Azathioprine for the treatment of early Parkinson's disease (AZA-PD): a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial

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BACKGROUND: The immune system is implicated in Parkinson's disease aetiology and prognosis. Although there are effective symptomatic treatments for Parkinson's disease, there are currently no therapies that slow down disease progression. We aimed to investigate the clinical efficacy of the broadly acting peripheral immunosuppressant drug azathioprine for patients with early Parkinson's disease. METHODS: We did a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial at a single site (the Parkinson's Disease Research Clinic) in Cambridge, UK. Eligible participants were aged 50-80 years and were within 3 years of Parkinson's disease diagnosis (as per UK Parkinson's Disease Society Brain Bank Diagnostic Criteria). Participants were randomly assigned (1:1) using a web-based system to receive daily oral azathioprine 2 mg/kg or placebo for 12 months. The primary outcome was change from baseline Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) gait-axial score in the off-state at 12 months, assessed in the intention-to-treat population, which included all randomly assigned patients who completed the baseline visit. Safety was assessed in all participants who were screened for eligibility. Mixed model repeated measures analysis was used to assess treatment effects. This study was registered with ISRCTN, 14616801, and EudraCT, 2018-003089-14. FINDINGS: Between May 13, 2021, and July 28, 2022, 78 participants were screened, of whom 66 were randomly assigned to azathioprine (n=32) or placebo (n=34), and included in the intention-to-treat analysis. 23 (35%) of 66 patients were female and 43 (65%) were male. At 12 months, the mean change in MDS-UPDRS gait-axial score was 0·54 points (SD 2·43) in the azathioprine group and 0·13 points (2·09) in the placebo group (effect size 0·438 [95% CI -0·694 to 1·57]; p=0·78). 159 adverse events were reported in the azathioprine group and 156 in the placebo group. Eight participants had a serious adverse event in the azathioprine group (24%) and four patients in the placebo group (12%). The most common adverse events in both groups were infections (20 [61%] of 33 participants in the azathioprine group vs 26 [76%] of 34 participants in the placebo group) and gastrointestinal disorders (19 [58%] participants vs 17 [50%] participants). INTERPRETATION: Azathioprine was well-tolerated in this population; however, the primary outcome was not met. Exploratory analyses suggested effects of azathioprine on peripheral and central immune biomarkers and on motor symptoms. Potential clinical effects could be greater in females than males, warranting further exploration. FUNDING: Cambridge Centre for Parkinson-Plus, Cure Parkinson's, National Institute for Health Research Biomedical Research Centre.

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