Parkinson's disease Nervous System Diseases
Conditions
Interventions
Experimental research arm: Dapansutrile tablets administered for 26 weeks, starting at 1,000 mg daily (500 mg twice daily) for 4 weeks, escalating to 2,000 mg daily (1,000 mg twice daily) thereafter (
Sponsors
Cambridge Clinical Trials Unit
Eligibility
Sex/Gender
All
Age
50 Years to 80 Years
Inclusion criteria
Inclusion criteria: 1. Have given written informed consent to participate 2. Be aged between 50 and 80 years (inclusive) at the time of the screening visit 3. Be a fluent English speaker 4. Have a diagnosis of clinically established early Parkinson's disease (PD) according to the Movement Disorder Society Criteria for Clinically Established Early Parkinson’s Disease 5. Have a disease duration of less than 5 years at the time of screening visit 6. Have early-stage PD, defined as Hoehn and Yahr stage =2 7. Be PD drug naïve or be receiving a stable dose of dopaminergic therapy for at least 3 months prior to the screening visit, or between screening and baseline 8. Have high sensitivity C-reactive protein (hsCRP) >1 mg/L at screening visit 9. Have adequate organ function, as defined below (to be rechecked prior to baseline/investigational medicinal product [IMP] initiation if >42 days from screening visit): 9.1. Haemoglobin =110 g/L 9.2. Platelet count =130 × 10^9/L 9.3. Neutrophil count =1.5 × 10^9/L 9.4. Renal function: estimated glomerular filtration rate (eGFR) >45 mL/min/1.73m^2 9.5. Hepatic function: alanine aminotransferase (ALT) and bilirubin < 1.5 times the institutional upper limit of normal 9.6. Thyroid stimulating hormone (TSH) within normal range 9.7. Corrected calcium = institutional upper limit of normal 9.8. Alkaline phosphatase (ALP) < 1.5 times the institutional upper limit of normal
Exclusion criteria
Exclusion criteria: 1. Low affinity binder for TSPO ligands based on genotyping for single nucleotide polymorphism (SNP) rs6971. 2. 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. 3. Any previous use of rituximab or alemtuzumab at any time. 4. 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. 5. Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) – including aspirin >75 mg, naproxen, ibuprofen and meloxicam – on more than 2 days per week. 6. Known inflammatory or autoimmune disease. 7. Chronic or latent infection. 8. Severe infection requiring the use of parenteral antimicrobial agents within 2 months prior to screening visit, or between screening and baseline. 9. Skin, solid organ or haematological malignancy within the 5 years prior to screening visit, or between screening and baseline. 10. The inability to take or swallow oral medication. 11. Parkinson’s Disease Dementia according to Movement Disorder Society (MDS) PD Dementia criteria. 12. A known genetic mutation associated with PD. 13. A positive test for human immunodeficiency virus (HIV), hepatitis B (HBV)/C (HCV) or syphilis. 14. Chronic liver disease. 15. 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. 16. 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. 17. Male participants must be surgically sterile or must agree to use effective contraception (as specified in the trial protocol) during the period of therapy and for 6 months after the last dose of the trial treatment. 18. Known hypersensitivity to dapansutrile or its excipients. 19. 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. 20. Contraindications to PET-magnetic resonance imaging (MRI) scanning including metal implants, claustrophobia or inability to lie flat for 90 minutes. 21. Concomitant treatment with any medications that could interfere with [18F]-DPA714 binding (e.g., benzodiazepines). 22. Current use of any drugs of abuse or average alcohol intake of >21 units per week over the last 3 months. 23. 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The number of adverse events (AEs) recorded during the 6-month double-blind treatment period, assessed at screening, baseline, day 1, and weeks 2, 4, 6, 12, 18, 23 and 26 | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Change in [18F]-DPA-714 non-displaceable binding potential (BPND) in subcortical and cortical regions of interest between baseline and week 23. 2. Change in levels of inflammatory biomarkers in blood including hsCRP, IL-1ß, IL-18, IL-6, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, ASC specks over 6 months of treatment, measured at day 1, and weeks 6, 18 and 26. 3. Change in levels of inflammatory biomarkers in CSF including hsCRP, IL-1ß, IL-18, IL-6, IFNgamma, TNF-alpha, ASC specks over 6 months of treatment, measured at baseline and week 26. 4. Pharmacokinetics as measured by changes in plasma dapansutrile concentrations and population pharmacokinetic (PK) parameters between baseline and end of treatment, measured at day 1, and weeks 6, 18 and 26. CSF levels will also be measured in select participants, at baseline and week 26 | — |
Countries
England, United Kingdom
Outcome results
None listed