Condition category
Nervous System Diseases
Date applied
02/08/2011
Date assigned
25/08/2011
Last edited
17/05/2016
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
The current widely-used treatment of Parkinson’s 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?
Over 30 months, 446 patients with newly diagnosed PD that don’t need symptomatic treatment, as judged by the treating neurologist, will be included.

What does the study involve?
For 40 weeks, patients will receive either levodopa/carbidopa or a dummy (placebo) three times a day; for the next 40 weeks, all patients will receive levodopa/carbidopa three times a day. There are 8 assessments, all of which will be performed by trained research nurses. The study will measure 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 December 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

Trial website

http://leapamc.nl/

Contact information

Type

Scientific

Primary contact

Dr Rob de Bie

ORCID ID

Contact details

Academisch Medisch Centrum
Postbus 22660
Amsterdam
1100DD
Netherlands

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

ZonMw 171102018 (Protocol) / 2011_057(Medical Ethical Committee)

Study information

Scientific title

Levodopa in EArly Parkinson’s disease: a prospective, randomized, double-blind, placebo-controlled, delayed start trial

Acronym

LEAP

Study hypothesis

Levodopa has a large direct symptomatic effect and may have a clinically relevant delayed beneficial effect.

Ethics approval

Medical Ethical Committee of the Academic Medical Center in Amsterdam, 19/04/2011, ref: AMC: 2011_057

Study design

Prospective randomized double blind placebo-controlled delayed start multi-center clinical trial

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 below to request a patient information sheet.

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

Phase

Not Applicable

Drug names

Levodopa

Primary outcome measures

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 trial start date

01/08/2011

Overall trial end date

31/12/2017

Reason abandoned

Eligibility

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 type

Patient

Age group

Adult

Gender

Both

Target number of participants

446

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., Wilson’s 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

Trial participating centre

Academisch Medisch Centrum
Amsterdam
1100DD
Netherlands

Sponsor information

Organisation

Academic Medical Center (AMC) (Netherlands)

Sponsor details

Department of Neurology
Postbus 22660
Amsterdam
1100DD
Netherlands

Sponsor type

Hospital/treatment centre

Website

http://www.amc.nl/

Funders

Funder type

Government

Funder name

Netherlands Organisation for Health Research and Development (ZonMw) (Netherlands) (ref: 171102018)

Alternative name(s)

Netherlands Organisation for Health Research and Development

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

Netherlands

Funder name

Stichting ParkinsonFonds (patient organisation, Netherlands)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Parkinsonismen Vereniging (patient organisation, Netherlands)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

As the last measurements for the last patient will be performed at the end of 2017, we expect to publish the results in the first half of 2018. If possible, we will present the results at the yearly Movement Disorder Society Congress. Further details will be confirmed at a later date.

Intention to publish date

Participant level data

Available on request

Results - basic reporting

Publication summary

2015 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/26584951

Publication citations

Additional files

Editorial Notes

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.