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    Summary
    EudraCT Number:2016-002943-40
    Sponsor's Protocol Code Number:ALN-CC5-003
    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:2016-09-30
    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 number2016-002943-40
    A.3Full title of the trial
    A Phase 2, Open-label, Single Dose, Study of Subcutaneously Administered ALN-CC5 in Patients with Paroxysmal Nocturnal Hemoglobinuria who are Inadequate Responders to Eculizumab
    Estudio en fase II, sin enmascaramiento de una dosis única de ALN-CC5 administrado por vía subcutánea en pacientes con hemoglobinuria paroxística nocturna que presentan una respuesta insuficiente al eculizumab
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Study with Investigational Drug, ALN-CC5, in patients with Paroxysmal Nocturnal Hemoglobinuria who are Inadequate Responders to Eculizumab
    Estudio clínico con fármaco en investigación, ALN-CC5, en pacientes con hemoglobinuria paroxística nocturna que presentan una respuesta insuficiente al eculizumab
    A.4.1Sponsor's protocol code numberALN-CC5-003
    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 SponsorAlnylam 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 supportAlnylam Pharmaceuticals Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlnylam Pharmaceuticals Inc
    B.5.2Functional name of contact pointClinical Trials Hotline
    B.5.3 Address:
    B.5.3.1Street Address300 Third Street
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 021242
    B.5.3.4CountryUnited States
    B.5.6E-mailclinicaltrials@alnylam.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code ALN-CC5
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNALN-62643
    D.3.9.2Current sponsor codeALN-62643
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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.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
    Paroxysmal nocturnal hemoglobinuria (PNH)
    Hemoglobinuria paroxística nocturna (HPN)
    E.1.1.1Medical condition in easily understood language
    Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal hematopoietic stem cell disorder of the blood characterized by destruction of red blood cells by the complement system.
    Hemoglobinuria paroxística nocturna es un raro trastorno clonal de células madre hematopoyéticas de la sangre caracterizado por destrucción de células rojas de sangre por el sistema del complemento.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10055629
    E.1.2Term Paroxysmal nocturnal hemoglobinuria
    E.1.2System Organ Class 100000004857
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the effect of ALN-CC5 on red blood cell (RBC) hemolysis
    Evaluar el efecto del ALN-CC5 en la hemólisis de eritrocitos (ERI)
    E.2.2Secondary objectives of the trial
    Evaluate the safety and tolerability of ALN-CC5
    Characterize the pharmacodynamic (PD) effect of ALN-CC5
    Evaluar la seguridad y tolerabilidad del ALN-CC5
    Caracterizar el efecto farmacodinámico (FD) del ALN-CC5
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age 18 years or older
    2. History of PNH
    3. Treatment with eculizumab at a stable dose for a minimum of 60 days before Screening
    4. Inadequate response to eculizumab as defined by elevated LDH level before eculizumab infusion at Screening as follows:
    • LDH≥3.0×ULN (with or without symptoms) attributable to hemolysis in the opinion of the Investigator; or,
    • LDH ≥2.0×ULN, 1 or more of the following at Screening and while receiving eculizumab treatment, and which in the opinion of the Investigator is/are attributable to PNH disease: PNH symptoms (eg, fatigue, abdominal pain, dyspnea, dysphagia, or erectile dysfunction); Hemoglobin level ≤10 g/dL; Any blood transfusions within 90 days before Screening; and/or Spontaneous vascular thrombosis at any time since starting eculizumab treatment.
    5. Women of child-bearing potential (WOCBP) must have a negative pregnancy test, cannot be breast feeding, and must be willing to use a highly effective method of contraception 14 days before ALN-CC5 administration, throughout study participation, and for 6 months after ALN-CC5 administration.
    6. Willing and able to comply with the study requirements and to provide written informed consent
    7. Vaccinated against Neisseria meningitides according to standard practice (patients may be rescreened if not previously vaccinated)
    1. Edad igual o superior a 18 años.
    2. Antecedentes de HPN.
    3. Tratamiento con eculizumab en una dosis estable durante un mínimo de 60 días antes de la selección.
    4. Respuesta insuficiente al eculizumab definida por una concentración elevada de LDH antes de la infusión de eculizumab en la selección como sigue:
    • LDH ≥ 3,0 veces el LSN (con o sin síntomas) atribuible a hemólisis en opinión del investigador; o,
    • LDH ≥ 2,0 veces el LSN, 1 o más de lo siguiente en la selección y durante el tratamiento con eculizumab, y que en opinión del investigador pueda atribuirse a la enfermedad de HPN:
    • Síntomas de HPN (cansancio, dolor abdominal, disnea, disfagia o disfunción eréctil);
    • Concentración de hemoglobina ≤ 10 g/dl;
    • Alguna transfusión de sangre en los 90 días previos a la selección; y/o
    • Trombosis vascular espontánea en cualquier momento desde el inicio del tratamiento con eculizumab.
    5. Las mujeres en edad fértil (MEF) deberán obtener un resultado negativo en la prueba de embarazo, no podrán estar amamantando y tendrán que estar dispuestas a utilizar un método anticonceptivo muy eficaz desde 14 días antes de la administración de ALN-CC5, durante todo el tiempo que participen en el estudio y hasta 6 meses después de la administración de ALN-CC5.
    6. Voluntad y capacidad de cumplir los requisitos del estudio y otorgar el consentimiento informado por escrito.
    7. Vacunación contra Neisseria meningitides con arreglo a la práctica habitual (los pacientes tendrán que repetir la selección si no estaban ya vacunados).
    E.4Principal exclusion criteria
    1. Alanine transaminase ≥2×ULN or total bilirubin ≥4×ULN (unless bilirubin elevation is due to Gilbert’s syndrome), which is considered clinically relevant in the opinion of the Investigator
    2. Clinically significant bone marrow suppression as defined by 2 or more of the following:
    • Absolute neutrophil count ≤1.0×10 to power of 9/L
    • Platelet count ≤50×10 to power of 9/L
    • Absolute reticulocyte count ≤60×10 to power of 9/L
    3. Clinical laboratory test results considered clinically relevant and unacceptable in the opinion of the Investigator
    4. Planned change in eculizumab dose within 60 days of administration of ALN-CC5 (patients may be re-Screened)
    5. Spontaneous vascular thrombosis within 30 days of randomization (patients may be re Screened)
    6. Known or suspected hereditary asymptomatic complement deficiency
    7. Known clinical laboratory evidence or clinical diagnosis of human immunodeficiency virus infection (HIV), hepatitis C virus (HCV) infection, or chronic hepatitis B virus infection as shown by hepatitis B surface antigen positivity in blood
    8. Suspicion of active viral, bacterial, fungal, or parasitic infection as a cause for breakthrough hemolysis and their presence within 14 days before ALN-CC5 administration (patients may be rescreened)
    9. Travelled to Saudi Arabia or Africa within 90 days of Screening, or planning to do so during the study (patients may be rescreened)
    10. Received an investigational agent within the last 90 days or are in follow-up of another clinical study before study enrollment
    11. Active serious mental illness or psychiatric disorder, including, but not limited to, schizophrenia, bipolar disorder, or severe depression requiring current pharmacological intervention
    12. Other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation
    13. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc
    14. History of intolerance to SC injection(s) at the proposed injection site(s) that could potentially hinder study drug administration or evaluation of local tolerability
    15. History of meningococcal infection within 12 months before Screening
    16. Known history of chronic liver disease or cirrhosis
    1. Elevación de la alanina transaminasa ≥ 2 veces el LSN o bilirrubina total ≥4 veces el LSN (salvo que la elevación de la bilirrubina se deba al síndrome de Gilbert), que el investigador considere clínicamente relevante.
    2. Supresión clínicamente significativa de la médula ósea definida por 2 o más de lo siguiente:
    • Recuento absoluto de neutrófilos ≤ 1,0 × 109/l.
    • Recuento de plaquetas ≤ 50 × 109/l.
    • Recuento absoluto de reticulocitos ≤ 60 × 109/l.
    3. Resultados de las evaluaciones analíticas que el investigador considere clínicamente relevantes e inaceptables.
    4. Cambio previsto en la dosis de eculizumab en los 60 días previos a la administración de ALN-CC5 (los pacientes podrán repetir la selección).
    5. Trombosis vascular espontánea en los 30 días previos a la aleatorización (los pacientes podrán repetir la selección).
    6. Sospecha o confirmación de deficiencia hereditaria asintomática del complemento.
    7. Signos analíticos conocidos o diagnóstico clínico de infección por el virus de la inmunodeficiencia humana (VIH), infección por el virus de la hepatitis C (VHC) o infección crónica por el virus de la hepatitis B, confirmada por un resultado positivo del antígeno de superficie del virus de la hepatitis B en sangre.
    8. Sospecha de infección activa por virus, bacterias, hongos o parásitos como causa de hemólisis intercurrente y su presencia en los 14 días previos a la administración de ALN-CC5 (los pacientes podrán repetir la selección).
    9. Haber viajado a Arabia Saudí o África en los 90 días previos a la selección, o tener previsto hacerlo durante el estudio (los pacientes podrán repetir la selección).
    10. Haber recibido un fármaco en investigación en los últimos 90 días o ser objeto de seguimiento para otro estudio clínico antes del reclutamiento para este estudio.
    11. Enfermedad mental o trastorno psiquiátrico grave y activo, como esquizofrenia, trastorno bipolar o depresión intensa que precise una intervención farmacológica en curso.
    12. Otras afecciones médicas o enfermedades que, en opinión del investigador, podrían interferir con el cumplimiento del estudio o la interpretación de los datos.
    13. Antecedentes de alergias múltiples a fármacos o antecedentes de reacción alérgica a un oligonucleótido o a GalNAc.
    14. Antecedentes de intolerancia a inyecciones SC en el lugar de inyección propuesto que podría dificultar la administración del fármaco del estudio o la evaluación de la tolerabilidad local.
    15. Antecedentes de infección meningocócica en los 12 meses previos a la selección.
    16. Antecedentes conocidos de cirrosis o hepatopatía crónica.
    E.5 End points
    E.5.1Primary end point(s)
    Percent change from baseline in LDH
    Cambio porcentual desde el inicio en la lactato deshidrogenasa (LDH)
    E.5.1.1Timepoint(s) of evaluation of this end point
    At Week 12
    En la semana 12
    E.5.2Secondary end point(s)
    • Incidence of AEs
    • Proportion of patients with LDH levels ≤1.5×ULN
    • Change in complement activity levels (CAP and CCP)
    • Incidencia de acontecimientos adversos (AA)
    • Proporción de pacientes con niveles de LDH ≤ 1,5 × el límite superior de la normalidad (LSN)
    • Cambio en los niveles de actividad del complemento (vía alternativa del complemento [VAC] y vía clásica del complemento [VCC])
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Incidence of AEs: throughout the study until the end of study visit
    • Proportion of patients with LDH levels ≤1.5×ULN: at Week 12
    • Change in complement activity levels (CAP and CCP): throughout the study until the end of study visit
    • Incidencia de acontecimientos adversos (AA): durante todo el estudio hasta la visita de final de estudio
    • Proporción de pacientes con niveles de LDH ≤ 1,5 × LSN a las 12 semanas
    • Cambio en los niveles de actividad del complemento (VAC y VCC): durante todo el estudio hasta la visita de final de estudio
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    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 No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    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
    Austria
    Belgium
    Bulgaria
    Canada
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Israel
    Korea, Republic of
    Netherlands
    Norway
    Russian Federation
    Spain
    Sweden
    Taiwan
    Turkey
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    UVUP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 14
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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 state1
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 8
    F.4.2.2In the whole clinical trial 15
    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
    Ninguno
    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 Decision2016-11-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-14
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2016-11-23
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