A Trial to Test the Use of Dapansutrile, an Anti-inflammatory Medication, in People With Parkinson's Disease

DAPA-PD is a randomised double-blind, placebo-controlled phase II trial investigating the safety and tolerability of dapansutrile (OLT1177), an NLRP3 inhibitor, in people with early PD (Hoehn and Yahr stage ≤2, disease duration ≤5 years) who have evidence of peripheral inflammation (high sensitivity C-reactive protein [hsCRP] ≥1) as an adjunct to dopaminergic therapies. 36 participants will be recruited at a single site and treated with either dapansutrile (1000mg twice daily) or placebo in a 2:1 ratio for a duration of 6 months. This randomised placebo-controlled phase of the trial will be followed by an optional 6-month open label phase, where all participants will receive the active drug. The primary endpoint will be the safety and tolerability of dapansutrile over the 6-month placebo-controlled phase.

Safety data will be collected throughout both phases of the trial, through venous blood sampling, electrocardiograms and clinical assessments. The trial will assess treatment efficacy on peripheral and central inflammation, using biomarkers in blood and CSF, and translocator protein (TSPO) positron emission tomography (PET) brain imaging. Pharmacokinetics of the drug will also be evaluated. Additionally, clinical outcomes, including motor and cognitive progression, will be assessed throughout.

Inclusion criteria

To be included in the trial, the potential participant must:

• 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 on a blood test done within 2 years prior to, or at, the 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 function: thyroid stimulating hormone (TSH) within normal range; or if TSH is abnormal, free T4 within normal range; Corrected calcium ≤ institutional upper limit of normal; Alkaline phosphatase (ALP) < 1.5 times the institutional upper limit of normal

Exclusion criteria

The presence of any of the following will preclude inclusion:

• 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.
• Clinically significant 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 which is active* at screening, or between screening and baseline (*defined as cancer which is under active management, with the exception of low-grade malignancy under observation of hormonal treatment).
• 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]-DPA714 binding (e.g., certain benzodiazepines), with the exception of medications which can be safely withheld for an appropriate washout period prior to imaging at the investigator's discretion.
• 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.