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NIHR Signal When is it best to start the Parkinson’s drug, levodopa?

Published on 16 April 2019

doi: 10.3310/signal-000761

Earlier treatment with levodopa provides symptomatic relief to those with symptoms but does not appear to slow Parkinson’s disease from progressing. Therefore, timing is best determined by symptoms.

The treatment of Parkinson’s disease is complex. Levodopa is the main drug used to reduce tremors and muscle stiffness. Whether it modifies the course of the disease or becomes less effective over time is debated, and it can have side effects, so patients and clinicians sometimes prefer to delay starting treatment.

This Dutch trial involved 445 participants with a recent diagnosis of Parkinson’s disease, enrolled over five years. About half took levodopa for 80 weeks, and half placebo for the first 40 weeks and levodopa for the last 40 weeks. There was no difference in symptoms between the groups at the end of the study.

This evidence supports current guidance to start levodopa when symptoms begin to affect the quality of life and confirm that it has insufficient impact on disease progression to justify earlier treatment.

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Why was this study needed?

Approximately 127,000 people in the UK have Parkinson’s disease, around two people in every 1,000. It mostly affects adults over the age of 50.

Parkinson’s disease is a progressive neurological condition that causes increasing disability. People experience, amongst other problems, muscle stiffness, slow movements and tremors.

There is no cure for Parkinson’s disease, but treatment can control symptoms. Levodopa is the main drug used to improve movement. It can cause side effects, such as jerky movements, and might become less effective. Therefore, treatment is sometimes delayed to avoid side effects.

Earlier research has suggested that levodopa might slow down the worsening of the disease itself, as well as relieving symptoms. This study aimed to demonstrate whether this was the case and chart the development of any symptoms over almost 18 months.

What did this study do?

The LEAP study was a randomised double-blind trial conducted in the Netherlands. It recruited 445 people with recently diagnosed Parkinson’s disease from 57 hospitals.

The early start group received 100mg of levodopa three times a day for 80 weeks plus another drug (carbidopa) to minimise side effects. The delayed start group received a placebo for the first 40 weeks, then the levodopa regimen for the remaining 40 weeks.

Change in functional ability of participants was measured at 80 weeks using the Unified Parkinson’s Disease Rating Scale (UPDRS), range 0 to 176, with higher numbers indicating worsening function. A four-point difference on this scale is thought to be clinically important.

Some participants (39%) in the delayed-start arm of the trial began treatment earlier than planned due to increasing symptoms, which might have reduced the difference between the two groups studied.

What did it find?

  • According to the UPDRS score, there was no difference in the progress of disease between the early-start group (mean difference from baseline to 80 weeks -1.0±13.1) and the delayed-start group (-2.0±13.0), (difference between mean scores 1.0, 95% confidence interval [CI] -1.5 to 3.5).
  • The estimated rate of change in progression of the disease, a secondary outcome, was similar in both groups between 4 and 44 weeks (estimated difference in mean UPDRS scores -0.02 points, 95% CI -0.07 to 0.03).
  • Due to needing symptomatic relief, 87 people in the delayed-start group had levodopa before week 40.
  • The estimated rate of change in progression was faster between weeks 44 and 80 in the early-start group (estimated mean difference in scores 0.07, 95% CI 0.03 to 0.10). This means starting levodopa earlier did not slow disease progression.
  • At 80 weeks, a similar proportion of participants were suffering complications, such as involuntary movements, from levodopa treatment (9.6% of the early-start group compared with 12% of the delayed-start group).

What does current guidance say on this issue?

The NICE guideline (2017) recommends levodopa as a first-line treatment in the early stages of Parkinson’s to control problems with movement if symptoms are affecting the quality of life. It does not discuss delayed treatment with levodopa.

If motor symptoms are not affecting the quality of life, the guideline recommends considering other drugs such as dopamine or monoamine oxidase inhibitors based on individual circumstances and preferences.

What are the implications?

According to this research, levodopa is unlikely to affect the progression of Parkinson’s disease in the first year and a half following diagnosis.

Symptoms had improved to the same extent by 80 weeks and side effects were similar, suggesting people can start treatment as early as they need to for symptomatic relief.

This supports current practice in giving levodopa when clinically needed. There is no cure for Parkinson’s disease, and further research is in progress to develop disease-modifying agents.

Citation and Funding

Verschuur CVM, Suwijn SR, Boel JA et al.; LEAP Study Group. Randomized delayed-start trial of levodopa in Parkinson's disease. N Engl J Med. 2019;380(4):315-24.

This project was funded by the Netherlands Organisation for Health Research and Development, Parkinson Vereniging (Dutch patient organisation) and Stichting Parkinson Nederland (Dutch funding organisation for Parkinson’s disease research).

Bibliography

NHS website. Parkinson’s disease. London: Department of Health and Social Care; updated 2016.

NICE. Parkinson’s disease in adults. NG71. London: National Institute for Healthcare Excellence; 2017.

Fahn S, Oakes D, Shoulson I et al.; Parkinson Study Group. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351:2498-508.

Bressman S, Saunders-Pullman R. When to start levodopa therapy for Parkinson’s disease. Editorial. N Engl J Med. 2019; 380(4):389-390.

Parkinson’s UK. Unified Parkinson’s Disease Rating Scale (UPDRS). London: Parkinson’s Disease Society of the United Kingdom; updated 2016.

Why was this study needed?

Approximately 127,000 people in the UK have Parkinson’s disease, around two people in every 1,000. It mostly affects adults over the age of 50.

Parkinson’s disease is a progressive neurological condition that causes increasing disability. People experience, amongst other problems, muscle stiffness, slow movements and tremors.

There is no cure for Parkinson’s disease, but treatment can control symptoms. Levodopa is the main drug used to improve movement. It can cause side effects, such as jerky movements, and might become less effective. Therefore, treatment is sometimes delayed to avoid side effects.

Earlier research has suggested that levodopa might slow down the worsening of the disease itself, as well as relieving symptoms. This study aimed to demonstrate whether this was the case and chart the development of any symptoms over almost 18 months.

What did this study do?

The LEAP study was a randomised double-blind trial conducted in the Netherlands. It recruited 445 people with recently diagnosed Parkinson’s disease from 57 hospitals.

The early start group received 100mg of levodopa three times a day for 80 weeks plus another drug (carbidopa) to minimise side effects. The delayed start group received a placebo for the first 40 weeks, then the levodopa regimen for the remaining 40 weeks.

Change in functional ability of participants was measured at 80 weeks using the Unified Parkinson’s Disease Rating Scale (UPDRS), range 0 to 176, with higher numbers indicating worsening function. A four-point difference on this scale is thought to be clinically important.

Some participants (39%) in the delayed-start arm of the trial began treatment earlier than planned due to increasing symptoms, which might have reduced the difference between the two groups studied.

What did it find?

  • According to the UPDRS score, there was no difference in the progress of disease between the early-start group (mean difference from baseline to 80 weeks -1.0±13.1) and the delayed-start group (-2.0±13.0), (difference between mean scores 1.0, 95% confidence interval [CI] -1.5 to 3.5).
  • The estimated rate of change in progression of the disease, a secondary outcome, was similar in both groups between 4 and 44 weeks (estimated difference in mean UPDRS scores -0.02 points, 95% CI -0.07 to 0.03).
  • Due to needing symptomatic relief, 87 people in the delayed-start group had levodopa before week 40.
  • The estimated rate of change in progression was faster between weeks 44 and 80 in the early-start group (estimated mean difference in scores 0.07, 95% CI 0.03 to 0.10). This means starting levodopa earlier did not slow disease progression.
  • At 80 weeks, a similar proportion of participants were suffering complications, such as involuntary movements, from levodopa treatment (9.6% of the early-start group compared with 12% of the delayed-start group).

What does current guidance say on this issue?

The NICE guideline (2017) recommends levodopa as a first-line treatment in the early stages of Parkinson’s to control problems with movement if symptoms are affecting the quality of life. It does not discuss delayed treatment with levodopa.

If motor symptoms are not affecting the quality of life, the guideline recommends considering other drugs such as dopamine or monoamine oxidase inhibitors based on individual circumstances and preferences.

What are the implications?

According to this research, levodopa is unlikely to affect the progression of Parkinson’s disease in the first year and a half following diagnosis.

Symptoms had improved to the same extent by 80 weeks and side effects were similar, suggesting people can start treatment as early as they need to for symptomatic relief.

This supports current practice in giving levodopa when clinically needed. There is no cure for Parkinson’s disease, and further research is in progress to develop disease-modifying agents.

Citation and Funding

Verschuur CVM, Suwijn SR, Boel JA et al.; LEAP Study Group. Randomized delayed-start trial of levodopa in Parkinson's disease. N Engl J Med. 2019;380(4):315-24.

This project was funded by the Netherlands Organisation for Health Research and Development, Parkinson Vereniging (Dutch patient organisation) and Stichting Parkinson Nederland (Dutch funding organisation for Parkinson’s disease research).

Bibliography

NHS website. Parkinson’s disease. London: Department of Health and Social Care; updated 2016.

NICE. Parkinson’s disease in adults. NG71. London: National Institute for Healthcare Excellence; 2017.

Fahn S, Oakes D, Shoulson I et al.; Parkinson Study Group. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351:2498-508.

Bressman S, Saunders-Pullman R. When to start levodopa therapy for Parkinson’s disease. Editorial. N Engl J Med. 2019; 380(4):389-390.

Parkinson’s UK. Unified Parkinson’s Disease Rating Scale (UPDRS). London: Parkinson’s Disease Society of the United Kingdom; updated 2016.

Randomized Delayed-Start Trial of Levodopa in Parkinson's Disease

Published on 24 January 2019

Verschuur, C. V. M.,Suwijn, S. R.,Boel, J. A.,Post, B.,Bloem, B. R.,van Hilten, J. J.,van Laar, T.,Tissingh, G.,Munts, A. G.,Deuschl, G.,Lang, A. E.,Dijkgraaf, M. G. W.,de Haan, R. J.,de Bie, R. M. A.

N Engl J Med Volume 380 , 2019

BACKGROUND: Levodopa is the main treatment for symptoms of Parkinson's disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in the course of the disease the treatment with this drug should be initiated. METHODS: In a multicenter, double-blind, placebo-controlled, delayed-start trial, we randomly assigned patients with early Parkinson's disease to receive levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks (delayed-start group). The primary outcome was the between-group difference in the mean change from baseline to week 80 in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS; scores range from 0 to 176, with higher scores signifying more severe disease). Secondary analyses included the progression of symptoms, as measured by the UPDRS score, between weeks 4 and 40 and the noninferiority of early initiation of treatment to delayed initiation between weeks 44 and 80, with a noninferiority margin of 0.055 points per week. RESULTS: A total of 445 patients were randomly assigned: 222 to the early-start group and 223 to the delayed-start group. The mean (+/-SD) UPDRS score at baseline was 28.1+/-11.4 points in the early-start group and 29.3+/-12.1 points in the delayed-start group. The change in UPDRS score from baseline to week 80 was -1.0+/-13.1 points and -2.0+/-13.0 points, respectively (difference, 1.0 point; 95% confidence interval [CI], -1.5 to 3.5; P=0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect. Between weeks 4 and 40, the rate of progression of symptoms, as measured in UPDRS points per week, was 0.04+/-0.23 in the early-start group and 0.06+/-0.34 in the delayed-start group (difference, -0.02; 95% CI, -0.07 to 0.03). The corresponding rates between weeks 44 and 80 were 0.10+/-0.25 and 0.03+/-0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10); the difference in the rate of progression between weeks 44 and 80 did not meet the criterion for noninferiority of early receipt of levodopa to delayed receipt. The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups. CONCLUSIONS: Among patients with early Parkinson's disease who were evaluated over the course of 80 weeks, treatment with levodopa in combination with carbidopa had no disease-modifying effect. (Funded by the Netherlands Organization for Health Research and Development and others; LEAP Current Controlled Trials number, ISRCTN30518857 .).

The Unified Parkinson’s Disease Rating Scale (UPDRS) is the most widely used clinical rating scale for rating the severity of Parkinson’s disease. It measures aspects such as activities of daily living, movement and mood. Scores range from 0 to 176, where a higher score indicates more severe disease.

Expert commentary

Aside from showing that earlier use of levodopa had no disease-modifying effect (as many would have expected), this article confirms that during the first 40 weeks of the study, the levodopa treated group had better symptomatic control than patients treated with placebo, which also translated to improved quality of life.

There was no suggestion in the data that there was any advantage from delaying Levodopa use, in terms of side effects nor in relation to efficacy at the 80-week timepoint. Patients frequently fear using levodopa, and these data should add to the reassurance we can give them regarding the appropriate use of this effective drug as soon as disabling motor features of the disease emerge.

Dr Thomas Foltynie, Consultant Neurologist and Senior Lecturer at the National Hospital for Neurology and Neurosurgery

The commentator declares no conflicting interests