Condition category
Nervous System Diseases
Date applied
14/04/2020
Date assigned
14/05/2020
Last edited
14/05/2020
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Suspended

Plain English Summary

Background and study aims
Parkinson's disease (PD) is a common neurological disorder that affects about 2% of people over 65. It is characterised by its effect on movement, but it can also cause a number of other problems including issues with mood, memory, sleep, swallowing, speech, bladder and bowel function. It is a progressive disorder: 10 years following diagnosis about two-thirds of patients have significant walking problems and half have developed dementia. There are treatments to help alleviate some of the symptoms, but no therapies to slow the underlying disease process. There is growing evidence suggesting that activation of the immune system plays a significant role in PD. This is a critical system for protecting the body from infections, but can become inappropriately activated in certain diseases, causing tissues to become inflamed and damaged. The aim of this study is to test whether suppressing the immune system with a drug called azathioprine can slow the progression of Parkinson’s disease. Azathioprine is a licenced, effective treatment for a number of inflammatory and autoimmune diseases.

Who can participate?
Patients aged over 50 with early-stage Parkinson’s disease (diagnosed within the last 3 years)

What does the study involve?
Half of the participants will receive azathioprine and half will receive placebo (dummy drug), with the treatments being allocated randomly. The azathioprine/placebo will be given in tablet form, once daily, for 1 year. The trial will be double-blinded so that neither the participants nor the researchers know who is taking the active drug. Detailed assessments will be carried out at the beginning of the trial, and at regular intervals until 6 months after the treatment is completed. The researchers will compare how measures of disease severity change over time in the azathioprine and placebo groups. They will look at markers of immune activation in the blood to assess the effect of azathioprine on immune changes in PD. Some participants will also have PET brain scans and lumbar punctures to assess immune activation within the brain and cerebrospinal fluid (these are optional assessments).

What are the possible benefits and risks of participating?
Participants will have their Parkinson’s closely monitored by a specialist team over the duration of the study. Although it is possible that suppressing the immune system with azathioprine might slow down PD progression, the researchers cannot be sure of this until the end of the study, and not all participants will receive azathioprine, so taking part may not benefit participants directly. However, the results of the study will help researchers to understand more about PD and may improve the treatment of other people with this disease in the future. There are potential risks associated with taking azathioprine. These include a risk of over-suppressing the immune system and causing increased susceptibility to infections, anaemia or bleeding. There is also a risk of gastrointestinal side-effects, including nausea, and a small chance of adversely affecting liver function. However, participants will be very closely monitored with regular blood tests to mitigate risks associated with the treatment, and the dose of the drug can be reduced if it causes side effects. Participants will be asked to temporarily refrain from taking their prescribed Parkinson’s medication before some of their visits. This may cause some Parkinson’s related symptoms to be more noticeable, such as body stiffness, slow walking and tremor. However, participants will be able to take their medication again as soon as they have completed a physical examination. Some participants will have PET brain scans at the beginning and end of treatment, and this type of scanning involves exposure to a small amount of radioactivity. All people are at risk of developing cancer during their lifetime, and the normal risk is that this will happen to about 50% of people at some point in their life. The radioactivity exposure from taking part in the PET scans will increase the chances of this happening by a very small amount, from 50% to 50.03%. Some participants will also have a lumbar puncture before and after completing their study medication, and a possible side effect of this procedure is headache. Recent studied using modern methods suggest this occurs in around 1 in 20 people.

Where is the study run from?
The study is being coordinated by Cambridge University Hospitals NHS Trust and the University of Cambridge. Assessments will take place at the John van Geest Centre for Brain Repair and the Clinical Research Facility at the Addenbrooke’s Hospital site in Cambridge (UK)

When is the study starting and how long is it expected to run for?
February 2018 to February 2023

Who is funding the study?
1. Cambridge Centre for Parkinson-Plus (UK)
2. The Cure Parkinson’s Trust (UK)

Who is the main contact?
Ms Sonakshi Kadyan
sonakshi.kadyan@addenbrookes.nhs.uk

Trial website

Contact information

Type

Public

Primary contact

Ms Sonakshi Kadyan

ORCID ID

Contact details

Clinical Trials Coordinator
Flat 61
Coton House
Cambridge University Hospitals NHS Foundation Trust
Hills Road
Cambridge
CB2 0QQ
United Kingdom
+44 (0)1223 349007
sonakshi.kadyan@addenbrookes.nhs.uk

Type

Scientific

Additional contact

Dr Julia Greenland

ORCID ID

Contact details

Sub-Investigator
John van Geest Centre for Brain Repair
Department of Clinical Neurosciences
University of Cambridge
Forvie Site
Robinson Way
Cambridge
CB2 0PY
United Kingdom
+44 (0)1223 331160
jcg69@cam.ac.uk

Type

Scientific

Additional contact

Dr Caroline Williams-Gray

ORCID ID

Contact details

Chief Investigator
John van Geest Centre for Brain Repair
Department of Clinical Neurosciences
University of Cambridge
Forvie Site
Robinson Way
Cambridge
CB2 0PY
United Kingdom
+44 (0)1223 331160
chm27@cam.ac.uk

Additional identifiers

EudraCT number

2018-003089-14

ClinicalTrials.gov number

Nil known

Protocol/serial number

CPMS 43695, IRAS 243918

Study information

Scientific title

AZAthioprine immunosuppression and disease modification in Parkinson’s Disease (AZA-PD): a randomised double-blind placebo-controlled phase II trial

Acronym

AZA-PD

Study hypothesis

There is growing evidence that implicates the immune system in both the development and progression of Parkinson’s disease (PD). Inflammation and immune activation occur both in the brain and in the periphery in PD, and a pro-inflammatory cytokine profile is associated with more rapid clinical progression. Furthermore, the risk of developing PD is related to genetic variation in immune-related genes, and reduced by the use of immunosuppressant medication.

There are treatments to help alleviate some of the symptoms of PD, but no therapies to slow the underlying disease process. The researchers propose that suppressing the peripheral immune system with azathioprine is a potential disease-modifying strategy and they are conducting a clinical trial in early PD to test this hypothesis.

Ethics approval

Approved 06/12/2019, London Westminster Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44 (0)207 1048310; nrescommittee.london-westminster@nhs.net), REC ref: 19/LO/1705

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Parkinson's disease

Intervention

This study is designed to investigate whether azathioprine can slow the progressive nature of early PD. In order to do this, the researchers propose setting up a clinical trial, where half the participants will take azathioprine and half placebo. It will be double-blinded, so neither the researchers or participants are aware who is taking the active agent. The researchers will then compare the extent to which both groups have progressed on measures which assess the symptoms of PD. They will also investigate markers of activation of the immune system, using blood, cerebrospinal fluid and imaging, to analyse the effect of the treatment.

Potential participants will be identified from the database of attendees of the PD research clinic at the John van Geest Centre for Brain Repair, based on the inclusion and exclusion criteria of the study and using their previous assessments on the database. These patients have previously indicated (provided consent) that they are interested in being contacted about further involvement in research. The researchers aim to randomise 60 patients in total, aged 50-80 years of age and within 2 years of their diagnosis. They are looking to recruit a cohort of patients who have a poor prognosis; greater than 50% chance dementia, postural instability or death within 5 years, based on a validated predictive calculator.

The potential participants will be sent the participant information sheet, and if interested, be invited to attend a screening visit. At this visit, they will first have the opportunity to raise any questions, before being asked to sign the consent form. They will then have their medical history and medication reviewed, before having some blood tests. These assessments are to ensure that they are eligible to participate in the trial, as per the inclusion/exclusion criteria. All visits will occur at either the John van Geest Centre for Brain Repair, or the Clinical Research Facility, Addenbrooke's Hospital with the exception of the imaging visits which will occur at the Wolfson Brain Imaging Centre. If they are eligible they will be given an appointment for their baseline visit, which will occur up to 42 days after screening. If during the consent process they had decided to participate in the optional parts of the study, they will also have appointments for a PET/MRI scan and/or a visit for a lumbar puncture. If so, their baseline PET scan should occur within approximately 2 weeks of screening. Following this, they will have a visit arranged for a lumbar puncture to collect CSF together with a blood sample.

During their baseline visit, they will have a clinical interview by a member of the research team. They will be assessed using the MDS-UPDRS, which scores their Parkinson’s disease related symptoms and includes a clinical examination. Part III of this assessment, the motor examination, will be videoed, which will allow for a second researcher to independently score the patient's examination. This part of the assessment will be performed first, and the appointment will be booked in the morning, as the researchers are asking patients to attend whilst OFF medication. As soon as they have completed the motor examination, they can take their medication as normal. They will then have their current concomitant medication and vital signs recorded. They will also have a cognitive assessment using the Addenbrooke’s Cognitive Examination-III and will have questionnaires administered, looking at depression, quality of life, activities of daily living and non-motor symptoms. If they had opted not to have a lumbar puncture as part of the trial, they will also have a baseline blood sample taken.

The participants will then be randomised to either azathioprine or placebo. Both the researchers and the participants will be blinded to the allocation. The treatment will be started at a low initial dose of 1 mg/kg. All participants will also be given a diary to complete. They will also be given a trial-specific information sheet, with potential side-effects and concerning symptoms to aware of. In addition, they will have the study team contact details and what to do in case of an emergency.

The participants will be asked to attend for regular monitoring visits during which they will be asked about any adverse events, their diary will be reviewed and they will have their vital signs and safety blood tests taken. The blood tests will be reviewed by an external assessor, who is unblinded. The external assessor will be an experienced clinician, who is able to make decisions regarding the test results and necessary dose changes. They will ensure the dose changes are communicated to the trial pharmacist so the new dose is dispensed and collected by the participant. The external unblinded assessor will contact the study clinician with the change in dose, who will then telephone the participant with instructions on the number of tablets to continue taking. If there are any significant concerns with the safety blood tests, the external assessor will also be able to trigger the participant withdrawal or unblinding procedure. It is important that an external assessor monitors the blood results rather than the trial team themselves, because azathioprine causes predictable changes to blood tests, and this may lead to unblinding of the trial team.

These monitoring visits will initially happen every 2 weeks. At four weeks, the dose of the trial drug will be increased, if appropriate according to the clinical profile (blood results and adverse events). Azathioprine will be increased to 2 mg/kg and the placebo dose will be doubled. The participants will then have monitoring visits every 2 weeks for a further 6 weeks, then a visit after a further 4 weeks. If they remain stable, according to the external assessor, they will then have visits every 12 weeks. Of course, if there are any problems in the interim, they can contact the trial team, who can arrange an additional visit if appropriate. If at any point the dose needs to be altered, they will have additional monitoring visits. These will be every 2 weeks for 6 weeks. Again, once the external assessor is happy that they are stable, the visits will occur every 12 weeks. To ensure that the trial team remains blinded, the placebo group will have random dose changes, with additional monitoring visits, to match the azathioprine group.

Six months after the start of the treatment, the participants will attend for a treatment midpoint visit. During this, they will have the same clinical and cognitive assessments as the baseline visit, as well as repeating the questionnaires. As before, part III MDS-UPDRS will be performed first, as the participant will be in the OFF state. It will also be videoed. They will also have their medication doses recorded and any change in their medical history. They will have a blood test taken, firstly for safety blood tests as part of the treatment monitoring protocol. However, a serum sample will also be stored for immune analysis.

They will have these assessments repeated at 12 months, as well as a blood sample for the final safety blood tests and immune analysis. At which point they will stop the treatment. During this visit, if they opted into this part of the trial, they will have a repeat lumbar puncture repeat for cerebrospinal fluid collection. Within three months of the end of treatment visit, if they opted into this part of the trial, they will have a repeat PET imaging visit.

Their final visit will occur 6 months after the end of treatment. The MDS-UPDRS III will be performed in the OFF state, and videoed. Immediately following this the participant can take their PD medication. The remainder of the MDS-UPDRS will then be performed. Their medical and medication history will be reviewed. They will complete the Addenbrookes Cognitive Examination-III. They will go through the same questionnaires related to depression, quality of life, activities of daily living and non-motor symptoms. Finally, they will have a blood sample taken.

The participants will be offered ongoing follow up through the PD research clinic at the John van Geest Centre for Brain Repair. They will remain under their standard clinical care throughout the trial.

Intervention type

Drug

Phase

Phase II

Drug names

Azathioprine

Primary outcome measure

Axial and gait symptoms measured using MDS-UPDRS gait/axial score in the OFF state at 12 months. This score is a sum of the points from the following sections of MDS-UPDRS part III (motor examination):
3.1. Speech
3.2. Facial expression
3.9. Rising from a chair
3.10. Gait
3.12. Postural stability
3.13. Posture
3.14. Body bradykinesia

Secondary outcome measures

Exploratory outcomes:
1. Axial and gait symptoms measured using MDS-UPDRS gait/axial score in OFF state at 18 months (6 months post treatment cessation)
2. Parkinson’s disease severity measured using MDS-UPDRS parts I, II and III in OFF state at 12 and 18 months
3. Bradykinesia and tremor measured using electromagnetic sensor (EMS) measurements whilst performing MDS-UPDRS tremor and bradykinesia assessments at 12 and 18 months
4. Proportion of patients developing postural instability measured using Hoehn and Yahr stage 3 or greater at 12 and 18 months
5. Global cognition measured using Addenbrooke's Cognitive Examination III (ACE-III) at 12 and 18 months
6. Patient-reported quality of life measured using Parkinson's disease questionnaire-39 (PDQ-39) at 12 and 18 months
7. Non-motor symptoms measured using non-motor symptom scale (NMSS) at 12 and 18 months
8. Parkinson’s disease treatment measured using the dose of symptomatic dopaminergic therapy (Levodopa-Equivalent Daily Dose [LEDD]) at 12 and 18 months
9. Safety and tolerability of azathioprine assessed by the number of adverse events (AEs) recorded during the 12-month treatment period
10. Total lymphocyte count measured using a blood test (full blood count) at 6, 12 and 18 months
11. Serum IgG levels measured using a blood test (immunoglobulins) at 6, 12 and 18 months
12. Levels of serum immune markers measured using cytokine immunoassays and immunophenotyping at 6, 12 and 18 months and CSF immune markers at 12 months
13. Microglial activation measured using [11C]-PK11195 PET non-dissociable binding potential (BPND) in subcortical and cortical regions of interest at 12 months

Overall trial start date

01/02/2018

Overall trial end date

01/02/2023

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. 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
2. Aged 50 years or over
3. Be a fluent English speaker
4. Have a diagnosis of PD according to UKPDS Brain Bank Criteria
5. Have a disease duration of < 3 years
6. Have a probability of poor outcome (postural instability/dementia/death) at 5 years from diagnosis > = 50%
7. Have adequate organ and marrow function, as defined below (measured within 42 days of first dose of trial medication):
7.1. Haemoglobin > = 110 g/L
7.2. Platelet count > = 130 x 109/L
7.3. Neutrophil count > = 1.5 x 109/L
7.4. Renal function- creatinine clearance > = 50mL/min
7.5. Hepatic function- alanine aminotransferase (ALT) < = 2 times the institutional upper limit of normal (ULN) and total bilirubin < = 2 times the ULN

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 60; UK Sample Size: 60

Participant exclusion criteria

1. Any use of immunomodulatory drugs such as azathioprine, mycophenolate, methotrexate, ciclosporin, cyclophosphamide within the last 12 months
2. Any previous use of rituximab or alemtuzumab
3. Previous treatment with corticosteroids for greater than 2 weeks, or any steroid use in the last 3 months
4. Regular use of non-steroidal anti-inflammatory drugs including aspirin > 75 mg, naproxen, ibuprofen, meloxicam on more than 2 days per week.
5. Known inflammatory or autoimmune disease
6. Chronic or latent infection
7. Active infection requiring the use of parenteral antimicrobial agents within 2 months prior to the first dose of study treatment.
8. Skin malignancy or solid organ malignancy within the last 5 years.
9. Current or previous haematological malignancy
10. Positive test for HIV or hepatitis
11. The inability to take or swallow oral medication
12. Dementia according to Movement Disorder Society dementia criteria
13. Thiopurine methyltransferase (TPMT) deficiency < 10 pmol/h/mg Hb
14. Lack of immunity to VZV
15. Negative EBV IgG
16. Chronic liver disease
17. Renal impairment - creatinine clearance < 50 mL/min
18. Concomitant use of allopurinol (increases risk of myelotoxicity)
19. 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 study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
20. Receipt of live, attenuated vaccine within the last 30 days. Note: enrolled patients should not receive live, attenuated vaccine while receiving azathioprine nor within 30 days of the last dose of azathioprine
21. 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.
22. 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
23. Known hypersensitivity to azathioprine or its excipients
24. Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before treatment protocol registration or is currently enrolled in an interventional investigational study

Recruitment start date

03/03/2020

Recruitment end date

03/03/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Cambridge University Hospitals NHS Foundation Trust
Addenbrookes Hospital Hills Road
Cambridge
CB2 0QQ
United Kingdom

Sponsor information

Organisation

Cambridge University Hospitals NHS Foundation Trust

Sponsor details

c/o Stephen Kelleher
Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
+44 (0)1223 217418
research@addenbrookes.nhs.uk

Sponsor type

Hospital/treatment centre

Website

http://www.cuh.org.uk/

Funders

Funder type

Charity

Funder name

Cambridge Centre for Parkinson-Plus

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

The Cure Parkinson’s Trust

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

A version of the protocol will be submitted for publication in BMJ Open shortly. The researchers will feedback trial results to participants and their wider cohort of research participants via our annual Parkinson’s Disease Open Day at the John van Geest Centre for Brain Repair, and via our annual newsletter to research participants. A lay summary of the results will be available on our website http://www.thebarkerwilliamsgraylab.co.uk/. The results will also be disseminated through publication in scientific journals and presentation at national and international conferences. The aim is to publish the results of the trial in autumn 2024.

IPD sharing statement
The data-sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

01/02/2024

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

14/04/2020: Trial's existence confirmed by the NIHR.