AZA-PD
(2025)Objective
To investigate the clinical efficacy of azathioprine, a broadly acting peripheral immunosuppressant, in patients with early Parkinson's disease
Study Summary
• Significant improvement in MDS-UPDRS II favoring azathioprine at 6 months (difference −1.55, p=0.048) and 12 months (difference −1.62, p=0.045)
• Significant sex-treatment interaction: female participants showed significant improvements in MDS-UPDRS I, II, total MDS-UPDRS, NMSS, and PDQ-39 at 6 and 12 months; no differences in males
• Azathioprine reduced peripheral lymphocyte counts (total CD3+ T cells, cytotoxic T cells, B cells) and CSF lymphocyte counts vs placebo
• 12 serious adverse events (8 azathioprine, 4 placebo); similar overall adverse event frequency between groups
Intervention
Oral azathioprine (25 mg tablets) for 52 weeks; initial dose 1 mg/kg, increased to 2 mg/kg after 4 weeks based on satisfactory blood results; dose reduction protocol for adverse effects (1.5 mg/kg then 1 mg/kg) vs Matched placebo tablets (visibly identical to azathioprine 25 mg) for 52 weeks; dose adjustments matched to corresponding azathioprine participant within same randomisation block
Inclusion Criteria
Age 50-80 years; Parkinson's disease diagnosis within 3 years per UK Parkinson's Disease Society Brain Bank Diagnostic Criteria; No immune comorbidities; No immunosuppressant medications; No contraindications to azathioprine
Study Design
Arms: Array
Outcome
Bottom Line
Azathioprine did not meet its primary endpoint of slowing progression on the MDS-UPDRS gait-axial score at 12 months in early Parkinson's disease. However, exploratory analyses showed a significant favourable effect on MDS-UPDRS II (activities of daily living) at 12 months, particularly in female participants who showed significant improvements across multiple clinical outcomes. Azathioprine was well tolerated with no excess safety concerns, supporting the feasibility of immunosuppressive trials in this population.
Major Points
- Primary outcome not met: no significant difference in MDS-UPDRS gait-axial score change at 12 months between azathioprine (0.54 points) and placebo (0.13 points); mean difference 0.438 (95% CI −0.694 to 1.57, p=0.779)
- Significant exploratory finding: MDS-UPDRS II favoured azathioprine at 6 months (difference −1.55, p=0.048) and 12 months (difference −1.62, p=0.045), a patient-reported measure of motor experiences of daily living
- Significant sex-treatment interaction observed across multiple outcomes: in females, azathioprine significantly improved MDS-UPDRS I, II, total MDS-UPDRS, NMSS, and PDQ-39 at 6 and 12 months; no differences in males
- In females at 12 months, mean score differences between azathioprine and placebo were clinically meaningful: 3.89 for MDS-UPDRS II, 8.59 for total MDS-UPDRS, and 10.8 for PDQ-39
- Azathioprine significantly reduced peripheral lymphocyte counts including total CD3+ T cells, cytotoxic T cells (CD3+CD8+), and B cells (CD19+), persisting to 18-month follow-up
- Greater reduction in CSF total lymphocyte count at 12 months in azathioprine group vs placebo (mean difference −125.3, p=0.034), including CD3+, CD4+, CD8+, and CD56+ natural killer cells
- In females, azathioprine also reduced monocyte count (p=0.021), not observed in males, suggesting sex differences in innate immunity may underlie differential clinical effects
- [11C]PK11195 PET imaging showed that placebo group had increased regional binding across multiple brain regions at 12 months, while azathioprine group binding remained restricted, suggesting potential attenuation of neuroinflammation spread
- 12 serious adverse events reported (8 azathioprine, 4 placebo); 2 in azathioprine group classed as treatment-related (pancreatitis and infection); overall adverse event frequency was comparable between groups
- Most common adverse events in both groups were infections (61% azathioprine vs 76% placebo) and gastrointestinal disorders (58% vs 50%)
Study Design
- Study Type
- Randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial
- Randomization
- Yes
- Blinding
- Double-blind (participants, investigators, and clinical assessors blinded; trial pharmacist unblinded)
- Sample Size
- 66
- Follow-up
- 12 months treatment + 6 months post-treatment follow-up
- Centers
- 1
- Countries
- United Kingdom
Primary Outcome
Definition: Change in MDS-UPDRS gait-axial score (off state) at 12 months
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0.13 (SD 2.09) | 0.54 (SD 2.43) | - (-0.694 to 1.57) | 0.779 |
Limitations & Criticisms
- Small sample size (n=66) limits power to detect clinically meaningful differences
- Single-site study in Cambridge, UK with predominantly White participants (98.5%) limits generalisability
- Short 12-month treatment period may be insufficient to detect disease-modifying effects on a slowly progressive outcome measure
- Exploratory subgroup analyses by sex were not corrected for multiple comparisons
- Change over the trial duration was minimal (IQR −1 to 1 for primary outcome), limiting ability to detect treatment effect
- Protocol was amended during the trial due to COVID-19 pandemic, removing restriction to high-risk progression participants only
- PET imaging substudy limited to only 23 participants (7 azathioprine, 16 placebo) with pre- and post-treatment scans
Citation
Lancet Neurol 2026; 25: 39-49