Conservative iron chelation as a disease-modifying strategy in Parkinson’s disease (FAIR-PARK II)
| ISRCTN | ISRCTN84188565 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN84188565 |
| EudraCT/CTIS number | 2015-003679-31 |
| ClinicalTrials.gov number | NCT02655315 |
| Secondary identifying numbers | 31933 |
- Submission date
- 19/06/2017
- Registration date
- 03/07/2017
- Last edited
- 03/10/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nervous System Diseases
Plain English Summary
Background and study aims
Parkinson’s disease is a long-term condition most commonly associated with changes in movement. It is classed as a neurodegenerative disorder because it is linked to progressive damage of nerve cells (neurons) in the brain. It is the second most common neurodegenerative disorder worldwide affecting millions of people including about 1% of people in their 60s and up to 4% of people in the oldest age groups. It is estimated that the number of people with a Parkinson’s disease diagnosis will double, at least, by 2030. Current medications for Parkinson’s disease treat only a person’s symptoms and do not slow down the worsening of the disease. Neurons are responsible for making a chemical called dopamine which passes messages to the brain for many functions including movement, memory and sleep. The symptoms seen in Parkinson’s disease such as slowness of movement, stiffness and tremors are thought to be due to loss of neurons. From the early stages of Parkinson’s disease, an excess amount of iron is seen in a part of the brain that contains neurons and this may contribute to their loss. The aim of this study is to investigate whether reducing excess iron using the medication deferiprone might decrease neuron loss and slow down the progression of Parkinson’s disease.
Who can participate?
Adults aged 18 and older with a Parkinson’s disease diagnosis who have not yet received any treatment.
What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive the treatment tablets with deferiprone. Those in the second group receive a dummy tablet. All participants take the tablets by mouth twice a day, once in the morning and once in the evening, 30 minutes before a meal. This is done daily for nine months and participants are followed up with for one month after treatment. During this period, participants visit the study centre six times to provide information about their health, medications, side effects. They also undergo a physical examination, heart monitors, mobility assessments, and provide blood and urine samples. Participants also provide extra blood samples weekly for the first six months of the trial and then monthly for the last three months of the study. There are also optional tests that participants can undergo and these include blood samples and lumbar puntures to collect spinal fluid (to analyse any biological effects of the treatment).
What are the possible benefits and risks of participating?
There are no direct benefits with participating. There are always risks when taking medication, however, Deferiprone is a widely prescribed treatment and is well tolerated. There is a risk of a drop of white blood cell count, which is corrected by stopping taking the medication. Participants will be monitored for this. Other risks are side effects such as fatigue, headaches, dizziness, nausea, muscular pain and diarrhoea. Participant may experience discomfort when providing blood samples. Participants who undergo optional lumbar puncture may experience headaches during the procedure and can be allergic to the anaesthetic used during the procedure. There is a risk of infection, damage to the nerves in the spine and bleeding.
Where is the study run from?
This study is a European clinical trial that is being run in France, Spain, Austria, the Czech Republic, Portugal, Germany, the Netherlands and the United Kingdom. In the United Kingdom the trial is being run from the Centre for Aging and Vitality (UK) in Newcastle upon Tyne and Addenbrooke’s Hospital (UK)
When is the study starting and how long is it expected to run for?
February 2016 to September 2020
Who is funding the study?
European Commission (EU)
Who is the main contact?
Dr Karen Nicholson
karen.nicholson2@newcastle.ac.uk
Contact information
Public
Newcastle Clinical Trials Unit
Newcastle University
1-4 Claremont Terrace
Newcastle upon Tyne
NE2 4AE
United Kingdom
| Phone | +44 (0)191 208 2519 |
|---|---|
| karen.nicholson2@newcastle.ac.uk |
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment, Efficacy |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | Conservative iron chelation as a disease-modifying strategy in Parkinson's disease |
| Study acronym | FAIRPARK II |
| Study hypothesis | The aim of this study is to establish whether conservative iron chelation with the prototype drug deferiprone slows down the progression of Parkinson’s disease and to determine the associated risk benefit balance. |
| Ethics approval(s) | North East – Tyne & Wear South Research Ethics Committee, 19/07/2016, 16/NE/0200 |
| Condition | Parkinson's disease |
| Intervention | Participants are randomly allocated to one of two groups. Those in the first group receive the treatment tablets with deferiprone (15 mg/kg). Those in the second group receive a dummy tablet. All participants take the tablets by mouth twice a day, once in the morning and once in the evening, 30 min before a meal. This is done daily for 9 months and participants are followed up for 1 month after treatment. During the trial participants will attend visits for screening, randomisation (visit V0), week 12 (visit V1), week 24 (visit V2), week 36 (visit V3) and week 40 (visit V4). During visits V0, V3 and V4 participants have three comprehensive examinations (i.e. rating of the total Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale [MDS-UPDRS] and all secondary criteria), at visits V1 and V2 assessments will include rating the total MDS-UPDRS and a check on all the safety criteria during a brief consultation. A weekly complete blood count (CBC, with the white blood cell count [WBC]) performed for the first 24 weeks and then monthly until week 36. Deferiprone or the placebo is taken from the day following randomisation until the morning dose on the day of the visit at week 36. Participants may also be asked whether they would like to have additional, optional, tests performed. These include: 1. Cerebrospinal fluid (CSF) analysis at the randomization visit and at week 36, in order to perform a full set of CSF biochemistry assays and with a view to determining the biological benefits of deferiprone treatment at the central nervous system level and to identifying biological markers. For the patient’s comfort, lumbar puncture will be performed under local anaesthesia and with administration of a 1:1 mixture of nitrous oxide and oxygen. 2. Additional blood analysis (extra volume of 40 ml) This is done to assess mitochondrial function, with functional assays on lymphocytes: mitochondrial membrane potential and reactive oxygen species production (flow cytometry). This is also done to evaluate the neural, endothelial and platelet microparticles. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Not Applicable |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Deferiprone |
| Primary outcome measure | Motor symptoms, non-motor symptoms and daily life activities are assessed using the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the change in the total score is measured between baseline and 36 weeks (i.e. the end of the placebo-controlled phase for analysis of both disease-modifying and symptomatic effects). |
| Secondary outcome measures | 1. The disease-modifying effect is measured as the changes in the overall MDS-UPDRS score between baseline and week 40 2. The global effect on motor and non-motor symptoms is analysed as the change in the different subscales of the MDS-UPDRS between baseline and week 36 and between baseline and week 40 3. Effects on quality of life and autonomy is analysed as the change in the Parkinson’s Disease Quality of Life (PDQ-39, via a 39-item self-questionnaire) and the Clinical Global Impression scored by the examiner and the patient between baseline and week 36 and between baseline and week 40 4. A health economics assessment is performed via a specific questionnaire and EQ-5D questionnaire between baseline and week 36 and between baseline and week 40 5. Safety criteria that is measured include: 5.1. Complete blood count (CBC, including a white blood cell (WBC) count and a differential, absolute neutrophil count (ANC) and platelet count) is assessed using weekly (± 3 days) blood tests from the start of treatment onwards for 24 weeks and then monthly until week 36 5.2. An iron status check (haemoglobin, serum iron, ferritinemia, transferrin, total binding capacity, transferrin saturation coefficient, 24-hour urine iron) is assessed at baseline and week 36 5.3. Clinical chemistry tests (fating glucose, urea, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT)) are assessed at screening and weeks 12 and 24 5.4. General health status and full physical exam (including vital signs, bodyweight, electrocardiogram and blood pressure) are assessed at baseline and weeks 12, 24, 36 and 40 5.5. Adverse events, concomitant medication(s) and observance are measured using questions about the occurrence of adverse events, the use of any medications and the compliance with the study therapy, at each scheduled or unscheduled visit 5.6 β HCG (for women of childbearing potential) is measured monthly through blood tests |
| Overall study start date | 08/02/2016 |
| Overall study end date | 20/09/2020 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned UK Sample Size: 42; Final UK recruitment: 17 |
| Total final enrolment | 372 |
| Participant inclusion criteria | 1. Adult patients aged 18 and older 2. Parkinson’s disease diagnosed according The Movement Disorder Society Clinical Diagnostic Criteria for Parkinson’s Disease (PD) 3. Treatment-naïve, i.e. the best population for assessing a disease-modifying effect without the interaction of dopaminergic treatment (no dopaminergic agonists, L-dopa, anticholinergics, monoamine oxidase B inhibitors (e.g. rasagiline) or deep brain stimulation) 4. Patients covered by a Health Insurance System in countries where required by law 5. Written informed consent dated and signed prior to the beginning of any procedures related to the clinical trial |
| Participant exclusion criteria | 1. Disease duration greater than 18 months 2. Patients with high frequency of comorbidity or vital risks that may reasonably impair life expectancy 3. Subject with handicap required dopaminergic treatment at the inclusion and therefore likely not to bear 9 months without symptomatic treatment 4. Hoehn and Yahr stage 3 or more 5. Significant cognitive impairment (a Mini Mental State Examination score <24 or an equivalent impairment on a similar scale) or dementia diagnosed in accordance with the Movement Disorders Society criteria (Emre et al., 2007) 6. Atypical or secondary parkinsonism (supranuclear palsy, multisystem atrophy, etc.) or anomalies on MRI suggestive of vascular involvement or significant cortical or subcortical atrophy (i.e. atypical for PD) 7. Progressing axis I psychiatric disorders (psychosis, hallucinations, substance addiction, bipolar disorder, or severe depression), in accordance with the Diagnostic and Statistical Manual of Mental Disorders 8. Subjects undergoing brain stimulation 9. Due to the high risk of agranulocytosis caused by the IMP and the unknown mechanism by which this agranulocytosis is induced, it is not allowed to combine deferiprone with other medicinal products causing agranulocytosis (as described in the IB). Such medicinal products are the already mentioned clozapine and also some NSAIDs (e.g. phenylbutazone or metamizole), antithyroid agents, sulphonamide antibiotics or methotrexate 10. A history of relapsing neutropenia 11. Hypersensitivity to deferiprone 12. Patients with agranulocytosis or with a history of agranulocytosis 13. Patients taking a treatment at risk of agranulocytosis (clozapine, Closaril®/Leponex®) 14. Patients with anaemia (regardless of the latter's aetiology) or a history of another haematological disease. Haemochromatosis is not an exclusion criterion 15. Pregnant or breastfeeding women or women of childbearing potential not taking highly effective contraception 16. Kidney or liver failure 17. Other serious diseases 18. Inability to provide informed consent 19. Participation in another clinical trial within 3 months prior to inclusion in the study 20. Patient who has suffered mild or moderate depressive episode and isn’t in remission and on a stable medication for at least 8 weeks Exclusion criteria for the biomarker study and the ancillary study: 1. Subjects for whom MRI is contraindicated (metal objects in the body, severe claustrophobia, pacemaker, incompatible surgical material) 2. Very severe rest tremor, which could induce MRI artefacts 3. Lumbar puncture 4. Blood coagulation disorders, antiplatelet drugs or anticoagulants 5. Intracranial hypertension 6. Contraindications to nitrous oxide 7. Ventilation with FiO2 >50%, emphysema or pneumothorax 8. Altered states of consciousness, non-cooperative patient (need to stop the nitrous oxide) |
| Recruitment start date | 07/07/2017 |
| Recruitment end date | 31/12/2019 |
Locations
Countries of recruitment
- Austria
- Czech Republic
- England
- France
- Germany
- Netherlands
- Portugal
- Spain
- United Kingdom
Study participating centres
Campus of Ageing and Vitality
Newcastle upon Tyne
NE4 5PL
United Kingdom
Cambridge
CB2 0QQ
United Kingdom
Sponsor information
Hospital/treatment centre
2 Avenue Oscar Lambret
Lille
59000
France
"ROR" |
https://ror.org/02ppyfa04 |
|---|
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- European Union, Comisión Europea, Europäische Kommission, EU-Kommissionen, Euroopa Komisjoni, Ευρωπαϊκής Επιτροπής, Европейската комисия, Evropské komise, Commission européenne, Choimisiúin Eorpaigh, Europskoj komisiji, Commissione europea, La Commissione europea, Eiropas Komisiju, Europos Komisijos, Európai Bizottságról, Europese Commissie, Komisja Europejska, Comissão Europeia, Comisia Europeană, Európskej komisii, Evropski komisiji, Euroopan komission, Europeiska kommissionen, EC, EU
Results and Publications
| Intention to publish date | 31/01/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication at conferences, in peer-reviewed scientific journals and on the study website. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository: European Clinical Research Infrastructure Network (ECRIN) Added 01/10/2020: As specified in the Consortium agreement of FAIR PARK II, the intellectual management board (IMB) oversees intellectual property management and dissemination of the consortium. The IMB is subdivided into two groups: the intellectual property division (IPD) and the scientific evaluation division (SED). The SED is subdivided into two groups: the scientific project assessment group (SPAG-SED) and the publication project assessment group (PAG-SED). The data are available to all the scientific community. People who want to have access to the data generated during THE FAIR PARK II study will address a scientific draft (specifying the types of analyses) to the project management team (pauline.guyon@chru-lille.fr and stephanie.lenaour@inserm-transfert.fr). The project management team will forward the document to the SPAG-SED. The SPAG-SED duties: 1. Advice and expertise on the opportunity of the submitted project 2. Assessment of the scientific value of the submitted project 3. Control of the validity of the research project proposed 4. Advice on the optimum use of the project resources 5. Advice and support regarding ongoing and validated projects 6. Review the submitted project pursuant to FP II grid If no written remark or comment has been made within 15 days. the project is approved and people can have access to the data. The data will be available for the end of April 2021 and for the moment, there is no duration specified regarding their availability. Patient's consent is obtained to share the data in the scientific community. Data are pseudo-anonymized (with the patient ID). The sharing of all data will be compliant with all legal and ethical requirements. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Other unpublished results | 13/06/2023 | 02/10/2023 | No | No | |
| Protocol file | version 7 | 14/10/2019 | 02/10/2023 | No | No |
| Results article | 01/12/2022 | 03/10/2023 | Yes | No |
Additional files
Editorial Notes
03/10/2023: Publication reference added.
02/10/2023: The following changes have been made:
1. A protocol file has been uploaded.
2. An unpublished results file has been uploaded.
12/10/2021: The intention to publish date
08/12/2020: The following changes were made to the trial record:
1. The overall trial end date was changed from 31/10/2020 to 20/09/2020.
2. The intention to publish date was changed from 30/04/2021 to 31/10/2021.
01/10/2020: The following changes were made to the trial record:
1. The overall trial end date was changed from 30/09/2020 to 31/10/2020.
2. The intention to publish date was changed from 31/03/2022 to 30/04/2021.
3. IPD sharing statement added.
13/01/2020: The following changes have been made:
1. The NCT code has been added.
2. The total target enrolment has been changed from 42, which was the expected UK enrolment, to 372, which was the total expected worldwide.
3. The total final enrolment was added.
4. The Participant inclusion criteria: Target number of participants has been changed from "Planned Sample Size: 42; UK Sample Size: 42" to "Planned UK Sample Size: 42; Final UK recruitment: 17".
09/07/2019: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/06/2019 to 31/12/2019.
2. The overall end date was changed from 01/03/2020 to 30/09/2020.
3. The intention to publish date was changed from 31/12/2019 to 31/03/2022.
4. The plain English summary was updated to reflect these changes.
03/04/2019: The condition has been changed from "Specialty: Dementias and neurodegeneration, Primary sub-specialty: Parkinson's Disease; UKCRC code/ Disease: Neurological/ Other degenerative diseases of the nervous system" to "Parkinson's disease" following a request from the NIHR.
23/01/2019: The recruitment end date was changed from 08/02/2018 to 01/06/2019.
21/01/2019: The contact details were updated, and the overall trial end date was changed from 08/12/2018 to 01/03/2020.
