Clinical trial NCT02680977: Mucuna Pruriens Therapy in Parkinson's Disease
Official title: Mucuna Pruriens Therapy in Parkinson's Disease: a Double-blind, Placebo-controlled, Randomized, Crossover Study.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Parkinson's Disease
Keywords: Mucuna pruriens
Levodopa
Lead sponsor: ASST Gaetano Pini-CTO
Sponsor class: OTHER
Collaborators: name: Grisons Foundation for Parkinson's Disease
First posted: 2016-02-12
Enrollment: 18
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: In low-income areas worldwide, most patients with Parkinson's disease (PD) cannot afford long-term Levodopa therapy. A potential therapeutic option for them is the use of a legume called Mucuna Pruriens var. Utilis (MP), which has seeds with a high levodopa content (5-6%) and grows in all tropical areas of the world. MP powder is very cheap (total annual cost for a PD patient: 10-15 US $). The aim of this study is to assess efficacy and tolerability of acute and chronic use of MP compared to standard Levodopa therapy.

The primary objective of this study is to investigate efficacy of acute levodopa challenge using MP in comparison to levodopa with a Dopa Decarboxylase Inhibitor (LD+DDCI) and without (LD-DDCI) and placebo.

The secondary objectives are to investigate safety of acute intake of MP as well as efficacy and safety of chronic intake of MP over a 8-week period in comparison to usual LD+DDCI home therapy.

Detailed description: Background: Levodopa is the gold standard in the treatment of Parkinson's disease (PD). However, in low-income areas worldwide, most patients with PD cannot afford chronic therapy with levodopa. It is therefore mandatory to identify an interventional strategy designed to ease the economic burden of pharmacological management of PD in developing countries. A potential therapeutic option for them is the use of a legume called Mucuna Pruriens variant Utilis (MP), which has seeds containing high LD concentrations and grows spontaneously in all tropical and subtropical areas of the world, including South America, Africa and Asia. It is considered an invasive plant, as it grows rapidly without any particular measure needed to ensure its growth. The cost of home preparation of MP roasted powder is negligible and it is easy to store for a long time. LD was isolated from MP seeds for the first time in 1937 and its concentration therein was estimated to be 4-6%. MP is also known as Ayurvedic remedy for PD since ancient times.

Preliminary data: Published studies in parkinsonian rats, primates and humans suggest that MP may be used to improve PD motor symptoms without major side effects.

In a preliminary study, we analyzed 25 samples of MP from Africa, Latin America and Asia and measured the content in LD and anti-nutrients. We found that LD concentration in roasted powder samples was consistent with previous literature (median\[Inter-Quartile Range\] 5.3%\[5.17-5.5\]) and found no harmful anti-nutrients in all MP samples.

Study population: patients with diagnosis of idiopathic PD, including sustained response to levodopa and presence of motor fluctuations defined as predictable wearing-off, unpredictable ON-OFF fluctuations and sudden OFF periods.

Setting: Clinica Niño Jesus, Santa Cruz (Bolivia). This setting is chosen because the local neurologist Dr. Janeth Laguna has long-term experience on MP therapy in patients with PD (approximately 10 years). She started using MP because patients living in rural areas asked her to use this cheap source of LD to reduce the monthly cost of anti-PD therapy. In her experience, J.L. never recorded any serious adverse event (personal communication).

Preliminary Laboratory Test: The levodopa content in the powder obtained from roasted seeds of Bolivian black ecotype of MP was tested in a laboratory in Milan (Italy) and found to be 5.7%. No alkaloids or major antinutrients were found.

Objectives:

The primary objective is to assess the efficacy of acute challenge of MP roasted powder compared to Levodopa formulations with a dopa-decarboxylase inhibitor (LD-DDCI) and without (LD+DDCI), and placebo. Levodopa dose with DDCI is administered at 3.5 mg/kg, while Levodopa without DDCI is administered at the equivalent dose. This conversion factor is 5-fold, based on published studies comparing clinical and pharmacokinetic Levodopa effects with and without a DDCI and a previous double blind study on MP in patients with PD. For example, 100mg of Levodopa plus DDCI (either Benserazide or Carbidopa) corresponds to 500mg of Levodopa without any DDCI, obtained by administration of 8.75 grams of MP roasted powder (considering 5.7% of Levodopa in the bolivian ecotype of MP). Levodopa dose from MP is planned to be administered at not only at the equivalent dose of LD+DDCI (i.e. 5-fold), but also at the lower dosage of 3.5-fold.

Design: double-blind, randomized, placebo controlled, crossover study of acute response to levodopa-based therapies Duration: 3-6 hours for each treatment arm.

The secondary objectives include additional measures of efficacy of acute intake of MP as well as efficacy and safety of chronic use of MP as the only source of levodopa compared to optimized home LD+DDCI therapy. This latter part is performed after completion of the acute challenge part of the study.

Design: single-blind, randomized, crossover study of chronic response to levodopa-based therapies.

Duration: 8 weeks per treatment arm plus 3-week dose adjustment period. Initial levodopa-based therapy regimen (either MP therapy or Levodopa/Benserazide) may be adjusted for a period up to 3 weeks to optimize daily motor status during waking hours. After this period, patients enter the study and levodopa daily dose must be left unchanged throughout the 16-week course of the study.

Eligibility criteria: Inclusion Criteria:

* Clinical diagnosis of idiopathic Parkinson's disease according to the United Kingdom Brain Bank criteria, defined by the presence of at least two of the cardinal signs of the disease (resting tremor, bradykinesia, rigidity) without any other known cause of parkinsonism.
* Sustained response to levodopa and presence of motor fluctuations for at least 1 h every day during waking hours, defined as predictable wearing-off, unpredictable ON-OFF fluctuations and sudden OFF periods.
* Patients had to receive optimum LD+DDCI, be stable for at least 30 days before baseline assessment.
* Availability to written informed consent

Exclusion Criteria:

* Cognitive impairment according to Mini-Mental State Examination \< 26/30
* Clinically significant psychiatric illness, including psychosis, major depression and addiction disorders (including compulsive levodopa intake).
* Hoehn and Yahr stage of 5/5 in the medication-OFF state
* Severe, unstable medical conditions (i.e. unstable diabetes mellitus, moderate to severe renal or hepatic impairment, neoplasms)
* Risk of pregnancy

Primary outcomes:
measure: Magnitude of motor response
timeFrame: up to 3 hours
Secondary outcomes:
measure: ON duration
timeFrame: up to 6 hours
measure: Latency to ON
timeFrame: up to 6 hours
measure: Severity of dyskinesias
timeFrame: up to 3 hours
measure: Changes in vital signs
timeFrame: up to 3 hours
measure: Change in mean total daily off-time without troublesome dyskinesias
timeFrame: 16 weeks
measure: Change in quality of life questionnaire scores
timeFrame: 16 weeks
measure: Change in Non-Motor Symptoms questionnaire scores
timeFrame: 16 weeks
measure: Frequency of spontaneously reported adverse events
timeFrame: 16 weeks
measure: Laboratory indices
timeFrame: 16 weeks
measure: Electrocardiography
timeFrame: 16 weeks
Other outcomes:
Locations:
city: Santa Cruz de la Sierra
country: Bolivia
facility: Clinica Niño Jesus
Study officials:
affiliation: ASST Gaetano Pini-CTO
name: Roberto Cilia, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: ASST Gaetano Pini-CTO
name: Gianni Pezzoli, MD
role: STUDY_CHAIR
References:
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