E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Parkinson’s Disease |
Enfermedad de Parkinson |
|
E.1.1.1 | Medical condition in easily understood language |
A progressive disease of the nervous system characterised by tremor, muscular rigidity, and slow, imprecise movement. |
Una enfermedad progresiva del sistema nervioso caracterizada por temblor, rigidez muscular y movimiento lento e impreciso |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061536 |
E.1.2 | Term | Parkinson's disease |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of 2 doses of PXT002331 as an adjunct to levodopa in the reduction of OFF time in subjects with PD. |
Evaluar la eficacia de 2 dosis de PXT002331 como tratamiento adyuvante de la levodopa para reducir el periodo OFF en sujetos con enfermedad de Parkinson (EP). |
|
E.2.2 | Secondary objectives of the trial |
To assess the effects of 2 doses of PXT002331 as an adjunct to levodopa on LID in subjects with PD.
To assess the pharmacokinetic profile of PXT002331 in subjects with PD.
To assess the safety and tolerability of 2 doses of PXT002331 in subjects with PD. |
- Evaluar los efectos de 2 dosis de PXT002331 como tratamiento adyuvante de la levodopa en la discinesia inducida por levodopa (DIL) en sujetos con EP. - Evaluar el perfil farmacocinético del PXT002331 en sujetos con EP. - Evaluar la seguridad y tolerabilidad de 2 dosis de PXT002331 en sujetos con EP. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects will be: 1.1. males or females of non-childbearing potential diagnosed after the age of 30 years with idiopathic PD (ie, not induced by drugs or other diseases) as defined by fulfilling Steps 1 and 2 of the United Kingdom (UK) PD Society Brain Bank clinical diagnostic criteria
1.2. between 35 and 85 years of age, inclusive, at the time of signing informed consent
2. Subjects will have: 2.1. a documented medical history of idiopathic PD for at least 3 years
2.2. disease severity of 2 to 4 on the modified Hoehn and Yahr scale when in the OFF state
2.3. been treated with a stable regimen of levodopa-containing therapy and should maintain the stability of their therapy throughout the study according to their usual regimen (dose level and frequency). The maximum allowed total levodopa dose must be ≤1600 mg per day.
2.3.1. subjects who are on an immediate-release formulation of levodopa-containing therapy, NOT including Apodespan PR (or equivalent), must be receiving at least 3 doses per day and must be on a stable dose for at least 2 weeks prior to the first screening visit.
2.3.2. subjects who are on a long-acting formulation of levodopa-containing therapy, including Apodespan PR (or equivalent), must be on a stable dose for at least 6 weeks prior to the first screening visit
2.4. experienced motor fluctuations with wearing off over a period of at least 3 months prior to randomisation, with a minimum daily OFF time of at least 2 hours per 24 hours, while awake (as measured during the Screening Period by subject home diary [Hauser diary] on each of the 3 consecutive days immediately preceding the baseline visit; ≥2 hours OFF time on each of the 3 days)
2.5. experienced predictable OFF periods, as assessed at screening and baseline by a MDS UPDRS Part IV B, Question 4.5 rating of 1 or 2
2.6. experienced LID over a period of at least 3 months prior to randomisation, with a minimum daily ON time with dyskinesia (troublesome and/or non troublesome) lasting at least 2 hours per 24 hours, while awake (as measured during the Screening Period by subject home diary [Hauser diary] on each of the 3 consecutive days immediately preceding the baseline visit; ≥2 hours ON time with dyskinesia on each of the 3 days)
2.7. experienced significant time spent with LID, as assessed at screening and baseline by MDS UPDRS Part IV A, Question 4.1 score ≥1
2.8. experienced impact from LID on daily function, as assessed at screening and baseline by MDS UPDRS Part IV A, Question 4.2 score ≥2
2.9. been on a stable regimen of any additional permitted anti-Parkinsonian drugs (ie, peripheral decarboxylase inhibitors, dopamine agonists [except apomorphine], MAO-B inhibitors [except safinamide] or COMT inhibitors) for at least 4 weeks prior to baseline.
3. Female subjects will be women of non-childbearing potential, defined as follows: 3.1. permanently sterile following hysterectomy, bilateral salpingectomy, bilateral oophorectomy or confirmed tubal occlusion (not tubal ligation)
3.2. postmenopausal, defined as at least 12 months post cessation of menses (without an alternative medical cause)
3.2.1. postmenopausal status will be confirmed with a screening serum follicle stimulating hormone (FSH) level greater than 40 mIU/mL.
4. Subjects must pass a Hauser diary concordance test, defined as at least 75% concordance in ON/OFF ratings between rater and subject over the 4 assessments made over a 2-hour period. Additionally, subjects must be concordant on at least 1 OFF period and 1 ON period across the 4 assessments.
5. If needed, in the opinion of the Investigator, subjects must have a caregiver (eg, family member, social worker, case worker or nurse that spends >4 hours/week with the subject) considered reliable by the Investigator in providing support to the subject to ensure compliance with study drug, assessment visits and protocol procedures.
6. Subjects are able, with or without the help of a caregiver, to understand the purpose and risks of the study and provide signed and dated informed consent and authorisation to use confidential health information in accordance with national and local subject privacy regulations. |
Los sujetos serán mujeres que no puedan tener hijos u hombres, de entre 35 y 85 años de edad y que cuenten con un diagnóstico de EP idiopática desde hace 3 años o más, con una intensidad de la enfermedad de entre 2 y 4 en la escala modificada de Hoehn y Yahr en el estado OFF. Los sujetos habrán recibido tratamiento con una pauta estable de terapia con levodopa (al menos 3 dosis al día para las formulaciones de liberación inmediata) (≤1600 mg al día) y seguirán una pauta estable de fármacos antiparkinsonianos permitidos (inhibidores periféricos de la descarboxilasa, agonistas de la dopamina [excepto la apomorfina], inhibidores de la monoamina oxidasa de tipo B [MAO-B] [excepto la safinamida] o inhibidores de la catecol-O-metil transferasa [COMT]) durante ≥4 semanas antes del momento basal. Además, los sujetos deberán haber experimentado: fluctuaciones motoras con esfumación de la respuesta al tratamiento durante un período ≥3 meses antes de la aleatorización, con un tiempo OFF diario mínimo ≥2 horas cada 24 horas durante la vigilia; períodos OFF predecibles; y DIL durante un período ≥3 meses antes de la aleatorización, con un tiempo ON diario mínimo con cualquier discinesia ≥2 horas cada 24 horas durante la vigilia, que haya afectado al funcionamiento diario. |
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E.4 | Principal exclusion criteria |
Medical conditions and diagnostic tests: 1. Subjects with atypical, secondary or drug-induced Parkinsonism (eg, metoclopramide, flunarizine), metabolic identified neurogenetic disorders (eg, Wilson’s disease), encephalitis, or Parkinson Plus syndromes, or other forms of atypical Parkinsonian syndromes (eg, progressive supranuclear palsy and multiple system atrophy)
2. Subjects with a Mini-Mental State Examination (MMSE) score <25
3. Subjects who have Long QT syndrome or a QTcF >450 ms (males) or >470 ms (females) that is considered clinically significant by the Investigator at screening or baseline
4. Subjects who have, or who have a history of, any clinically significant hepatic or gallbladder disorder, as determined by the Investigator
5. Subjects who have dementia, currently active psychosis or hallucinations. Previous psychotic episodes that were brief and considered drug-induced are not exclusionary; inclusion of such subjects is at the Investigator’s discretion.
6. Suicide attempt within 1 year prior to the first screening visit, or severe suicidal ideation within 6 months prior to the first screening visit (ie, the subject answers “yes” to Questions 4 or 5 in the Baseline/Screening C SSRS assessment performed at the first screening visit), or subject is at significant risk of suicidal behaviour in the opinion of the Investigator
7. Subject has a current diagnosis of epilepsy, has a history of seizures as an adult, has a history of stroke or has had a transient ischemic attack within 1 year prior to the first screening visit
8. Subjects who have a known genetic disorder of human UDP-glucoronosyltransferase
9. Any known contraindication to the use of levodopa, including a history of malignant melanoma or a history of narrow-angle glaucoma
10. Subject has cancer, with the exception of the following: basal cell carcinoma or successfully treated squamous cell carcinoma of the skin; cervical carcinoma in situ; prostatic carcinoma in situ; or other malignancies curatively treated and with no evidence of disease recurrence for at least 3 years
11. Positive serology test (hepatitis B virus surface antigen [HBsAg], hepatitis C virus [HCV] antibody, human immunodeficiency virus [HIV] 1 and 2 antibodies)
12. Subjects who have had a clinically significant illness within 4 weeks of first dose, as determined by the Investigator
13. Subjects with scheduled surgeries during the study period
14. Any advanced, severe or unstable disease (other than PD) that may interfere with the primary and secondary study outcome evaluations
Prior/concomitant medication and surgery: 15. Subjects who have undergone prior neurosurgical operation for PD or transcranial magnetic stimulation
16. Subjects currently taking (or expected to be administered during the course of the study) any of the prohibited medications.
Prior/concurrent clinical study experience: 17. Subjects who are participating in another clinical study (eg, attending follow-up visits) or who have participated in a clinical study involving administration of an investigational drug (new chemical entity) in the past 3 months prior to the baseline visit
18. Subjects who have previously taken part in or withdrawn from this study
Other exclusions: 19. Male subjects who do not agree to use a barrier method of contraception (ie, a condom with spermicide) in addition to a second highly effective method of contraception used by their female partners or to refrain from donating sperm from the time of the first dose until 3 months after the final dosing occasion.
20. Female subjects of childbearing potential 21. Subjects who have donated: 21.1. blood in the 3 months prior to the first screening visit 21.2. plasma in the 7 days prior to the first screening visit 21.3. platelets in the 6 weeks prior to the first screening visit
22. Subjects who have a significant history of alcoholism or drug/chemical abuse, as determined by the Investigator
23. Positive test for ethanol or drugs of abuse at the first screening visit or at the baseline visit. The following items would not necessarily be an exclusion to participation in the study, depending on the subject’s known use and discussion with the Investigator and medical monitor: cannabinoids, benzodiazepines, barbiturates, opiates, nicotine, and amphetamines for treatment of Attention Deficit Hyperactivity Disorder (ADHD). Use of cocaine, phencyclidine, methadone or amphetamines (for non-medical use) is unconditionally exclusionary.
24. Subjects who are pregnant (as determined by positive serum pregnancy test at screening and/or positive urine pregnancy test at baseline), breastfeeding or lactating
25. Subjects who, in the opinion of the Investigator, should not participate in this study |
- Afecciones y pruebas diagnósticas: 1. Sujetos con parkinsonismo atípico, secundario o medicamentoso (p. ej., metoclopramida, flunarizina), trastornos neurogenéticos metabólicos identificados (p. ej., enfermedad de Wilson), encefalitis, síndromes de Parkinson plus u otras formas de síndromes parkinsonianos atípicos (p. ej., parálisis supranuclear progresiva y atrofia sistémica múltiple).
2. Sujetos con una puntuación <25 en el mini-examen cognoscitivo (MEC).
3. Sujetos con síndrome del QT largo o QTcF >450 ms (hombres) o >470 ms (mujeres) que el investigador considere clínicamente significativo en la selección o al inicio.
4. Sujetos que presenten, o tengan antecedentes de, cualquier trastorno hepático o biliar clínicamente significativo según determine el investigador.
5. Sujetos que tengan demencia, psicosis activa en la actualidad o alucinaciones. Los episodios psicóticos anteriores breves y considerados inducidos por sustancias no son excluyentes; la inclusión de estos sujetos queda a criterio del investigador.
6. Intento de suicidio en el año anterior a la primera visita de selección, ideas suicidas graves en los 6 meses anteriores a la primera visita de selección (es decir, el sujeto responde "sí" a las preguntas 4 o 5 de la evaluación de la C-SSRS al inicio/en la selección realizada en la primera visita de selección) o sujeto que presenta un riesgo significativo de conductas suicidas en opinión del investigador.
7. Sujetos con un diagnóstico actual de epilepsia, antecedentes de convulsiones en la etapa adulta, antecedentes de apoplejía o accidente isquémico transitorio en el año anterior a la primera visita de selección.
8. Sujetos que sufran un trastorno genético conocido de la UPD-glucoronosiltransferasa humana.
9. Cualquier contraindicación para el uso de levodopa, incluidos los antecedentes de melanoma maligno o de glaucoma de ángulo estrecho.
10. Sujetos con cáncer, con la excepción de los siguientes: carcinoma basocelular o carcinoma espinocelular de la piel tratado con éxito; carcinoma cervical localizado; carcinoma prostático localizado; u otras neoplasias tratadas curativamente sin signos de recurrencia de la enfermedad durante al menos 3 años.
11. Prueba serológica positiva (antígeno de superficie del virus de la hepatitis B [HbsAg], anticuerpo contra el virus de la hepatitis C [VHC], anticuerpos contra el virus de inmunodeficiencia humana [VIH] 1 y 2).
12. Sujetos que hayan sufrido una enfermedad clínicamente significativa en las 4 semanas anteriores a la primera dosis, según determine el investigador.
13. Sujetos con cirugías programadas durante el período del estudio.
14. Cualquier enfermedad avanzada, grave o inestable (distinta de la EP) que pudiera interferir en los criterios de valoración principal y secundarios del estudio.
- Medicamentos previos o concomitantes y cirugía: 15. Sujetos que se hayan sometido a una operación neuroquirúrgica para la EP o a estimulación magnética transcraneal.
16. Sujetos que estén tomando actualmente alguno de los medicamentos prohibidos en la sección 7.6.1.3 (o que se prevea que lo recibirán durante el transcurso del estudio).
- Experiencia previa o simultánea en estudios clínicos: 17. Sujetos que estén participando en otro estudio clínico (p. ej., realizando visitas de seguimiento) o que hayan participado en un estudio clínico que implique la administración de un fármaco en fase de investigación clínica (una nueva entidad química) en los 3 meses anteriores a la visita basal.
18. Sujetos que hayan participado anteriormente en este estudio o se hayan retirado del mismo.
- Otras exclusiones: 19. Sujetos de sexo masculino que no accedan a usar un método anticonceptivo de barrera (es decir, un preservativo con espermicida) además de un segundo método anticonceptivo altamente eficaz usado por su pareja femenina o a abstenerse de donaresperma desde el momento de la primera dosis hasta 3 meses después de la administración de la última dosis.
20. Participantes de sexo femenino que puedan tener hijos
21. Sujetos que hayan donado: 21.1. sangre en los 3 meses anteriores al a primera visita de selección; 21.2. sangre en los 7 días anteriores al a primera visita de selección; o 21.3. trombocitos en las 6 semanas anteriores al a primera visita de selección.
22. Sujetos con antecedentes significativos de alcoholismo o abuso de fármacos o sustancias, según determine el investigador.
23. Prueba de alcoholemia o drogas positiva en la primera visita de selección o en la visita basal. Los puntos siguientes no excluirán necesariamente la participación en el estudio, en función del consumo conocido del sujeto y de lo que se acuerde con el investigador y el monitor médico: cannabinoides, benzodiazepinas, barbitúricos, opiáceos, nicotina y anfetaminas para el tratamiento del trastorno por déficit de atención e hiperactividad (TDAH). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy outcome measure will be change from baseline to end of Treatment Period (Day 28) in the daily awake OFF time based on subject Hauser diary entries (average of 3 consecutive days). |
La medida de resultado de eficacia primario será el cambio desde el inicio hasta el final del período de tratamiento (día 28) en el tiempo de inactividad diaria acordada basado en las entradas del diario Hauser (promedio de 3 días consecutivos). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline to Day 14 Baseline to Day 28 |
Inicio al Día 14 Inicio al Día 28 |
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E.5.2 | Secondary end point(s) |
• Change from baseline to end of Treatment Period (Day 28) in the total objective score (Parts 3 and 4) for dyskinesia impairment and disability assessed by Unified Dyskinesia Rating Scale (UDysRS)
• Change from baseline to end of Treatment Period (Day 28) in UDysRS total score
• Proportion of subjects achieving a clinically significant reduction in OFF time (at least 1 hour as defined by Hauser et al.15) from baseline to end of Treatment Period (Day 28) based on subject Hauser diary entries (average of 3 consecutive days)
• Change from baseline to end of Treatment Period (Day 28) in the percentage of daily awake OFF time based on subject Hauser diary entries (average of 3 consecutive days)
• Change from baseline to end of Treatment Period (Day 28) in the daily awake ON time without troublesome dyskinesia (defined as ON time without dyskinesia plus ON time with non-troublesome dyskinesia) based on subject Hauser diary entries (average of 3 consecutive days)
• Change from baseline to end of Treatment Period (Day 28) in the percentage of daily awake ON time without troublesome dyskinesia (defined as ON time without dyskinesia plus ON time with non-troublesome dyskinesia) based on subject Hauser diary entries (average of 3 consecutive days) |
• Cambio desde el inicio hasta el final del período de tratamiento (día 28) en el puntaje objetivo total (partes 3 y 4) para el deterioro de la discinesia y la discapacidad evaluada por la Escala Unificada de Clasificación de Discinesia (UDysRS).
• Cambio desde el inicio hasta el final del período de tratamiento (día 28) en puntuación total UDysRS.
• Proporción de sujetos que logran una reducción clínicamente significativa del tiempo de APA (al menos 1 hora según Hauser et al.15) desde el inicio hasta el final del Período de Tratamiento (Día 28) basándose en las entradas del diario de Hauser (promedio de 3 días consecutivos).
• Cambio desde el inicio hasta el final del período de tratamiento (día 28) en el porcentaje de tiempo de inactividad despierto diario basado en las entradas del diario de Hauser (promedio de 3 días consecutivos).
• Cambio desde el inicio hasta el final del período de tratamiento (día 28) en el tiempo de activación diaria sin necesidad de discinesia problemática (definida como tiempo de activación sin discinesia más tiempo de activación con discinesia no problemática) ).
• Cambio desde el inicio hasta el final del período de tratamiento (día 28) en el porcentaje de tiempo de activación diaria sin perturbación (definido como tiempo de activación sin discinesia más tiempo de activación con discinesia no problemática) días consecutivos) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Baseline to Day 14 • Baseline to end of Treatment Period (Day 28) |
- Inicio al Dïa 14 - Inicio al final del Oeriodo de Tratamiendo (Día 28) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability |
Tolerabilidad |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 46 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
|
The end of the study will be defined as the date of the final clinical database lock. This provides for a single and conservative definition across all study sites (protocol section 15). |
El final del estudio se definirá como la fecha del cierre final de la base de datos clínicos. Esto proporciona una definición única y conservadora en todos los centros del estudio (sección de protocolo 15). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |