- Trials in setup
Azathioprine immunosuppression and disease modification in Parkinson’s disease (AZA-PD): a randomised double-blind placebo-controlled phase II trial
Parkinson’s disease (PD) is a common neurodegenerative disorder affecting approximately 2% of those over 65 years. It is characterised by problems with movement including bradykinesia, rigidity, tremor and gait dysfunction, but also causes a wide range of non-motor symptoms including cognitive and neuropsychiatric problems, impaired swallowing, bladder and bowel dysfunction, sleep problems, pain and sensory disturbance.
Our work to date has led to the hypothesis that peripheral immune activation in PD can exacerbate inflammation and neurodegenerative pathology within the brain and contribute to more rapid clinical progression. The only way to definitively test this hypothesis in human subjects is an interventional clinical trial of an immunosuppressive therapy, conducted early in the disease before neurodegenerative pathology is widespread.
On this background, there is a strong argument for repositioning a readily available immunosuppressive therapy with well-established effects on the human immune system, and doing this in a cohort at high risk of rapid disease progression, to definitively test the concept that peripheral suppression of immune overactivation in PD will attenuate disease progression.
Azathioprine is an immunosuppressant drug which is widely used in clinical practice for a range of immune-related conditions. It is a purine analogue which inhibits nucleic acid synthesis, hence reducing proliferation of lymphocytes involved in targeting and amplification of the immune response. It affects both the cell mediated and antibody mediated immune responses through reducing T and B lymphocyte proliferation. It is a good candidate for use in this population for a number of reasons:
- Efficacy as an immunosuppressive therapy for a range of conditions is well established
- It has an acceptable safety profile and is generally well-tolerated in older populations
- There are well-established protocols in place in clinical practice for monitoring toxicity
- It is administered once daily as an oral preparation and thus is practical to use and acceptable to patients
- It is a low-cost option
Hence the proposed trial is a ‘proof of concept’ trial which will investigate whether immunosuppression in early PD using the drug azathioprine has an effect on subsequent disease course over 12 months treatment and whether this is maintained over 6 months subsequent follow-up. In addition, the trial will also investigate ‘proof of mechanism’ by evaluating the impact of azathioprine on blood, CSF and neuroimaging parameters of immune activation in the trial population and determining the relationship between these parameters and clinical measures of disease progression.
Main inclusion criteria
To be included in the trial the participant must:
- Be capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
- Be aged over 50 years
- Be a fluent English speaker, as assessed by the trial team during the screening assessment
- Have a diagnosis of PD according to UK Parkinson’s Disease Society (UKPDS) Brain Bank Criteria, though a positive family history of PD will not be used to exclude participants
- Have a disease duration of <3 years
- Have a probability of poor outcome (postural instability/dementia/death) at 5 years from diagnosis ≥50% (see section 11.1 for further details)
- Have adequate organ and marrow function, as defined below (measured within 42 days of first dose of trial medication):
- Haemoglobin (Hb) ≥ 110 g/L
- Platelet count ≥ 130 x 109/L
- Neutrophil count ≥ 1.5 x 109/L
- Renal Function- Creatinine clearance ≥50mL/min
- Hepatic function- Alanine aminotransferase (ALT) ≤2 times the institutional upper limit of normal (ULN) and total bilirubin ≤2 times the ULN.
Main exclusion criteria
The presence of any of the following will preclude participant inclusion:
- Any use of immunomodulatory drugs such as azathioprine, mycophenolate, methotrexate, ciclosporin, cyclophosphamide within the 12 months prior to screening
- Any previous use of rituximab or alemtuzumab at any time
- Treatment with oral corticosteroids for greater than 2 weeks within the 12 months prior to screening, or any oral steroid use in 3 months prior to screening
- Regular use of NSAIDs including aspirin >75mg, naproxen, ibuprofen, meloxicam on more than 2 days per week
- Known inflammatory or autoimmune disease
- Chronic or latent infection
- Active infection requiring the use of parenteral antimicrobial agents within 2 months prior to the first dose of trial treatment
- Skin malignancy or solid organ malignancy within the last 5 years prior to screening assessment
- Current or previous haematological malignancy
- Positive test for human immunodeficiency virus (HIV) or hepatitis
- The inability to take or swallow oral medication
- Dementia according to Movement Disorder Society (MDS) dementia criteria
- Thiopurine methyltransferase (TPMT) deficiency <10 pmol/h/mg Hb
- Lack of immunity to varicella zoster virus (VZV)
- Negative Epstein-Barr virus (EBV) IgG
- Chronic liver disease
- Renal impairment - creatinine clearance <50mL/min
- Concomitant use of allopurinol (increases risk of myelotoxicity)
- Any concurrent medical or psychiatric condition or disease (e.g. active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary 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
- Receipt of live, attenuated vaccine within the last 30 days prior to the screening assessment. Note: enrolled patients should not receive live, attenuated vaccine while receiving azathioprine nor within 30 days of last dose of azathioprine
- Women of childbearing potential. Female patients must be surgically sterile or be postmenopausal.
- Postmenopausal is defined as spontaneous cessation of regular menses for at least 12 consecutive months or follicle-stimulating hormone (FSH) blood levels in the testing laboratory’s respective postmenopausal range with no alternative pathological or physiological cause.
- Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy and for 6 months after completion of trial drug
- Known hypersensitivity to azathioprine or its excipients
- Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before the screening assessment or is currently enrolled in an interventional investigational trial.
Funders and sponsors
Dr Caroline H. Williams-Gray
Clinical Trial Coordinator: Sonakshi Kadyan
Telephone: 01223 349007 | Email: email@example.com