changes from baseline in quality of life (QOL), measured via patient-reported outcome (PRO) at each visit beginning with Week 12
    Los criterios de valoración secundarios de la eficacia son:
    • El cambio en el porcentaje desde la semana 6 en la FGe en la semana 108.
    • El cambio en el porcentaje desde el valor inicial en la p/C en orina en la semana 36 evaluada en el análisis final.

    Otros criterios de valoración de la eficacia incluyen:
    • El cambio absoluto y el cambio en el porcentaje respecto al valor inicial de la FGe en cada visita
    • El cambio en el porcentaje desde la semana 6 en la FGe en cada visita
    • La proporción de los pacientes que logran una p/C en orina ≤1,5 g/g Y una reducción de >40 % a partir del valor inicial en p/C en orina en cada visita
    • El cambio en el porcentaje respecto al valor inicial de la p/C en orina en cada visita
    • El tiempo transcurrido hasta lograr la reducción deseada en la p/C en orina (es decir, ≤1,5 g/g Y una reducción de >40 %)
    • Nueva aparición o recaída de la proteinuria de rango nefrótico (es decir, p/C en orina >3,5 g/g) en los pacientes que han logrado la reducción deseada en la p/C en orina (es decir, ≤1,5 g/g Y una reducción de >40 %) en cualquier momento durante el estudio
    • Cambios respecto al valor inicial de la tensión arterial en cada visita
    • La proporción de pacientes que necesitan una intensificación de la medicación con inmunodepresores durante el estudio
    • La proporción de pacientes que se someten a una reducción de la medicación con inmunodepresores durante el estudio
    • Cambios respecto al valor inicial de la calidad de vida (CdV), medidos mediante los resultados comunicados por el paciente (RCP) en cada una de las visitas empezando desde la semana 12
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be assessed at the final analysis (Week 108)
    Los criterios de valoración secundarios se evaluarán en el análisis final (Semana 108)
    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 Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    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
    Australia
    Canada
    Czech Republic
    Denmark
    France
    Germany
    Hungary
    Italy
    Korea, Republic of
    Poland
    South Africa
    Spain
    Taiwan
    United Kingdom
    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
    LVLP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days14
    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: 60
    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: 30
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 180
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state26
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 130
    F.4.2.2In the whole clinical trial 300
    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)
    None. The Investigator should resume standard of care treatment, including treatment with appropriate medications, as deemed appropriate.
    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 Decision2018-09-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-17
    P. End of Trial
    P.End of Trial StatusOngoing
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