DAPA-PD

Anti-inflammatory Intervention with Dapansutrile (OLT1177®) for Parkinson's Disease Modification (DAPA-PD): a Randomised Double-Blind, Placebo-Controlled Phase II Trial

Research summary

In Parkinson's disease (PD), there is inflammation in the brain, the gut and the blood, which is thought to contribute to the development and progression of the disease. The NLRP3 inflammasome is a complex of proteins which plays a critical role in mediating inflammatory responses, and tehre is growing evidence that the inflammasome is involved in PD. Laboratory research has shown that aggregated alpha-synuclein (the key pathogenic protein which deposits in the brain in Parkinson's) can trigger NLRP3 inflammasome activation in immune cells, leading to production of a cascade of molecules causing inflammation. This in turn exacerbates damage of dopamine-producing cells in the brain, which underlies the symptoms of Parkinson's.

Dapansutrile is a new drug (developed by Olatec Therapeutics) which has highly specific effect on the NLRP3 inflammasome. In animal models, dapansutrile can protect against inflammation in the brain and prevent loss of dopamine cells. Initial 'in human' studies have indicated that this drug can effectively reduce inflammation without causing significant side effects. Hence it may be a promising drug for the treatment of Parkinson's in humans. 

This clinical trial will test dapansutrile in people with Parkinson's to confirm its safety, and to test whether it can reduce inflammation in the brain, spinal fluid and blood. We will also assess changes in clinical symptoms.

 

Main 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 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 (28).
  • Have a disease duration of less that 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 high sensitivity C-reactive protein (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

    -- Heratic function: alanine aminotransferase (ALT) and bilirubin < 1.5 times the      institutional upper limit of normal

    -- Thyroid stimulating hormone (TSH) within normal range

    -- Corrected calcium phosphatase (ALP) < 1.5 times the institutional upper limit of    normal

         

Main 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 drug (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 agent 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.

 

Chief investigator

Investigator: Dr Caroline Williams-Gray

Contact details

Clinical Trials Coordinators: Meisha Davies, Kerry Dresser

Email: [email protected]