Resumen del Estudio
En la enfermedad de Parkinson, la inflamación presente en el cerebro, el intestino y la sangre contribuye activamente al desarrollo y progresión de la enfermedad. Existe un complejo de proteínas llamado 'inflamasoma NLRP3' que desempeña un papel crítico en esta inflamación. El dapansutrile es un nuevo medicamento altamente específico diseñado para bloquear este inflamasoma, demostrando en modelos de laboratorio que puede reducir la inflamación y proteger las células cerebrales sin causar efectos secundarios importantes. El objetivo de este ensayo clínico es responder si el dapansutrile puede ser un tratamiento útil para las personas con Parkinson. Específicamente, buscamos confirmar si es seguro, si los pacientes lo toleran bien y si efectivamente logra reducir la inflamación en el cerebro, el líquido cefalorraquídeo y la sangre. También se vigilarán de cerca los cambios en los síntomas clínicos, motores y cognitivos durante el estudio. Los participantes recibirán diariamente dapansutrile o un placebo (una sustancia sin efecto) durante 6 meses, acompañados de chequeos regulares, análisis de sangre, punciones lumbares y escáneres cerebrales. Una vez completado este periodo, todos los voluntarios tendrán la opción de recibir el medicamento activo (dapansutrile) de forma gratuita durante otros 6 meses adicionales.
Criterios de Elegibilidad
Resumen de Elegibilidad:Pueden participar: Personas entre 50 y 80 años con diagnóstico de Parkinson temprano (menos de 5 años desde el diagnóstico), que tengan un marcador de inflamación elevado en sangre (PCR > 1) y buena función orgánica. No pueden participar: Personas con otras enfermedades inflamatorias o autoinmunes, infecciones crónicas, demencia por Parkinson, antecedentes de cáncer reciente, uso regular de antiinflamatorios (como ibuprofeno o aspirina alta) o inmunosupresores recientes. Las mujeres participantes deben estar en la menopausia o esterilizadas quirúrgicamente.
- Have given written informed consent to participate.
- Be aged between 50 and 80 years (inclusive) at the time of the screening visit.
- Be a fluent English speaker.
- Have a diagnosis of clinically established early PD according to the Movement Disorder Society Criteria for Clinically Established Early Parkinson's Disease.
- Have a disease duration of less than 5 years at the time of screening visit.
- Have early-stage PD, defined as Hoehn and Yahr stage ≤2.
- Be PD drug naïve or be receiving a stable dose of dopaminergic therapy for at least 3 months prior to screening visit, or between screening and baseline.
- Have hsCRP \> 1 mg/L at screening visit.
- Have adequate organ function, as defined below (to be rechecked prior to baseline/investigational medicinal product \[IMP\] initiation if \>42 days from screening visit): Haemoglobin ≥ 110 g/L; Platelet count ≥ 130 × 109/L; Neutrophil count ≥ 1.5 × 109/L; Renal function: estimated glomerular filtration rate (eGFR) \>45 mL/min/1.73m2; Hepatic function: alanine aminotransferase (ALT) and bilirubin \< 1.5 times the institutional upper limit of normal; Thyroid stimulating hormone (TSH) within normal range; Corrected calcium ≤ institutional upper limit of normal; Alkaline phosphatase (ALP) \< 1.5 times the institutional upper limit of normal
- Low affinity binder for TSPO ligands based on genotyping for single nucleotide polymorphism (SNP) rs6971.
- Any use of immunomodulatory drugs or biologic agents (such as azathioprine, mycophenolate, methotrexate, ciclosporin, cyclophosphamide etc.) within 12 months prior to screening visit, or between screening and baseline.
- Any previous use of rituximab or alemtuzumab at any time.
- Treatment with oral corticosteroids for greater than 2 weeks within 12 months prior to screening visit, or any oral or injected steroid use within 3 months prior to screening visit, or between screening and baseline.
- Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) - including aspirin \> 75 mg, naproxen, ibuprofen and meloxicam - on more than 2 days per week.
- Known inflammatory or autoimmune disease.
- Chronic or latent infection.
- Severe infection requiring the use of parenteral antimicrobial agents within 2 months prior to screening visit, or between screening and baseline.
- Skin, solid organ or haematological malignancy within the 5 years prior to screening visit, or between screening and baseline.
- The inability to take or swallow oral medication.
- Parkinson's Disease Dementia according to Movement Disorder Society (MDS) PD Dementia criteria.
- A known genetic mutation associated with PD.
- A positive test for human immunodeficiency virus (HIV), hepatitis B (HBV)/C (HCV) or syphilis.
- Chronic liver disease.
- Any concurrent medical or psychiatric condition or disease that is likely to interfere with the trial procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this trial.
- Women of childbearing potential - female participants must be surgically sterile or be post-menopausal. (A post-menopausal state is defined as no menses for 12 months without an alternative medical cause).
- Male participants must be surgically sterile or must agree to use effective contraception during the period of therapy and for 6 months after the last dose of the trial treatment.
- Known hypersensitivity to dapansutrile or its excipients.
- Received an investigational drug or used an invasive investigational medical device within 12 weeks before the screening assessment, or is currently enrolled in another interventional investigational trial. Participants currently enrolled in other observational studies may be recruited.
- Contraindications to PET-magnetic resonance imaging (MRI) scanning including metal implants, claustrophobia or inability to lie flat for 90 minutes.
- Concomitant treatment with any medications that could interfere with \[18F\] DPA-714 binding (e.g., benzodiazepines).
- Current use of any drugs of abuse or average alcohol intake of \>21units per week over the last 3 months.
- Any other significant disease, disability or investigation result which, in the opinion of the Chief Investigator (CI), may either put the participant at risk, or may influence the result of the trial, or the participant's ability to participate in the trial.