Levodopa in early Parkinsons disease
| ISRCTN | ISRCTN30518857 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN30518857 |
| Secondary identifying numbers | ZonMw 171102018 (Protocol) / 2011_057 (Medical Ethical Committee) |
- Submission date
- 02/08/2011
- Registration date
- 25/08/2011
- Last edited
- 18/10/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nervous System Diseases
Plain English Summary
Background and study aims
The current widely-used treatment of Parkinsons disease (PD) consists of dopamine replacement with levodopa or dopamine agonists. There is considerable debate about when and how to start treatment with drugs. Although current guidelines indicate that treating the symptoms of PD should be started when normal movement becomes difficult, most neurologists still delay starting treatment of these symptoms. This results in an acceptance of disability early in the disease. The results of recent studies suggest that early treatment with levodopa might have a delayed positive effect on PD symptoms. The aim of this study is to investigate whether early treatment with levodopa has a delayed positive effect on PD symptoms and functional health, improves the ability to (maintain) work; and reduces the use of (informal) care, caregiver burden, and costs.
Who can participate?
Patients with newly diagnosed PD who dont need symptomatic treatment as judged by the treating neurologist
What does the study involve?
For 40 weeks, patients receive either levodopa/carbidopa or a dummy (placebo) three times a day; for the next 40 weeks, all patients receive levodopa/carbidopa three times a day. There are 8 assessments, all of which are performed by trained research nurses. The study measures disability, side effects, quality of life, ability to (maintain) work, the use of (informal) care, caregiver burden, and costs.
What are the possible benefits and risks of participating?
If the study shows a cost effective delayed positive effect of levodopa in newly diagnosed PD patients, treatment of symptoms should start as early as possible, i.e. immediately when the diagnosis is made. Subsequently, PD patients functional health and quality of life may improve substantially. This could prolong the normal level of social functioning and participation in the workforce. Levodopa has been the most commonly used medication for Parkinson's disease for over 40 years, with mostly minor side-effects. You can ask your neurologist for more information.
Where is the study run from?
Academic Medical Center (Netherlands)
When is the study starting and how long is it expected to run for?
August 2011 to November 2017
Who is funding the study?
Netherlands Organisation for Health Research and Development (ZonMw, Netherlands), the Stichting ParkinsonFonds (patient organisation, Netherlands) and Parkinsonismen Vereniging (patient organisation, Netherlands)
Who is the main contact?
Dr Rob de Bie
r.m.debie@amc.uva.nl
Contact information
Scientific
Academisch Medisch Centrum
Postbus 22660
Amsterdam
1100DD
Netherlands
Study information
| Study design | Prospective randomized double blind placebo-controlled delayed start multi-center clinical trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | Levodopa in EArly Parkinsons disease: a prospective, randomized, double-blind, placebo-controlled, delayed start trial |
| Study acronym | LEAP |
| Study hypothesis | Levodopa has a large direct symptomatic effect and may have a clinically relevant delayed beneficial effect. |
| Ethics approval(s) | Medical Ethical Committee of the Academic Medical Center in Amsterdam, 19/04/2011, ref: AMC: 2011_057 |
| Condition | Parkinson's disease |
| Intervention | Patients will be randomised to 40 weeks treatment with levodopa / carbidopa 100 / 25 mg three times a day (TID) (including 2 weeks of dose escalation) or 40 weeks placebo TID (phase 1). Following phase 1, all patients will receive levodopa / carbidopa 100 / 25 mg TID for 40 weeks, including 2 weeks of dose escalation for the placebo-group (phase 2). |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Levodopa |
| Primary outcome measure | The difference in the mean total Unified Parkinson's Disease Rating Scale (UPDRS) scores between the early and delayed groups at 80 weeks |
| Secondary outcome measures | Current secondary outcome measures as of 01/04/2016: 1. The progression of symptoms between Visit 2 and Visit 4 (phase 1) and between Visit 5 and Visit 8 (phase 2) measured with the UPDRS: 1.1. Progression in Phase 1: Superiority of the UPDRS slope during phase 1 of the early group as compared to the delayed group 1.2. Progression in Phase 2: Non-inferiority of the UPDRS slope in phase 2 of the early group as compared to the delayed group 2. Disability measured with the AMC Linear Disability Scale (ALDS); The difference between the early group and the delayed group in median change scores (change score = difference between baseline and 80 weeks assessment score) of the ALDS-score. The ALDS is a flexible and feasible instrument to assess the level of disability in patients with newly diagnosed PD 3. Between-group difference in mean total UPDRS scores at 80 weeks and the progression of UPDRS scores during phases 1 and 2 in patients who followed the study ‘per protocol’ 4. Between-group difference in mean total UPDRS scores at 80 weeks and the progression of UPDRS scores during phases 1 and 2 in patients with UPDRS scores in the highest quartile of scores at baseline who followed the study ‘per protocol’ 5. Number of patients that need additional medication for PD 6. Cognitive impairment, measured with the MMSE 7. Depression, measured with the BDI-II 8. Perceived quality of life measured with the PDQ-39 9. Quality Adjusted Life Years (QALY), after applying existing scoring algorithm to derive health utilities from observed European Quality of Life-5 Dimensions (EQ-5D) data 10. Working status and absence from paid work measured with a standardized questionnaire 11. Caregiver burden with a standardized questionnaire 12. Resource utilisation outside of the participating hospitals measured with a standardized questionnaire (for 10, 11 and 12 we used an adjusted version of the Short Form – Health and Labour Questionnaire and iMTA Valuation of Informal Care Questionnaire targeted at the study population) 13. Cost per unit decrease of the UPDRS and cost per QALY 14. Number of patients withdrawn from the study or lost to follow up 15. Dyskinesias, measured with items 32 to 35 of the UPDRS part IV 16. Levodopa-induced motor response fluctuations throughout the course of the study measured with items 36 to 39 of the UPDRS part IV and three standardized questions concerning wearing-off phenomena 17. (Serious) adverse events defined as the frequency, severity, nature, and duration of any adverse event throughout the course of the study Previous secondary outcome measures: 1. The progression of symptoms between Visit 2 and Visit 4 (phase 1) and between Visit 5 and Visit 8 (phase 2) measured with the UPDRS 1.1. Progression in Phase 1: superiority of the UPDRS slope during phase 1 of the early group as compared to the delayed group 1.2. Progression in Phase 2: non-inferiority of the UPDRS slope in phase 2 of the early group as compared to the delayed group 2. Disability measured with the Academic Medical Center Linear Disability Score (ALDS). The difference between the early group and the delayed group in median change scores (change score = difference between baseline and 80 weeks assessment score) of the ALDS score. The ALDS is a flexible and feasible instrument to assess the level of disability in patients with newly diagnosed PD 3. Number of patients that need additional medication for PD 4. Number of patients that proceed early to phase 2 5. Number of patients withdrawn from the study or lost to follow up 6. Levodopa-induced motor response fluctuation; the frequency, severity, nature and duration of any levodopa-induced motor response fluctuation throughout the course of the study 7. (Serious) adverse events; the frequency, severity, nature and duration of any adverse event throughout the course of the study 8. Perceived quality of life measured with the PDQ-39 9. Cognitive impairment, measured with the MMSE 10. Depression, measured with the BDI-II 11. The utility measure in the cost-utility analysis measured with the EQ-5D 12. Working status and absence from paid work measured with a standardized questionnaire 13. Caregiver burden 14. Resource utilization outside of the participating hospitals through a standardized questionnaire |
| Overall study start date | 01/08/2011 |
| Overall study end date | 29/11/2017 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | 446 |
| Total final enrolment | 445 |
| Participant inclusion criteria | 1. Iidiopathic Parkinson's disease (PD) with bradykinesia and at least two of the following signs: 1.1. Resting tremor 1.2. Rigidity 1.3. Asymmetry 2. Newly diagnosed PD within the past two years 3. Age 30 years and over 4. A life expectancy of more than two years 5. No limitations in functional health for which the patient needs PD-medication |
| Participant exclusion criteria | 1. Tremor as most prominent symptom, such as: 1.1. A severe resting tremor that is present (almost) continuously 1.2. Tremor of medium to large amplitude which results in functional disability (such as interfering with feeding) 2. Previous treatment with PD-medication, e.g., levodopa, dopamine agonist (DA), monoamine oxidase (MAO)-B-inhibitor, catechol-Omethyl transferase-inhibitor (COMT-inhibitor), or amantadine 3. Cognitive impairments, i.e., Mini Mental State Examination (MMSE) of 23 points or lower; 4. More than 28 points on the Beck Depression Scale II (BDI-II) 5. Diagnosis of depression by a psychiatrist in the last year 6. History of psychosis 7. History of glaucoma 8. The presence of signs indicating atypical or secondary parkinsonism such as: 8.1. The use of drugs that may cause parkinsonism (e.g., metoclopramide, cinarizine, anti- psychotics, natrium-valproate, lithium, amiodarone) 8.2. Metabolic disorders (e.g., Wilsons disease) 8.3. Encephalitis 8.4. Vascular parkinsonism 8.5. Repeated head-trauma 9. Alcohol abuse 10. Legally incompetent adults 11. Inability to provide written informed consent |
| Recruitment start date | 17/08/2011 |
| Recruitment end date | 17/05/2016 |
Locations
Countries of recruitment
- Netherlands
Study participating centre
1100DD
Netherlands
Sponsor information
Hospital/treatment centre
Department of Neurology
Postbus 22660
Amsterdam
1100DD
Netherlands
| Website | http://www.amc.nl/ |
|---|---|
"ROR" |
https://ror.org/03t4gr691 |
Funders
Funder type
Government
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- Netherlands Organisation for Health Research and Development
- Location
- Netherlands
No information available
No information available
Results and Publications
| Intention to publish date | 01/07/2018 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | As the last measurements for the last patient will be performed at the end of 2017, the trialists expect to publish the results in the first half of 2018. If possible, they will present the results at the yearly Movement Disorder Society Congress. Further details will be confirmed at a later date. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Dr. R.M.A. de Bie (r.m.debie@amc.uva.nl). The output will be in SPSS. Consent of participants was obtained to perform analyses on the data. All data is anonymized. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 19/11/2015 | Yes | No | |
| Results article | results | 24/01/2019 | Yes | No | |
| Results article | 17/10/2022 | 18/10/2022 | Yes | No |
Editorial Notes
18/10/2022: Publication reference and total final enrolment added.
07/02/2019: Publication reference added.
26/01/2018: The intention to publish date and IPD sharing statement were added.
02/01/2018: The overall trial end date was changed from 31/12/2017 to 29/11/2017.
01/04/2016: The following changes were made to the trial record:
1. The overall trial end date was changed from 01/06/2016 to 31/12/2017.
2. Parkinsonismen Vereniging was added to the list of funders.
09/04/2014: The overall trial end date was changed from 01/02/2014 to 01/06/2016.
The registration was initiated on 02/08/2011 and finalised on 25/08/2011. The recruitment started on 17/08/2011, after initiation of public registration.
