Protocol of a randomised delayed-start double-blind placebo-controlled multi-centre trial for Levodopa in EArly Parkinson’s disease: the LEAP-study

Abstract

BackgroundThe aim of this study is to investigate if early treatment with levodopa has a beneficial disease modifying effect on Parkinson’s disease (PD) symptoms and functional health, improves the ability to (maintain) work, and reduces the use of (informal) care, caregiver burden, and costs. Additionally, cost-effectiveness and cost-utility of early levodopa treatment will be assessed.MethodsTo differentiate between the direct symptomatic effects and possible disease modifying effects of levodopa, we use a randomised delayed-start double-blind placebo-controlled multi-centre trial design. Patients with early stage PD whose functional health does not yet necessitate initiation of PD-medication will be randomised to either 40 weeks of treatment with levodopa/carbidopa 100/25 mg TID including 2 weeks of dose escalation or to 40 weeks placebo TID. Subsequently, all patients receive levodopa/carbidopa 100/25 mg TID for 40 weeks. There are 8 assessments: at baseline and at 4, 22, 40, 44, 56, 68, and 80 weeks. The primary outcome measure is the difference in the mean total Unified Parkinson’s Disease Rating Scale scores between the early- and delayed-start groups at 80 weeks. Secondary outcome measures are rate of progression, the AMC Linear Disability Score, side effects, perceived quality of life with the Parkinson’s Disease Questionnaire-39, the European Quality of Life-5 Dimensions (EQ-5D), ability to (maintain) work, the use of (informal) care, caregiver burden, and costs. 446 newly diagnosed PD patients without impaired functional health need to be recruited in order to detect a minimal clinical relevant difference of 4 points on the total UPDRS at 80 weeks.DiscussionThe LEAP-study will provide insights into the possible disease modifying effects of early levodopa.Trial registrationISRCTN30518857, EudraCT number 2011-000678-72

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

“…In the case of exenatide, as discussed later, the difference between the active treatment and placebo groups was largely indicative of an early but sustained symptomatic effect. Finally, special mention should be made of the most potent symptomatic therapy for PD, levodopa . In the Earlier vs Later L‐DOPA (ELLDOPA) trial, in which 3 doses of levodopa were compared to placebo over 9 months, UPDRS scores in the levodopa‐treated groups never declined to the level seen in the placebo group after up to 4 weeks of drug washout.…”

“…Although it is generally believed that this could simply relate to a very long‐duration symptomatic effect of levodopa, the difference between the 2 groups was greater than has been seen in any other similar trial in early PD. This encouraged the conduct of the delayed‐start Levodopa in Early Parkinson's disease‐study (LEAP‐study), which will report results sometime later this year …”

l‐3,4‐dihydroxyphenylalanine (l‐DOPA) modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha‐synuclein mouse models of Parkinson's disease

“…The Earlier versus Later Levodopa Therapy in Parkinson Disease (ELLDOPA) trial, designed specifically to investigate neurotoxicity of L-DOPA in humans, was inconclusive (Fahn et al 2004). The subsequent Levodopa in EArly Parkinson's disease (LEAP) study (Verschuur et al 2015) is currently underway (EudraCT number 2011-000678-72) and will add valuable new insight, though until conclusive evidence that L-DOPA is neurotoxic in humans is presented, it will remain a front-line treatment for Parkinson's disease. Between these in vitro studies and clinical trials, murine models that recapitulate progressive iron accumulation, with dysfunctional a-syn and impaired DA trafficking are the ideal testbed to test the hypothesis that L-DOPA accentuates DA neurotoxicity in a high-Fe environment.…”

Updates and advances in the treatment of Parkinson disease

“…However, the 2 mg treatment arms of the same study did not show a difference. Similar study designs with pramipexole and, most recently, levodopa also did not show a difference between the immediate and delayed start arms, arguing against a neuroprotective effect of those drugs.…”