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Summary
EudraCT Number:2014-004806-14
Sponsor's Protocol Code Number:TKS-2014-001
National Competent Authority:Spain - AEMPS
Clinical Trial Type:EEA CTA
Trial Status:Completed
Date on which this record was first entered in the EudraCT database:2015-11-25
Trial results View 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
A. Protocol Information
A.1Member State ConcernedSpain - AEMPS
A.2EudraCT number2014-004806-14
A.3Full title of the trial
Single-Arm Study to Assess the Efficacy of UVADEX® (methoxsalen) Sterile Solution in Conjunction with the THERAKOS® CELLEX® Photopheresis System in Pediatric Patients with Steroid-Refractory Acute Graft Versus Host Disease (aGvHD)
Estudio de un solo grupo para evaluar la eficacia de UVADEX® (metoxsaleno) solución estéril en conjunto con el sistema de fotoféresis CELLEX® de THERAKOS® en pacientes pediátricos con enfermedad del injerto contra el huésped aguda (EICHa) refractaria a esteroides
A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
Single-Arm Study to see if UVADEX® together with the THERAKOS® CELLEX® Photopheresis System is effective in Pediatric Patients with Steroid-Refractory Acute Graft Versus Host Disease (aGvHD)
Estudio de un solo brazo de tratamiento para ver si UVADEX® junto con el Sistema Fotoferesis THERAKOS® Cellex® es eficaz en pacientes pediátricos con enfermedad del injerto contra el huésped aguda (EICHa) refractaria a esteroides
A.4.1Sponsor's protocol code numberTKS-2014-001
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 SponsorTherakos, 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 supportTHERAKOS, Inc.
B.4.2CountryUnited States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1Name of organisationTherakos, Inc.
B.5.2Functional name of contact pointProject Management
B.5.3 Address:
B.5.3.1Street Address10 North High Street
B.5.3.2Town/ cityWest Chester
B.5.3.3Post codePA 19380
B.5.3.4CountryUnited States
B.5.4Telephone number610-235-2828
B.5.6E-mailChristian.peters@therakos.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 Yes
D.2.1.1.1Trade name Uvadex 20 microgramos/ml solución de para modificación de las fracciones sanguíneas.
D.2.1.1.2Name of the Marketing Authorisation holderTherakos UK Ltd.
D.2.1.2Country which granted the Marketing AuthorisationSpain
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/3/06/374
D.3 Description of the IMP
D.3.4Pharmaceutical form Solution for blood fraction modification
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPExtracorporeal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNmethoxsalen
D.3.9.1CAS number 298-81-7
D.3.9.3Other descriptive nameMETHOXSALEN
D.3.9.4EV Substance CodeSUB14541MIG
D.3.10 Strength
D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
D.3.10.2Concentration typeequal
D.3.10.3Concentration number20
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 Yes
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
Enfermedad agudadel injerto contra el huésped (EICHa)
Acute graft-versus-host disease (aGvHD)
E.1.1.1Medical condition in easily understood language
La enfermedad del injerto contra el húesped es una complicación del trasplante de médula ósea en la que la células inmunes trasplantadas reconocen y atacan antígenos de los órganos del receptor.
Graft-versus-host disease is a complication of bone marrow
transplantation in which immune cells in the transplanted marrow
recognize the recipients as "foreign" and mount an immunological attack
E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
MedDRA Classification
E.1.2 Medical condition or disease under investigation
E.1.2Version 18.1
E.1.2Level PT
E.1.2Classification code 10018651
E.1.2Term Graft versus host disease
E.1.2System Organ Class 10021428 - Immune system disorders
E.1.3Condition being studied is a rare disease Yes
E.2 Objective of the trial
E.2.1Main objective of the trial
To evaluate the efficacy of extracorporeal photopheresis (ECP) in pediatric patients with steroid-refractory aGvHD
Evaluar la eficacia de la fotoféresis extracorpórea (FEC) en pacientes pediátricos con EICHa refractaria a esteroides
E.2.2Secondary objectives of the trial
?To assess the safety of ECP
?To assess the duration of response to ECP
?To assess the steroid-sparing effect of ECP
?To assess the organ-specific response to ECP
?Evaluar la eficacia de la FEC
?Evaluar la duración de la respuesta a la FEC
?Evaluar el efecto ahorrador de esteroides de la FEC
?Evaluar la respuesta específica de órgano a la FEC
E.2.3Trial contains a sub-study No
E.3Principal inclusion criteria
Patients must meet all of the following criteria:
1.Male or female 1 to 21 years of age at the time of consent
2.Steroid-refractory grade B-C aGvHD
­Steroid-refractory is defined as progressive aGvHD within 3 days of, or no response within 7 days of, starting systemic steroids at a dose of 2.0 mg/kg/day of methylprednisolone equivalents
3.A Karnofsky/Lansky Performance Status score ? 30
4.Laboratory values are within the following limits, assessed within 3 days of the first study treatment:
­Absolute neutrophil count > 0.5 × 109/L
­Creatinine level < 2 times the upper limit of normal
5.For patients with isolated upper GI symptoms, pre-Screening biopsy results to confirm diagnosis of aGvHD
6.Female patients of childbearing potential and nonsterilized males who are sexually active with a female partner are committed to using effective methods of contraception, including abstinence, throughout their participation in the study and for 3 months following the last ECP treatment; females of childbearing potential are those who have reached the onset of menarche or 8 years of age, whichever comes first
7.Signed informed consent/assent is obtained before conducting any study procedures; the parent, legal guardian or legally authorized representative of a minor must also provide written informed consent
Los pacientes deben cumplir todos los siguientes criterios:
1.Hombres o mujeres de 1 a 21 años de edad en el momento del consentimiento
2.EICHa de grado B-C refractaria a esteroides
­La refractariedad a los esteroides se define como EICHa progresiva en los 3 días siguientes al inicio de los esteroides sistémicos a una dosis de 2,0 (mg/kg)/día de equivalentes de metilprednisolona, o falta de respuesta en los 7 días siguientes al inicio de dicho tratamiento
3.Puntuación del estado funcional de Karnofsky/Lansky ? 30
4.Los parámetros de laboratorio están dentro de los límites siguientes, evaluados en los 3 días previos al primer tratamiento del estudio:
­Recuento absoluto de neutrófilos > 0,5 × 109/l
­Concentración de creatinina < 2 veces el límite superior de la normalidad
5.Para pacientes con síntomas GI superiores aislados, resultados de la biopsia previa al cribado para confirmar el diagnóstico de EICHa
6.Las mujeres con capacidad de procrear y los hombres no esterilizados que mantengan relaciones sexuales activas con una mujer deben comprometerse a utilizar métodos anticonceptivos eficaces, como abstinencia, durante toda su participación en el estudio y en los 3 meses siguientes al último tratamiento con FEC; las mujeres con capacidad de procrear son aquellas que han llegado al inicio de la menarquia o que tienen 8 años de edad, lo que ocurra primero
7.Se debe obtener el consentimiento/asentimiento informado y firmado antes de realizar cualquier procedimiento del estudio; el progenitor, el tutor legal o un representante legalmente autorizado del menor también debe dar su consentimiento informado por escrito
E.4Principal exclusion criteria
Any of the following would exclude the patient from participation in the study:
1.Currently enrolled in another clinical trial for the treatment of acute GvHD
2.Use of any experimental regimens or medication(s) for acute GvHD treatment
3.Treatment with > 2.0 mg/kg/day of methylprednisolone equivalents for aGvHD within 30 days prior to the first study treatment
4.Development of aGvHD after donor lymphocyte infusion
5.Overt signs of relapse of the underlying condition
6.Uncontrolled viral, fungal, or bacterial infection
7.Platelet count < 20.0 × 109/L, despite platelet transfusion
8.Total bilirubin value ? 15 mg/dL
9.Inability to tolerate the extracorporeal volume shifts associated with ECP treatment
10.Uncontrolled GI bleeding
11.Veno-occlusive liver disease
12.Life expectancy < 4 weeks
13.Patient requires invasive ventilation or vasopressor support
14.Known human immunodeficiency virus (HIV) or hepatitis B or C virus infection
15.Known hypersensitivity or allergy to methoxsalen
16.Known hypersensitivity or allergy to heparin or Anticoagulant Citrate Dextrose Formula-A (ACD-A)
17.Co-existing photosensitive disease (e.g., porphyria, systemic lupus erythematosus, albinism) or aphakia
18.Female patient is breastfeeding or pregnant
19.Any psychological, familial, sociological, and/or geographical condition that may potentially hamper compliance with the study protocol and the follow-up schedule
Cualquiera de los siguientes impediría que el paciente participara en el estudio:
1.Incluido actualmente en otro ensayo clínico para el tratamiento de la EICH aguda
2.Uso de regímenes o fármacos experimentales para el tratamiento de la EICHa
3.Tratamiento con >2,0 (mg/kg)/día de equivalentes de metilprednisolona por EICHa en los 30 días previos al primer tratamiento del estudio
4.Aparición de EICHa después de la infusión de linfocitos de donante
5.Signos manifiestos de recurrencia de la enfermedad subyacente
6.Infección vírica, micótica o bacteriana no controlada
7.Recuento de plaquetas < 20,0 × 109/l, a pesar de la transfusión de plaquetas
8.Concentración de bilirrubina total ? 15 mg/dl
9.Imposibilidad de tolerar los desplazamientos del volumen extracorpóreo asociados al tratamiento con FEC
10.Hemorragia GI no controlada
11.Enfermedad venooclusiva hepática
12.Esperanza de vida < 4 semanas
13.El paciente precisa soporte ventilatorio o con vasopresores
14.Infección conocida por el virus de la inmunodeficiencia humana (VIH) o por el virus de la hepatitis B o C
15.Hipersensibilidad o alergia conocida al metoxsaleno
16.Hipersensibilidad o alergia conocida a la heparina o al anticoagulante de citrato dextrosa fórmula A (ACD-A)
17.Enfermedad con fotosensibilidad coexistente (p. ej., porfiria, lupus eritematoso sistémico, albinismo) o afaquia
18.Lactancia o embarazo
19.Cualquier situación psicológica, familiar, social o geográfica que pueda dificultar el cumplimiento del protocolo del estudio y el calendario de seguimiento
E.5 End points
E.5.1Primary end point(s)
The proportion of patients reaching an overall response (CR+PR) after 4 weeks (Day 28) of ECP treatment, regardless of steroid tapering.
La proporción de pacientes que alcanzaron una respuesta total (respuesta completa [RC] + respuesta parcial [RP]) después de 4 semanas (día 28) de tratamiento con FEC , independientemente de la reducción de la dosis de esteroides
E.5.1.1Timepoint(s) of evaluation of this end point
after 4 weeks (Day 28) of ECP treatment, regardless of steroid tapering.
después de 4 semanas (día 28) de tratamiento con FEC , independientemente de la reducción de la dosis de esteroides
E.5.2Secondary end point(s)
?Safety parameters including vital signs, laboratory tests, and spontaneously reported AEs and SAEs
?Proportion of patients who achieve an overall response 8 weeks (Day 56) after initiation of ECP treatment
?Duration of response, defined as the length of time a patient maintains a response through Week 16 of the Follow-up Period on a per-patient basis
?Proportion of patients who achieve an overall response after 4 weeks (Day 28) and 8 weeks (Day 56) of ECP treatment according to the modified Glucksberg criteria (see Appendix B: Modified Glucksberg Criteria)
­Source data will be collected for each patient and entered into the eCRF, and a scoring algorithm will be applied to calculate the grade of aGvHD using the Modified Glucksberg Criteria
?Cumulative dose of daily steroids administered from diagnosis of aGvHD to 12 weeks (Day 84) after initiation of ECP treatment
?Organ-specific CR+PR rates at 4 weeks (Day 28) and 8 weeks (Day 56) after initiation of ECP treatment
?Parámetros de seguridad incluyendo constantes vitales, análisis de laboratorio, y acontecimientos adversos (AA) y acontecimientos adversos graves (AAG) notificados espontáneamente
?Proporción de pacientes que alcancen una respuesta total 8 semanas (día 56) después del inicio del tratamiento con FEC
?Duración de la respuesta, definida como el tiempo que un paciente mantiene una respuesta hasta la semana 16 del período de seguimiento, de manera individual
?Proporción de pacientes que alcanzan una respuesta total después de 4 semanas (día 28) y 8 semanas (día 56) de tratamiento con FEC según los criterios de Glucksberg modificados. Se recogerán los datos originales de cada paciente y se introducirán en el CRDe, y se aplicará un algoritmo de puntuación para calcular el grado de la EICHa utilizando los criterios de Glucksberg modificados
?Dosis acumulada de esteroides diarios administrada desde el diagnóstico de EICHa hasta 12 semanas (día 84) después del inicio del tratamiento con FEC
?Tasas de RC + RP específicas de órgano 4 semanas (día 28) y 8 semanas (día 56) después del inicio del tratamiento con FEC
E.5.2.1Timepoint(s) of evaluation of this end point
see above
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 No
E.8.1.1Randomised No
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 concerned3
E.8.5The trial involves multiple Member States Yes
E.8.5.1Number of sites anticipated in the EEA10
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
Austria
France
Germany
Hungary
Italy
Poland
Spain
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
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 months1
E.8.9.1In the Member State concerned days
E.8.9.2In all countries concerned by the trial years1
E.8.9.2In all countries concerned by the trial months1
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: 48
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) Yes
F.1.1.4.1Number of subjects for this age range: 4
F.1.1.5Children (2-11years) Yes
F.1.1.5.1Number of subjects for this age range: 20
F.1.1.6Adolescents (12-17 years) Yes
F.1.1.6.1Number of subjects for this age range: 20
F.1.2Adults (18-64 years) Yes
F.1.2.1Number of subjects for this age range: 4
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 No
F.3.3.7Others Yes
F.3.3.7.1Details of other specific vulnerable populations
children
F.4 Planned number of subjects to be included
F.4.1In the member state6
F.4.2 For a multinational trial
F.4.2.1In the EEA 24
F.4.2.2In the whole clinical trial 48
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)
Once a subject completes the participation in the trial, the subject will be treated according to standard care of treatment or may continue ECP treatment on commercial product at the discretion of the Principal Investigator.
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 Decision2015-11-24
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2015-11-04
P. End of Trial
P.End of Trial StatusCompleted
P.Date of the global end of the trial2019-07-16

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