Clinical Trials Register

Summary
EudraCT Number:	2014-004996-22
Sponsor's Protocol Code Number:	7962-CL-0022
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:	2016-02-03
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

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2014-004996-22

A.3

Full title of the trial

A Phase 2a, Randomized, Double-blind, Placebo- and Naproxen-controlled, Parallel-group Study to Assess the Analgesic Efficacy of ASP7962 in Patients with Pain Due to Osteoarthritis of the Knee

Estudio Fase IIa, aleatorizado, doble-ciego, paralelo, controlado con placebo y Naproxeno para evaluar la eficacia analgésica de ASP7962 en pacientes con dolor secundario a osteoartritis en rodilla

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A trial to investigate the efficacy of ASP7692 in patients with pain due to arthritis in the knee

Estudio para investigar la efficacia del ASP7692 en pacientes con dolor debido a osteoartritis en la rodilla

A.3.2

Name or abbreviated title of the trial where available

OAK Study

Estudio OAK

A.4.1

Sponsor's protocol code number

7962-CL-0022

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Astellas Pharma Europe B.V.
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Astellas Pharma Europe B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Chiltern International Spain S.A
B.5.2	Functional name of contact point	Ricardo Diaz
B.5.3	Address:
B.5.3.1	Street Address	Centro Empresarial Euronova 3, Ronda de Poniente 10, Planta 2
B.5.3.2	Town/ city	Tres Cantos, Madrid
B.5.3.3	Post code	28760
B.5.3.4	Country	Spain
B.5.4	Telephone number	3491187 27 00.
B.5.5	Fax number	3491187 28 49.
B.5.6	E-mail	spain.regulatory@chiltern.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	ASP7962
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ASP7962
D.3.9.3	Other descriptive name	ASP7962
D.3.9.4	EV Substance Code	SUB124281
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	NAPROXEN Tablets USP
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Pharmaceuticals USA Inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NAPROXEN
D.3.9.3	Other descriptive name	NAPROXEN
D.3.9.4	EV Substance Code	SUB09159MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Osteoarthritis of the knee

Osteoartritis de la rodilla

E.1.1.1

Medical condition in easily understood language

Osteoarthritis of the knee

Osteoartritis de la rodilla

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10031165
E.1.2	Term	Osteoarthritis knee
E.1.2	System Organ Class	100000004859

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate the analgesic efficacy of ASP7962 relative to placebo

Evaluar la eficacia analgésica de ASP7962 en comparación con placebo

E.2.2

Secondary objectives of the trial

Secondary
Evaluate the efficacy of ASP7962 relative to placebo on pain on walking, function and stiffness Evaluate the time course of efficacy of ASP7962 relative to placebo
Evaluate the improvement in overall patient status of ASP7962 relative to placebo
Evaluate the safety and tolerability of ASP7962 relative to placebo

Evaluar la eficacia de ASP7962 en comparación con placebo en cuanto al dolor al andar, a la funcionalidad y a la rigidez
Evaluar el curso temporal de la eficacia de ASP7962 en comparación con placebo
Evaluar la mejoría en el estado general del paciente de ASP7962 en comparación con placebo
Evaluar la seguridad y la tolerabilidad de ASP7962 en comparación con placebo

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations.
2. Patient is a male or female patient and aged 18 to 75 years, at screening.
3. Patient has a primary diagnosis of OA of the index knee with symptoms for at least 6 months prior to screening and patient meets American College of Rheumatology clinical classification criteria for OA of the knee, defined by the following.
Knee pain and at least 3 of the following 6 (a-f):
a) Age > 50 years
b) Morning stiffness < 30 minutes
c) Crepitus on active motion
d) Bony tenderness
e) Bony enlargement
f) No palpable warmth of synovium
4. Patient has a radiographic image of the index knee (according to the minimum quality criteria for radiographic image as set by the central radiology reader) showing evidence of OA with a Kellgren-Lawrence grade 2 or 3 at screening.
5. Patient has moderate to severe index knee pain (pain due to OA of the knee at least 5 days per week for the last 3 months prior to screening, as determined by patient?s medical history).
6. Patient is ambulatory and the index knee must not contain any orthopedic and/or prosthetic device.
7. WOMAC pain subscale score (with a 48-hour recall period) in the index knee ? 4 at baseline (visit 2 predose, mean of all questions on pain subscale).
8. Mean daily index knee average pain score between ? 4 and ? 9 (0-10 NRS), from the available recordings in the last 4 days prior to visit 2.
9. WOMAC physical function subscale score ? 4 at baseline (visit 2 predose, mean of all questions on the physical function subscale with a 48-hour recall period).
10. Patient is willing to discontinue all current pain medications during the baseline and treatment periods (until day 57) (except for allowed rescue medications). Low dose aspirin for cardioprophylaxis is allowed.
11. Patient is compliant with daily pain recording.
12.Male patient and their female spouse/partners who are of childbearing potential must be using a barrier method* and 1 form of highly effective birth control** starting at screening and continuing throughout the study period and for 90 days after the final study drug administration.
13. Male patient must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration.
14. Female patient must either:
Be of non childbearing potential:
post-menopausal (defined as at least 1 year without any menses) prior to screening, or
documented surgically sterile
Or, if of childbearing potential:
agree not to try to become pregnant during the study and for 28 days after the final study drug administration,
and have a negative pregnancy test at screening and at baseline (visit 2 predose),
and if heterosexually active, agree to consistently use a barrier method* and 1 form of highly effective birth control** starting at screening and continuing throughout the study period and for 28 days after the final study drug administration15. Female patient must agree not to breastfeed starting at screening and continuing throughout the study period and for 28 days after the final study drug administration.
16. Female patient must not donate ova starting at screening and continuing throughout the study period and for 28 days after the final study drug administration.
17. Patient agrees not to participate in another investigational study from screening through the follow-up period (until day 57).
* Barrier methods of birth control include:
?Condom or occlusive cap (diaphragm or cervical/ vault caps) with spermicidal foam/gel/film/cream/suppository
** Highly effective forms of birth control include:
?Consistent and correct usage of established oral contraception (including progestogen-only oral contraception associated with inhibition of ovulation).
?Established intrauterine device (IUD) or intrauterine system (IUS).
Waivers to the inclusion criteria will NOT be allowed.

1. Debe obtenerse del paciente el consentimiento informado por escrito aprobado por el Comité independiente de ética (CIE) o el Consejo institucional de revisión (CIR) y la comunicación de privacidad según estipule la normativa nacional antes de que se realice ningún procedimiento relacionado con el estudio (incluida, si es pertinente, la retirada del tratamiento prohibido).
2. El paciente es un varón o una mujer y tiene entre 18 y 75 años en la selección.
3. El paciente tiene un diagnóstico principal de artrosis en la rodilla de referencia con síntomas que duran como mínimo 6 meses antes de la selección y el paciente cumple los criterios de clasificación clínica de artrosis de rodilla del American College of Rheumatology, definidos por lo siguiente:
Dolor de rodilla y por lo menos 3 de los 6 puntos siguientes (a-f):
a) Edad >50 años
b) Rigidez matutina < 30 minutos
c) Crepitación con el movimiento activo
d) Dolorimiento óseo
e) Aumento de tamaño óseo
f) Ausencia de calor palpable de la membrana sinovial
4. El paciente tiene una imagen radiográfica de la rodilla de referencia (de acuerdo con los mínimos criterios de calidad de una imagen radiográfica establecidos por el lector radiológico central) que muestra evidencia de artrosis con un grado de Kellgren-Lawrence de 2 o 3 en la selección (según la lectura central).
5. El paciente tiene dolor de moderado a intenso en la rodilla de referencia (dolor secundario a la artrosis de la rodilla un mínimo de cinco días a la semana durante los tres últimos meses anteriores a la selección, determinado en función de la historia clínica del paciente).
6. El paciente no está encamado y la rodilla de referencia no debe contener ningún dispositivo ortopédico ni protésico.
7. Puntuación de la subescala del dolor del WOMAC (con un periodo de recuerdo de 48 horas) en la rodilla de referencia ? 4 en la visita basal (Visita 2 antes de la dosis, media de todas las preguntas de la subescala del dolor).
8. Puntuación media diaria del dolor promedio de la rodilla de referencia entre ? 4 y ? 9 (0-10 NRS), de los registros disponibles en los 4 últimos días anteriores a la visita 2.
9. Puntuación de la subescala de la función física del WOMAC ? 4 en la visita basal (visita 2 antes de la dosis, media de todas las preguntas de la subescala de la función física con un periodo de recuerdo de 48 horas).
10. El paciente está dispuesto a dejar de tomar todos los analgésicos actuales durante los periodos basal y de tratamiento (hasta el día 57) (excepto para los tratamientos de rescate permitidos). Se permite una dosis baja de aspirina como cardioprofilaxis.
11.Paciente cumple el registro diario del dolor. Se definirá cumplimiento con respecto a la cumplimentación del diario si se anotan valoraciones promedio diarias del dolor al menos 5 días en el periodo basal, de los cuales como mínimo 3 días correspondan a los últimos 4 días anteriores a la visita 2.
13. El paciente varón no debe donar esperma empezando en la selección y continuando durante todo el periodo del estudio y durante 90 días después de la administración final del fármaco experimental.
14. Una paciente debe:
? O bien no ser fértil:
? Posmenopáusica (como mínimo 1 año sin menstruaciones) antes de la selección, o bien
? haber sido esterilizada quirúrgicamente, y documentado
? O, si es fértil:
? aceptar no intentar quedarse embarazada durante el estudio y durante 28 días después de la administración final del fármaco experimental,
? Tener una prueba de embarazo negativa en la selección y en la visita basal (visita 2 antes de la dosis), y
? si es heterosexualmente activa, aceptar utilizar constantemente 2 formas de control de la natalidad muy eficaces* (como mínimo una de las cuales debe ser un método de barrera) empezando en la selección y continuando durante todo el periodo del estudio y durante 28 días después de la administración final del fármaco experimental.
15. La paciente debe aceptar no dar el pecho empezando en la selección y continuando durante todo el periodo del estudio y durante 28 días después de la administración final del fármaco experimental.
16. La paciente no debe donar óvulos empezando en la selección y continuando durante todo el periodo del estudio y durante 28 días después de la administración final del fármaco experimental.
17. El paciente acepta no participar en otro estudio en fase experimental desde la selección hasta acabar el periodo de seguimiento (hasta el día 57).

E.4

Principal exclusion criteria

1.CH of suicide attempt/ suicidal behavior. Suicidal ideation within last 12m or significant risk to commit suicide, judged by inv. at Scr & rando 2.Current or prior psychosis, major depressive disorder or other CS psychiatric disorder 3. Current or prior CS neurologic disease: peripheral neuropathy, stroke, cognitive impairment and seizure 4.CS musculoskeletal disorder (exception OA), CV,GI, endocrinologic (DM allowed if controlled HbA1c? 7.1% and no peripheral neuropathy), hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, dermatologic, renal &/or other major disease judged by inv. 5.Active malignancy or CH of malignancy (except treated nonmelanoma skin cancer) within past 5y. 6.CH of inflammatory arthritis: rheumatoid arthritis or CH of RPOA, osteonecrosis or avascular necrosis of bone &/or joints or other Dx that may increase risk of RPOA 7.Findings suggestive of RPOA/increased risk for RPOA on Scr X-ray of index or non-index joints (central reading) 8.CH of shoulder Sx ,CS trauma or current symptoms: pain or impaired range of motion at shoulder joint 9.Coagulopathy, anticoagulant tt or diagnosed thrombocytopenia or functional platelet disorder 10.CH of paracetamol intolerance or existence of medical condition or use of concomitant medication (CM) being paracetamol contraindicated 11.Naproxen(Nx) contraindication: hypersensitivity to Nx or Nx sodium; asthma, rhinitis, nasal polyps, urticarial or allergic-type reactions after taking aspirin or other NSAIDs; anticipated CABG during study; active or CH of peptic ulceration; active or CH of GI bleeding (exception hemorrhoids) or perforation 12.Tramadol (TD) contraindication: TD hypersensitivity; monoamine oxidase inhibitor used within 2w prior to Scr or during Scr or BSL periods 13.BMI>39 kg/m2. 14.CS abnormality on 12-lead ECG at Scr or BSL (v2 predose) 15.CH of acute coronary syndrome, ischemic or hemorrhagic stroke, transient ischemic attack, coronary or peripheral revascularization procedure, HF, ischemic heart disease, unexplained syncope, cardiac arrest, CS cardiac arrhythmias, heart block (first degree heart block allowed if PR<210msec), torsade de pointes, structural heart disease or personal/family CH of long QT syndrome 16.Resting FR<50or>100bpm; SBP>160mmHg;DBP>90 mmHg at Scr or BSL(v2 predose). If repeat measurement meets above criteria, pt to be excluded 17.CH of unexplained syncopal events or symptomatic orthostatic hypotension at Scr or BSL (v2 predose) 18.According to inv. CS abnormalities in clinical chemistry, hematology or urinalysis at Scr 19.AST, ALT,TBL>1.5 times ULN at Scr 20.GFR?60mL/min/1.73m2(MDRD calculation) at Scr 21.Positive result for HBSLAg, anti-HBc, anti-HAV [IgM], anti-HCV or HIV 1 antibodies &/or HIV 2 at Scr 22.Any IP within 28 d (or 5 half-lives of IP, whichever longer) before Scr or scheduled to receive IP other than blinded study tt during the course of study 23. Pt previously received NGF antibodies 24.Major Sx/orthopedic Sx within 3m before Scr or plans for surgical intervention during study 25.Not suitable candidate for joint replacement & unable to stop chronic NSAID use 26.Intra-articular corticosteroidwithin3m prior to Scr, intraarticular hyaluronic acid within6m prior to Scr or intra-articular local anesthetic within 12m prior to Scr or any of these therapies during Scr or BSL periods 27.Systemic corticosteroids within 30d before Scr or during Scr or BSL periods 28. Any med. or nonmed therapy effective reducing pain of OA of the knee:OTC products (exception ice packs, rest &paracetamol) during BSL period 29.Pt started or stopped physiotherapy, acupuncture or transcutaneous electrical nerve stimulation related to tt of the index knee within 4w prior to Scr or during the Scr or BSL periods.Stable regimens of introduced >4w prior to Scr will be allowed if regimen continues unchanged during study 30.Used opioids >4 days during week preceding Scr/Scr period; or received any opioids during BSL period 31.Used DPP4 inhibitors within 12m prior to v2 32.Systemic inducer of CYP450 3A metabolism in 3m before v2. 33.No complied with requirements for restricted and prohibited medications and nonmed therapies during BSL period 34.Positive drug Screen for alcohol or recreational drugs or nonprescribed controlled substances at Scr or BSL 35.CH of alcohol or drug abuse/dependence/misuse within 1y prior to Scr 36.Painful condition syndrome/other concurrent medical/arthritic condition with potential to confound assessment of pain in index knee 37. HADS score>12 on either subscale at Scr or BSL (v2 predose) 38.Pt involved in ongoing or settled workers compensation claim, disability or litigation related to index knee or pain problem 39.Condition (inv. opinion) makes pt unsuitable for study participation 40. Employee of Astellas Group, CRO involved or inv. site executing the study.

1Ant suicidio/comp/ideas suicidas en últimos 12m a juicio del inv en v.sel. y aleatorización.2Psicosis/TDM/otros trastornos Psiquiátricos.3Enf.Neurológica:neuropatía periférica, ACV, deterioro cognitivo y convulsiones.4Trast. musculoesquelético (excep. de OA), cardiovascular, gastrointestinal, endocrinológico (DM permitida si controlada:HbA1c ? 7,1 % sin neuropatía periférica),hematológico,hepático, inmunológico, metabólico,urológico, pulmonar, dermatológico, renal u enf mayor a juicio del inv.5Neoplasia maligna activa o ant de neoplasia maligna (excep. cáncer cutáneo no melanoma tratado) en los 5a ant.6Ant artritis inflamatoria:AR o OAPR, osteonecrosis o necrosis vascular del hueso/articulaciones u otros q pueden aumentar riesgo de OAPR.7Rx en v.sel de las articulaciones de ref o no ref sugestivas de OA de progresión rápida(según lab.central).8Ant.Cx de hombro, traumatismo o síntomas actuales:dolor o deterioro amplitud del mov en articulación del hombro.9Coagulopatía, tto con ACO o con trombocitopenia o trast. funcional plaquetario.10Ant. intolerancia a paracetamol o enf.o tto concomitante para los q. esté contraindicado paracetamol.11Contraindic. naproxeno(Nx),hipersensibilidad conocida a Nx o a Nx sódico;asma, rinitis,pólipos nasales,reacciones urticariales o alérgicas tras aspirina o AINE,previsión de Cx de revasculariazación aortocoronaria durante el estudio,ant.de úlcera péptica, o úlcera péptica activa, Hemorragia (excep. hemorroides) o perforación.12Contraindicación tramadol (TD):hipersensibilidad conocida a TD. Pac ha tomado IMAO en las 2s ant. a v.sel. o durante periodo v.sel o basal.13IMC>39 kg/m2.14.Anomalía ECG 12 derivac. en v.sel. o basal (V2 predosis).15Ant SCA, ACV isquémico/hemorrágico, AIT, procedimiento de revascularización coronaria o periférica, IC, cardiopatía isquémica, síncope idiopático, parada cardíaca, arritmias cardiacas, bloqueo de rama (bloqueo de 1er grado permitido si intervalo PR?210ms), torsade de pointes, cardiopatía estructural o ant. personales/familiares SQT prolongado.16FC en reposo<50ó>100lpm;TAS>160mmHg,TAD>90 mmHg en v.sel. o v.basal (V2predosis)Si la medida repetida cumple crit.anteriores, el pac será excluido.17Ant.de síncope idiopático o hipotensión ortostática sintomática en v.de sel. o en v.basal (V2 predosis).18Valores anormales en BQ, hematología o análisis de orina en v.sel.19Perfil hepático ALT,AST,BLT>1,5 veces LSN en sel.20TFG ? 60 ml/min /1,73 m2,MDRD en selecc.21 Análisis + HBsAg, anti-HBc, AcHepA,Ig M anti-VHA, IgM anti-VHC o AcVIHI/VIHII en sel.22Pac en tto en fase experimental en 28d(o 5semividas del fármaco,lo que sea más largo) antes de sel o está programado para recibir tto experimental distinto de los ttos enmascarados del estudio.23Ha recibido con anterioridad AcFCN.24Pac sometido a Cx mayor o Cx ortopédica en 3m ant a sel o prevista una Cx durante estudio.25Pac no adecuado para artroplastia y no puede dejar de tomar AINE crónicos.26Ha recibido corticosteroides intraarticulares en los 3ms ant a la sel, Ac. hialurónico intraarticular en los 6m ant a la sel o anestesia local intraarticular en 12m ant a la sel o cualquiera de estos ttos durante los periodos de sel o basal.27Ha recibido corticosteroides sistémicos en los 30d antes de la sel. o drante los periodos de sel. o basal (corticosteroides vía tópica, nasal o inhalación permitidos).28Ha recibido ttos o terapias no medicamentosas con eficacia en reducción dolor de OAR:OTC, (salvo compresas de hielo, reposo y paracetamol) durante el periodo basal.29Ha iniciado/interrumpido fisioterapia,acupuntura o estimulación nerviosa eléctrica transcutánea relacionada con tto rodilla de ref en las 4sem ant a la sel o durante periodos de sel o basal.Se permitirán pautas estables de ttos introducidos >4sem antes de la sel si la mantiene invariable durante el estudio.30Opioides durante>4 d en la sem precedente a la sel./durante periodo de sel./ha recibido cualquier opioide en el periodo basal.31DPP-4 en 12m ant a la V2.32Uso de inductores sistémico de CIP 450 3A en los 3m ant a V2.33No cumple requisitos relativos a ttos restringidos y prohibidos y ttos no medicamentosos en el periodo basal.34Cribado + en alcohol/drogas/sustancias controladas no recetadas en periodo de sel/basal.35Ant. de toxicomanía/dependencia/abuso de alcohol/drogas en año ant a v.sel.36Pac con Sdr. Doloroso/otras enf.médicas/artríticas concurrentes que pueden confundir la evaluacion de dolor en rodilla de ref.37Puntuación HADS>12 en cualquier subescala en periodo de sel o basal (V2 predosis).38Pac implicado en solicitud de indemnización por acc.laboral, incapacidad o litigio en curso o resuelto relacionado con rodilla de ref. o cualquier problema doloroso.39Otra enf. q hace q no sea adecuado para participar en el estudio.40Pac. empleado del G.Astellas, de la CRO participante o del centro donde se lleve a cabo el estudio

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is change from baseline to week 4 in WOMAC pain subscale score.

Cambio en la puntuación de la subescala de dolor del WOMAC desde la visita basal hasta la semana 4

E.5.1.1

Timepoint(s) of evaluation of this end point

week 4

Semana 4

E.5.2

Secondary end point(s)

Analysis of Secondary Endpoints
The secondary efficacy endpoints are defined in [Section 2.3.2]
Treatment Period
The change from baseline to EOT in WOMAC pain subscale score will be analyzed using an
Analysis of Covariance (ANCOVA) with treatment group and study site as fixed effects and
baseline value as a covariate. The EOT refers to the last assessment during the treatment
period. The ANCOVA will present LS mean, SE and 2-sided 90% CI for mean changes from
baseline within each treatment group (placebo, ASP7962, and naproxen). Difference in
LS means between ASP7962 and placebo with corresponding 2-sided 90% CI and the
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difference in LS means between naproxen and placebo with corresponding 2-sided 80% CI
will be derived. The differences in the LS mean estimates will be used to obtain 1 -sided
P values for ASP7962 versus placebo and naproxen versus placebo.
The change from baseline to EOT for WOMAC physical function and stiffness subscale
scores, WOMAC total score, WOMAC walking pain, mean daily average pain NRS score,
and PGA will be analyzed using the same ANCOVA model as described above for the
change from baseline to EOT in WOMAC pain subscale score.
The MMRM analysis as described in [Section 7.4.1.1] for the primary efficacy analysis will
be used to analyze the following secondary efficacy endpoints during the treatment period:
? Change from baseline to weeks 1 and 2 for WOMAC pain subscale score (WOMAC
pain subscale scores from the MMRM model with weeks 1, 2 and 4 included)
? Change from baseline to weeks 1, 2 and 4 for WOMAC physical function and stiffness
subscale scores, WOMAC total score, and WOMAC walking pain
? Change from baseline to weeks 1, 2, 3 and 4 for mean daily average pain score based on
the NRS
? Change from baseline to weeks 1, 2 and 4 for PGA
The proportion of patients who have a ? 30% reduction and ? 50% reduction from baseline to
EOT in WOMAC pain subscale score will be summarized for each treatment group, as well
as the difference in proportion between ASP7962 and placebo and between naproxen and
placebo. The difference in proportion between ASP7962 and placebo and between naproxen
and placebo will be analyzed using a 1 -sided Fisher?s exact test.

7.4.2 Análisis de los criterios de valoración secundarios
Los criterios prendarios de las variables secundarias de eficacia se definen en la [Sección 2.3.2].
Periodo de tratamiento
El cambio en la puntuación de la subescala de dolor del WOMAC desde el valor basal hasta el FdT se analizará utilizando un análisis de la covarianza (ANCOVA) con el grupo de tratamiento y el centro del estudio como efectos fijos y el valor basal como una covariable. FdT se refiere a la última evaluación durante el periodo de tratamiento. El ANCOVA presentará la media de los MC, el EE y el IC bilateral del 90% para los cambios medios con respecto al valor basal dentro de cada grupo de tratamiento (placebo, ASP7962 y naproxeno). Se obtendrá la diferencia de las medias de los MC entre ASP7962 y placebo con el correspondiente intervalo de confianza bilateral del 90% y la diferencia en las medias de los MC entre naproxeno y placebo con el correspondiente intervalo de confianza bilateral del 80%. Las diferencias en las estimaciones de las medias de los MC se utilizarán para obtener valores de P unilaterales para ASP7962 en comparación con placebo y naproxeno en comparación con placebo.
El cambio desde el valor basal hasta FdT para las puntuaciones de la subescala de función física y de rigidez del WOMAC, la puntuación total del WOMAC, el dolor al caminar del WOMAC, la puntuación NRS media del dolor promedio diario y la EGP se analizará utilizando el mismo modelo ANCOVA que se acaba de describir para el cambio en la puntuación de la subescala de dolor del WOMAC entre el valor basal y el FdT.
El análisis del MMRM como se describe en [Sección 7.4.1.1] para el análisis principal de eficacia se utilizará para analizar los siguientes criterios secundarios de valoración de la eficacia durante el periodo de tratamiento:
? Cambio en la puntuación de la subescala de dolor del WOMAC desde la visita basal hasta las semanas 1 y 2 (puntuaciones de la subescala de dolor del WOMAC del modelo MMRM con las semanas 1, 2 y 4 incluidas)
? Cambio en las puntuaciones de la subescala de la función física y la rigidez del WOMAC, la puntuación total del WOMAC y el dolor al caminar del WOMAC entre la visita basal y las semanas 1, 2 y 4
? Cambio en la puntuación media del dolor promedio diario evaluada según la NRS desde la visita basal hasta las semanas 1, 2, 3 y 4
? Cambio desde la visita basal hasta las semanas 1, 2 y 4 para la EGP

Para cada grupo de tratamiento se resumirá la proporción de pacientes que tengan una reducción ? 30% y una reducción ? 50% desde el valor basal hasta FdT en la puntuación de la subescala de dolor del WOMAC, así como la diferencia en la proporción entre ASP7962 y placebo y entre naproxeno y placebo. La diferencia en la proporción entre ASP7962 y placebo y entre naproxeno y placebo se analizará utilizando una prueba exacta unilateral de Fischer.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 1, week 2, week 3, week 4

Semana 1, semana 2, semana 3, semana 4

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial 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

Ultima visita del último paciente

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

150

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

165

F.4.2

For a multinational trial

F.4.2.1

In the EEA

205

F.4.2.2

In the whole clinical trial

205

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

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-03-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-03-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-09-29

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